I was about to agree that this was all in my head. That my ongoing chest discomfort was just anxiety or maybe some referred pain from old sports related musculoskeletal injuries.

For those that have been following along, you will know that almost two years ago now I ended up having to get a stent after having persistent palpitations and minor chest pressure. A CT angiogram found an 80% obstruction that ended up getting stented.

What I haven’t spoken about too much is that I’ve continued to have the same sensation of chest pressure. Earlier this year I had a CT angiogram and an echo repeated. Both were normal and re-assuring that my program was working and my heart was structurally sound and treatment was working as I had no other areas of evident atherosclerosis. I again wore a holter monitor, with normal results. However, the pressure continued. My cardiologist had mentioned the word anxiety and I was starting to go along with that idea. I had been reading about microvascular disorder, and some of that fit my case, so I decided to push on one more appointment and the cardiologist moved me up the ladder to the Mayo Clinic Chest Pain clinic, a specialty clinic.

The doctor at that clinic took a different approach. I was hoping for a special type of MRI or a PET CT scan that can help to rule in or out microvascular disease. However, they recommended I go back to the cath lab. Admittedly, this invoked a lot of anxiety in and of itself. Thinking back to having to get stented. I found myself literally making that argument that maybe this was just anxiety compounded with some disc degeneration. He politely said: “go home and think about it” and left the ball in my court.

After about a week I decided to go ahead with a second visit to the cath lab. I am glad I did, because I found out it was never in my head.

In this post I am going to be walking through the story and how this discovery, this past Wednesday, has only strengthened my resolve to write. Next week’s post is the science: what a diagnostic catheterization can actually find, how spasm testing works, what microvascular testing adds, and why the version of this condition most Westerners have is not the version we were taught in school.

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I was the best-case scenario, and it still took two years

I need to establish something first, not to impress anyone, but because it is one of my main points about the difficulties of navigating what it means to be healthy and what exactly you should do if you start to feel like something is just not quite right.

I have been inside the health and wellness world for about 25 years: personal training, diet, supplementation, human optimization, fifteen of those years running companies in the supplement industry itself. I have advanced training in biochemistry, molecular biology, nursing, advanced practice, epidemiology and public health. I work in a Mayo Clinic emergency room and I am friends with many physicians and scientists - all who I spoke personally with about my own case. I read the primary literature for a living as a PhD candidate and as an APRN student focusing on cardiology. I know the wellness world, the biohacking world, the medical world, and the research world from the inside.

However, I was about to accept that my chest pain was “mostly in my head.”

It’s not that the medical system was doing anything wrong. It was doing what it was intended to. Slowly escalate invasiveness of tests until either the doctor or the patient say ‘no more’. I had two cardiologists that already thought enough tests had been performed, so I was sent to a third one. And, even with all my training and background, I was about ready to consent that this was all just in my head. My point is, if even I was at this point, imagine the regular person who would have stopped at the first cardiologist and, after a battery of tests, accepted that he probably just had anxiety.

Nearly two years of chest pressure

The stent went in early 2025, after an 80% blockage was found in my right coronary artery. I went through a period of denial and anger, honestly, I was flat out pissed off that I had to get stented even though I was doing all the right things with diet, exercise, optimization, etc. However, that didn’t last too long and I decided I had to admit that my own feelings about diet (I was a keto guy) and LDL (I was convinced that mildly high LDL was ok on keto) were obviously wrong, and I needed to attack the problem. I quickly drove my cholesterol down to numbers you would expect in a baby, with an ApoB of 38. As I mentioned, my repeat imaging looked good, and a couple of very minor areas of plaque in other vessels (atherosclerosis) had actually regressed. In the eyes of the radiologists, three cardiologists, and even in the eyes of my physician friends, the problem was solved. I was fixed. The stent was sound and my cholesterol levels were at the levels all relevant studies said result in regression of coronary artery disease.

Except the discomfort kept coming. Not constantly, just episodes. The first occurring probably four to five months after the stent. It was just a pressure that builds, never feels or looks like a true heart attack, and eventually passes. With my ER training I could work through the logic in real time: I could check an ECG at home and more or less rule out the big one, the heart attack that does not subside. No ER nurse wants to rush into his own work every time he has some chest discomfort, so I bought the tools and had them at home. And the fact that these episodes subsided, well, that ruled out the catastrophe as heart attacks do not subside. But, this didn’t change the fact that there was no clean answer for what was causing these symptoms, so a familiar story moved into the vacuum: anxiety. A word discussed with every ER patient who comes in with chest pain, has a perfectly normal workup, and heads home. And now I was living it.

So the anxiety explanation hardened, and eventually I started to believe it myself. My rescue plan for the episodes became an anxiety medication and a quiet room. It worked, sort of, in the way that lying down for forty minutes works. Each time, it also deepened the story: see, you took the anxiety pill and it passed.

But, in the back of my head it still just didn’t fit right. I had never been an anxious guy my entire life. I have sat in countless tense board room meetings. I run heart-attack codes in an emergency room without my own pulse even moving. My life today, busy as it is with family and work and a doctorate, is genuinely less stressful than my 20s and 30s, when I was in the business world cutting deals, constantly traveling, living in meetings. I went through two category five hurricanes while living in and operating a business in the US Virgin Islands that decimated life as we knew it. If I was prone to anxiety and my chest discomfort was being caused by this, it should have reared its head then. But it never did.

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Pushing, and almost quitting at the finish line

I kept pushing, and I want to be honest about what that took, because I had advantages here too. I knew the exact words to use to keep a care team thinking instead of closing the chart. I knew which possibilities there still were and which tests had not been done. After a nuclear stress scan came back partially unreadable, my final ask was to push for a cardiac MRI stress test as the next step. It’s eerily ironic that the third cardiologist, instead of saying, yep, this is anxiety, jumped ahead to the most invasive test that even I wasn’t pushing for. And that I almost declined it.

As an ER nurse, “cath lab” is a phrase you never want aimed at you; it is where we send the emergencies. I had spent two years fighting for an answer, and when the definitive test was finally offered, my first instinct was that it was too much, too invasive, too far. The procedure has risks. Major ones, like heart attack and stroke. I had been pushing for a less invasive scan, and the irony is that the test I nearly declined was the only one on earth that could see what was wrong with me. It’s not something that can show on a CT scan or MRI machine. It has to be provoked, live, with a catheter already in place to watch it happen.

For this testing I was awake on the table, and I felt the exact discomfort I had been describing for two years arrive on command, watched by a team that could finally see its cause: arteries constricting in response to a provoking medication, the ECG shifting into the signature of heart muscle not getting enough blood (ischemia). This is exactly what happens when someone has severe angina caused by atherosclerosis and its also what happens in a heart attack itself. But, the lack of blood flow to my heart was not coming from a heart attack or arteries narrowed from cholesterol deposits, this was something else.

Somebody finally saw “it” and “it” was not anxiety. I cannot fully describe what that did to me. Relief is the wrong word, because the finding is not good news. Vindication is closer, but it misses how much grief came with it. But, that grief quickly cleared as having a diagnosis allowed me to finally move forward with a plan.

My own primary care doctor, who has known me a long time, put it plainly when we talked after the procedure, paraphrasing he said:

He has never seen anyone argue for a diagnosis that hard, and the typical guy in my position would never have gotten this answer. He would have just gone on, mislabeled and on a treatment that would continue worsening his condition. His heart disease would have continued to worsen from ongoing periods of low blood flow. And, he would have died prematurely, to be blunt.

What this condition actually is, briefly

Coronary artery spasm is exactly what it sounds like: the muscular wall of a coronary artery clamps down and narrows the vessel, sometimes severely, and sometimes without a speck of cholesterol, let alone a mass amount of it causing a blockage. Blood flow drops, the heart muscle complains, and you get real cardiac chest pain. If the lack of blood flow is bad enough you get ECG changes, and, if it goes on long enough, real damage. However, in most cases the vessel relaxes and everything, including the tests, goes back to normal. It’s not something an emergency room can find unless you have such a bad case of it that your ECG changes show up exactly how a heart attack does. Then, you quickly get rushed to the cath lab where they are expecting to have to put in a stent, but sometimes end up seeing no atherosclerosis and nothing to stent at all.

As I will delve into more next week with the full post, most of us in medicine were only taught one version of this in basic classes: Prinzmetal’s angina, a dramatic form that announces itself with a specific ECG pattern and tends to get caught because it looks like a heart attack in progress. However, as I am learning, this is not the version most Western patients have. The commoner form is quieter, more diffuse, and much easier to mislabel, which is exactly what happened to me.

Is coronary artery spasm dangerous?

My research on this for the article has just begun, but what I am seeing is that among people with real angina whose arteries look clean on imaging, provocation testing finds a vasomotor problem, spasm of the large vessels or dysfunction of the small ones, in a clear majority. So, this is not as rare as one would first think. It is under-looked-for, probably because you need the most expensive and most invasive test available to cardiology to find it. Untreated, it is not benign: over years it carries a real risk of heart attack and death, and it keeps sending people to emergency rooms that run the standard workup, find nothing, and send them home. Most of these people, myself included, are told that this is anxiety. However, as I learned, the most common BP med that also helps anxiety can worsen the attacks. Meanwhile, the medication used to treat vasospasm works just as well for blood pressure and is cheap and readily available.

Why I write, revisited

I started Calibrated Signal because I was frankly pissed off. I was angry that I had been doing all the right things and spending all the money on a sophisticated longevity routine and I still ended up needing a stent. I’m building a tool as part of my PhD project that systematically grades and weights longevity interventions by mechanism and evidence strength and I will be offering a consumer version of this. I write because I realize that that is the only way to get the word out there. I sit at an interesting intersection of someone that has formulated the supplements and written the marketing copy for longevity and wellness routines. But, now I sit on the other side, as a clinician-scientist and someone angry that I almost died in my 40s yet thought I was optimized. Most of my future writing will be aging biology, grading interventions, exposing conflicts of interest, and helping you make wise decisions. But, intertwined with that will be my personal perspective on patient advocacy. How to argue for yourself when you are being told something that you feel is off. Most people accept the first treatment handed to them. Even I, with all my advantage, almost continued to take a treatment that was actually making the problem worse and accept that anxiety had just gotten the best of me. Trust your gut if you feel like something is off and never be afraid to ask for a second opinion.

So the writing continues, with more resolve than I had last month. The plan does not change: I will take the complex topics apart carefully, one at a time, including the longevity interventions everyone is selling and almost nobody is auditing. What changes is how personally I hold the assignment. Somewhere out there is a reader with episodes their workup cannot explain, halfway talked into a label that does not fit. This post is for them, and if your symptoms involve chest discomfort, so is the more detailed one coming up.

What I changed

• I stopped accepting “anxiety” as a diagnosis of exclusion for a symptom nobody had finished excluding things for.

• My treatment changed to match the actual disease, starting with a medication class that relaxes the spasm instead of one that can aggravate it. The details of that, and why drug choice matters so much in this condition, are next week’s post.

• I got my baseline documented, on my own ECG and my own wearables, so every change from here is measured against data instead of memory.

The Final Signal

• Two years of post-stent chest pain, a clean workup, and several satisfied cardiologists still added up to the wrong answer.

• The right answer, coronary artery spasm, could only be seen by provoking it live in a cath lab, a test I nearly declined.

• A mislabel is not neutral: the anxiety story chose my medications, and one of them can make this condition worse.

• Spasm is a clear-majority finding when properly looked for in unexplained angina, and untreated it carries real risk. Details, with the evidence, come next week.

• If your symptoms are real and your workup is clean, but your gut tells you something is still off, do not be afraid to get a second opinion (or maybe even a third). Your health is truly in your hands. Not your doctor’s.

This piece was first published at calibratedsignal.com.

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Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

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Not medical advice.

Every test I have shown you in this series reads a single moment. The calcium score, the angiogram, the ultrasound probe inside my own artery. Each one is a photograph. Last time I said the real disease is a process, something that runs for years, and that learning to read the process instead of the picture is where this goes next.

CHIP (clonal hematopoiesis) is the purest version of that idea I know. It is a disease that is not a lump or a blockage or anything a scan can photograph. It is a spelling error in your bone marrow, one rogue blood cell quietly out-breeding its neighbors over a decade or two, and the damage it does happens everywhere and nowhere you could point a camera. There is no picture of it. So I went looking for the one blood test that could actually see it.

Both my hematologist and my cardiologist told me there was no real reason to run it due to low likelihood for my age, that there is little that can be done about it, and that insurance typically doesn’t cover it. While I disagree and am awaiting an appointment to get a second opinion from yet another cardiologist, I may ultimately end up conceding for now and not pursue arguments for further testing. However, of all potential drivers of cardiovascular disease, this one has been the most interesting to research as it is a great case study for understanding the biological mechanisms at play with aging, and how they interconnect.

Vocabulary that matters

• Clone, or clonal expansion: one cell’s descendants quietly taking over more than their fair share of your blood.

• Somatic mutation: a DNA typo you pick up during life, in one cell. You are not born with it and you do not pass it on.

• CHIP (clonal hematopoiesis of indeterminate potential): a detectable blood clone carrying a known mutation, with no blood cancer and no anemia. Just a clone, sitting there.

• Variant allele fraction, or VAF: how big the clone has gotten, as a percentage of your blood cells. By convention, once it reaches 2 percent, we start calling it CHIP.

• IL-1 beta and the inflammasome: the specific inflammatory alarm the rogue clone’s cells blare. It is the bridge that carries a blood mutation over to the artery wall.

Why a blood mutation I’d never heard of got under my skin

My story does not add up. At 36, a CT angiogram of my heart was clean. At 44, I had an 80 percent blockage in my right coronary artery, the kind that puts you on a table with a stent going in. My LDL was borderline, not wild. My blood pressure only ever flirted with the low end of high. My Lp(a), the mostly-genetic risk factor, sits near zero. My inflammation markers have always been quiet. I did not have insulin resistance and experimented with a continuous glucose monitor several times a year and it was also flat. No family history. Never smoked. By the standard math, I am not the guy this happens to.

When your numbers don’t explain your disease, “idiopathic” is the word medicine reaches for. It means “we don’t know why.” I have never been able to accept that word about my own heart, and CHIP is one of the very few suspects that could quietly build focal damage in someone who looks low-risk on paper. It is the kind of thing you go looking for when the usual explanations have run out.

And I had a second reason to go looking, one that has nothing to do with my arteries. Before I ever worked a shift in an emergency room, I spent three years in a cancer lab studying epigenetics, the layer of switches that decides which of your genes get read and which stay silent, without changing the underlying DNA at all. CHIP, it turns out, sits at the exact crossroads of everything I have spent a large chunk of my life trying to understand. The two mutations that most often drive it, in genes called DNMT3A and TET2,²³⁴ are not random damage. They are that epigenetic switchboard, the cell’s own on/off control for which genes get read.⁶ One writes the marks that silence a gene, the other strips them off. Jam those genes in a single blood stem cell and one typo fans out into four different worlds at once: it drives heart disease, like mine; it is a pre-cancerous state, the first step on the road to blood cancers;¹ it is a textbook case of the exact epigenetic breakdown I used to study at the bench; and underneath all of it, it is aging itself, made visible. One obscure mutation, standing on the precise spot where cardiology, oncology, epigenetics, and the biology of aging all collide. Of course it got its hooks in me.

I should say plainly why that lab work matters here, because it is not a credential I am waving. I was not studying melanoma because I wanted to cure melanoma. I was studying epigenetic alterations, transcriptional regulation, cellular identity, metabolic rewiring, and genomic instability. It took me years to realize those are not cancer topics. They are hallmarks of aging. Cancer is simply where the machinery breaks loudly enough to study. Aging is the same machinery breaking slowly, in everyone, all the time. I spent three years staring at the loud version without understanding that I was looking at the quiet one.

That is the pattern of my whole career, if I am honest about it. Fifteen years in the supplement industry taught me how health claims get built from the boardroom outward, and then I hit the ceiling of what that world could tell me. Cancer epigenetics taught me how a cell changes its own instructions, and I hit that ceiling too. Bioinformatics taught me to look for patterns across systems instead of memorizing facts inside one. The emergency room taught me what disease actually looks like when it walks through a door. Each time, the honest move was to admit the discipline I was standing in could not answer the question, and to cross into the next one. CHIP is the first thing I have studied that required all of them at once.

So I did. And here is the part that still gets me. I work for the hospital. I read the primary literature. I argued my own way onto the scan that found the blockage in the first place. And I still could not get this one looked at. Both hematology and cardiology gave me the same answer: no real indication. And with the way it bills, insurance was never likely to cover it anyway.

I want to be fair about why, because it is not laziness and they are not wrong. It is that the system had already decided my case was closed. The emergency was handled: the stent is in. The obvious lever was pulled: my ApoB, the cholesterol number that actually drives the plaque, is crushed. Mission accomplished. And when the system files your case under “accomplished,” nobody goes digging for the mechanism underneath. However, my case was an outlier, and a voice in the back of my head keeps telling me I need to search for more answers. What if lowering ApoB isn’t enough to keep this from happening again?

What CHIP actually is, and how likely I am to have it

Start with what it is. Clonal hematopoiesis just means a chunk of your blood is descended from one mutated stem cell instead of the usual sprawling mix. Add a known leukemia-associated driver gene, subtract any actual blood cancer or anemia, and you have CHIP.¹ It is common, and it climbs steeply with age: detectable in about 1 percent of people under 50, roughly 1 in 10 over 65, and up past 18 percent in the very old.²³ I am 45. At the standard testing threshold, my odds of carrying it sit down around that 1-in-100 floor. Low. Worth saying plainly, because it is the first honest strike against CHIP as my answer.

But here is the wrinkle that makes CHIP such a good teacher, and it is the first place the whole thing starts to bend the way I want you to see. Whether you “have” CHIP depends entirely on how hard someone looks. The 2 percent line is not biology. It is the detection floor of a standard sequencing machine. When researchers used error-corrected sequencing, which reaches down to clones a hundred times smaller, they found clonal mutations in 95 percent of healthy people in their fifties.⁴ Read that again. Look hard enough and almost everyone middle-aged is already carrying a rogue clone. We just drew a line at 2 percent and named the far side of it a condition. “Do I have CHIP” turns out to be less a fact about my blood and more a question about the sensitivity of the test.

Does it actually cause heart disease

Short answer: yes, and I am going to keep the two halves of that honest, because this is exactly where health content usually cheats.

The association is real. People with CHIP carry roughly double the risk of coronary disease, and the studies find this holds even after you account for the traditional risk factors.⁵⁶ That “independent of the usual risk factors” part is what made me sit up, because the usual risk factors are exactly what look clean on me. And in younger people with early heart attacks, the group I actually belong to, the association runs stronger, closer to four times the risk.⁵

Now the honesty. Those are relative risks, and the absolute reality is far more modest. Most people who carry CHIP never have a cardiac event, and most heart attacks happen in people who don’t carry it. It is a multiplier sitting on top of a baseline, not a diagnosis that explains a disease. And the risk is not one uniform thing: it runs higher with some mutations, and is genuinely murkier with the single most common one, which behaves differently from one study to the next.⁶ I am not going to pretend to be a CHIP expert. I am a clinician-scientist who can read the papers, and the papers themselves are still arguing about the gene-by-gene detail. That uncertainty is the point here, not a footnote.

How we know it is not just a coincidence

Here is where CHIP earns its place, because you can actually watch the mechanism work. Researchers took mice bred to develop atherosclerosis and gave them bone marrow engineered to carry one of these mutations. The plaques got markedly bigger. The mutant immune cells were running an inflammatory alarm called the NLRP3 inflammasome, pouring out IL-1 beta, and when the researchers blocked that alarm, the extra plaque protection came back.⁷ One mutation, one inflammatory signal, more plaque, and you can turn it off.

Then it got confirmed in people, in about the cleanest way cardiology has ever managed. A large trial called CANTOS took a drug that blocks that exact signal, IL-1 beta, and gave it to more than ten thousand heart-attack survivors. It cut their rate of major cardiac events by about 15 percent. That figure comes from the 150 milligram dose, the only one of the three doses tested that cleared the trial’s own bar for significance, and it is worth saying so rather than quoting the number bare. And it did that without lowering their cholesterol at all.⁸ That last part is the whole ballgame. It means the inflammation itself was doing damage, on its own, separate from lipids. You could prove, in humans, that quieting one inflammatory pathway prevents heart attacks. And CHIP is one of the cleanest natural sources of that exact inflammation.

The one-sentence version of the whole disease

Strip out the jargon and here is the entire arrow, start to finish. One DNA typo, in one blood stem cell. The gene it lands on happens to be one of the cell’s own off-switches for inflammation. So the clone’s descendants, your white blood cells, run hot. They travel to the artery wall, the same wall where cholesterol is already causing trouble, and they pour accelerant on the fire.

The way I would explain it to a patient at the bedside: it is like one bad hire quietly cloning himself until a big chunk of your security staff are all the same guy, and that guy never got the memo to stand down. Everywhere they go, they escalate. That is CHIP in an artery.

Now notice what we just did

Stop and look at the move we just made, because it is the actual reason I am writing about a disease I probably don’t even have.

We took something that sounds impossibly exotic, a somatic driver mutation in a blood stem cell, and we made it make sense by ignoring the name and following the mechanism. We didn’t ask “what is the diagnosis.” We asked “what is the broken machine, and what does it break next.” And the second we did that, a disease almost no one has heard of turned into a story you can follow.

That move is a lens, and it is the one I have quietly been using this entire series. Here is the lens, said plainly: the chronic diseases we treat as a hundred separate enemies are, underneath, a small number of shared root mechanisms wearing different masks. Inflammation. Damaged DNA. Cells that have stopped listening to one another. The mask is the diagnosis on your chart. The mechanism is what is actually happening. Treating each disease one at a time while ignoring the machinery underneath all of them is like mopping up water in one room after another while the roof keeps leaking.

CHIP is the perfect place to learn this, because it is the leak made visible. You can trace one water stain, a single DNA change, all the way up to the hole in the roof. Most of the machinery of aging is diffuse and hard to point at. CHIP you can sequence, measure, and follow from one mutation to a heart attack. That is why I led with the hardest possible example instead of an easy one. If you can see the mechanism under CHIP, you can see it under almost anything.

There is a name for this, and I have been too coy about it for too long. It is called the hallmarks of aging, a map, in its current form published in 2023, of about a dozen root mechanisms that drive nearly every age-related disease we have.⁹ I have been quietly citing that one paper at the bottom of these posts for months without ever telling you what it was. I am done doing that, because CHIP is the single cleanest way I know to show you what it means.

CHIP does not touch one hallmark. It lights up several at once, and you have already met all of them in this post. The somatic mutation itself is genomic instability, the accumulated DNA damage of aging, finally made visible in a clone big enough to sequence. The genes it lands on, DNMT3A and TET2, are epigenetic alteration, the cell’s own control switches for which genes get read, jammed in place.⁶ And the inflammatory alarm those cells blare is chronic inflammation, what the field calls inflammaging: the hallmark that a growing body of aging science treats as a connecting thread running far beyond the artery, into the long list of age-related diseases we file in separate folders and treat as separate enemies.⁹¹³

That is the entire thesis of what I am building here, compressed into a single disease. These are not a hundred different enemies. They are a small handful of the same broken machines, showing up in different tissues wearing different masks. CHIP just happens to be the one where you can watch a single typo travel the whole distance, from a spelling error in your bone marrow to the wall of your artery, without ever losing sight of it. From here on, I am going to name these machines out loud.

Why there is no test for someone like me

Here is the thing I did not expect to find. It is not that the guidelines say “don’t test a younger patient with unexplained, fast-moving heart disease.” It is that they don’t mention him at all. The current cardiology position is simple: no cardiology society recommends screening people without symptoms for CHIP, full stop.⁶ The way almost everyone with CHIP actually gets diagnosed is by accident, when a hematologist or oncologist sequences their blood for some other reason, usually a cancer workup.⁶ There is no door marked “premature heart disease, come get sequenced.” I am not the kind of accident this gets found in.

So when hematology and cardiology told me there was no indication, they weren’t blowing me off. They were describing a real gap. The science has gotten far enough to say CHIP matters, especially for people who look exactly like me. The system has not built the part where you act on that. The silence is the story.

Four specialties, one mutation, four different answers

Here is what I did not understand until I had been turned down twice.

Hand the exact same finding to four different doctors and you get four different diseases.

A hematologist sees a small clone in the marrow sitting under the threshold that would make it a blood cancer. Nothing to treat. Watch it.

An oncologist sees a pre-malignant state, the first step toward a leukemia that will probably never come. Real, but not enough risk to act on.

A cardiologist sees a cardiovascular risk factor with no screening pathway and no approved treatment. Which means, correctly, no indication.

A geroscientist sees something else entirely: aging itself, finally big enough to sequence. A single cell’s accumulated damage, expanded into a clone you can actually measure.

Every one of those readings is correct. Not one of them is the whole thing. And critically, not one of those specialties owns the problem, so the patient standing in the middle of it falls into the gap between them. That is not a story about four doctors being wrong. It is a story about a mutation whose consequences cross boundaries that medicine drew for its own convenience, decades before anyone knew this mutation existed.

I want to be careful here, because there is a lazy version of this argument that I am not making. Specialists are not the problem. Specialization is the reason medicine works at all. When my artery closed, I did not want a generalist with a systems-level worldview. I wanted an interventional cardiologist who had done that exact procedure a thousand times, and I got one, and I am here because of it. Depth is not the enemy.

But depth has a cost, and the cost is that nobody’s map covers the whole territory. Each specialty is looking at a real part of the elephant. The mechanism does not care where we drew the lines. One mutated stem cell in the marrow produces inflammatory cells that end up in an artery wall, and the same clone raises the odds of a blood cancer, and the same underlying process is what we call aging. The biology is one continuous thing. The medical system that has to interpret it is cut into departments with separate journals, separate conferences, separate billing codes, and separate ideas about what counts as a real indication.

I learned this in the least academic way possible, by working in an emergency room.

The ER is the one place in medicine that is structurally forbidden from thinking in specialties. The patient arrives undifferentiated. No label, no department, no chart that tells you which bucket they belong in. Chest pain is a heart attack or a pulmonary embolism or a dissection or a panic attack or an ulcer, and you have to hold all of it at once and reason across every system in the body before anyone gets to hand the patient to a specialist. That is not a bedside manner. That is a way of thinking, and it is the only part of clinical medicine organized the way biology actually is.

I did not choose that job by accident, and I did not choose cardiology at Duke by accident either. But the ER is where I learned the habit this whole article is built on: when the label does not explain what you are seeing, stop arguing about the label and go find the mechanism.

That is what the hallmarks of aging give you. Not a new specialty to add to the list. A layer underneath all of them, where the shared machinery lives. The specialties are still necessary. They are just downstream.

What I actually changed, and why I stopped chasing the test

Not a supplement. Not a hack. A decision, and it is the honest-broker payoff of this whole post: I put the suspect in the file instead of the trash, and I stopped trying to run the test for now.

Walk through the math with me, because it is the same calibration this brand is named for. My odds of carrying it at 45 are low. The test runs a few hundred to over a thousand dollars out of my own pocket, with no established reason to run it and no reimbursement behind it.¹⁰ And here is the one that actually settles it. Even if it came back positive, the recommended move would be to drive my LDL and blood pressure down hard and control my risk factors,⁶ which is exactly what I am already doing. There is no approved treatment aimed at CHIP itself; the people writing the guidelines say so plainly.¹¹ A positive result would not hand me a single new lever.

That is what Calibrated actually looks like. It is not testing everything and fearing everything, which is the influencer move. It is weighing a real suspect honestly, deciding the answer would not change what I do, and choosing to spend my attention elsewhere. The door stays open. If the math changes, if the price drops or an actual treatment shows up, I will revisit it. For now, shelving it is the disciplined call, not the lazy one.

One thread is worth flagging, because it is the “what could you even do about it” question, and it has a live answer. There is a century-old gout drug, colchicine, that works on this exact inflammatory switch. It is now FDA-approved to lower cardiovascular risk,¹² and early work hints it might even slow the rogue clones themselves, though the human evidence is genuinely split and the effects look small.⁶ It is one of the interventions moving through the Calibrated Age evidence pipeline right now, and it deserves an honest workup rather than a name-drop in passing. That is a post of its own, and it is coming. I mention it now only because some circles do recommend this as a treatment when CHIP is discovered, despite the split evidence.

One last thing, because I keep landing here. The point of this year was never to collect diagnoses. It was to learn to see. CHIP is a suspect I am likely giving up chasing, and it still taught me the most useful thing I have learned since the stent: read the mechanism, not the label, and see what dots can get connected back to core aging mechanisms that are consistent across all disease. That habit is worth more to me than any single test result.

Recalibrated: August 2026

In July I wrote that even a positive CHIP test would not hand me a single new lever. That sentence is now too strong. I would rather write the correction than leave a post standing quietly wrong, so here is what changed, what did not, and the part of it that almost nobody is repeating. The paper came out five weeks before I published this, and I missed it. It happens.

A team led by researchers at Mount Sinai asked a question nobody had answered: does how you live change what these clones do?¹⁴

First, people. They took two large research databases, the UK Biobank and the All of Us program, and analyzed 82,834 people from one and 8,404 from the other. Everyone in that group had worn a wrist activity monitor, so the exercise number is measured rather than remembered, and had their blood sequenced. More moderate-to-vigorous physical activity tracked with fewer clones. The size of it was modest. For each additional hour per day of that kind of activity, the odds of carrying a clone ran about 14 percent lower (odds ratio 0.86, which means the odds in the more active group were 0.86 times the odds in the less active group). It held after the researchers adjusted for body weight, so this is not just the observation that people who exercise are leaner.

Then, mice, where you can run the experiment you are not allowed to run in a person. They built mice whose blood was 10 percent mutant and 90 percent normal, fed them a high-cholesterol diet, and randomized them to running wheels, to deliberately fragmented sleep, or to nothing at all for twelve weeks. In the sedentary animals the mutant clones expanded on schedule. With exercise, the expansion stopped. With fragmented sleep it ran faster and the plaques got worse.

The signal underneath all of it is IL-1 beta, the same inflammatory alarm this post already walked you through in the mouse work and in CANTOS. Exercise lowered it. Fragmented sleep raised it. Inside the artery wall the researchers found a second route: exercise switched on neurons in the brainstem that raise noradrenaline, the body’s own adrenaline-family signal, and that lands on a receptor sitting on the mutant immune cells and turns their inflammatory program down. The clone is still there. It behaves differently.

Now the part that did not travel with the coverage, and it is the part that matters most to you. The effect is mutation-specific, and the mutation it does not reach is the most common one.

DNMT3A is the single most frequent CHIP driver in people, and it is one of the two genes this entire post is built around. In the human data, activity was associated with fewer non-DNMT3A clones and showed no association whatsoever with DNMT3A clones. In the mice, sleep and exercise did not slow DNMT3A clone expansion, and did not reduce DNMT3A-driven plaque either. Null on both counts. This is not me finding a hole in someone else’s work. It is the paper’s own title: mutation-dependent responses.

So the honest version of the finding is narrower than “sleep and exercise stop the clones.” It is this: in mice, sleep and exercise constrain some clones and calm the inflammatory behavior of most of them, and in people, more measured activity tracks with fewer of some of them. If you carry the most common driver, the evidence we have today does not show that either one reaches it.

What that does to my own decision is smaller than it first looks, and it points the same direction I was already pointing. The two things with CHIP-specific evidence behind them are sleep and exercise. I already do both, on purpose, and I have written about why I train the way I do. If a test came back positive tomorrow it would tell me to keep doing them. And if I do carry a clone, the odds say it is DNMT3A, which is the one where the lever may not reach anyway.

The amendment, then, is this. In July I said a positive result would not change what I do. That is still true, and now it is true for a better reason. The things this new work points at are free, I am already doing them, and nobody needs a thousand-dollar sequencing panel to justify sleeping properly.

Here is what would change my mind, and it is a specific thing to watch for. The human half of this study is cross-sectional, meaning it photographs a population once and measures who happens to have what. It cannot tell you that exercise shrank anyone’s clone, only that active people carried fewer of certain kinds. The causal work is in mice. What would move this from interesting to actionable is a trial that sequences people’s blood, intervenes, and sequences it again to report what actually happened to the clones. Nobody has run that yet.

One last thing, and it is the reason I am adding a section instead of quietly repairing a sentence. I did not have to rewrite this post to fit the new paper in, because the post was organized around the mechanism instead of the diagnosis. IL-1 beta was the spine in July and it is the spine in the new work. That is the practical argument for organizing around mechanisms instead of diagnoses. New evidence arrives as an addition to what you already understand, not a replacement for it.

About “reverse atherosclerosis in one year”

A second study is circulating next to this one, usually under a headline about reversing atherosclerosis in a year. The study is real. The headline is not what it found, and the gap between the two is worth walking through, because it is the exact move I spent fifteen years watching get made from the other side of the table.

It is a prespecified secondary analysis of a trial called S-LiTE.¹⁵ 130 adults with obesity finished a low-calorie diet, then were randomized for 52 weeks to placebo, exercise, the GLP-1 drug liraglutide, or exercise plus liraglutide. What got measured was carotid intima-media thickness: an ultrasound of the artery in your neck that reports the combined thickness of the wall’s inner two layers. In the exercise group that thickness fell 7 percent. In the exercise plus drug group, 6 percent. The drug by itself did nothing.

Four things about that number. It is wall thickness, not plaque, and the authors themselves call it a surrogate marker. Its size is about 0.04 millimeters against a starting value near 0.57, so four hundredths of a millimeter, read off an ultrasound. The exercise arm that produced it was 26 people. And the authors wrote the sentence I wish had traveled with the 7 percent, which I will quote directly:

“whether such a change indeed translates into clinical benefit remains uncertain.”

One thing in the other direction, because honest runs both ways. Several of the authors have Novo Nordisk ties, and liraglutide is Novo Nordisk’s drug. They reported the drug arm as null anyway. A null published against your own sponsor-adjacent interest is more believable, not less, and it deserves to be said out loud.

None of this makes exercise less worth doing, and nothing here is an argument against exercising. It means the accurate sentence is that exercise reduced carotid wall thickness and inflammatory markers in adults with obesity maintaining a weight loss, while the drug alone did not. “Reverse atherosclerosis in one year, proven” is a different claim wearing that one’s evidence.

Worth adding, since the two studies keep getting told as one story: the S-LiTE analysis never measured clonal hematopoiesis. Not once. It shares no participants and no measurement with the CHIP paper above. They are two separate papers about two separate things, joined in the retelling by the word inflammation.

If the surrogate-versus-signal problem is the part that interests you, I took it apart at length in the post on AI plaque scans, where the question was whether the number moves because your artery changed or because the machine measured it differently the second time.

The Final Signal

• What’s real. A rogue blood clone can genuinely inflame your arteries from the inside. The mechanism is causal for the inflammation arm, proven in mice and in a human drug trial.

• What’s overstated. That it is a common answer for early heart disease. At my age it is a low-probability suspect, and the risk it carries is a modest multiplier, not a verdict.

• What I changed. I learned to read disease as a broken mechanism instead of a label on a chart, and I calibrated my way to not chasing a test I could not act on.

• What I got wrong. I wrote that a positive test would hand me no new lever. A Nature paper I had missed made that too strong: sleep and exercise now have CHIP-specific evidence behind them. They also do not appear to reach the most common driver, and I was already doing both, so the testing decision stands. See “Recalibrated: August 2026” above.

• What the system gets wrong, and right. There is no pathway to order this for someone in my situation, and no treatment if it were positive. That gap is real. But given the odds and the absence of any different action, the restraint is not crazy. Both things are true at once.

• Why nobody owns it. Hematology, oncology, cardiology, and geroscience each read this same mutation as a different disease, and each of them is right. Specialists are not the problem; specialization is why medicine works. The problem is that the biology is one continuous process and the system reading it is cut into departments. When no specialty owns a mechanism, the patient standing on top of it falls through the gap.

• What’s next. I keep saying “chronic inflammation” like it is one thing in one artery. It is not. Next I want to pull that single hallmark out of my own chest and show you it is the same fire burning in diseases we treat as completely unrelated, and then get to the only question that actually matters: what, if anything, actually turns it down? That became the post on the small vessels nobody measured, where the inflammation stops being an abstraction and starts explaining a symptom.

The Calibrated Claim Audit

How much does CHIP explain a heart attack like mine, and is it worth chasing the test?

Commercial distortion risk: low. There is no product being sold here, and the intervention with the best new evidence behind it costs nothing. The distortion pressure runs the other way, toward selling a $1,000 test that would not change what you do.

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

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References

1. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9-16. PMID: 25931582 [Finding: The paper that named CHIP. Defines it as a blood-cell clone driven by a leukemia-associated mutation, without anemia or blood cancer. Note: the 2 percent size threshold comes from the sequencing studies, not this paper.]

2. Genovese G, Kähler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477-2487. PMID: 25426838 [Finding: In 12,380 people, clonal mutations were found in about 10 percent of those over 65 but only about 1 percent of those under 50. Prevalence rises steeply with age.]

3. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488-2498. PMID: 25426837 [Finding: Detectable clones were rare under 40 and climbed with age, reaching 9.5 percent at 70 to 79 and 18.4 percent in the very old. CHIP also tracked with higher all-cause mortality.]

4. Young AL, Challen GA, Birmann BM, Druley TE. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat Commun. 2016;7:12484. PMID: 27546487 [Finding: Standard sequencing detects clones in about 10 percent of 70-year-olds. Error-corrected sequencing, which reaches far smaller clones, found them in 95 percent of healthy people in their fifties. Prevalence depends on how hard you look.]

5. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377(2):111-121. PMID: 28636844 [Finding: Across four case-control studies, CHIP carriers had roughly a 1.9-fold higher risk of coronary heart disease, and about 4-fold in early-onset myocardial infarction. This is an association, though the paper pairs it with causal mouse data.]

6. Oren O, Laffin LJ, Singh A, Nissen SE, Carraway HE. Clonal hematopoiesis of indeterminate potential and heart disease: what every internist needs to know. Cleve Clin J Med. 2026;93(5):289-295. doi:10.3949/ccjm.93a.26003 [Finding: A current clinician review from a dedicated CHIP cardiology clinic. States no cardiology society recommends routine CHIP screening in asymptomatic adults, that risk is heterogeneous across driver genes, and that management if positive is intensive risk-factor control, with off-label colchicine or vitamin C only as small-effect, emerging options.]

7. Fuster JJ, MacLauchlan S, Zuriaga MA, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355(6327):842-847. PMID: 28104796 [Finding: Mice given marrow engineered to carry a CHIP mutation developed markedly larger plaques, driven by NLRP3-inflammasome IL-1 beta signaling. Blocking that pathway was protective, arguing the mutation plays a causal role.]

8. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease (CANTOS). N Engl J Med. 2017;377(12):1119-1131. PMID: 28845751 [Finding: In 10,061 heart-attack survivors, a drug blocking IL-1 beta cut major cardiovascular events by about 15 percent at the effective dose, with no reduction in cholesterol. Human proof that reducing inflammation alone prevents events.]

9. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243-278. PMID: 36599349 [Finding: The framework paper cataloguing the twelve shared root mechanisms of aging, including genomic instability, epigenetic alterations, and chronic inflammation. This post uses it to name three of those hallmarks that CHIP engages at once.]

10. Vanner RJ, Zeng AGX, Kim RH, Chan S, Bankar A. Clinical decisions in clonal hematopoiesis: a contemporary review for clinicians. Haematologica. 2026;111(5):1584-1609. PMID: 41641651 [Finding: A targeted CHIP sequencing panel runs about $200 to $1,000 out of pocket, and CHIP clinics run on grant funding because there is no established reimbursement model. The clinical value of testing remains unsettled.]

11. Rhee J-W, Bolton KL, Gupta D, et al. Clonal hematopoiesis and its cardiovascular implications: a scientific statement from the American Heart Association. Circulation. 2026;153(11):e940-e952. PMID: 41664921 [Finding: The AHA’s position statement. Notes that no CHIP-specific therapy has yet proven efficacy for treating or preventing cardiovascular disease.]

12. LODOCO (colchicine) 0.5 mg tablets. Prescribing information. AGEPHA Pharma, FDA NDA 215727. Approved June 2023. FDA label [Finding: In 2023 the FDA approved low-dose colchicine to reduce the risk of heart attack, stroke, and cardiovascular death. This is the cardiovascular indication for an old anti-inflammatory drug, distinct from its off-label use against CHIP clones.]

13. Jaiswal S, Ebert BL. Clonal hematopoiesis in human aging and disease. Science. 2019;366(6465):eaan4673. PMID: 31672865 [Finding: A landmark review establishing clonal hematopoiesis as a common feature of human aging whose consequences reach beyond blood cancer into the non-malignant diseases of aging and immune dysfunction. Frames CHIP as a visible window into the somatic mutation and selection that occurs across all aging tissues.]

14. Gerhardt T, Jacob W, Gaebel L, et al. Mutation-dependent responses to sleep and exercise in clonal haematopoiesis. Nature. 2026;655(8125):1309-1319. PMID: 42271062 [Finding: In 82,834 UK Biobank and 8,404 All of Us participants, accelerometer-measured moderate-to-vigorous activity was associated with lower prevalence of non-DNMT3A clonal hematopoiesis (odds ratio 0.86 per hour per day) but showed no association with DNMT3A. In mice, sleep and exercise curtailed JAK2 and TET2 clone expansion and reduced plaque through IL-1 beta signaling, with DNMT3A null on both counts.]

15. Sandsdal RM, Holt J, Alkhefagie HGA, et al. Effects of exercise and liraglutide on vascular health and inflammation during weight loss maintenance: a prespecified secondary analysis of the S-LiTE trial. Nat Metab. 2026;8(7):1483-1488. PMID: 42342869 [Finding: In 130 adults with obesity maintaining a diet-induced weight loss, 52 weeks of exercise reduced carotid intima-media thickness by 7 percent (about 0.04 mm) while liraglutide alone did not. The authors state that whether a change of this size translates into clinical benefit remains uncertain.]

This piece was first published at calibratedsignal.com.

This is a different kind of post than most of what I have written here. If you have been following along, you have mostly gotten cardiology: LDL, blood pressure, plaque, the reasons a low-risk person can still end up with a stent. This one goes upstream of all of that, into raw aging biology, and I want to say plainly why.

The hallmarks of aging are the language I use to judge almost every health, wellness, and longevity claim I run into. It is the closest thing biology has to a unifying map of why we break down with age.

Calibrated Age is the system I am building on top of that map: which hallmarks an intervention plausibly touches, what evidence supports each link, and whether that evidence stops at a mechanism, a biomarker, a mouse, or a human outcome. A paper like this one matters because it changes the map itself. It shows that something sold as simply “anti-inflammatory” might really be touching senescence, mitochondrial metabolism, chromatin, and cell-to-cell signaling all at once. Or maybe it isn’t touching any at all, and just moving a biomarker upstream of biology that has has already occurred and had its impact.

Soon, my writing will begin including specific interventions where I bring in a hundred-plus studies and map those studies to the hallmarks of aging via proxies such as associated biomarkers, known pathways, and disease states. True longevity studies that analyze things at the intervention level do not exist, because of economic and time-constraint realities. So, to use existing evidence as it is available, we must use proxies. I will analyze mechanism strength and evidence quality, along with important side criteria such as bioavailability, dosage realities, conflict of interest, and safety data from a half-dozen sources.

The piece I am writing today is an evidence breakdown. To effectively study and map interventions to the framework that makes up aging biology, I must stay on top of the headline literature surrounding how these hallmarks actually function. So, literature reviews pertaining to landmark studies will land when I think they truly move the needle. This one is foundational, and it is primarily mechanistic, so read it as a look at the machinery rather than a list of things to do or items to consider adding or tossing from your own health and wellness routine.

This paper also lands in a corner of the map I already know. I found my way into aging biology through cancer, and one of the epigenetic markers that changed in a melanoma study I worked on sits at the same spot this Mayo paper lands on: lysine 27 of histone H3 (H3K27). Same residue, different chemistry, and I will come back to why that matters.

The Mayo connection is more literal. The study came out of the Kogod Center on Aging. I work in Mayo’s emergency department and am finishing my PhD through the University of Minnesota bioinformatics and computational biology program, which is run jointly with Mayo Clinic. I am not part of the Passos lab and had nothing to do with this paper. I follow the work because its biology sits at the intersection of the clinical system I work in, the PhD program I am completing, and the epigenetic machinery I once studied. Now onto the paper.

Vocabulary that matters

• Senescent (”zombie”) cell: a cell locked into durable growth arrest by damage, stress, or a biological program. It stays metabolically active and can alter the tissue around it through what it secretes.

• SASP (senescence-associated secretory phenotype): the mixture of cytokines, chemokines, growth factors, proteases, and other signals a senescent cell releases. The inflammatory part is the focus of this paper. In plain terms, it is the signal leaking out of the cell.

• Inflammaging: chronic, low-grade, whole-body inflammation that rises with age. It is now counted as one of the hallmarks of aging.

• Acetyl-CoA: the cell’s only currency for attaching an “acetyl” tag to a protein. Here it is the raw material the cell needs to keep its inflammation genes open.

• Histone acetylation (H3K27ac): a chemical mark associated with active regulatory regions of DNA. It keeps the packaging around a gene loose enough for the cell’s reading machinery to reach it. H3K27ac means the mark sits at lysine 27 of histone H3.

• SLC25A1: the transporter that carries citrate out of the mitochondria so the cell can turn it into acetyl-CoA. The valve on the fuel line.

The old plan was to kill the senescent cell

Senescent cells earn their keep early in life. They stop damaged cells from dividing, which is one of the body’s oldest defenses against cancer, and they help with wound healing and development. The problem is that they pile up with age and overstay their usefulness, sitting in tissue and leaking the SASP for years.

The dominant response, pioneered in large part at Mayo, has been to clear them out. Drugs called senolytics selectively kill senescent cells, and in aged mice a senolytic combination improved physical function and even extended lifespan. That work is a genuine milestone, and it is tied to Mayo through the foundational contributions of James Kirkland and his colleagues. It put cellular senescence on the map as something you might actually treat.

This paper asks a different question. What if you do not have to kill the cell to stop the harm? What if you leave it in place, still holding its brakes on cell division, and just switch off the inflammation it is broadcasting? That is what the group set out to test, and the paper’s own summary of the result is direct:

“Pharmacological inhibition of this pathway in aged mice selectively suppresses SASP-associated inflammation without reversing cellular senescence, reducing tissue inflammation and improving healthspan.”

— Martini et al., Nature (2026)

Why chronic inflammation matters as you age

Chronic inflammation is one of those phrases everyone uses and almost no one can define at the level of mechanism. It got formal status in 2023, when the field’s most-cited map of aging added chronic inflammation to its list of hallmarks, the core processes that drive biological aging. Inflammaging is the name for the version that matters here: not the sharp, useful inflammation of a cut or an infection, but a low, constant background hum that never resolves and slowly damages tissue.

That hum is upstream of a lot of the diseases I usually write about. The inflamed immune cells that circulate in an aging body are part of why plaque turns unstable and why a heart attack can arrive with no warning, which is the ground I covered in the piece on clonal hematopoiesis. This post is one layer underneath that one. It is about one place age-related inflammation is manufactured in the first place.

The old story: the alarm

The first half of this story has been understood for a few years now. When a cell becomes senescent, its mitochondria, the small structures that produce most of its energy, start to malfunction. Damaged mitochondria leak their own DNA into the body of the cell, where it does not belong. The cell has an ancient alarm system, called cGAS-STING, that treats loose DNA as the signature of a virus and trips the inflammation response. That was the accepted account of how a senescent cell starts to inflame: broken mitochondria set off an internal alarm.

The trouble is that the alarm alone did not fully explain the picture. Something else had to decide whether that alarm produced a loud, sustained inflammatory program or just a whisper. That missing piece is what this paper found.

The new story: the fuel line and the valve

The Mayo group showed that the same broken mitochondria do a second job. They run a metabolic assembly line, pyruvate to citrate to acetyl-CoA, and crank it up in senescent cells. Acetyl-CoA is the cell’s raw material for a specific epigenetic tag, the acetyl mark on histones, and that tag is what keeps the DNA packaging around the inflammation genes loose enough to be read at full volume. The mark they tracked sits at lysine 27 of histone H3, written H3K27ac.

The cleaner way to picture it is that the cell needs two separate inputs. Mitochondrial DNA sets off the alarm through cGAS-STING. Mitochondrial citrate metabolism supplies the acetyl-CoA that keeps the SASP genes accessible enough for that alarm to become a full transcriptional program. In the paper’s own words these are “distinct but complementary pathways that converge to enable full SASP gene expression.” Blocking either input lowers the SASP, and pushing on both produces a stronger response, which means there is no single master switch to find here. The alarm and the fuel line each do something the other one cannot.

That is the part worth zooming in on, because it is key.

Then they did the cool part. They interrupted the assembly line at three points: pyruvate import through a carrier called MPC, citrate export through SLC25A1, and citrate conversion to acetyl-CoA through an enzyme called ACLY. The SASP fell at all three while the cell-cycle arrest stayed intact. At the SLC25A1 and ACLY steps, the acetyl tags on the inflammation genes fell too. And with the SLC25A1 blocker specifically, the cell’s energy production, its mitochondrial respiration, and its overall shape were largely preserved. They were not reversing senescence or broadly poisoning the mitochondria. They were selectively turning down one output.

The cleanest lever was that middle valve, SLC25A1, and there is a tool compound that blocks it, called CTPI-2. That let them run the experiment that matters.

I am going to digress for a moment. A key point here is that this is all investigational at the most foundational level of biology. These are research compounds not intended to be taken by humans. As a word of caution, recall that my connection to studying aging biology came from my work in cancer. The two are inextricably interwoven. I say that to say this: while I am not against “biohacking” and people doing personal experiments, one reason I am not a huge fan of experimenting with research-grade peptides (the ones with zero or near-zero human data) and research compounds is that, not only is the legality questionable and in the gray, but these same compounds could pull a lever in the wrong way and cause cancer. I’m not saying that about the compound in this study, or about any peptide in particular, precisely because most don’t have enough data for us to conclude one way or another. It is only a word of caution from a guy who spent years in a cancer lab seeing how complicated biology is, and how a treatment can be a near cure in one population and actually make things worse in another. Biology is complicated. Humans are complicated. What works in mice doesn’t always translate, and may actually do the opposite in a human. Rant over.

What happened in the animals

They took aged mice, both male and female, and gave them CTPI-2 by mouth three times a week for three months, from 19 to 22 months of age, which is late life for a mouse. The treated animals were measurably less frail on a 31-parameter frailty index, had stronger grip, and grew larger muscle fibers. All of this happened without wiping out the senescent cells.

I want to be careful about the tiers of evidence here, because they matter. This is mouse healthspan data plus human cells in a dish. There is no human trial. This was also healthspan, not lifespan: they measured frailty, strength, and tissue inflammation, not how long the animals lived.

And the effects were not uniform. Muscle function improved, but bone microarchitecture did not. In the heart, the treatment lowered both the secretory factors tied to the working heart-muscle cells and the classic SASP signals from the surrounding connective-tissue cells, and the drop in inflammatory immune-cell markers showed up more clearly in females. One lever, and the body did not respond as a single unit. Hold that thought, because it is the whole point of the last section.

The part that is personal for me

The tag at the center of this paper sits at lysine 27 of histone H3. That is the same histone position I was looking at years ago in cancer, from the other direction.

In the melanoma work I was part of, we found that as cells survived a targeted drug, they lost di- and trimethylation at that same lysine 27. Methylation and acetylation are two different chemical tags, and they are not interchangeable. On this spot they tend to do opposite jobs: those methyl marks are generally linked to silencing a gene, the acetyl mark to switching it on. We reported this as an association, part of the response of the surviving cells, not as proof that the single change caused the drug tolerance. In this Mayo paper, the acetyl mark at the very same residue appears to sustain inflammation in aging.

So the same tiny position on the same histone is a control point that cells write in more than one direction. I studied it changing one way as cancer cells escaped a drug. This group is studying it changing the other way as old cells learn to inflame. Cancer and aging are not separate biological worlds. They repeatedly corrupt the same regulatory machinery, sometimes in opposite directions and at very different speeds. That machinery has a name on the hallmarks map, epigenetic alteration, and it happens to be the corner of the map I know best. It is a large part of why I think aging is understood better through this kind of molecular detail than through any single disease label.

What I would actually do with this

This is where a good mechanism gets turned into bad marketing. Start with the supplement aisle.

What does a lower CRP actually tell you?

CRP is the sharpest example. C-reactive protein is a blood marker of inflammation, and a lot of people, including plenty of clinicians, treat lowering it as if it were treating the underlying problem. It is not that simple. When researchers used genetics to test this directly, comparing people who inherit naturally higher or lower CRP for life, the lifelong difference in CRP did not translate into a difference in heart disease. That argues CRP is riding along with the fire rather than being the fire. I am not saying that a falling or rising CRP is meaningless. An intervention that changes an upstream pathway may lower CRP with it. But the number cannot tell you which source moved, whether the senescent-cell SASP was touched at all, or whether any hard outcome will improve. Marker movement is not mechanism, and mechanism is not outcome. This same logic will follow us into intervention analysis in the future.

The CANTOS trial makes the distinction clean. Canakinumab, an antibody aimed at one specific inflammatory signal (interleukin-1β), lowered high-sensitivity CRP by 37 percentage points more than placebo at its 150-mg dose, and cut the primary cardiovascular event rate from 4.50 to 3.86 events per 100 person-years, a hazard ratio of 0.85. Real, but modest. And in the same trial, all-cause mortality did not improve, while fatal infections rose. A large drop in a marker, a genuine but small outcome benefit, and no net change in dying. That is what “targeting inflammation” actually looks like when it works: a precise, expensive biologic with real tradeoffs, not a scoop of powder, and a reminder that the marker and the outcome are different questions. It is also worth noting the contrast in incentives. CANTOS was funded by the drug’s maker; the Mayo senescence paper was funded by public and non-profit sources with no competing interests declared.

You will hear a lot of discussion about conflicts of interest and economic incentives in my writing. As a guy who used to be in the boardroom before spending time at the scientific bench and the patient bedside, I believe conflict can be a true concern. However, conflict of interest and bias are not one and the same. Plenty of conflicted studies have zero bias and are very high quality, methodologically sound studies. Some, however, should have your eyebrow raised as high as Dwayne “The Rock” Johnson.

The Mayo paper does not get a free pass just because I like the mechanism. SLC25A1 and the citrate-to-acetyl-CoA line it feeds are not some isolated aging switch. That chemistry sits at the center of normal metabolism throughout the body. The mouse results are genuinely exciting, and they are also a live demonstration of the problem: one clean lever produced a scattered, tissue-specific, sex-specific set of effects, with bone left untouched. That is what tinkering with one component of a deeply connected system tends to look like. The upside is real and so is the unpredictability. Both are the message.

The Calibrated Claim Audit

Thesis: Chronic inflammation in aging is not one dial. Inside a senescent cell, several hallmarks run as one circuit, and a marker is not a mechanism.

1. The citrate-to-acetyl-CoA pathway helps sustain SASP transcription in senescent cells.
Evidence: strong, in human cells with both genetics and drugs, plus aged mice.
My read: supported. This is the core finding, and it is mechanistically clean.
What would change my mind: independent labs failing to reproduce the acetyl-CoA and H3K27ac dependence.

2. CTPI-2 improved healthspan measures in aged mice without clearing senescent cells.
Evidence: promising. One aged-mouse study, both sexes.
My read: unproven. One study, not yet replicated.
What would change my mind: replication with pharmacokinetics and longer safety follow-up.

3. SLC25A1 inhibition will improve human aging outcomes.
Evidence: none. There is no human intervention trial.
My read: unproven. No basis for a human claim yet.
What would change my mind: human safety and outcome trials.

4. A lower CRP proves the upstream cause of inflammation was corrected.
Evidence: refuted. CRP is nonspecific and genetic elevation is not causal for coronary disease.
My read: overstated. A marker is not the mechanism.
What would change my mind: evidence that CRP itself drives the disease process.

5. A large drop in an inflammatory marker means a large clinical benefit.
Evidence: refuted. In CANTOS, hs-CRP fell 37 points and the hazard ratio was 0.85.
My read: overstated. Marker size did not predict benefit size.
What would change my mind: trials where the size of the marker change tracks the size of the outcome.

Commercial distortion risk: low in the paper, higher downstream. The study declared no competing interests and was funded by NIH and non-profit foundations, and CTPI-2 is a research tool rather than a marketed product. The predictable distortion comes next: supplement marketing turning “mitochondrial metabolism controls the SASP” into unsupported claims that some ingredient is senomorphic. By contrast, the CANTOS trial cited here was funded by the drug’s maker, which is normal for a pharmaceutical trial but worth naming.

The Final Signal

• What this paper gets right. It moves chronic inflammation from a vague phrase to a specific, testable mechanism, and it shows several hallmarks of aging working as one connected circuit: cellular senescence, mitochondrial dysfunction, epigenetic alteration, altered intercellular communication, and the inflammation they produce.

• What it cannot claim yet. Everything downstream of “improves healthspan” is in mice and cells. It measured healthspan, not lifespan; there is no human outcome data, and CTPI-2 is a laboratory research compound that no one can be prescribed.

• What it changes for me. It sharpens how I read the word inflammation. It is a system output, not a single dial, and I will keep asking of any “anti-inflammatory” claim whether it moved a marker, a mechanism, or an outcome.

• What would change my mind. A human trial showing that selectively quieting the SASP, without clearing the cells, improves a real outcome and not just a marker.

• What comes next. More of these foundational reads, hallmark by hallmark, and a companion primer on chronic inflammation over at Calibrated Age.

This piece was first published at calibratedsignal.com.

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X · LinkedIn

Not medical advice.

References

1. Martini H, Birch J, Marques FDM, et al. Mitochondrial metabolism and epigenetic crosstalk drive SASP. Nature. 2026. PMID: 42527602. Finding: in senescent cells, mtDNA-cGAS-STING signaling and a mitochondrial citrate-to-acetyl-CoA pathway act as distinct but complementary inputs that together drive histone acetylation and full SASP expression; blocking SLC25A1 reduced inflammation and improved healthspan in aged mice without clearing the cells.

2. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243-278. PMID: 36599349. Finding: the updated hallmarks-of-aging framework that formally added chronic inflammation as a core hallmark.

3. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014;69 Suppl 1:S4-9. PMID: 24833586. Finding: foundational review defining inflammaging as chronic, low-grade inflammation that rises with age.

4. Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24(8):1246-1256. PMID: 29988130. Finding: in aged mice, drugs that selectively kill senescent cells improved physical function and extended lifespan.

5. C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC). Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ. 2011;342:d548. PMID: 21325005. Finding: using inherited genetic differences in CRP, lifelong differences in CRP were not associated with coronary heart disease risk, arguing CRP is a marker rather than a cause.

6. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131. PMID: 28845751. Finding: canakinumab lowered hs-CRP and cut the primary cardiovascular event rate, but did not reduce all-cause mortality and raised fatal infections.

7. Grigore F, Yang H, Hanson ND, VanBrocklin MW, Sarver AL, Robinson JP. BRAF inhibition in melanoma is associated with the dysregulation of histone methylation and histone methyltransferases. Neoplasia. 2020;22(9):376-389. PMID: 32629178. Finding: as melanoma cells survived BRAF-inhibitor therapy, H3K9 and H3K27 di- and trimethylation were lost, changes the authors associated with the surviving drug-tolerant state.

This post is not about that one.

There is a quieter version of the exact same disease. Same plaque, same clot, same biology. It just ends differently. It does not drop you on the kitchen floor, and it does not come through my doors as a code. Most of the time nobody knows it happened at all, including the person it happened to. I think it may be what built the blockage in my own artery. And almost nobody talks about it.

Here is the part I am not proud of. For years, a doctor told me to start a statin. For years, I said no. I am an emergency nurse. I am a scientist who has spent a career reading the primary literature, even before I had the formal degrees. I had every advantage a person could ask for, and I argued my way out of the one cheap, proven thing that I now believe would have helped. It took an eighty percent blockage in my right coronary artery and a trip to the cath lab to make me listen.

I never lacked information. I had enough of it to build a better argument for the answer I already wanted, and more reading would not have fixed that. If you have ever taken one reassuring test, one good number, or the plain fact that you feel fine, and used it to wave off a risk you would rather not deal with, then this is not only my story.

Vocabulary that matters

• Plaque rupture: the thin cap stretched over a soft plaque tears, exposing the raw material underneath to the blood.

• Plaque erosion: a clot forms on a plaque without a full tear. Same result, different trigger, and it shows up more in younger people and on plaque that is not heavily calcified.

• Thrombus: a clot. When blood meets the damaged inside of a plaque, clotting can start fast.

• Healed plaque rupture: the artery survived the event, organized the clot, repaired the surface, and was left with scar tissue that narrows it a little more than before.

Every standard test I took early on told me I was fine, and I have written before about how a calcium score would have called my severe blockage a zero. But there is a deeper problem with the slow-pipe story, and this one is not about the test. It is about the disease itself.

Atherosclerosis does not begin as sludge in a tube. It begins inside the wall of the artery. ApoB particles, the cholesterol-carrying kind, cross the artery’s lining and get trapped there, and the body treats that trapped material like a wound: immune cells move in, swallow the fat, and a soft, inflamed lesion forms.¹ It does not take a cut or a classic injury to start it. The trapped particles are the injury. Calcium, if it shows up at all, comes later, as the body scars the wound over.

A lesion like that does not just sit quietly and grow. It can fail. And it can fail two ways. It can rupture, where the thin cap stretched over it tears.² Or it can erode, where a clot forms on the surface without a classic tear, a pattern that turns up more often in younger people and on plaque that is not heavily calcified.³

Either way, the next step is the same, and it is the whole story. Blood hits the damaged surface and a clot forms. If that clot slams the artery shut and enough muscle starves, you get the heart attack everyone pictures, the code I help run in the ER. But if the clot is smaller, or it forms and partly dissolves, or there is enough flow around it, the artery survives. And then the body does what it does with any wound. It organizes the clot, heals the surface, and lays down scar. That scar leaves the artery more narrowed than it was the day before.

Is that a heart attack? Strictly, no, not unless enough heart muscle actually dies, because that is what a heart attack is. Most of these silent events kill nothing. They just narrow the artery a little more. Some might nudge a troponin no one thought to draw, or flicker on an ECG no one was recording. And a few might cross the line into a real heart attack you never felt, the kind that only turns up later as a scar on the right scan.

Which of those happened inside my own artery, I cannot tell you yet. A cardiac MRI could answer one piece of it: whether a silent event ever killed enough muscle to leave a scar behind. That is worth knowing, and it is not a long shot. In the autopsy work, healed ruptures traveled together with healed heart attacks.⁴ But a clean MRI would not close the question either, because an episode that clots and heals without starving much muscle leaves that scan very little to find.

The artery wall is the harder problem, and here I have to be honest about what I already had. During my stent they ran an ultrasound probe inside the artery to size the lesion. It described moderate atherosclerosis and discrete eccentric disease, which was exactly what it was there to do. It was not looking for the layered signature of an old healed rupture, and intravascular ultrasound is not the tool that finds it. The imaging validated against pathology for that is optical coherence tomography, which also means a catheter, and even then it reads a pattern rather than replaying the history. Nobody was asking my artery that question on the day they were busy fixing it. That gap is where this goes next.

This is not a fringe idea. When pathologists examined the hearts of people who died suddenly of coronary disease, they found healed ruptures in 61 percent of them, and the more healed ruptures a person carried, the worse their narrowing.⁴ A separate autopsy study found that among severely narrowed segments, 52 of 71 bore the fingerprint of a healed disruption, and argued the mechanism explains something cardiologists had already been seeing on repeat angiograms in living patients.⁵

“...the phasic rather than linear progression of coronary disease observed in angiograms carried out annually in patients with chronic ischaemic heart disease.”

Mann and Davies, Heart, 1999

There is a second gut-punch buried in this data. The plaque most likely to hurt you is often not the biggest one on the scan. When researchers imaged people before and after a heart attack, the artery that eventually closed had been less than 50 percent blocked beforehand in 66 percent of cases, and the heart attack came from the previously-worst spot only 34 percent of the time.⁶ The dangerous plaque is frequently the soft, modest one nobody was watching. So when someone tells you a lesion is mild, that is a measurement, not a forecast. Modern serial scans point the same way: progression is not a steady creep. Over just a few years, most patients show measurable plaque growth, and a meaningful subset are outright rapid progressors.⁷

My case, as honestly as I can tell it

At thirty-six, a CT angiogram of my heart was clean. At forty-four, a second scan found a severe blockage in my right coronary artery, with no calcification noted on it. Eight years, clean to critical. My cholesterol was borderline, not wild. My blood pressure was only ever on the mildest end of elevated. My Lp(a), a mostly genetic risk factor, sits near zero. My inflammation markers have always been low, and I have never had a problem with metabolic health. By the numbers, I am not the guy this is supposed to happen to.

A slow, steady pipe-clog never explained that to my satisfaction. A handful of silent wounds that tore, clotted, and healed does. And one detail makes me sit up: erosion, the quieter of the two failure modes, shows up most in people right around the age I was, and on soft, non-calcified plaque exactly like mine.³ I cannot prove this is my story. But of every explanation I have chased, it is the one that fits the shape of what happened.

Why your cardiologist may never mention this

None of mine ever did. Not one. And here is my honest guess at why, because it is not incompetence. Look at it from their side. They have a plan that, followed, gives you the best odds of staying alive: lower what damages the artery wall, and do not stop. Telling you that your blockage might be a string of silent, healed near-heart-attacks does not change that plan by a single milligram. It just scares you. Why frighten a person with a fact they can do nothing extra with, let alone prove? In a calmer world, that restraint is almost a kindness.

We live in one where you cannot open an app without someone confident and miked-up telling you the opposite of the plan. That you do not need to treat your cholesterol as long as your other numbers look good. That the medications do not work. That the treatment, not the disease, is the real thing to fear. I spent fifteen years inside the wellness industry. I know exactly how good that pitch sounds, and exactly who profits from it.

So this is where I step off the gentle path my doctors stayed on. When the loudest voices in the room are talking people out of the best-proven lever we have, “you will be fine, just take this” does not stand a chance. A quiet doctor leaves a vacuum, and the vacuum fills with whoever is the most confident and, sometimes, the most dead wrong. That is exactly when you need the truth to land hard enough to stick. Not to manipulate you. To compete for your attention with the people who are already trying to.

And I get to see how that competition ends. In the ER, I meet the people who may have listened to the wrong voice, and I meet them at their worst, on the worst day of their lives. The cardiologist gets a luckier version of them, the one who still has time to choose. I landed somewhere in between: the guy who got scared straight just before he became the version of himself that ends up on a table in his own department, or a statistic that never makes it to the ER at all. I had the training to know better, and I still let those voices win for years. I will say this much: I do not think the people preaching metabolic health are evil. I think they believe their version of the story, about metabolic health and where lipids fit into it. After a year spent going back through the real data, I no longer believe that version. Unfortunately, it took a cath lab to undo that line of thinking and make me do something about my cholesterol.

What I changed, and what I think you should take from it

Not a hack, and not one thing. A few changes, most of them boring, and it started with taking the advice of the man who put the stent in my heart.

First, I stopped treating any single test as a verdict. A calcium score, a stress test, a clean troponin in my own ER: each answers one narrow question, and the relief it hands you stops at the edge of that question.

Second, and this is the one that counts: I take the treatment now, and I do not argue with it. The thing that actually blunts this quiet, stepwise process is the same risk-factor control I spent years talking myself out of. Lower the particles that cross the wall and seed damage even in the absence of inflammation.¹ Keep the pressure down. Do not smoke. Build cardiovascular fitness. None of it trends on a podcast. It just works, slowly, in the background, by keeping fewer dangerous particles in circulation: fewer to lodge in the wall and start the process, and fewer to do harm if a small injury or bit of inflammation ever does occur.

I have driven my numbers about as low as they go, and the evidence behind that turned out to be stronger than I expected when I finally went looking. Aggressive lowering does not just slow plaque, it can shrink and stabilize it: in imaging trials, the majority of patients on intensive therapy showed actual regression.⁸ Across 170,000 people in 26 randomized trials, the benefit kept growing the lower the LDL went, with no threshold within the range studied where it stopped mattering.⁹

There is one complication in that, and it is why I am not fully settled. Erosion looks biologically different from rupture, and because statins lower LDL rather than triglycerides, the argument goes that erosion-driven risk may answer better to treatments aimed at triglyceride-rich lipoproteins than to pushing LDL lower still.¹⁰ Those are still ApoB particles, so this is not an argument against the lever. It is an argument that the lever may not be the whole job. That is a hypothesis, not outcome data. Nobody has run the trial that would settle it. That is not in the patient handout, and it is where the evidence stops.

And do not mistake any of this for “trust the experts and go quiet.” I am the guy who fought the system. I argued my way into the scan that found my blockage. I dug up my own possible mechanisms when no one handed them to me. Pushing is good. Pushing got me answers. Just aim it the right way: push for more looking and more honest conversation. Do not aim it at refusing the one treatment with fifty years of evidence behind it. That is not skepticism. That is the thing I nearly died of.

Your details will not be mine. The part that transfers is smaller and more irritating than a protocol: feeling fine is not evidence that nothing changed. An artery does not need to produce pain, a positive troponin, or an event you remember in order to get worse. Mine did all of that quietly while every number I was tracking looked acceptable.

I may never know whether my blockage grew through rupture, erosion, or some mix of both. If the disease that built it was never the slow kind, is lowering ApoB enough? I do not think we honestly know yet. I take the medication every morning anyway, because the evidence that it helps against the slow, linear, cumulative-exposure version of this disease is not in question. I am still asking whether it is enough. I stopped asking whether it is necessary.

I did not need more information. I needed to stop using the information I had to defend the answer I wanted. It took a cath lab to teach me that, and I would rather it did not take one to teach you.

Next: what a cardiac MRI could reveal about an injury I never felt, and what even a normal scan still could not prove.

The Final Signal

• What’s right. Plaque does build slowly over years, and cumulative exposure is real. The boring stuff matters.

• What’s incomplete. The slow-buildup story misses the silent version: the wound that tears, clots, heals, and leaves you more blocked with no warning at all.

• What I changed. I stopped reading any one test as a verdict, and I stopped arguing with the treatment that makes my artery wall harder to wound.

• What would change my mind. A cardiac MRI showing clean muscle, plus intravascular imaging built to look for a healed rupture finding a wall with no layering. Either result alone leaves the question open. Both clean, and I would drop this hypothesis for my own artery.

• What’s next. If an artery can hide a history like this, the question is whether anything could have caught it, or can catch it now.

Commercial distortion risk: low for the biology, which is decades of pathology with nothing to sell. It rises the moment the conversation turns to which scan or test could prove it, because imaging carries its own commercial gravity. And it runs the other way too: a whole ecosystem profits from telling you the proven treatments are unnecessary. That does not make either side automatically wrong. It means I read both with my hand on my wallet.

This piece was first published at Calibrated Signal, where the original lives with its full reference list. That’s the original. Everything I write there is filed by topic, so if you want the rest of what I have covered on plaque biology, cardiovascular risk, or what the standard tests can and cannot see, follow the topic tags from any article and you can read the whole thread of it.

This is not medical advice. It’s one clinician’s experience and a review of the published data. Talk to your doctor about what testing is appropriate for your individual risk profile.

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X · LinkedIn

Not medical advice.

References

1. Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis. Circulation. 2007;116(16):1832–1844. PMID 17938300 [Finding: Atherosclerosis begins when ApoB cholesterol particles cross into the artery wall and get trapped there. The inflammation that builds plaque is the body’s response to that trapped material, not the trigger.]

2. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47(8 Suppl):C13–C18. PMID 16631505 [Finding: Defined the thin-cap fibroatheroma, the lipid-rich plaque under a cap thinner than 65 microns that is the classic setup for a rupture. These dangerous lesions often narrow the artery very little before they fail.]

3. Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion without rupture into a lipid core. Circulation. 1996;93(7):1354–1363. PMID 8641024 [Finding: Described plaque erosion, a clot forming on a plaque’s surface without a classic rupture. Erosions turned up in younger patients (average age 44 versus 53 for ruptures) and on less-calcified plaque.]

4. Burke AP, Kolodgie FD, Farb A, et al. Healed plaque ruptures and sudden coronary death. Circulation. 2001;103(7):934–940. PMID 11181466 [Finding: In 142 men who died suddenly of coronary disease, healed (silent) plaque ruptures were present in 61 percent, were associated with healed myocardial infarction, and narrowing worsened with each additional healed site. The core evidence that plaque can advance in silent, stepwise jumps.]

5. Mann J, Davies MJ. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart. 1999;82(3):265–268. PMID 10455072 [Finding: Among severely narrowed coronary segments, 52 of 71 carried the fingerprint of a healed disruption. The authors concluded this mechanism explains the “phasic rather than linear” progression already seen on annual angiograms in living patients.]

6. Little WC, Constantinescu M, Applegate RJ, et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation. 1988;78(5 Pt 1):1157–1166. PMID 3180375 [Finding: The artery that later caused a heart attack had been under 50 percent blocked beforehand in 66 percent of cases, and was the patient’s tightest prior lesion only 34 percent of the time. The plaque that gets you is usually not the biggest one on the scan.]

7. Won KB, Lee BK, Park HB, et al. Quantitative assessment of coronary plaque volume change related to triglyceride glucose index (PARADIGM registry). Cardiovasc Diabetol. 2020;19(1):113. PMID 32682451 [Finding: Serial CT scans of 1,143 patients found plaque progressed in 77 percent over about three years, including a defined “rapid progressor” group whose atheroma volume rose at least 1 percent a year. Progression is common and uneven, not a slow uniform creep.]

8. Nicholls SJ, et al. Effect of two intensive statin regimens on progression of coronary disease (SATURN). N Engl J Med. 2011;365(22):2078–2087. PMID 22085316 [Finding: With intensive cholesterol-lowering, coronary plaque regressed in the majority of patients (63 to 69 percent, depending on the measure). Aggressive treatment does not just slow plaque, it can shrink it.]

9. Cholesterol Treatment Trialists’ (CTT) Collaboration; Baigent C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–1681. PMID 21067804 [Finding: A meta-analysis of 170,000 people across 26 trials: each reduction in LDL cut cardiovascular events proportionally, with no evidence of a threshold within the cholesterol range studied. Lower really is better.]

10. Crea F, Libby P. Acute coronary syndromes: the way forward from mechanisms to precision treatment. Circulation. 2017;136(12):1155–1166. PMID 28923905 [Finding: A review arguing plaque erosion is biologically distinct from rupture. Because statins lower LDL rather than triglycerides, the authors suggest therapies targeting triglyceride-rich lipoproteins may address erosion-driven residual risk better than more intense LDL lowering. Framed as a hypothesis, not settled outcome data.]

The Bottom Line

In 2024 a scan found a severe blockage in my right coronary artery. Seventy to ninety-nine percent narrowed, the kind they stent within days. The same scan called my total plaque burden severe. Across three separate scans of my heart, not one ever found a trace of calcium.

That should not be possible if you trust the test most people are handed as their heart screen. A coronary calcium score measures one thing: calcium. Mine would have read zero. A zero would have sent me home reassured, with a severe blockage sitting in a life-sustaining artery.

Here is the part that matters for you, not me. If you ever leave a clinic with some chest discomfort, a normal ECG, and a calcium score of zero, you have not been told your arteries are clear. You have been told they are not heavily calcified. Those are different sentences, and the space between them is where I spent eight years.

Vocabulary that matters

• CAC (coronary artery calcium): a quick CT scan, no dye, that measures hardened, calcified plaque and turns it into a single number.

• CCTA (coronary CT angiogram): a CT scan with contrast dye that maps the artery itself, the channel and the wall and the plaque, calcified or not.

• Noncalcified (”soft”) plaque: plaque a calcium score can’t see. Not all of it is dangerous, but the young, lipid-rich, rupture-prone kind lives here.

• Calcified (”hard”) plaque: plaque with visible calcium. Older, denser, on average more stable.

• Stenosis: narrowing. A 70 percent stenosis means the channel blood actually flows through is about 70 percent blocked.

Every standard test I took said my heart was fine. I wrote about that already: a clean ECG, a clean echo, a clean Holter. What I did not say is that even the tests built to look at the coronary arteries can miss the real problem, depending on what your plaque is made of. Mine was made of the kind that hides.

In 2016, at thirty-six, I had a CT angiogram that was spotless. Eight years later a second one found a severe narrowing in my right coronary artery and called my plaque burden severe. The plaque it could characterize, it described in one word: noncalcified. Soft. Across that scan, the angiogram that followed, and a third scan since, the word calcium never appears.

I have never had a formal calcium score. I do not need one. Calcium is the one thing these scans show loudly, bright white and impossible to miss. Three of them found none. My score would have been zero. A severe, flow-limiting blockage, and the test millions of people trust to catch it would have called me clean.

I am not a freak case. In the SCOT-HEART trial, more than a third of patients with chest pain had a calcium score of zero. Of those, about one in six still had coronary plaque on a CT angiogram. Soft plaque the calcium score never saw. Forty-one people in that study went on to have a heart attack. Ten percent of them had scored zero on calcium.¹ A 2024 meta-analysis of nearly thirty-eight thousand asymptomatic people found about one in ten with a zero score still carried soft, noncalcified plaque, though only about one in a hundred had a blockage serious enough to choke the artery.² The zero is reassuring. It is not the same as clean.

Plaque starts before calcium

To see how a calcium test misses a severe blockage, drop the picture of plaque as sludge clogging a pipe. Atherosclerosis is not debris in a tube. It is a wound in the wall of the artery.

It begins when cholesterol-carrying particles lodge in the artery wall and the body treats them like an injury. Immune cells move in, swallow the fat, and a soft, greasy, inflamed lesion forms.³ Calcium comes later, if it comes at all, as the body scars the wound over.

That timing is everything. Calcium on a scan is not the fire. It is the scar left after the fire. A calcium score reads the scars and stays blind to the wounds that have not scarred yet. At thirty-six my arteries were clean. By forty-four one of them held a soft, active, unscarred lesion a calcium scan was never built to see.

Two tests, two different questions

This is why the two coronary tests are not interchangeable.

A calcium score is a quick CT with no dye. It counts calcified plaque and hands you a number. It is cheap, fast, low radiation, and genuinely useful for one job: sharpening risk estimates in people who feel fine.⁴⁵ What it cannot do is see soft plaque.

A CT angiogram uses contrast dye to light up the inside of the artery. It shows the channel, the wall, plaque of both kinds, and how much any of it narrows the vessel.⁶ It answers the question that actually matters when something feels wrong: what does the artery look like.

Calcium is not simply good or bad

Now the part that surprised me, and the reason calcium is more interesting than the meme.

If soft plaque is the dangerous kind and calcified plaque is the settled kind, you would expect a high calcium score to be good news. It is not that simple. When researchers split coronary calcium into how much there is versus how dense it is, the two pulled in opposite directions. More calcium tracked with higher risk. But at the same amount, denser calcium tracked with lower risk.⁷ Dense, solid calcium looks like the fingerprint of a plaque that truly healed.

Here is the fact that should retire the calcium-equals-bad reflex for good. Cholesterol-lowering therapy can raise your calcium score while it lowers your risk. In pooled imaging trials, statins shrank soft plaque and increased calcification at the same time.⁸ In a large CT-angiogram study, people on statins shifted toward denser calcium and fewer dangerous plaque features.⁹ The drug is not making the disease worse. It is turning unstable, greasy plaque into stable scar. So a rising calcium score can mean your treatment is working, though the score alone can’t tell you whether the calcium climbed because plaque is hardening or because there is simply more of it. Read without that context, it looks like an alarm.

The plaque that gets you may not be the biggest one

One more thread. The plaque most likely to drop you is not always the biggest one on the scan. Soft, noncalcified plaque, the exact kind a calcium score misses, predicts future heart attacks on its own.¹⁰ A lesion can be modest in size, silent on every standard test, and still be the one that matters.

And there is a way the slow story falls apart entirely. A soft plaque can rupture. The thin cap over it tears, blood hits the raw contents, and a clot forms. Sometimes that clot closes the artery and you have a heart attack. Sometimes it heals over and scars, leaving a bigger blockage than was there before. Pathologists have found these healed ruptures stacked in layers, each one ratcheting the narrowing up a notch.¹¹

I cannot prove that is my story. But it fits what the slow-buildup version cannot: how an artery goes from spotless at thirty-six to severely blocked at forty-four. What if it was never slow? That is the next post.

What “it’s not your heart” actually means

Now the part I see from the other side, every week. Picture the common version. You have some vague chest pain or pressure. Maybe you call your doctor, maybe you come into an emergency department like the one I work in. We run the standard workup: labs, a chest X-ray, a 12-lead ECG, and a troponin. Troponin is a protein that lives inside heart muscle and spills into the bloodstream when that muscle is actually dying, so a troponin test is how we catch a heart attack as it’s happening. We draw it once when you arrive, then again an hour or two later, because it takes time to rise. If that second troponin is still normal, your heart muscle isn’t dying. The ECG is clean. We tell you the truth, as far as it goes. You are not having a heart attack. And you go home.

Here is exactly what that ruled out, and what it didn’t. It ruled out the emergency, the thing that kills you in the next few hours: a heart attack in progress, a clot in the lungs, a tear in the aorta. An emergency department is built to answer one question and it answers it well. Are you dying right now.

What it did not do is look at your coronary arteries. A normal ECG and a normal troponin mean your heart muscle is not yet starving or dying. They say nothing about whether a soft plaque is sitting in an artery at seventy or eighty percent. Sometimes we do run a CT angiogram in the emergency department, but it is to rule out a clot in the lungs, and it is not the scanner protocol that examines the coronary arteries in detail. Some emergency departments do run a dedicated coronary CT angiogram, the test that would actually see your plaque, but from what I have seen it is still pretty rare and limited. The one I work in does not run them at all. And a calcium score is not an emergency department test in the first place.

So here is a thing that happens, and it is not rare. Someone walks in with real chest pain and a seventy or eighty percent blockage in a coronary artery. But the plaque has not ruptured, the muscle is not yet dying, so the troponin stays flat and the ECG stays clean. The X-ray is normal. The lung scan finds no clot. Every test comes back reassuring, and we send them home, because by the rules of the emergency in front of us, that is the right call. The blockage was there the whole time. We were never looking for it.

I am not telling you to distrust the emergency department. Go there for chest pain. We catch the thing that would kill you today, and that matters more than I can say. I am telling you that “it isn’t your heart” means “you are not having a heart attack.” It does not mean your arteries are clear. Those are different sentences, and I had an eighty percent blockage living in the space between them.

So the question to carry out of that visit is not “am I fine.” It is “has anyone actually looked at my arteries.” A clean emergency department trip does not close that question. The test that answers it, a coronary CT angiogram, is an outpatient conversation with your doctor, and I have written before about how to have it.

What I Changed

What I changed is smaller than a supplement or a workout. I stopped reading any one test as a verdict. A calcium score, a stress test, a lipid panel: each answers one narrow question, and the comfort it offers stops at the edge of that question. When a result comes back now, I ask what it actually ruled out, not what I am hoping it means. I had every advantage walking into this, the training, the vocabulary, a major medical center, and a calcium score would still have told me I was fine.

Commercial distortion risk: Moderate. The main incentive ecosystem around this is cardiac imaging and heart screening. That does not make either test wrong. It makes claims about what each test can prove worth reading carefully, especially when a scan is being sold as a clean bill of health.

The Final Signal

• What’s right. A calcium score is a real, useful test for the calcified plaque it can see, and for sharpening risk in people who feel fine.

• What’s oversold. That a zero means clean arteries. It means no hardened plaque. The soft kind it misses can still be severe, as my own scans show.

• The counterintuitive part. A rising calcium score can be your treatment working, not your disease winning.

• What to do with it. If you have symptoms and your workup stops at clean labs, a clean ECG, and a zero calcium score, your arteries themselves have not been looked at. That is a CT angiogram’s job. Ask the question.

• What’s next. If a calcium score would have called my severe blockage a zero, and the dangerous plaque is not always the biggest, then the real question is not how my blockage built up slowly. It is whether it built up slowly at all.

This piece was first published on my own site, Calibrated Signal, where the full reference list lives. That’s the original.

This is not medical advice. It’s one clinician’s experience and a review of the published data. Talk to your doctor about what testing is appropriate for your individual risk profile.

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X · LinkedIn

Not medical advice.

References

1. Osborne-Grinter M, et al. Association of coronary artery calcium score with adverse plaque on CCTA in SCOT-HEART. Eur Heart J Cardiovasc Imaging. 2022;23(9):1210–1221. PMID 34529050 [Finding: In stable chest-pain patients, 36 percent had a zero calcium score; among them 16 percent still had plaque on a CT angiogram and 2 percent had an obstructive lesion, and 10 percent of the trial’s heart attacks struck people who scored zero.]

2. Sama C, et al. Non-calcified plaque in asymptomatic patients with zero CAC: systematic review and meta-analysis. J Cardiovasc Comput Tomogr. 2024;18(1):43–49. PMID 37821352 [Finding: Across 37,808 asymptomatic people with a zero calcium score, about 10 percent still had noncalcified plaque and 1.1 percent had an obstructive one. The hidden burden is low, but not zero.]

3. Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis. Circulation. 2007;116(16):1832–1844. PMID 17938300 [Finding: Atherosclerosis begins when ApoB cholesterol particles are retained beneath the artery lining. The inflammation that builds plaque is the body’s response to that trapped material, not the trigger.]

4. Agatston AS, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15(4):827–832. PMID 2407762 [Finding: The original 1990 method for turning coronary calcium on CT into a single score, tested in 584 people. The foundation of today’s calcium score, and where the “a zero has a high negative predictive value” idea comes from.]

5. Detrano R, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups (MESA). N Engl J Med. 2008;358(13):1336–1345. PMID 18367736 [Finding: In 6,722 people across four racial and ethnic groups, the calcium score predicted coronary events beyond standard risk factors, with a doubling of the score raising major-event risk 15 to 35 percent. The evidence that CAC is a real risk-stratification tool.]

6. Budoff MJ, et al. Diagnostic performance of 64-detector CCTA (ACCURACY). J Am Coll Cardiol. 2008;52(21):1724–1732. PMID 19007693 [Finding: In 230 chest-pain patients, 64-detector CT angiography ruled out obstructive narrowing with a 99 percent negative predictive value against invasive angiography. The scan that images the artery itself, not just its calcium.]

7. Criqui MH, et al. Calcium density of coronary artery plaque and risk of incident cardiovascular events. JAMA. 2014;311(3):271–278. PMID 24247483 [Finding: In MESA, calcium volume tracked with higher cardiovascular risk, but at any given volume, denser calcium tracked with lower risk. Amount and density are opposite signals.]

8. Puri R, et al. Impact of statins on serial coronary calcification during atheroma progression and regression. J Am Coll Cardiol. 2015;65(13):1273–1282. PMID 25835438 [Finding: Pooled ultrasound from 8 trials: intensive statins shrank plaque volume while calcification rose in every group, independent of that regression. Statins harden plaque as a way of stabilizing it.]

9. van Rosendael AR, et al. Association of statin treatment with progression of coronary atherosclerotic plaque composition. JAMA Cardiol. 2021;6(11):1257–1266. PMID 34406326 [Finding: On serial CT angiography of 857 patients, statins moved plaque away from the dangerous low-attenuation and fibro-fatty kind toward dense calcium, and denser calcium meant slower progression. Rising calcium on a statin can be stabilization, not worsening.]

10. Williams MC, et al. Low-attenuation noncalcified plaque on CCTA predicts myocardial infarction (SCOT-HEART). Circulation. 2020;141(18):1452–1462. PMID 32174130 [Finding: In 1,769 stable chest-pain patients, soft low-attenuation plaque burden predicted heart attacks better than the calcium score, the risk score, or the degree of narrowing. The plaque that gets you is the soft kind calcium can’t see.]

11. Burke AP, et al. Healed plaque ruptures and sudden coronary death. Circulation. 2001;103(7):934–940. PMID 11181466 [Finding: In 142 men who died suddenly of coronary disease, silent healed plaque ruptures were present in 61 percent, layered on top of each other, and the narrowing worsened with each additional healed site. Plaque can advance in silent, stepwise jumps.]

Every morning before the gym, I turned sideways, looked for what had changed, and let the reflection tell me the work was paying off. The mirror was the scoreboard, the coach, and the whole training plan. And it lied to me by omission, because it can only grade the one system you can see.

Ninety percent of my training was resistance work. Four, sometimes five hard sessions a week, an hour at a time, most sets pushed to failure. Cardio was a warm-up I skipped. Mobility was for other people. Recovery wasn’t in my vocabulary. Every session was max effort toward one target: how I looked with my shirt off.

Here’s the part that still stings. I’ve held a personal training certification for years, and my first job out of high school was as a fitness trainer. I knew the textbook answer to “what should a middle-aged man train for,” and I coached the balanced version to every friend who asked. Then I went home and ran the vanity program on myself. For twenty-five years I never once turned that lens on my own training, right up until they threaded a stent into my right coronary artery at 44 and I finally read the literature I should have read at 20.

So let me be precise about what this is and isn’t. I am not going to tell you my cardio fitness was garbage before the stent, because I never measured it. That’s not a hedge. That’s the whole indictment: a certified trainer with a stent in his heart who had never once measured one of the most powerful survival numbers in medicine, because he let a mirror tell him it didn’t matter. I wasn’t lazy and I wasn’t unfit. I was highly trained in one dimension and completely untrained in another, and I couldn’t see the gap because the half I trained was the half that shows.

That’s the trap this whole post is about. A hard program is not the same as a complete one. The system you train best is the one that hides the systems you never test.

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Vocabulary that matters

• VO₂max: the most oxygen your body can use at full effort. The single best lab number for cardio fitness.

• Cardiorespiratory fitness (CRF): how well your heart, lungs, and muscles move and use oxygen when you push hard.

• MET: a simple unit of effort. Sitting still is 1; the higher the number you can hold, the bigger your engine.

• Zone 2: easy aerobic work, right around the pace where you can still talk in full sentences but not sing. The intensity that builds your aerobic base.

• Epigenetic clocks: blood tests that estimate your biological age from chemical tags on your DNA that shift with age, lifestyle, and disease.

Exercise doesn’t play by the rules the last two did

My last two posts were about exposures that behave like a running tab. Carry a borderline-high LDL for twenty years and the damage stacks up. Same with blood pressure: every year above the line adds to the total your arteries have to eat. More exposure, more harm.

Exercise refuses to behave that cleanly. It isn’t a “more is always better” story or a “less is always safer” one. It’s a question of which kind, in what balance, and the honest answer moves as you age. The program that builds the body you want at twenty-five is not automatically the program that keeps your heart beating at fifty-five. Sometimes they’re the same workout. Usually they’re not.

The number I never measured

Start with the one I ignored completely: cardiorespiratory fitness. How well your heart, lungs, and muscles move and use oxygen when you push hard. The gold-standard version is VO₂max, the most oxygen your body can burn at full effort, estimated on a treadmill test in METs. Bigger number, bigger engine.

In 2018, Cleveland Clinic researchers ran the largest study of its kind: 122,007 adults who took a treadmill stress test, followed for a median of about eight years, more than 13,000 deaths across 1.1 million person-years.¹ Fitter people died less, and it didn’t stop. At every level they measured, more fitness meant less death, with no ceiling where the benefit finally ran out.

Sit with the scale of that. In the same data, being unfit carried a mortality risk comparable to or greater than coronary artery disease, smoking, or diabetes. Low fitness tracked with as much excess death as the named diseases we spend billions screening for. And it’s the one that doesn’t get its own screening test.

Here’s the honesty this brand runs on, and it cuts both ways. This was an observational study. It shows a brutal association, not proof of cause. Fit people differ from unfit people in a hundred ways a model can’t fully catch, and some of those differences move the survival needle on their own. So I won’t tell you fitness causes the lower death rate. I’ll tell you it’s one of the strongest, most consistent associations in all of preventive cardiology, and it holds whether you cut the data by age, sex, or existing disease. That’s not a number you get to wave off because it’s “only” observational.

It’s strong enough that in 2016 the American Heart Association argued fitness should be treated like a vital sign, measured as part of routine care.² A vital sign. And I was a certified trainer who ended up with a stent in his heart having never once taken the test.

The Read
Aerobic fitness is one of the strongest survival signals we can measure, with no ceiling anyone has found. It’s also the exact thing I spent decades treating as optional and never bothered to measure.

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The gauge I was maxing out

Now the one I obsessed over: lifting. This reckoning is subtler, because the answer isn’t “lifting was a mistake.” Lifting is genuinely protective. The question is how much of that protection you can actually bank, and how fast you hit the wall.

A 2022 meta-analysis in the British Journal of Sports Medicine pooled sixteen long-term studies on muscle-strengthening activity.³ Independent of any cardio, strength work was associated with roughly a 10 to 17 percent lower risk of dying from any cause, and of getting or dying from heart disease, cancer, and diabetes.³ Real, meaningful, worth doing.

But the dose-response is what stopped me cold. It looked nothing like the fitness curve. It was front-loaded. The biggest risk reductions clustered around 30 to 60 minutes of strength work per week, then flattened. A separate 2022 meta-analysis found the same shape, with the largest mortality reduction near 60 minutes a week and shrinking returns past that.¹³

I was doing four to five hours.

Now here’s the trap I almost walked into, and where a lot of “cardio beats weights” content face-plants. These two findings are not a head-to-head. They don’t even measure the same kind of thing. The fitness study measured an objective physical capacity: your actual output on a treadmill. The strength studies measured reported behavior: how many minutes a week people said they lifted. One is a number a machine reads off your body. The other is a number you write on a questionnaire. Stacking them side by side and crowning a winner is comparing a blood test to a food diary.

So read the curves separately, for what each honestly says. Measured aerobic fitness keeps tracking with survival all the way up. Reported strength minutes buy most of their survival benefit early, then flatten. And here’s what made me put down the barbell and pick up a heart-rate strap: I was four or five times past the point where the lifting signal peaked, while scoring a zero on the system with the bigger, steeper survival curve. Not because I was lazy. Because I only ever trained the gauge I could see in the mirror.

To be crystal clear about what that flat curve is not: it is not proof that lifting past an hour a week is bad for you. If your goal is muscle, strength, bone, or still being able to deadlift your grandkid at 80, more volume keeps paying off. It’s a mortality curve, not a strength curve. What the data won’t yet promise is that hour six of lifting buys you more years the way hour one of cardio does. The strength numbers are also pooled, often self-reported, and some outcomes were rated low-certainty. Directionally real, not carved in stone.

The Read
Strength training lowers your risk, but in the cohort data the benefit is front-loaded, strongest in the first 30 to 60 minutes a week. More volume builds more muscle, strength, and bone. It just hasn’t been shown to keep buying more years. And it was never measured the way treadmill fitness was, so don’t read the two curves as a fair fight.

So the answer is endless cardio? Not so fast.

Before anyone reads this as “ditch the weights and run forever,” the aerobic side has its own catch, and an honest post has to show it.

Scan the arteries of lifelong, high-volume endurance athletes and the most active ones often have more coronary calcium, not less. In the MARC study of 284 middle-aged male athletes, the highest-volume group had roughly three times the odds of detectable coronary calcium versus the least active.⁴ That scared a lot of runners for a while. But a parallel study of 152 masters endurance athletes, three decades of training behind them, looked at what kind of plaque was forming: in the male athletes, 73 percent of the plaques were the calcified, denser, more stable kind, while sedentary men skewed the other way, toward the mixed, more rupture-prone kind (62 percent).⁵ The training seemed to build a different type of plaque, not just more of it.

Then it gets more complicated, which is the honest part. A cohort of nearly 22,000 men found the very active were slightly more likely to have high calcium, but high activity was not tied to a higher death rate, even among those with elevated scores.⁶ Reassuring, but not a green light. In 2023 the MARC team followed up and traced the calcium signal to intensity, not volume: very vigorous exercise tracked with faster progression of coronary calcium, while total training volume on its own did not.⁷ And the newest cohort, MASTER@HEART, knocked down the tidy “athlete plaque is the safe kind” story: lifelong endurance athletes had more plaque of every type than healthy non-athletes, calcified, non-calcified, and mixed.¹⁶ Nobody has shown those plaques turn into more heart attacks. Nobody has shown they don’t.

So hold the reassurance loosely, and here’s the honest landing: the athlete-plaque literature is a reason not to treat extreme endurance volume as automatically protective. It is not a reason to skip ordinary aerobic exercise. Those are not the same thing.

Because the two cardio findings only sound contradictory. They measure different things. Measured fitness, the treadmill number, tracks with survival all the way up, though the biggest drop is getting off the bottom, from unfit to fit; the gap from “very fit” to “elite” is real but small. The scary plaque signal lives at the far extreme: ten-plus hours a week of hard racing for decades. For anyone aiming at aging instead of a podium, the math closes cleanly. Most of the survival protection is in getting off the floor of that fitness curve, and that takes maybe three to five hours a week of structured aerobic work: a Zone 2 base plus one harder session that actually pushes your VO₂max. The minimum effective dose for cardio isn’t zero. It’s moderate, structured, and consistent. You don’t need the elite end. You need off the bottom.

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Train both, and get honest about “reversing aging”

The same strength-training meta-analysis pointed straight at what I’d been ignoring: people who did both strength and aerobic work had roughly a 40 percent lower risk of dying from any cause, a bigger benefit than either kind of training managed on its own.³ Not one or the other. Both.

There’s real biology under that. Aerobic training does its quiet work in your mitochondria, the tiny engines inside cells that fade with age, and on the endothelium, the living inner lining of your blood vessels where nitric oxide keeps the pipes flexible.⁸ Lifting protects a different set: muscle, bone, the machinery that clears glucose. The systems overlap, but neither one fully covers for the other. Train half the map and you leave the other half unguarded.

Now the part where the longevity influencers lose the plot.

You’ve heard it: this cardio zone “reverses your biological age,” that protocol “turns back your epigenetic clock.” Epigenetic clocks are blood tests that read chemical tags on your DNA to estimate how fast you’re aging, and the newer ones (PhenoAge, GrimAge, DunedinPACE) are the closest thing we have to a real-time aging readout.⁹ They’re early-stage and openly noisy: run the same person twice and the readings don’t always agree, and plenty of serious aging researchers still think the tools need years more validation. But noisy isn’t useless. Right now they’re the best window we have into aging biology, and they’re improving fast. I read them as the strongest imperfect tool on the table, not a verdict. Here’s what the exercise data on them actually say.

The biggest look yet landed in 2026: a Lancet Healthy Longevity meta-analysis pooling 44 studies and 145,465 people.¹⁷ More activity did track with a younger biological age, echoing earlier cohorts where active adults read a year or two younger on the clocks.¹⁰ But read the fine print. Only seven cross-sectional studies made it into the pooled math. The effect showed up on two clocks, Horvath and GrimAge, and vanished on two others, Hannum and PhenoAge. And the size of it was tiny, fractions of a standard deviation. The authors say it outright: the evidence is mostly cross-sectional, which means it can’t tell you exercise caused the younger reading, only that people who move more tend to show one.

The randomized data are thinner and less flattering. In DO-HEALTH, 777 older adults followed for three years, the exercise arm was a simple home strength program, and on its own it didn’t meaningfully move the major clocks. The clearest signal came from omega-3, and the omega-3 plus vitamin D plus exercise combo nudged PhenoAge by the equivalent of looking a few months younger over three years.¹⁴ A small Finnish twin study lands the same punch: among older twins split by decades of leisure-time activity, the active twin’s DNA-methylation age didn’t clearly differ from the inactive one’s.¹⁵

So here’s the calibrated read, and I won’t soften it: the mechanism is plausible, the observational signal is consistent, and the randomized evidence is nowhere near strong enough to say exercise reverses your systemic biological age. Anyone selling you a specific zone or protocol that “rewinds your clock” is running miles ahead of the data.

Where the modality-specific evidence does bite harder is one level down, at the hallmarks of aging, the actual machinery that drives aging in the first place. HIIT, short bursts of hard work with recovery between, threw one of the strongest mitochondrial signals in the Mayo Clinic training trial, especially in older adults, reversing age-related differences in mitochondrial proteins.¹¹ Resistance training, in a small muscle-biopsy study, rejuvenated the mitochondrial methylation pattern inside aged muscle.¹² Real levers, both. Different levers. Do only one and part of the machine goes untouched. That’s the case for training both, not for crowning a winner.

I’ll come back to clocks and hallmarks again and again, because they’re the lens I now run every health claim through. For this post the takeaway is smaller and more honest than the influencer version: the evidence says balance aerobic and resistance work. It does not say any single kind of exercise turns back your biological clock.

The Read
Exercise is one of the most defensible healthspan bets we have. But calling it proven biological-age reversal runs past the clock data, which is mostly cross-sectional, clock-dependent, and small. Train for the hallmarks it clearly moves, not for a clock number nobody has reversed on demand.

What I Changed

This is what I do now, offered as my own interpretation of the evidence and my own situation, not as a prescription for yours.

• Lift 2–3x/week for about 30 minutes instead of 4–5x/week at an hour. Strength is protective, but the survival benefit is front-loaded. I stopped assuming every extra hour of lifting buys another year of life.

• Stop taking every session to failure. Recovery is now part of the intervention, not an afterthought.

• Add real Zone 2 cardio. I needed the aerobic base I had treated as optional.

• Add one weekly VO₂max-focused session. Cardiorespiratory fitness was the number I had never measured.

• Treat mobility and recovery as training. The program was all output and almost no restoration.

• Measure VO₂max. You cannot improve the number you refuse to look at.

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What this still can’t explain

I don’t think the training style I’ve run since high school football is what put a stent in my heart at 44. Plenty of untrained men with worse habits than mine never get an 80 percent blockage that young. A lopsided program is a missing layer of protection, not a smoking gun. And here’s the gap nobody names: almost all the “high training volume tracks with more coronary calcium” data is on endurance athletes, runners, cyclists, masters racers. I lifted heavy and skipped cardio. There is essentially no published cohort asking whether that pattern accelerates coronary disease. We don’t know. That’s a hole in the map, not a reassurance.

And that’s the problem I keep hitting. Borderline LDL, borderline blood pressure, a diet I trusted that may not have suited me, a program tilted hard toward the mirror. Every one is a plausible contributor. Stack them all together and they still don’t explain how an artery goes from clean to 80 percent blocked in the window I’m looking at. The math doesn’t close.

Which raises the question I’d been dodging: what if the slow-buildup story is the wrong story for what happened to me? What if it wasn’t slow?

The Final Signal

• What this gets right. Strength training is genuinely protective. Cardiorespiratory fitness is one of the strongest survival signals we can measure. Both belong in an aging program. And if your goal is longevity, not winning a powerlifting meet or an ultra, the dose that gets you there is smaller than the one the mirror demanded.

• What gets oversold. The mortality benefit of lifting appears front-loaded in cohort data. Extra volume past roughly an hour a week may keep buying muscle, strength, and bone, but the longevity dividend is not yet established. And exercise as a standalone lever on reversing aging via systemic epigenetic clocks is mostly null in the randomized data we have.

• What I changed. Rebalanced to 2–3 strength sessions a week, stopped chasing failure on every set, added real Zone 2 cardio, added one weekly VO₂max-targeting session, started treating recovery as training, and measured my VO₂max.

• What would change my mind. Long-term cohorts or trials showing high-volume lifting buys clinically meaningful added longevity, or exercise-specific randomized clock data showing systemic biological-age reversal that maps to actual outcomes.

• What this opens next. I don’t think lifting gave me a stent. I think a lopsided program left a layer of protection on the table. But none of my cracks, LDL, BP, diet, or training, alone or stacked together, fully explains how an artery goes from clean to 80 percent blocked in eight years. What if the standard slow-buildup story is the wrong story for what happened to me?

That’s where this goes next.

This is not medical advice. It’s one clinician’s experience and a review of the published data. Talk to your doctor about what exercise programming and screening is appropriate for your individual risk profile.

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Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X / @nickhansonrn · LinkedIn

Not medical advice.

References

1. Mandsager K, et al. Association of Cardiorespiratory Fitness With Long-term Mortality Among Adults Undergoing Exercise Treadmill Testing. JAMA Netw Open. 2018;1(6):e183605. PMID 30646252 [Finding: In 122,007 adults, higher cardiorespiratory fitness tracked with lower death at every level with no ceiling, and being unfit carried a risk on par with coronary disease or smoking (observational).]

2. Ross R, et al. Importance of Assessing Cardiorespiratory Fitness in Clinical Practice: A Case for Fitness as a Clinical Vital Sign (AHA Scientific Statement). Circulation. 2016;134(24):e653–e699. PMID 27881567 [Finding: An AHA scientific statement arguing fitness predicts mortality as strongly as smoking or diabetes and should be measured as a clinical vital sign.]

3. Momma H, et al. Muscle-strengthening activities are associated with lower risk and mortality in major non-communicable diseases: a systematic review and meta-analysis of cohort studies. Br J Sports Med. 2022;56(13):755–763. PMID 35228201 [Finding: Across 16 cohorts, strength training was tied to 10 to 17 percent lower mortality, with the benefit peaking around 30 to 60 minutes a week.]

4. Aengevaeren VL, et al. Relationship Between Lifelong Exercise Volume and Coronary Atherosclerosis in Athletes. Circulation. 2017;136(2):138–148. PMID 28450347 [Finding: In 284 male athletes, the highest training volume carried roughly triple the odds of coronary plaque, though skewed toward the more stable calcified type (observational).]

5. Merghani A, et al. Prevalence of Subclinical Coronary Artery Disease in Masters Endurance Athletes With a Low Atherosclerotic Risk Profile. Circulation. 2017;136(2):126–137. PMID 28465287 [Finding: Among 152 masters athletes, most had normal calcium scores, but those with plaque skewed toward the calcified, more stable kind versus mixed plaque in sedentary men.]

6. DeFina LF, et al. Association of All-Cause and Cardiovascular Mortality With High Levels of Physical Activity and Concurrent Coronary Artery Calcification. JAMA Cardiol. 2019;4(2):174–181. PMID 30698608 [Finding: In about 21,800 men, the most active were slightly more likely to have high coronary calcium but were not at higher risk of death.]

7. Aengevaeren VL, et al. Exercise Volume Versus Intensity and the Progression of Coronary Atherosclerosis (MARC-2). Circulation. 2023;147(13):993–1003. PMID 36597865 [Finding: Over six years in 289 athletes, exercise intensity, not total volume, tracked with faster coronary calcium progression.]

8. López-Otín C, et al. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243–278. PMID 36599349 [Finding: The landmark review defining the twelve hallmarks of aging, the biological processes that drive aging and that interventions aim to slow.]

9. Belsky DW, et al. DunedinPACE, a DNA methylation biomarker of the pace of aging. eLife. 2022;11:e73420. PMID 35029144 [Finding: Introduced DunedinPACE, a DNA-methylation blood test estimating how fast a person is aging, shown to track with later illness and death.]

10. Ammous F, et al. Physical Activity Is Associated With Decreased Epigenetic Aging: Findings From the Health and Retirement Study. J Cachexia Sarcopenia Muscle. 2025;16(3):e13873. PMID 40511567 [Finding: In the Health and Retirement Study, active adults read one to two years younger on several epigenetic clocks, but the analysis was cross-sectional (association, not cause).]

11. Robinson MM, et al. Enhanced Protein Translation Underlies Improved Metabolic and Physical Adaptations to Different Exercise Training Modes in Young and Old Humans. Cell Metab. 2017;25(3):581–592. PMID 28273480 [Finding: A 12-week Mayo Clinic trial where high-intensity interval training drove the strongest mitochondrial gains, reversing many age-related protein differences (small, mechanistic).]

12. Ruple BA, et al. Resistance training rejuvenates the mitochondrial methylome in aged human skeletal muscle. FASEB J. 2021;35(9):e21864. PMID 34423880 [Finding: In ten older men, six weeks of resistance training shifted aged-muscle mitochondrial methylation toward a younger pattern (very small, mechanistic).]

13. Shailendra P, et al. Resistance Training and Mortality Risk: A Systematic Review and Meta-Analysis. Am J Prev Med. 2022;63(2):277–285. PMID 35599175 [Finding: A meta-analysis of ten cohorts where any resistance training was tied to about 15 percent lower mortality, peaking near 60 minutes a week (mostly self-reported).]

14. Bischoff-Ferrari HA, et al. Individual and additive effects of vitamin D, omega-3 and exercise on DNA methylation clocks of biological aging in older adults from the DO-HEALTH trial. Nat Aging. 2025;5(3):376–385. PMID 39900648 [Finding: In a 3-year randomized trial of 777 older adults, exercise alone didn’t meaningfully move the major epigenetic clocks; omega-3 gave the clearest signal.]

15. Sillanpää E, et al. Leisure-time physical activity and DNA methylation age: a twin study. Clin Epigenetics. 2019;11(1):12. PMID 30660189 [Finding: A co-twin study where twins discordant in activity for 32 years showed essentially no difference in DNA-methylation age.]

16. De Bosscher R, et al.; Master@Heart Consortium. Lifelong endurance exercise and its relation with coronary atherosclerosis. Eur Heart J. 2023;44(26):2388–2399. PMID 36881712 [Finding: A balanced cohort where lifelong endurance athletes had more coronary plaque of every type than equally healthy non-athletes.]

17. Shan J, et al. Physical activity and biological age measured by DNA methylation clocks: a systematic review and meta-analysis. Lancet Healthy Longev. 2026;7(4):100835. PMID 42068988 [Finding: Pooling 44 studies and 145,465 people, more activity was linked to younger biological age on two clocks but not two others, with tiny, mostly cross-sectional effects.]

If you’ve been reading these in order, you came for the arteries: the stent at 44, the tests that called me healthy, the plaque a calcium score can’t see. This one deviates from that storyline, and the pivot is on purpose. Getting a stent at 44 despite doing all the right things made me stop and start running a systematic process over every claim, podcaster opinion, and longevity-guru recommendation I’d folded into my life. The first one I put to the test was the claim that LDL doesn’t matter if you’re metabolically healthy. It didn’t stop there. I’d been spending thousands of dollars a year on supplements, routines, and biohacking gear, and I realized everything I thought I knew had to be checked.

I’ll keep writing about cardiovascular disease, because that was the event that forced me to reevaluate my whole outlook on health, wellness, and longevity. But my own story doesn’t end with a villain. There’s no single thing to point at and blame for how fast my disease moved. I’m still exploring it, and I’ll bring you along, but I’ve started to doubt a true smoking gun exists. It was probably a combination of factors, high LDL among them, plus other risks that still slip past the modern diagnostic stack.

The reason I built Calibrated was never that I’m angry about a stent at a stupidly young age. It’s this. For years I was the guy spending thousands of dollars a year on longevity and health: the supplements, the compounds, the protocols, chasing every edge the marketing promised. More recently I spent years doing the harder version, running those same interventions through rigorous, academic-quality computational analysis and evidence pipelines. Every study I can find, the conflicts behind them, whether the stuff even absorbs, how the evidence was actually built. Not the mechanism cartoon on the sales page. Stories start with mechanism. They shouldn’t end there.

Here’s the part people expect me to say, and I’ll get ahead of it before I’m written off as a reflexive skeptic: I didn’t stop spending. I still put real money into my health every year. I just got a lot smarter about where it goes.

This is the first full examination of a compound making the rounds online for health and longevity. I wanted it to be real.

A newsletter I follow spent last week promoting a compound called 5-Amino-1MQ: better muscle, less fat, sharper focus, maybe even a healthier heart. It rides the same NAD+ wave you’ve heard about with NMN and NR, the supplements sold to top up the cell’s energy currency. But it takes a different route. Instead of adding raw material, it’s proposed to block an enzyme, NNMT, that drains the supply. And the biology underneath it isn’t stupid. NNMT is a real enzyme. The mouse data aren’t imaginary. If a molecule could do half of what’s on that list, I’d want it in my own life.

Before I pivoted to graduate school, molecular biology, computational biology, the bench, and now clinical medicine, I spent fifteen years inside the supplement industry. Long enough to raise an eyebrow as high as Dwayne “The Rock” Johnson when a science post ends with the author’s personal dose and a discount code. So I didn’t take the pitch. I read the papers. Not just the few the article pointed at. All of them, run through the evidence pipeline.

Here’s what stopped me, and it wasn’t that the evidence is animal-only. The author concedes that part himself.

THE BOTTOM LINE

To get from these studies to justifying real money on that capsule, you’re asked to cross four bridges. Not one of them has been built.

1. From mice to humans. Eleven studies of this compound exist. Every one is in cells or rodents. Not a single human has ever been dosed in a trial, even for safety.

2. From a needle to a pill. Every result worth quoting came from injecting rodents. The compound has never been shown to absorb by mouth in people, and they’re selling you a tablet.

3. The people who patented it run the studies. Every study behind the muscle and fat claims traces to the one lab whose founder patented the molecule and started the company that sells it. No independent group has reproduced any of it.

4. From a chalkboard arrow to your heart. The “it protects your heart” claim rests on one pathway sketch that has never been measured, while the better-established biology runs the other way and might point toward harm. That one stopped me cold, as a guy with a recent stent.

Cross all four and you’ve got a longevity protocol. Build none of them and you’ve got an interesting mouse study with a price tag. I looked hard at this one. I changed nothing. For the full analysis, keep reading.

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Vocabulary that matters

• NNMT: an enzyme that uses up two of your cells’ resources (a methyl group and a piece of the NAD+ supply chain). Block it, the theory goes, and you free those resources back up.

• NAD+: a molecule central to how cells make energy. It falls with age, which is why “raises NAD+” is catnip in the longevity world.

• 1-MNA: the product NNMT makes. Remember this one. It matters more than the marketing lets on.

• Research chemical: not a supplement, not a drug. A compound sold “for research use only, not for human consumption,” with no FDA approval and no quality standard you can lean on.

Why a stent patient reads this one heart-first

The pitch for compounds like this is always some version of trust the mechanism. The biology makes sense, the animal data look great, conventional medicine is just too slow to catch up. I understand the appeal. I spent fifteen years in the supplement industry selling optimism exactly like it. That’s why I can smell it a mile away now.

Here’s the thing about “trust the mechanism”: if mechanism is your whole case, you have to read all of it and trace out every side of the pathway, not just the flattering half. When I read all of it on 5-Amino-1MQ, three things jumped out that the newsletter never mentioned.

What the marketing skips

It has never been tested in a human. Every result you’ve seen, the 40% strength gain, the muscle regeneration, the fat loss without dieting, came from mice. Eleven studies of the real compound, and the count of human trials is zero. No efficacy data. No safety data. Nothing. When someone calls a compound “low-risk” with no human safety record, understand what that sentence actually means: nobody has checked. There’s a whole graveyard of molecules that never made it into humans for exactly one reason. They turned out to be unsafe in some population. With no human data, there is no way to know whether you’re in that population.

The interesting animal results were injected, and they’re selling you a pill. Every one of those animal benefits was produced by injection, into the bloodstream or the belly (in the lab we call the latter intraperitoneal). Not one efficacy study used the oral route the capsules are sold in. And that’s not an accident. One research team wrote, in plain text, that they injected the compound because it absorbs so poorly by mouth. Oral absorption is poor in mice and only partial in rats; in humans it has never been measured at all. So the headline numbers came from a needle and a controlled dose of pure compound. The pill on the website is an unmeasured dose of an unverified powder, betting that whatever survives your gut does what the injection did. That bet has no study behind it.

Follow the money, because this is the part that’s genuinely unusual. I’ve mapped the evidence behind thousands of studies across more than a hundred interventions, and I rarely see one this captured. Every animal study behind the metabolic and muscle claims comes out of a single lab: the lab whose principal investigator went on to found the company that now licenses and sells the compound. Four of those papers disclose that company tie in their competing-interests statement. The other two state “no conflict of interest,” even though they come from that same lab. I’m not alleging anyone hid anything. I’m telling you what the public record shows: no unaffiliated group has ever reproduced these results, and there is not one null result in the entire library.

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The heart arrow points the other way

Now the fourth bridge, the cardiovascular claim, because this is where I live.

The story being sold is tidy: NNMT drives up homocysteine, homocysteine is bad for arteries, so block NNMT and you protect the heart. Clean arrow on a slide.

First problem: it has never been measured. Not one study has shown 5-Amino-1MQ changes homocysteine in anything, human, animal, or cell. It’s a chalkboard mechanism, asserted, not demonstrated. And even the next link is shaky. When large human trials actually lowered homocysteine with B vitamins, across more than 37,000 people, heart attacks and strokes didn’t budge.

Second problem, and the bigger one: the arguably better-established evidence runs the other way. Remember 1-MNA, the molecule NNMT makes? In humans, 1-MNA improves the function of the lining of your blood vessels, the nitric-oxide system your arteries run on. In atherosclerosis-prone animals it reduces arterial plaque and calms platelets, both anti-atherosclerotic and anti-clotting. It’s one of the only pieces of this whole story with any human cardiovascular data at all, and it points toward protection.

Now connect the dots. 5-Amino-1MQ works by shutting down NNMT, the exact enzyme that produces 1-MNA. Lowering 1-MNA isn’t a side effect; it is the mechanism. A study of a related NNMT blocker confirmed the drop, about 77%. So the thing sold as cardioprotective directly suppresses a molecule shown, in people, to protect blood vessels. And the enzyme itself looks protective under stress: when researchers blocked NNMT in blood-vessel cells under oxidative pressure, the cells survived worse.

Here’s a wrinkle I’ll come back to in a future post. A meaningful share of people carry genetic variants in that same nitric-oxide pathway and have never been tested for them. If you’re one of them, this is a compound that could, in theory, push your cardiovascular health the wrong way. That’s still chalkboard mechanism. But it’s the exact same kind of reasoning being used to sell the benefits.

I’ll be fair to the other side, because honest is the whole job here. That related-compound study ran in already-sick “stiff-heart” mice, and it did show cardiac benefit, but through reducing a different set of byproducts, not the homocysteine route on the slide. There’s even a real twist that could favor the compound: blocking NNMT also lowers two niacin byproducts, 2PY and 4PY, that are independently tied to heart attacks in large human studies. But notice that this is a completely different mechanism than the one being marketed, and it’s still mouse-and-association data, not a human outcome.

What the aging clocks say

One thing I do whenever I run any intervention through my computational biology pipeline that has any potential association with longevity, is to systematically check every single epigenetic clock result I can find and aggregate them. For this one, nothing yet. No validated epigenetic-clock data exist for this compound. And there’s a trap worth naming: because 5-Amino-1MQ might shift the cell’s methylation economy, a “younger” reading on a methylation clock could be a measurement artifact rather than real rejuvenation. If a vendor ever waves a clock result at you, that’s the first question to ask.

What I changed: absolutely nothing

This was never part of my routine, and it won’t be any time soon.

Not because the biology is stupid. It’s actually interesting. Because the case is built on injected mice, sold as an oral pill; because the entire pro-aging evidence base comes from the people who profit from it; because there is not one human data point on safety or benefit; and because what looks good in the animal data, read honestly, also points at a cardiovascular downside I’m in no position to gamble on. For a guy with a stent, that’s not a hard call. It’s not even close.

That’s the whole point of how I do this. I’m not here to hand you a stack and a discount code. I’m here to tell you what the evidence actually supports, and sometimes the honest answer is I looked, and I walked away.

This is what these are going to be, more and more. Take the thing the longevity world is selling and run it all the way down. Not just the mechanism, which is one step out of ten, but the conflicts, the bioavailability, the dose nobody has actually established, the quality of the evidence itself. The point was never to stop spending. I still spend plenty on my own health. It was to stop guessing.

Most of the time the answer won’t be don’t take this, it’s here’s what the evidence really is, now you decide. This time, for me, it happened to be no. I don’t eyeball it, either. Every compound runs through a full bioinformatics pipeline: every study pulled and read, every potential conflict surfaced and traced to its source, product source and bioavailability analyzed, the full mechanism uncovered through systems biology analysis, and every claim graded against the hallmarks of aging. This post is one thread of that work.

The Calibrated Claim Audit

EVERY BENEFIT SOLD — GRADED

• “Boosts strength up to 40%.” Overstated. Real in injected mice; never tested orally or in a human.

• “Strips fat without eating less.” Unproven. A mouse result on a needle; zero human data, oral or injected.

• “Protects your heart (lowers homocysteine).” Weakened. Never measured for this compound, and the human level evidence points the other way if we are relying on biochemical pathways.

• “Low-risk, well-tolerated.” Unproven. There is no human safety record to call it safe in general let alone in specific subpopulations.

Commercial distortion risk: High. Every animal study of the metabolic and muscle benefits traces to the one lab that founded and licensed the company selling it. No independent replication. And the version making the rounds came with a discount code.

The Final Signal

• What the claim gets right. The mechanism is real and the animal data are genuine. NNMT inhibition does what they say, in mice, with a needle.

• What it gets wrong. It sells injected-mouse results as an oral human protocol, on zero human data.

• The heart angle. “Cardioprotective” is unmeasured, and the compound suppresses a molecule that protects human blood vessels.

• What would change my mind. One randomized human trial, dosed orally, run by someone who doesn’t sell it.

• What I changed. Nothing.

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X / @nickhansonrn · LinkedIn (linkedin.com/in/nickhanson)

Not medical advice.

References

1. Neelakantan H, et al. Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice. Biochem Pharmacol. 2018;147:141-152. PMID 29155147. In obese mice, the injected compound raised NAD+, cut body weight and fat mass, and lowered cholesterol, with no change in food intake.

2. Dimet-Wiley AL, et al. Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice. Sci Rep. 2024;14:15554. PMID 38969654. Injected aged mice gained ~40% grip strength, additive to exercise. First author affiliated with the commercializing company.

3. Neelakantan H, et al. Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochem Pharmacol. 2019;163:481-492. PMID 30753815. Injected aged mice showed improved muscle regeneration and ~70% greater peak torque after injury.

4. Babula JJ, et al. Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction. Diabetes Obes Metab. 2024;26(11):5272-5282. PMID 39161060. 28-day subcutaneous dosing improved glucose tolerance in obese mice; oral bioavailability in mice was poor. First author affiliated with the commercializing company.

5. Awosemo O, et al. Development & validation of LC-MS/MS assay for 5-amino-1-methylquinolinium in rat plasma. J Pharm Biomed Anal. 2021;204:114255. PMID 34304009. Oral bioavailability in rats was ~38%, partial, and the only oral absorption figure that exists in any mammal.

6. Sampson CM, et al. Combined nicotinamide N-methyltransferase inhibition and reduced-calorie diet normalizes body composition in obese mice. Sci Rep. 2021;11:5637. PMID 33707534. Representative of the efficacy base; the competing-interests statement discloses the company founder and a paid employee as authors.

7. US Patent Application US20200102274A1. Quinoline derived small molecule inhibitors of nicotinamide N-methyltransferase (NNMT) and uses thereof. Assignee: Board of Regents of the University of Texas System. Priority 2017-03-30. 5-amino-1-methylquinolinium iodide is named as exemplar compound “1j”; the originator lab’s lead scientists are listed inventors.

8. Domagała TB, et al. Nitric oxide production and endothelium-dependent vasorelaxation ameliorated by N1-methylnicotinamide in human blood vessels. Hypertension. 2012;59(4):825-832. PMID 22353616. In humans, oral 1-MNA increased nitric-oxide-dependent dilation of the brachial artery, the molecule 5-Amino-1MQ suppresses.

9. Mateuszuk Ł, et al. Antiatherosclerotic effects of 1-methylnicotinamide in apolipoprotein E/LDL receptor-deficient mice. J Pharmacol Exp Ther. 2016;356(2):514-524. PMID 26631491. In atherosclerosis-prone mice, 1-MNA reduced plaque, improved NO/prostacyclin-dependent endothelial function, and inhibited platelet activation.

10. Ferrell M, et al. A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. Nat Med. 2024;30(2):424-434. PMID 38374343. In ~4,300 humans, the niacin terminal metabolites 2PY and 4PY tracked with higher 3-year major-adverse-cardiac-event risk, the two-sided part of the biology, since NNMT inhibition lowers them too.

11. Li S, et al. Nicotinamide-N-methyltransferase inhibition improves cardiac function and structure in a heart failure with preserved ejection fraction mouse model. Pharmacol Res. 2025. PMID 40484359. In aged “stiff-heart” mice, NNMT inhibition cut 1-MNA ~77% and improved cardiac function, but the inhibitor was AMO-NAM, a different NNMT blocker, not 5-Amino-1MQ, and the benefit was not via homocysteine.

12. Campagna R, et al. Nicotinamide N-methyltransferase in endothelium protects against oxidant stress-induced endothelial injury. Biochim Biophys Acta Mol Cell Res. 2021;1868(10):119082. PMID 34153425. Inhibiting NNMT in human endothelial cells reduced their survival under oxidant stress. Used the related compound 5-amino-1-methylquinoline (5MQ), not the 5-amino-1-methylquinolinium sold as 5-Amino-1MQ.

13. Clarke R, et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: meta-analysis of 8 randomized trials involving 37,485 individuals. Arch Intern Med. 2010;170(18):1622-1631. PMID 20937919. Folic acid lowered homocysteine ~25% but had no significant effect on heart attacks, strokes, or vascular death across 37,485 people.

In the emergency department, when someone is sick enough, we stop treating blood pressure as a single number. We thread a thin catheter into an artery, an arterial line, and the monitor draws the pressure out continuously, beat after beat. It climbs with pain. It drops after sedation. It swings with every fluid bolus and every breath. That is blood pressure as the artery actually lives it: not a reading, a moving signal.

Almost no one healthy ever sees their blood pressure that way. They get the opposite, one rushed cuff reading at a yearly physical, after the coffee and the traffic and ten minutes in a bright waiting room. The number gets a label, fine or borderline or high, and the conversation moves on. It is a little like judging your blood sugar from a single random fingerstick once a year and pretending you understand the curve. Keep that gap in mind, the continuous signal against the once-a-year sample, because it turns out to be the whole story.

Imagine a 35-year-old whose blood pressure reads 132/85 at their annual physical. Their physician glances at the number and calls it “borderline.” Maybe a vague suggestion to cut back on salt, lose a few pounds, recheck in a year. Nothing in the conversation feels alarming.

Now imagine that same person, twenty years later, being wheeled into a cath lab with a critical occlusion in their right coronary artery. The plaque didn’t show up overnight. It accumulated, every year, while their blood pressure was “borderline.” The number at 35 didn’t move the conversation. The number at 45 didn’t either. The number at 55 finally did, but by then it was a procedure rather than a prevention. Unfortunately this was me. I didn’t visit the doctor often in my 20s and 30s. I was healthy and rarely got sick, and I skipped most yearly physicals. But I know my blood pressure was never that “perfect” 120/80 or below. It also was never horrible, even though by today’s guidelines I had hypertension.

The numbers behind this aren’t soft. In the largest meta-analysis ever assembled on the topic, pooling individual data from over one million adults across sixty-one cohort studies, the relationship between blood pressure and cardiovascular mortality was continuous and linear all the way down to a systolic of 115 mmHg and a diastolic of 75 mmHg.² From there upward, every additional 20 mmHg systolic or 10 mmHg diastolic roughly doubled the risk of death from heart disease and stroke. No inflection point. No threshold below which it stopped mattering. The artery was logging the damage at every reading, every year, regardless of whether the doctor called the number “borderline” or “fine.”

The problem isn’t that 132/85 is a medical emergency. It almost never is, and the medical system typically doesn’t treat blood pressure as an emergency until it gets up around 180/120. But the damage starts long before that. The standard visit measures blood pressure as a snapshot, treats anything short of stage 2 hypertension as discretionary, and acts as if the years between snapshots don’t count. They do. And the cleanest evidence all points the same way: Mendelian dose-response curves on lifelong exposure, a million-person meta-analysis of cardiovascular cohorts, decades of longitudinal data on cumulative pressure load, and a marquee randomized trial stopped early because the benefit was unmistakable. All of it says the same thing. What’s happening between your readings is doing most of the work.

Last week I walked through the cumulative math of borderline LDL and what twenty years of mildly elevated cholesterol does to an artery wall. This week I want to put borderline blood pressure through the same treatment. The construct is identical. The numbers are different. The arithmetic is the chapter nobody walked through with me.

Because for most of my adult life, from my early thirties through the day I got carted into the cath lab, my blood pressure averaged something like 132 over 85. Sometimes higher on the diastolic side. Not dramatic, not the kind of number that gets you a prescription. Just, as I wrote when I named the cracks I’d dismissed, “not optimal.” I knew what optimal looked like. I had run a hundred blood pressures a shift in the ER. I wrote mine off as white coat effect, or training stress, or just close enough. It was always “close enough.” And twenty years of close enough is not a holding pattern. It’s an unfolding cost, and that cost is the math I want to walk through here, because I should have read it myself fifteen years ago.

The Bottom Line

A single office blood pressure is a weak sample of a signal that never stops moving. The artery doesn’t experience a number once a year; it absorbs pressure continuously, every beat, for decades. That’s why a reading the system calls “borderline” stops being reassuring the moment you carry it across time: the damage is the running total, not the snapshot.

I’m not saying a 35-year-old at 132/85 needs a pill tomorrow. I’m saying “it’s borderline, we’ll recheck in a year” is an incomplete answer to a problem that unfolds over thirty years. The cheapest cardiovascular intervention I never made was the home-cuff average and the honest conversation I could have had at thirty.

Vocabulary that matters

• Systolic pressure: the top number, the push on your artery walls each time the heart beats.

• Diastolic pressure: the bottom number, the pressure that remains while the heart relaxes between beats.

• Stage 1 hypertension: 130/80 or higher, under the current U.S. guideline. The range once waved off as “borderline” is now a named diagnosis.

• mmHg-years: excess pressure above a sensible reference line, multiplied by the years you carry it. Blood pressure’s version of pack-years.

• Arterial line: a catheter placed in an artery that reads blood pressure continuously, beat to beat. How we watch it in the ER, and how the artery actually experiences it.

• Endothelium: the living inner lining of the artery, one cell thick, where pressure does its daily work and where plaque begins.

What “borderline” actually means in current practice

For decades, primary-care medicine treated 140/90 as the line. Below it, fine. Above it, hypertension. That worked, more or less, when the ten-year horizon was the only horizon. It does not work anymore.

In August 2025, the American College of Cardiology and the American Heart Association, with eleven other professional societies, published the most consequential update to the U.S. blood pressure guideline since 2017.³Two changes matter for anyone with a systolic in the 130s.

The first: “borderline” is no longer a clinical category. Anything 130/80 or above is now formally Stage 1 hypertension. Not “elevated,” not “prehypertension.” Stage 1, the same word the framework used to reserve for numbers that triggered a prescription. The threshold didn’t move because anyone changed their mind about biology. It moved because the cumulative-exposure evidence finally got too loud to ignore.

The second is more clinically active. The 2025 guideline replaces the old Pooled Cohort risk equation with a calculator called PREVENT, and it tightens the medication trigger for adults whose 10-year predicted risk is below 7.5%. If your average blood pressure is 130/80 or higher and a three-to-six-month trial of lifestyle change doesn’t bring it under 130/80, the recommendation is now to start medication. The ACC’s own commentary acknowledges this will prescribe more younger patients, because the cumulative exposure starts earlier than the old ten-year score was ever designed to see.

That, in plain terms, is the framework moving toward the math. The thirty-five-year-old at 132/85 isn’t a soft call anymore. They’re a stage-1 hypertensive on a twenty-year clock.

The advice that’s supposed to bridge the gap

The standard playbook for stage-1 hypertension still leads with lifestyle, and it should. The right answer for someone at 132/85 is rarely “start medication tomorrow.” Sodium restriction, alcohol moderation, weight loss, physical activity, the DASH eating pattern, treating sleep apnea when it’s present: each can move a borderline number measurably.

But the size of the move is where the framework quietly underperforms the math. The best dietary trials in well-controlled settings produce systolic drops on the order of 5 to 8 mmHg, and real-world adherence over years cuts that further. Even a sustained 5 mmHg reduction is meaningful at the population level. It is also not enough, on its own, to close a 15-to-20 mmHg gap on a dose-response curve that runs down to 115 systolic. The gap is bigger than the lifestyle prescription, as typically delivered, actually closes.

This isn’t an argument against lifestyle. It’s an argument for honesty about what lifestyle alone does and doesn’t do for someone whose true average is in the low 130s. “We’ll watch it” only works if someone is actually watching, and that means the patient and the clinician looking at the same thing: not the snapshot, but the trajectory.

Why we measure cigarettes in years and blood pressure in moments

Consider how we talk about a different cumulative exposure. A pack a day for twenty years is twenty pack-years. No physician shrugs at twenty pack-years because the patient happens not to be smoking the morning of the appointment. The cumulative number is the diagnosis. Lung cancer risk, COPD risk, even smoking-attributable heart risk all scale with pack-years, not with whether the patient inhaled in the parking lot. The unit was invented because the moment was misleading and the running total was honest.

Blood pressure works the same way at the cellular level, with one important difference. The artery doesn’t experience a number; it experiences a force, every beat, every year. The endothelial cells lining the vessel wall are mechanically stressed continuously, and the damage they accumulate is a function of pressure times time, not pressure at one office visit. The screening framework just hasn’t absorbed that arithmetic the way it did for smoking.

Here’s the difference, because the analogy isn’t clean. Cigarettes have a defensible zero: no cigarettes, no exposure, no harm. Blood pressure does not. Pressure isn’t bad; it’s necessary. The heart spends every beat producing it to perfuse the brain, the kidneys, and the coronary tree. Drop it low enough and the system fails the other way: syncope, ischemia, organ injury, death. I see the dangers of low blood pressure regularly in the ER. The relationship between blood pressure and harm is J-shaped, not a straight line to zero. So the right metric isn’t the running total of pressure across a lifetime, which would score a dead person at zero. It’s excess blood-pressure years: the running total of pressure above a sensible reference baseline, accumulated across the years you spend above it.

Take 120/80 as the reference, since that’s what most people associate with “normal” and the line above which the 2025 guideline starts calling blood pressure elevated. Honest caveat: the cleanest evidentiary floor in the Lewington data sits closer to 115/75, below which the dose-response simply runs out of cohort data. The exact baseline you pick changes the size of the numbers below but not the direction. Call the unit mmHg-years, or vessel wall exposure above baseline. What matters is that the framework starts taking the running total seriously, the way it already does for cigarettes.

What cumulative blood pressure exposure actually measures

Cumulative excess exposure is the area between your actual systolic curve and the 120 reference line, added up across the years you spend above it. Someone whose systolic averages 120 from age 20 to 65 accumulates zero excess mmHg-years; the artery is doing exactly the work it was built for. Someone who averages 134 across the same forty-five years accumulates 14 × 45 = 630 excess mmHg-years, the total “above baseline” load their artery has absorbed every day for forty-five years.

That number doesn’t look enormous in isolation, but it’s an extra fourteen millimeters of mercury pushing on the inside of your arteries, continuously, for forty-five years. Every endothelial cell in your coronary tree, your renal arteries, your cerebral vessels has done its job under a slightly heavier load every minute of every day. That cumulative cellular cost is what the snapshot can’t see.

Illustrative arithmetic across forty-five years. A systolic average of 134 is only 14 mmHg above the 120 reference line, but from age 20 to 65 that becomes 630 excess mmHg-years of exposure. Using 115 instead of 120 changes the size of the number, not the direction of the argument. Schematic, not individual risk prediction.

This isn’t a thought experiment. The major cardiovascular cohorts have begun computing exposure metrics like this directly, adding up each person’s blood-pressure trajectory across decades and asking whether the running total predicts events better than any single measurement. It does. The Lifetime Risk Pooling Project, combining five racially diverse U.S. cohorts followed into middle age, found that higher cumulative systolic exposure predicted both higher event rates and earlier age at first event, after adjusting for whatever the blood pressure happened to be at the moment of measurement.⁶ The CARDIA cohort, which followed young adults from their late teens into their fifties, found cumulative exposure in young adulthood to be a strong predictor of heart failure, coronary disease, and stroke decades later, with hazard ratios that rose steadily with accumulated exposure.⁵ The unit may not be on your lab report yet. The biology has been computing it the whole time.

SPRINT: what happens when you actually pull the trigger

If cumulative exposure is the construct, the next question is whether lowering it earlier produces fewer events. That is what SPRINT was built to answer, and the answer was decisive enough that the trial was stopped early on its safety board’s recommendation.¹

SPRINT enrolled 9,361 adults aged 50 and older with a systolic of 130 mmHg or higher and at least one additional risk factor, excluding patients with diabetes and prior stroke. One group was treated to a target below 140 mmHg, the conventional goal at the time. The other was treated to a target below 120. At one year the standard group averaged 136.2 mmHg systolic and the intensive group 121.4, a roughly 15-mmHg separation, sustained.

The primary outcome, a composite of myocardial infarction, acute coronary syndrome, stroke, heart-failure hospitalization, and cardiovascular death, occurred in 1.65% per year of the intensive group versus 2.19% of the standard group. The hazard ratio was 0.75: a 25% relative reduction, p < 0.001, with a 95% confidence interval (0.64 to 0.89) that didn’t come close to crossing one. All-cause mortality showed a hazard ratio of 0.73, a 27% relative reduction in death from any cause (95% CI 0.60 to 0.90, p = 0.003). The number needed to treat to prevent one primary event was 61; to prevent one death, 90.

Those are large effect sizes for a cardiovascular trial, and they’re why the safety board halted it early. A couple of caveats shape how to apply it to a younger reader. SPRINT’s readings were taken by an automated device after five minutes of rest, alone in the room, which reads several millimeters lower than a typical office cuff slapped on mid-conversation. So a SPRINT target of “below 120” corresponds to something more like “low 130s” in casual office settings, the same range we’re talking about for the borderline patient. SPRINT also excluded diabetes and prior stroke, and serious adverse events like syncope and acute kidney injury were more frequent in the intensive arm, which is exactly why treatment intensity belongs in the clinical encounter, not a blog post. But the central finding survives all of it: lowering pressure earlier and harder, in a high-risk middle-aged population, cut events by a fourth and death by more than a fourth.

The Read
The running total isn’t only descriptive; SPRINT shows it bends. Lower the pressure earlier and the events and the deaths actually fall. The start date is part of the dose.

The million-adult dose-response

If SPRINT is the trial, Lewington 2002 is the field map. Published in The Lancet, it pooled individual data from sixty-one cohort studies, more than one million adults and around twelve million person-years of follow-up.² It remains the most widely cited estimate of dose-response in the field.

The finding belongs at the center of every “borderline” conversation. Across the systolic range of roughly 115 to 185 mmHg, in adults aged 40 to 69, each 20 mmHg rise in systolic (or 10 mmHg diastolic) was associated with roughly a doubling of mortality from both ischemic heart disease and stroke. The relationship was continuous and steadily rising all the way down, with no observable threshold above 115/75 below which it flattened.

This is what people miss when they hear “borderline.” They picture a soft category between “fine” and “high.” The Lewington data show no soft category. The difference between 116 and 136 systolic, sustained over decades, is the same shape of risk as the difference between 156 and 176. The artery doesn’t know “borderline” from “moderate hypertension” any more than the lung knows “social smoker” from “pack-a-day.” It just adds up the exposure.

CARDIA: real-time confirmation in young arteries

Lewington gives the dose-response across the broad adult population. CARDIA, the Coronary Artery Risk Development in Young Adults study, anchors it in a younger cohort with continuous longitudinal data, enrolling adults aged 18 to 30 in 1985 and 1986 and following them for decades.

When investigators computed each participant’s area under the systolic curve from young adulthood forward and tracked events into midlife, the pattern paralleled Lewington in an older population.⁵ Higher cumulative exposure in young adulthood was associated with later heart failure, coronary disease, stroke, and overall cardiovascular events, and the relationship held even after adjusting for the blood pressure at the time of the event. In plain terms: take two participants who reach midlife with the same current blood pressure, and the one whose accumulated exposure was higher carries the higher risk. The running total matters after controlling for the snapshot. That is exactly what the snapshot framework can’t account for.

What this means for a 35-year-old at 132/85

Let me run the math three ways for a thirty-five-year-old whose systolic has averaged around 134 mmHg since their early twenties, using 120 as the reference and counting excess mmHg-years above it. Same structural exercise I used for cumulative LDL in last week’s chapter.

Both lumens are still open. The point isn’t a sudden blockage. It’s the quieter difference the cuff can’t show: years of extra mechanical load on a living vessel wall. Schematic, not diagnostic.

Case A. Systolic has averaged 134 since age 20. Excess above the 120 reference: 14 mmHg. By age 35 they’ve banked 15 × 14 = 210 excess mmHg-years. If nothing changes, by 45 they reach 350, and by 65, 630.

Case B. Same start, but at age 30 they (or their physician) take it seriously, and lifestyle plus medication if needed brings the sustained systolic to the 120 reference. By 45 their cumulative excess is 10 × 14 (ages 20 to 30) + 15 × 0 = 140 excess mmHg-years, and it stays 140 at 65. The meter stopped the day the pressure came back to baseline. Relative to Case A, they’ve avoided 490 excess mmHg-years of wall stress by 65.

Case C. Same person, acting at 35 instead of 30. Cumulative excess by 45 is 15 × 14 = 210, holding at 210 by 65. The five-year delay costs about 70 excess mmHg-years locked in for life, and the savings compound with every additional decade above baseline avoided.

Comment

These numbers are illustrative, not prescriptive. Real blood pressure doesn’t sit flat; it drifts with age, stress, weight, sleep, training, and sodium. Pick 115 as the reference instead of 120 and every number gets larger. But the direction is right, the magnitudes are plausible, and the lesson is the one cholesterol taught too: the timeline of your pressure isn’t a backdrop to your risk. Once you’re above the line, it’s the primary driver.

The math your physician probably hasn’t done with you is this. At thirty-five, a low-grade hypertensive reading isn’t a holding pattern. It’s an unfolding excess, with a meter that’s been running since adolescence.

The Read
A single 132/85 is not an emergency. Twenty years of 132/85 is a bill your arteries collect with interest. The cuff gives you a moment; the artery keeps the running total.

The 35-year window

Most cardiology risk calculators, including the new PREVENT score, estimate event probability over the next ten years. That’s useful for some decisions and deeply misleading for others. A thirty-five-year-old’s ten-year score almost always comes back low, because the next ten years genuinely don’t carry much absolute risk. The score isn’t broken; it’s doing its job. But the next thirty years, where Lewington and CARDIA both say the most damage compounds, aren’t on its clock.

So the right question for a thirty-five-year-old isn’t “what’s my ten-year risk?” It’s “what’s my thirty-year exposure trajectory, and what’s the leverage of intervening now versus in fifteen years?” SPRINT and the cumulative-exposure literature both answer: substantial. This is the leverage window, and it’s also the window where most people with low-grade readings do nothing, because the calculator tells them they don’t have to. The 2025 guideline is the first major U.S. document to push the other way, recommending medication for stage-1 patients whose pressure stays elevated after a serious lifestyle attempt, even at low ten-year risk. The framework is finally catching up to the cumulative reality.

The artery wall is alive, and we’ll come back to that

A note on what “wall stress” means at the cellular level, because the math can sound abstract.

The inner lining of every artery is a single layer of cells, the endothelium. It is not a passive surface. It senses pressure, flow, and chemical signals continuously, and it regulates tone, permeability, clotting, immune-cell adhesion, and the production of a key signaling molecule called nitric oxide. Expose that layer to higher mechanical stress over years and its signaling biology starts to change. The protective phenotype that keeps the wall calm and non-adhesive begins to erode, most readily where the artery’s geometry creates disturbed flow, particularly at the branch points where one vessel splits into two.

Branch points are where flow becomes complicated. Over time, pressure, shear, cholesterol, and inflammation converge on the same living surface: the endothelium.

That biology is the through-line connecting borderline blood pressure to borderline cholesterol to subclinical inflammation to early plaque. It’s the engine of everything the cardiac story turns toward over the next several posts, and it deserves its own chapter with the mechanism walked through carefully rather than waved at. For now, the through-line is enough: the wall is alive, the pressure is doing real work on it every minute of every year, and the running total of that work is what eventually shows up on a CT angiogram.

What I’m telling people in their thirties and forties

Three things, in practical terms.

Measure with a home cuff, not just at the office. A single office reading is a sample size of one, taken under conditions that bias the result, usually upward. A validated upper-arm cuff used at home over a few weeks, with proper technique (seated, back supported, feet flat, arm at heart level, after several minutes of rest, two readings a minute apart, twice a day for a week), is the standard the 2025 guideline now formally endorses for diagnosis.³ A home average is what you should track, not a clinic snapshot. One honest caveat: a brachial cuff measures peripheral pressure, the pressure in your upper arm. The pressure that matters most to your heart, brain, and kidneys is central pressure, at the aortic root, and the two can diverge with age and arterial stiffening. That’s a layer of resolution worth knowing about, and a topic for a future post.

Reframe the question from “is my reading borderline?” to “what’s my mmHg-years trajectory?” The first gets a snapshot answer. The second forces a conversation about time. Ask a primary-care physician, “what does my cumulative exposure look like over the next twenty years if we don’t change anything?” and you’ve moved the dialogue from one inflection point to a curve, even with a physician who has never thought in mmHg-years.

If your reading has been in the low 130s or upper 80s for a decade, that’s not a snapshot. That’s data. Bring the time series. Ten readings of 132/85 over fifteen years isn’t “borderline.” It’s a confirmed exposure pattern. Your physician’s instinct will be to look at the most recent point; the instinct that serves you, the same one I learned when I had to fight for the right cardiac scan, is to show them the full picture and ask for what it warrants.

If your reading is in stage 1, here’s what to do this week

Future posts will go deep on the specific things that move cumulative blood pressure. For now, the foundations. None of this substitutes for the conversation with your own physician; treat them as the conversation starters worth raising at your next visit.

• Ask about a confirmed home-cuff average.This is the conversation the 2025 guideline tells your physician to have with you. Ten readings a week, taken correctly, for a month is enough to land an honest baseline.

• If you smoke, this is the single highest-leverage change you can make. Nothing else is close. Pack-years compound the same way mmHg-years do, and quitting moves the curve faster than any other lever.

• If you don’t have a structured exercise routine, start one. Most-days brisk walking plus a couple of strength sessions a week moves blood pressure and a long list of downstream variables. Next week’s post on cardiovascular training goes deeper.

• If you snore loudly, gasp awake, or wake up unrefreshed, ask about obstructive sleep apnea. Untreated OSA pushes blood pressure up overnight, and a meaningful share of “treatment-resistant” hypertension is undiagnosed OSA.

• If you carry excess weight, particularly around the midsection, losing it reliably moves the number, especially paired with the changes above. Five to ten percent of body weight is roughly where the response becomes measurable on a home cuff.

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What I Changed

This is what changed for me, offered as my read of the evidence and my own situation, not a prescription for yours.

I stopped treating the office reading as the number. One cuff in a bright room, taken after the waiting-room rush, is a sample of one, and usually a biased one. The number I track now is a home-cuff average over time.

I started thinking in trajectories instead of snapshots: not “is today’s reading borderline,” but “what does my mmHg-years curve look like over the next twenty years if nothing changes.” And I bring that time series into the room instead of accepting the single most recent dot. The version of me at thirty could have bent that curve for the price of a conversation. He never had it.

The Calibrated Claim Audit

Claim 1: “A single office reading tells you your blood-pressure risk.”
Mechanism strength: Weak · Evidence quality: Weak for individual trajectory
My read: It’s a sample of one, not the signal.

Claim 2: “Chronically elevated blood pressure damages arteries over time.”
Mechanism strength: Very strong · Evidence quality: Very strong (million-adult dose-response, decades of cohorts, a randomized trial)
My read: High confidence. The artery logs every reading.

Claim 3: “Lowering sustained pressure earlier reduces events.”
Mechanism strength: Very strong · Evidence quality: Strong randomized evidence (SPRINT) in higher-risk adults
My read: The direction is settled; the intensity is individualized.

Commercial distortion risk: Low. This is foundational cardiovascular physiology, not a supplement sector. The distortion here isn’t a product being sold. It’s clinical inertia: a system that measures a continuous signal once a year and treats anything short of stage 2 as discretionary.

What’s next, and where we’re heading

The cumulative-exposure framework I just walked through for LDL and now for blood pressure isn’t a coincidence. It’s the same idea applied to two inputs. Both add up over decades, both do most of their damage between snapshots, and both are largely modifiable above a sensible reference.

Next week I want to step away from lab values and toward the way I trained my body for thirty years, the next crack in the list I named a few weeks ago. I trained for the mirror. I didn’t train for the running total. The literature on what aging-adapted cardiovascular training actually looks like has gotten clearer in the last decade, and that’s the chapter I want next.

One last thing. Across the next several posts you’ll see me reach for a framework called the hallmarks of aging: the molecular and cellular processes biologists now think drive aging itself, first laid out by Carlos López-Otín and colleagues in 2013 and expanded in 2023 to twelve interlinked hallmarks.⁴ I’m going to start anchoring health concepts back to which hallmark they touch, because that’s the lens through which I now think about every intervention. Borderline blood pressure isn’t just a cardiology story. In my reading it intersects altered intercellular communication, chronic inflammation, and mitochondrial dysfunction in the vessel wall, among others. We’ll trace those out as we reach each one.

Comment

The Final Signal

• What this gets right. Blood pressure is a moving signal, and a single office reading is a weak sample of it. Repeated, validated home measurement is the honest baseline, and the 2025 AHA/ACC guideline now says so too.

• What gets missed. A “borderline” annual number can hide decades of excess mmHg-years. The damage compounds between the readings, where the snapshot model can’t see it.

• What I changed. I stopped treating the office number as the number. I track a home-cuff average and the trajectory, and I bring the time series into the clinician conversation.

• What not to overclaim. One reading isn’t destiny, and low blood pressure has a real danger floor; the relationship is J-shaped, not a straight line to zero. The goal is excess mmHg-years above a sensible reference, not the lowest possible number.

• What this opens next. The artery wall is alive. Blood pressure is where the endothelium, nitric oxide, and the earliest plaque all connect, the through-line the next several posts trace, and the first place the hallmarks-of-aging lens earns its keep.

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References

1. The SPRINT Research Group. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015;373(22):2103-2116. PMID 26551272. Finding: In 9,361 higher-risk adults over 50, a systolic target below 120 instead of below 140 cut major cardiovascular events by 25% and deaths by 27%. The trial was stopped early.

2. Lewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360(9349):1903-1913. PMID 12493255. Finding: Across more than a million adults in 61 cohorts, the link between usual blood pressure and vascular death was continuous down to 115/75, with each 20 mmHg systolic (or 10 mmHg diastolic) roughly doubling the risk. No threshold.

3. Jones DW, et al. 2025 AHA/ACC Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults. Hypertension.2025;82(10):e212-e316. PMID 40811516. Finding: The current U.S. guideline reclassifies 130/80 and up as Stage 1 hypertension, adopts the PREVENT risk calculator, lowers the bar to start medication in younger adults, and endorses validated home-cuff measurement for diagnosis.

4. López-Otín C, et al. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243-278. PMID 36599349. Finding: The 2023 update to the hallmarks-of-aging framework, naming twelve interlinked processes that drive aging, including altered intercellular communication and chronic inflammation.

5. Nwabuo CC, et al. Long-term cumulative blood pressure in young adults and incident heart failure, coronary heart disease, stroke, and cardiovascular disease: The CARDIA study. Eur J Prev Cardiol. 2021;28(13):1445-1451. PMID 34695218. Finding: In adults tracked from young adulthood, higher cumulative blood-pressure exposure predicted later heart failure, coronary disease, and stroke, adding prognostic value beyond any single reading.

6. Reges O, et al. Association of Cumulative Systolic Blood Pressure With Long-Term Risk of Cardiovascular Disease and Healthy Longevity: Findings From the Lifetime Risk Pooling Project Cohorts. Hypertension. 2021;77(2):347-356. PMID 33342241. Finding: Across five diverse U.S. cohorts, higher cumulative systolic exposure predicted more cardiovascular events and an earlier age of onset, even after accounting for blood pressure measured at a single point.

If this was useful, a restack helps it reach someone who needs it. I read every comment.

Hard science, delivered honestly. No sponsors. No cheerleading. Just signal.

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X / @nickhansonrn · LinkedIn (linkedin.com/in/nickhanson)

Not medical advice.

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My LDL was never the horror-show number.

That was the trap.

For most of my adult life it sat in the 130s, 140s, sometimes brushing 150. High enough to matter. Never high enough to make anyone slam a chart shut and say, “We need to deal with this now.” Starting around age thirty I got the same line at almost every visit: borderline. Watch your diet. Recheck in a year. And a statin wouldn’t be a horrible idea, but never was a full court press to get me to start one.

I should have been the patient most likely to catch this. Bioinformatics training. Fifteen years inside the supplement industry. An ER nurse and PhD/APRN student who reads the primary papers, not the blogs about the papers. I was wearing the trackers, pulling my own labs, running the diet, buying the argument that the rest of my markers looked clean so the cholesterol could wait. And not one person, including me, ever did the math that actually mattered.

Because the artery doesn’t experience LDL as a number on a printout. It experiences a running total: how high, multiplied by how long. By the time a CT angiogram found an 80% blockage in my right coronary artery, I had already paid for twenty years of “borderline” that nobody ever added up.

Here’s the part that should make you angry, because it’s the part that fooled me. The villain in this story isn’t LDL, and it isn’t cardiologists. It’s a single word, and the way the whole screening framework is built around it. “Borderline” is a label for the lab value. Exposure is what the artery lives through. Those are not the same thing, and the gap between them is where the damage hides.

Vocabulary that matters

• LDL-C: the cholesterol carried inside LDL particles. The number on your standard panel. Useful, but a rough proxy.

• ApoB: a direct count of the artery-clogging particles themselves. Tracks risk better than the cholesterol number alone.

• Lp(a): a separate, mostly genetic risk particle most doctors won’t test unless you ask. Worth knowing once in your life.

• Cumulative exposure (mg-years): your LDL level multiplied by the years you’ve carried it. What your arteries have actually been absorbing, added up.

• 10-year risk: the short-term event odds the standard calculators estimate. Not the same thing as your lifetime arterial burden.

What “borderline” actually means in current practice

The screening framework treats LDL like a thermostat reading. You walk in, get a number, and the number gets dropped into a bucket: under 100 is optimal, 100 to 129 near optimal, 130 to 159 borderline, 160 to 189 high, 190-plus very high.

The action threshold for starting a statin in someone with no prior cardiac disease usually requires LDL above 190, or LDL between 70 and 189 paired with a 10-year risk score above some cutoff, typically 7.5% to 10% depending on the guideline. The risk score does what it was built to do: estimate ten-year event odds in middle-aged adults, and it does that reasonably well. The trouble starts when it gets pointed at a thirty-five-year-old. Their 10-year risk is dominated by one variable: age. The score can’t see fifteen more years of accumulating exposure. It only sees the next ten.

So the visit goes: borderline, recheck in a year, watch your diet, see you in twelve months. The patient walks out without alarm, because in the framework’s own terms there’s no alarm to sound. That’s not a bad doctor. That’s a measurement model asking the wrong question and getting a reassuring answer to it.

And the reassurance is dangerous precisely because of how this disease tends to announce itself. For some people, sudden cardiac death is the first sign of coronary disease they ever get, with no warning symptoms beforehand. By the time the snapshot finally has something alarming to show you, the answer has, for too many people, already arrived. That’s the cost of treating a running total as if it were a single dot.

And the diet advice doesn’t close the gap

The dietary advice the borderline patient gets is, on average, undersized for the problem. Trials of standard cardio-protective diets, Mediterranean-style eating included, generally show modest LDL reductions in tightly controlled settings, and the effect shrinks further once you account for how real people adhere over years. More aggressive plant-forward patterns can push the number harder, though long-term adherence in diet trials falls off steeply.

None of that means diet is irrelevant. Diet matters enormously, in both directions. Keto and high-saturated-fat patterns can drive LDL up sharply in certain people, which is the argument I made in Post 2 about the keto trial that got retracted, and individual response varies wildly. The point here is narrow: the generic “eat Mediterranean and recheck in a year” advice handed to the borderline patient does not, on average, move the exposure curve at the size the math is asking for.

The cigarette analogy

Think about how we talk about a different kind of cumulative exposure. A pack a day for twenty years is twenty pack-years. No physician looks at twenty pack-years and calls the smoking “borderline.” The cumulative number is the diagnosis. Lung cancer risk, COPD risk, even smoking-attributable heart disease, all of it scales with pack-years, not with whether the patient happened to be smoking on the morning of the appointment. Pack-years live inside the medical vocabulary because the arithmetic is what predicts the outcome.

LDL works exactly the same way. The screening framework just hasn’t absorbed the arithmetic yet.

What cumulative LDL exposure actually measures

Here’s what the framework doesn’t measure. Elevated LDL damages the artery every year it’s elevated. Not in proportion to today’s level, but in proportion to the running total of that level across time. Twenty years of LDL 145 isn’t twenty data points of “borderline.” It’s a continuous buildup of ApoB-carrying particles crossing the inner wall of the artery, lodging in the lining, and kicking off the cascade that becomes plaque. The unit that captures it is mg-years: your LDL number multiplied by the years you’ve carried it. Some lipidologists call it LDL-years or mmol-years. Same idea, different label.

And here’s the part that reframes the whole thing, the part I came to appreciate late. That buildup doesn’t need an injury to get started. The older teaching was that an artery had to be damaged first, by inflammation or some other insult, before cholesterol could move in and do harm. The better-supported model is close to the reverse. The retention of ApoB particles in the wall is itself the initiating event, and in the words of the researchers who named the response-to-retention model, it is “both necessary and sufficient to provoke lesion initiation in an otherwise-normal artery.” The inflammation everyone talks about comes after, as the wall’s response to the particles it has already trapped and chemically modified, not as the ticket those particles needed to get in. That is why duration is so unforgiving. You don’t have to damage the artery first and then wait. Carry enough ApoB for enough years and the particle is the insult. (Why some walls retain more than others, the endothelium, blood pressure, the geometry of flow, is its own chapter, and it’s coming later in this series.)

A 35-year-old who has run an LDL of 145 since age 20 has already banked roughly 2,175 mg-years of exposure. Their panel today reads “borderline.” Their artery has been logging the damage since college.

Caption: Snapshot vs. exposure. A lab value gets judged in a single moment; the artery experiences the running total of ApoB-containing particles over time. Illustrative exposure math, not individual risk prediction.

What Mendelian randomization actually shows

In 2012, Brian Ference and his colleagues published a Mendelian randomization study in the Journal of the American College of Cardiology that, for my money, is the cleanest evidence we have on the question of when mattering as much as how much. With my background in bioinformatics and epidemiology, I put serious weight on this design. A well-run Mendelian randomization isn’t ordinary observational epidemiology. It’s a way to draw something close to a causal arrow from genetics to outcome.

Here’s the intuition. A regular observational study compares people who have low LDL because of something, diet, a statin, exercise, body weight, plain luck, against people with higher LDL. Pulling the LDL effect out from everything else tangled up with it is brutally hard. A Mendelian randomization study instead compares people who inherited gene variants that lower their LDL from birth, assigned by chance at conception, before they made a single lifestyle decision, against everyone else. The genetics randomize the exposure the way a clinical trial randomizes a drug, except the assignment happens at conception and runs for a lifetime.

Ference’s team pooled nine such variants across six genes. The meta-analysis covered 312,321 participants. The finding: each 1 mmol/L (about 38.7 mg/dL) of genetically lower LDL was associated with a 54.5% reduction in coronary heart disease risk (95% CI 48.8% to 59.5%). All nine variants pointed the same direction, with no meaningful heterogeneity.

Now set that against a statin started later in life. In Ference’s comparison with the long-running statin-trial meta-analyses, midlife treatment that achieves the same drop in the LDL number cuts coronary risk by roughly a third as much as the genetic effect. Both numbers are real. The drug works. The genetics work. They produce the same delta in the LDL number. But the genetic version is associated with roughly three times the reduction in coronary risk per unit of LDL. The difference isn’t the molecule. It’s the duration. Same change in the number, different starting line on the timeline, and the timeline is where most of the damage gets done.

And the trials confirm the direction independently. Pooling 26 randomized trials and 170,000 people, the Cholesterol Treatment Trialists found that each 1 mmol/L drop in LDL cut major vascular events by about a fifth, and found no threshold down to the lowest levels studied. Lower is better, and there’s no point on the curve where the benefit suddenly stops. Genetics, cohorts, and randomized trials all converge on the same line.

The CARDIA cohort: real-time confirmation in 4,958 humans

If Mendelian randomization gives the gene’s-eye view, the CARDIA study gives the longitudinal one. It enrolled 4,958 asymptomatic adults aged 18 to 30 in 1985 and 1986 and followed them for decades. In 2020, Michael Domanski and colleagues computed each participant’s running total of LDL across age, essentially mg-years, and tracked cardiovascular events after age 40. Median follow-up after 40 was 16 years, with 275 events.

Finding one. Cumulative LDL exposure was significantly associated with event risk: every additional 100 mg-years of accumulated LDL raised the hazard of a cardiovascular event by about 5%, in a straight-line, dose-response fashion. No inflection point. More exposure, more risk, all the way down.

Finding two, the one most people miss. The same total exposure carried more risk when it accumulated earlier in life than when it accumulated later. Two thousand mg-years banked by the time you’re thirty-five is more dangerous than the same two thousand accumulated between forty-five and sixty. The total was identical. The risk was not. The years that mattered most were the early ones.

Honest framing: this is one observational cohort, and it wants replication. What makes me lean on it is the coherence, with Ference’s genetic data, with the young-adult hyperlipidemia work I cited in Post 6, and with what we already know about how plaque actually forms. Several independent lines all point the same direction.

What this means for a 35-year-old with LDL 145

Run the math three ways. Take that thirty-five-year-old at an LDL of 145. If nothing changes, by forty-five they’ve banked a serious load of exposure. If they’d acted at thirty instead, with lifestyle and a drug if needed, they would avoid roughly a 30% lower hazard of events. And here’s the kicker: if they wait just five years, from thirty to thirty-five, that delay alone throws away about a third of the savings they were on track to capture. Five years of “we’ll watch it” is not a neutral choice. It’s a third of the available risk reduction, walked away from.

Caption: Five years of “we’ll watch it” is not neutral. Lowering LDL at 30 instead of 35 avoids roughly 225 mg-years of exposure by age 45. Illustrative exposure math, not a treatment recommendation or individual risk prediction.

These numbers are illustrative, not prescriptive. Real lifetime LDL doesn’t sit flat at any value. But the direction is right, the magnitudes are plausible, and the lesson is this: the timeline of your LDL isn’t the backdrop to your cardiac risk. It’s the main character.

One more honest point, because it’s the obvious objection and it’s a fair one. None of this is an argument that zero is the goal. The math here is a comparison between trajectories, not a tally counted down from some perfect number. This is also where LDL and blood pressure part ways. Blood pressure has a real floor: drop a systolic much below 90 and I’m helping run a code in the ER, which is exactly why, when I put borderline blood pressure through this same math, I measured exposure above a sensible reference instead of down to zero. LDL has no such floor that anyone has found in the range a human body can reach. People who inherit lifelong-low LDL don’t do worse; they have dramatically less heart disease, on the order of an 88% lower risk in one classic study of a natural gene variant that lowers LDL from birth. So lower really does look better, much further down than most people assume. What we genuinely don’t know yet is whether aggressively medicating an otherwise-healthy, low-risk person from the low 70s down into the 40s is worth the drug, the cost, and the decades on it. That marginal call at the bottom of the range is unsettled. “Zero” was never the point, and neither is putting every thirty-year-old on a pill. The point is the trajectory, and how early you bend it.

The 35-year window

Most cardiology screening tools, the old ASCVD risk score, the Framingham equation, QRISK, were built for people in their fifties. They estimate ten-year event risk, and a thirty-five-year-old’s ten-year risk is dominated by age, so it almost always comes back low. But the next thirty years, the stretch where the most damage compounds, are nowhere on that score’s clock.

Caption: The wrong clock. The 10-year score sees only the flat early window and calls it low; most of the damage compounds across the next thirty years. The 2026 dyslipidemia guideline now adds a 30-year horizon, but the exam-room conversation hasn’t caught up. Illustrative, not individual risk prediction.

The right question for a thirty-five-year-old isn’t “what’s my ten-year risk?” It’s “what’s my thirty-year exposure trajectory, and what’s the payoff of acting now versus in fifteen years?” This is the leverage window. It’s also the window where most people with borderline numbers do nothing, because the screening tools tell them they don’t have to.

The guidelines are moving toward the clock. The exam room hasn’t caught up.

Here’s the encouraging part, and the reason this post isn’t an attack on cardiology. In March 2026, the ACC, the AHA, and nine other societies released the first full rewrite of the US cholesterol guideline since 2018. It swaps the old risk equation for a newer calculator called PREVENT, and for the first time it explicitly endorses estimating 30-year risk alongside the 10-year number. It recommends measuring ApoB, and it says Lp(a) should be measured at least once in adulthood.

But two honest caveats keep this from being a victory lap. First, even the 2026 guideline stops short of treating cumulative exposure, the mg-years running total, as a formal metric you track over time. It moved the horizon out to thirty years; it didn’t adopt the odometer. Second, a guideline update does not change the exam-room conversation. A thirty-five-year-old can still walk in, hear “borderline,” and leave thinking the number is basically fine. The guideline is the manual. The conversation is what the patient actually lives, and the conversation lags the manual by years.

What I changed

This is what I do now, offered as my read of the evidence and my own situation, not a prescription for yours.

I stopped asking whether my LDL was “borderline.” It’s the wrong question. I ask what my ApoB and my LDL trajectory look like over time, and I had my Lp(a) measured once so I’d know the card I was dealt.

I stopped treating a clean glucose panel, low hsCRP, decent triglycerides, and a hard training habit as proof that my LDL exposure didn’t count. That was the exact bargain that let me ignore the number for two decades. Metabolic health is real and worth having. It is not a shield against the arithmetic.

And I stopped thinking about lipids as a this-year decision. They’re a time decision. The earlier you bend the slope, the less your arteries have to carry for the rest of your life, and the years you give back to inaction are the ones you can’t buy back later.

The conversation I wish I’d had at thirty

If I could hand my thirty-year-old self one thing, it wouldn’t be a prescription. It would be a better question to bring into the room. The system rewards the patient who walks in with the full picture and asks for what it actually warrants, the same lesson I learned fighting to get the right cardiac scan.

“I understand my 10-year risk is probably low. What I want to understand is my lifetime exposure. Can we look at my LDL-C trend, my ApoB, a one-time Lp(a), my blood pressure trend, and my family history together, and talk honestly about whether my current trajectory is acceptable over the next twenty or thirty years?”

That question moves the visit from “is the number high enough today” to “is the trajectory acceptable over time,” and it forces even a physician who’s never thought in mg-years to engage you on the curve instead of the dot. If your borderline number has been borderline for ten years already, that’s not “monitor and recheck.” That’s data. Bring the time series, not just the most recent point.

The Calibrated Claim Audit

The Final Signal

• What this gets right. A single LDL in the 130s or 140s rarely looks dramatic on a lab report, and the 10-year math agrees. Both are reading the wrong window.

• What gets oversold. That a clean metabolic panel, a good diet, or a training habit buys you out of cumulative lipid exposure. It doesn’t. The arithmetic runs underneath all of it.

• What I changed. I track ApoB and my LDL trajectory instead of a single “borderline” snapshot, measured my Lp(a) once, and started treating lipids as a time decision.

• What the system is doing. The 2026 guideline is moving toward the clock. The exam-room conversation is still years behind it. Don’t wait for it to start the conversation for you.

• What this opens next. LDL is one input. Next, the other “borderline” number I underestimated: blood pressure, through the same exposure math. The exposure math explains more of my own timeline than I wanted it to. It doesn’t explain all of it, and that gap is where the next few posts go.

More to come next week.

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X / LinkedIn

Not medical advice.

References

1. Ference BA, et al. Effect of long-term exposure to lower LDL cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012;60(25):2631-2639. PMID 23083789. Finding: across 312,321 people, each 1 mmol/L of genetically lower lifelong LDL was tied to a 54.5% lower CHD risk, ~3x the benefit of a midlife statin. The gap reflects duration, not the drug.

2. Domanski MJ, et al. Time Course of LDL Cholesterol Exposure and Cardiovascular Disease Event Risk. J Am Coll Cardiol. 2020;76(13):1507-1516. PMID 32972526. Finding: in 4,958 adults, cumulative LDL exposure predicted later events, and the same exposure carried more risk when accumulated earlier in life.

3. Myerburg RJ, Junttila MJ. Sudden cardiac death caused by coronary heart disease. Circulation. 2012;125(8):1043-1052. PMID 22371442. Finding: a review of sudden cardiac death from coronary disease, including that sudden death can be the first sign in people with no prior symptoms.

4. 2026 ACC/AHA Guideline on the Management of Dyslipidemia. Circulation. 2026;153(17):e1154-e1276. PMID 41824552. Finding: replaces the 2018 guideline; adopts PREVENT 10- and 30-year risk, ApoB, a one-time Lp(a), and earlier treatment in younger adults.

5. Borén J, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights (EAS consensus). Eur Heart J. 2020;41(24):2313-2330. PMID 32052833. Finding: LDL is causal; retention in the artery wall initiates plaque, with inflammation arising as a response to the retained particles.

6. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995;15(5):551-561. PMID 7749869. Finding: introduced the response-to-retention model: retention of ApoB lipoproteins is necessary and sufficient to start atherosclerosis in an otherwise-normal artery.

7. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681. PMID 21067804. Finding: each 1 mmol/L LDL reduction cut major vascular events by about a fifth, with no threshold down to the lowest levels studied.

8. Navar-Boggan AM, et al. Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation. 2015;131(5):451-458. PMID 25623155. Finding: longer cumulative exposure to elevated cholesterol in young adulthood predicted higher later CHD risk, dose-dependently.

9. Cohen JC, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272. PMID 16554528. Finding: a natural PCSK9 variant lowering LDL from birth was associated with up to an 88% lower risk of coronary heart disease.

For fifteen years, my job was to make people feel certain about their health.

I ran wellness companies. We came close to going public, appeared on Shark Tank, and collected the business awards. And the part I was actually good at was not the ingredient in the bottle. It was the story: taking a messy pile of biology and handing you one confident takeaway you could act on by Friday. Certainty sells. Nuance does not.

Following this my career took a detour back to graduate school and I spent years at the lab bench doing cancer research, and today I run codes as an emergency nurse at Mayo Clinic while obtaining my APRN license from Duke. So when I tell you I got fooled by a health story, understand that I am not a bystander. I am the guy who manufactured the exact thing that fooled me.

Here is the number that still bothers me. It is not the 80 that was the percent my right coronary artery was blocked. It is the 0.45.

That 0.45 was my hsCRP, a blood marker of inflammation. Textbook low. My long-term blood sugar sat in the low fives. My continuous glucose monitor stayed flat. No insulin resistance. Lp(a), the inherited particle most people are never tested for, was not a problem. Lean. Thirty years of consistent exercise since I was about 14 years old. By every marker the low-carb, metabolic optimization, world calls safe, I was the safe candidate.

Then a CT angiogram found an 80% blockage in my right coronary artery. At 44. Eight years prior? 100% patent arteries. Zero calcified or non-calcified plaque. How the hell did this happen to me - an odd mix of denial and anger flooded my veins for a long while after finding out.

I have spent a year understanding how all of those things were true, and the answer is not really about cholesterol or carbs. I had mistaken a claim for a diagnosis. A diagnosis looks at the actual thing. It images the artery, counts the particles, reads the pressure. A claim does something quieter: it takes a few numbers that are genuinely reassuring and makes a leap, that because these are clean, the thing nobody looked at must be clean too. A normal panel is real information about a narrow question, dressed up as the answer to a much bigger one.

A good story does not lie to you. It just goes quiet at the right moments.

The numbers never lied to me. They went silent. So instead of retelling my whole story, let me hand you the thing I wish someone had handed me a decade ago: the questions a clean panel does not answer. Bring them along with your own labs, and to your clinician at your next visit. Each is a real gap, not a scare tactic, and I will tell you where the science is solid and where it honestly is not.

Question one: am I counting cholesterol, or counting particles?

Your standard panel reports LDL-C, the mass of cholesterol your particles carry. What actually lodges in an artery wall is the particles themselves, and each one carries a single tag called ApoB. So ApoB counts the particles; LDL-C weighs their cargo. Usually the two agree. When they disagree, risk follows the particle count, not the cargo (the mechanism is laid out in a 2022 physiological review). You can be the "healthy" patient waved through on a normal panel while running a particle count that belongs in a different conversation. Ask whether your ApoB has ever been measured. Mine had not. Not until after the stent. It is cheap and widely available, and it is the one number I would want most.

Question two: does my inflammation marker actually see my arteries?

hsCRP measures inflammation across your whole bloodstream. It is genuinely useful. It is also not a camera pointed at your artery wall, where the inflammation that drives plaque lives locally and can stay quiet in the blood. My 0.45 measured the system. It did not measure the place the damage was happening. The honest framing is not "my CRP was wrong." It is "my CRP answered a question I was not actually asking." There is no perfect consumer test for arterial-wall inflammation yet, which is exactly why a low systemic number should reassure you about systemic inflammation, and nothing more.

Question three: is my blood pressure optimal, or just not bad enough to treat?

A reading in the low 130s over the mid-80s is the kind most clinicians glance at and move past. It is not a disease. It is also not ideal. Borderline pressure works on the thin living lining of your arteries every single day, quietly and cumulatively, and "not medication territory" is a treatment threshold, not a verdict that your vessels are fine. There is a real difference between "not horrible" and "fine." Ask where your number sits relative to optimal, not just relative to the line where the pills start.

Question four: have I filed something as cosmetic that my arteries would call inflammatory?

A number of chronic conditions share inflammatory machinery with heart disease and can quietly speed up plaque, including the mild versions people ignore for years as "just a skin thing" or "just a joint thing." I carried one of those most of my adult life, filed under cosmetic. I never had a category that said this might be talking to my coronaries, and no one ever offered me one. I am still working through that piece of my own story, so I will not overstate the size of the effect. But the question is free to ask: is anything I have dismissed as minor actually a low-grade inflammatory condition? (There is a fifth I will only gesture at, because it is the frontier and not settled screening: the inherited genetics of how your arteries handle daily stress. Mine, I learned this year, are not generic. Most people have simply never looked.)

Notice what every one of these shares. The clean result was real. It was just answering a narrower question than I thought it was. That is the trap, and it is a quiet one.

There is hard science under the part the story waves away, and it comes down to one idea: duration is the dose. Cholesterol does not damage an artery in a snapshot. It does it over years. A 2015 study in Circulation followed young adults carrying moderately high cholesterol and found their mid-life heart risk climbed with how long they had carried it, even at levels too low to trigger a statin. A 2012 genetics analysis found that people born with naturally lower cholesterol got roughly three times the protection, for the same drop in the number, as someone who lowers it with a drug in middle age. Same magnitude. The difference was the years. I probably carried an LDL between 130 and 160 for fifteen years, told the whole time that it did not count. The story was describing today. It said nothing about the more than five thousand days of particles already in the wall.

This is what makes me uneasy about where smart-health is heading next, including the trendy biological-age clocks. I take that science seriously; my own bench work read a related layer of that same machinery. But I will flag this plainly as my own read, not a study finding: those clocks track the same clean inputs that were already green on my panel. A lean, well-trained person scores young. So the most sophisticated test we have would have done exactly what my 0.45 did. It would have handed me one more reassuring number while a soft plaque built in an artery it never looks at.

No single clean number is a camera pointed at the thing that kills you.

I had the bench, the boardroom, and the bedside. I read the primary papers. I had access most patients never get. And I still mistook a confident story for a diagnosis. So if you take one thing from my expensive mistake, let it be this. The next time a clean result makes you feel safe, sit with the question it is actually answering, and then ask what it is staying silent about. That instinct, more than any diet, is the thing I wish I had ten years ago.

That was the story, the version I would tell you over coffee. The full investigation lives at calibratedsignal.com, free, no paywall and no sponsors, because that is the whole model. Over there you get every study and every citation behind these numbers, the full Calibrated Claim Audit graded line by line (Substack drops tables, so it can only live there), and the complete deep dive narrated in my own voice, about sixteen minutes of it.

But the question that actually matters is not what happened to me. It is where you stand. So I turned the exact blind spots that nearly cost me my life into a free, three-minute heart-risk check. It asks the things a routine visit usually skips, and it is the most useful first step I can hand you.

Take it here: calibratedsignal.com/heart-risk-quiz

Next time, I stay on the one crack I had the most control over and the most false confidence about, and I do the plain math on it: what "borderline" cholesterol actually costs you across twenty years, not one annual physical. If you want the full receipts for today's story now, they are here.

Hard science. Honest signal. No sponsors.

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X / @nickhansonrn · LinkedIn

I want to tell you the version of this story I would tell you over coffee, not the one with all the footnotes.

For most of my adult life, I was probably the most measured person you knew. Thirty years of training behind me. A garage full of recovery gear. A ring and a watch tracking my sleep, my heart rate, my recovery. A sensor in my arm reading my blood sugar in real time. Filtered water, filtered air, food driven in from a farm. I read the actual research papers, not the summaries, because that is what I was trained to do. I work at Mayo Clinic and I have a graduate background in the molecular biology of disease.

I was not winging my health. I was auditing it.

And at 44, while merging onto the interstate, I got a notification that said there was a severe, flow-limiting blockage in my right coronary artery. A few blood cells at a time were getting through. I was one bad day from a heart attack.

Here is the part that took me months to see, and it is the reason I am writing this.

All of that data told me how my body was performing today. My sleep score. My glucose curve. My resting heart rate. My inflammation markers, which were rock bottom. Every one of those was useful, and every one of those read fine. But not a single one of them was measuring the thing that actually almost killed me: what was happening inside the wall of my artery.

That sounds obvious now. It did not feel obvious then. I had quietly collapsed a stack of different questions into one reassuring answer. Metabolic health is one question. Vascular health is a completely different one. Being fit is another. Your blood pressure carried over twenty years is another. Looking good in the mirror told me nothing about the lining of my blood vessels, and a clean glucose curve did not prove my arteries were safe.

I had mistaken a pile of reassuring signals for a complete picture.

The math still does not fully add up. I had a pristine artery scan at 36. Zero plaque, not a speck. Eight years later, an 80 percent blockage. None of my numbers, alone or together, should produce that.

And I had every advantage chasing it down. The training, the access to world-class specialists, the language to push back in a doctor’s office. It still took me a year to even start getting close.

So I think about the person who has none of that. The 42-year-old who works out, eats what he believes is right, gets told his numbers are fine, and never gets the one scan that would have shown the truth. That person is who this is for.

The biggest thing that changed for me was not a supplement, a test, or a new training plan. It was the question. I stopped asking, “Am I doing more than the average person?” and started asking, “What important thing am I still not measuring?”

That was the version I would tell you over coffee. The full account is at calibratedsignal.com, free, no paywall and no sponsors: the complete story, the whole investigation in order, and the entire thing narrated in my own voice if you would rather listen than read.

But here is the question that actually matters: where do you stand? I took the exact blind spots that nearly cost me my life and turned them into a free, three-minute heart-risk check. It is the best first step I can hand you.

Take it here:

The next article is the crack in my protocol that I trusted the most: the diet I was convinced was protecting me.

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X / @nickhansonrn · LinkedIn

My cardiologist had every reason to say no.

I had already been through the full workup. 12-lead ECG. Echocardiogram. Holter monitor. Nuclear stress test. All normal. All clean. A coronary CT angiography, or CCTA, a scan that produces detailed images of the arteries feeding your heart, just eight years earlier had come back pristine. Zero atherosclerosis. Not a speck. I was 44, with no diabetes, no hypertension, no smoking history. My high-sensitivity C-reactive protein, the standard blood marker for systemic inflammation, was 0.45. That is rock bottom. By the usual checklist in front of him, I looked low risk.

To be fair, he was not ignoring obvious heart disease. I had a clean coronary scan only eight years earlier. My mid-back and chest-wall symptoms had another plausible explanation: cervical disc degeneration from decades of heavy lifting, sports, and spinal wear-and-tear, possibly amplified by the hypervigilance that comes with knowing too much. My Holter did show PVCs (premature ventricular contractions, the occasional out-of-sequence beat), but the burden was very low and benign, which could explain a palpitation-type feeling without pointing to dangerous rhythm disease. From his side of the table, there were reasonable non-coronary explanations for what I was feeling.

That is what makes this story matter. The standard explanations were not stupid. They were just incomplete. Something still was not right, and I knew it. My workouts had lost their pep. I was getting tired sooner than normal. Small things that add up but do not show up on an ECG.

I asked for the CCTA again. He hesitated. I kept asking. He agreed.

That scan found the thing every other test missed: an 80% blockage in my right coronary artery.

In the previous post I walked through the standard testing problem: useful tests can still leave the coronary anatomy question unanswered. This post is about what happened next, and about the question I could not stop asking afterward: how did I go from zero disease to an 80% blockage in eight years, with none of the usual explanations?

The fight was not against my cardiologist. It was against the false comfort of being statistically unlikely.

And the harder question underneath it: if the system almost missed someone like me, how many people is it actually missing?

Vocabulary that matters

• CCTA (CT coronary angiography): a CT scan with contrast dye that images the coronary arteries directly, showing plaque and narrowing.

• Ischemia vs. anatomy: ischemia testing asks whether the heart muscle is starved for blood right now; anatomy testing asks what the artery actually looks like. Different questions.

• hsCRP: a blood test for systemic (whole-body) inflammation. Low is generally good, but it reads your blood, not your artery wall.

• SMuRF-less: shorthand for a patient with none of the Standard Modifiable Risk Factors (no diabetes, hypertension, high cholesterol, or smoking) who has a heart attack anyway.

• CHIP: clonal hematopoiesis of indeterminate potential, an age-related blood-cell mutation increasingly linked to atherosclerosis. More on this below.

Caption: Standard cardiac tests check function. CCTA checks anatomy. Both can come back “normal” on the same patient with severe coronary disease.

I’m the Patient the Literature Says Doesn’t Exist

Let me be honest about something uncomfortable: the medical literature was mostly on my cardiologist’s side.

A 2022 JACC state-of-the-art review on managing cardiovascular risk in young adults focused on the risk factors that predict early-onset disease: family history of premature events, severe hypercholesterolemia, chronic inflammatory conditions, smoking, diabetes.¹ I did not check those boxes. My LDL was mildly elevated, not severe. No family history. No diabetes. Clean prior imaging.

Young adults who have a heart attack with none of the standard modifiable risk factors are uncommon. When researchers queried five years of U.S. hospital admissions in the National Inpatient Sample, of 41,990 STEMI (the most severe, fully-blocked-artery heart attack) patients aged 18 to 45, about 8% were SMuRF-less: 3,495 people with no diabetes, hypertension, high cholesterol, or smoking history.² And here is the unsettling part: those patients had roughly 2.6 times the adjusted odds of dying in the hospital compared with patients who carried the traditional risk factors.² The system is not just slower to find these people. When it does find them, they are sicker than expected.

My cardiologist looked at a 44-year-old with no red flags and a clean CCTA from years earlier. In his position, most clinicians would have made the same call. The guidelines supported it. The statistics supported it. The prior imaging supported it.

The problem is that “statistically unlikely” is cold comfort when you are the outlier.

The Inflammation Problem Nobody Talks About

If you spend any time in the keto, carnivore, or low-carb world, you have heard the argument: mildly elevated LDL cholesterol does not matter as long as your inflammation markers are low and you are “metabolically healthy.” The idea is that it is not the cholesterol that does the damage, it is the inflammation. Keep your CRP low and your metabolism clean, and elevated LDL is harmless cargo floating through clean arteries.

I believed this for a long time. My hsCRP was 0.45 mg/L and my continuous glucose data showed excellent metabolic control. By any standard definition, I had no systemic inflammation. And I spent roughly a decade on a ketogenic diet without worrying much about my LDL creeping upward, because the influencers and podcasters I followed told me it was fine.

It was not fine.

Here is what that framework gets wrong, and it is not a small thing: hsCRP measures systemic inflammation, the overall inflammatory state of your blood. What it does not measure is what is happening inside the wall of your arteries.

Researchers at Lund University in Sweden tested this directly. They measured hsCRP in patients undergoing carotid endarterectomy, a surgery where plaque is physically removed from the artery, and compared those blood levels with the actual inflammatory activity inside the extracted plaque tissue. They found no meaningful correlation.³ Your blood marker for inflammation can read clean while the inside of your artery wall is active.

That does not make hsCRP useless. It means a low hsCRP cannot prove the artery wall is quiet. The inflammatory processes that drive atherosclerosis, things like interleukin-6 and other local cytokines, operate at the tissue level, right where the plaque is forming, not at concentrations high enough to reliably show up on a standard blood panel.

The Read
A low systemic inflammation marker tells you about your blood, not about the wall of your artery. “My CRP is low, so my LDL is safe” is measuring the wrong thing in the wrong place.

I am not saying keto caused my blockage. I am saying the framework the keto community uses to dismiss LDL risk rests on a measurement that does not measure what they think it does. I broke down the study they rely on most in an earlier post. And I am saying this as someone who followed that framework for years and paid for it.

Commercial distortion risk here is moderate: the “low CRP and metabolically healthy means high LDL is safe” message is amplified by a metabolic-health content ecosystem that sells the reassurance. That does not make any single study wrong. It changes how carefully I read the claim.

Why I Might Be an Outlier (And Why You Might Be One Too)

So if it was not the standard risk factors, what was it?

I do not have a definitive answer. Neither do some of the interventional cardiologists at Mayo who have looked at my case and scratched their heads. But there are emerging explanations worth paying attention to, and they are part of why this blog exists. I will go deep on each in its own post. Here they are as breadcrumbs.

Psoriasis. I have it. Mostly in remission for years, a few spots on my knees now and then, minor by any standard. Most people, including many physicians, think of psoriasis as a skin condition. It is not only that. It is a systemic inflammatory disease that shares biological machinery with atherosclerosis. A 2022 study in Nature Communications mapped genetic risk factors shared between psoriasis and coronary artery disease and found evidence of a causal link between the two, tied to systemic inflammation rather than coincidence.⁴ The same molecules that drive psoriatic skin lesions, IL-17 and TNF-alpha, have been shown to drive vascular inflammation and damage the inner lining of arteries in experimental models.⁵ Even when the skin looks calm, that machinery may not be. (More in a future post on the inflammation-biologic connection.)

CHIP. Clonal hematopoiesis of indeterminate potential. One of the most important emerging risk factors in cardiovascular medicine, and almost nobody outside academic cardiology is talking about it. CHIP happens when an acquired mutation in a blood stem cell lets one clone of white blood cells expand and take over a disproportionate share of your blood production. Those cells do not just sit there. A 2024 study in Nature Medicine provided longitudinal human evidence that CHIP can precede and promote new atherosclerosis, and that the relationship appears to run one way: CHIP drives the atherosclerosis, not the reverse.⁶ It is invisible to every standard cardiac workup and blood panel. I have not been tested yet. I am pushing for it, and none of my cardiologists have raised it, which tells you how new this is. (Its own deep dive is coming.)

Or maybe it was not slow at all. Every explanation so far assumes eight years of gradual buildup. But plaque does not only grow slowly. A plaque can rupture or erode, throw a clot that narrows the artery without fully closing it, and then heal over, organizing into a tighter and tighter stenosis. Repeated quiet episodes like that can drive stepwise jumps in blockage that a slow-growth model would never predict.⁷ And not every one of those events announces itself as a crushing-chest-pain heart attack. Unrecognized, silent heart attacks are more common than most people assume; in one cardiac-MRI study of older adults, the silent ones actually outnumbered the recognized ones and still carried real prognostic weight.⁸ I do not know yet whether something like that happened to me. It is one of the threads I am pulling.

Microvascular disease. The arteries you can see on a CCTA are the big pipes. Downstream of them is a network of vessels too small to image, and they can malfunction on their own. Coronary microvascular dysfunction is its own corner of cardiovascular disease, not the same thing as plaque in the large arteries, and it can produce real symptoms and real ischemia while the big vessels look clean.⁹ It matters to my case for two reasons: it is one more way to have normal large-artery tests and still have something genuinely wrong, and the specialized function testing for it is part of how I would try to separate a microvascular cause from the thrombotic story above. It is a test I am actively pushing for.

The point of the breadcrumbs is this: the list of things that can damage a coronary artery, or convincingly mimic that damage, is far longer than a lipid panel and a risk calculator. Some accelerate plaque. Some bypass the slow-growth story entirely. If you carry one that is not on the checklist, the standard system is not built to find you.

The Test That Answers the Anatomy Question

The evidence for CCTA early in the workup for suspected coronary disease is not ambiguous anymore.

The SCOT-HEART trial randomized 4,146 patients to standard care versus standard care plus CCTA. At five years, the CCTA group had a 41% relative reduction in coronary death or nonfatal heart attack: 2.3% versus 3.9%.¹⁰ The 10-year follow-up held: 6.6% versus 8.2% for coronary death or nonfatal myocardial infarction.¹¹ The benefit did not come from more procedures. It came from seeing plaque and acting on it. Think of it this way: telling someone their cholesterol numbers suggest they might develop heart disease someday is like telling them their house might flood. Showing them an actual image of plaque forming in their artery is like showing them water already in the basement. One is a statistic. The other is a reason to act. Doctors started preventive therapy earlier. Patients took it more seriously.

A meta-analysis confirmed the behavioral shift: patients whose imaging showed plaque were nearly three times more likely to start a statin and more than two and a half times more likely to start aspirin.¹² Seeing is believing. It should not have to be, but it is.

The Read
The value of the scan is not more stents. It is that no one acts on a risk they cannot see, and seeing the plaque makes it impossible to ignore.

The guideline bodies have moved. The 2021 AHA/ACC chest-pain guideline gives CCTA a Class I recommendation for symptomatic patients without known coronary disease.¹³ The evidence has been there for years; everyday practice is what lags.

PROMISE is the guardrail here. In a large trial of stable, low-to-intermediate-risk chest pain, an anatomy-first CCTA strategy did not beat functional testing on outcomes over short follow-up.¹⁴ So my argument is not “scan everyone.” My argument is narrower and, I think, more useful: anatomy and function are two different questions, and a workup that answered everything except the anatomy question is exactly how someone like me gets reassured right up until the scan that changes everything.

One more layer worth knowing about: AI analysis of the scan. A standard CCTA read tells you there is plaque and roughly how much. AI-powered quantitative analysis measures it precisely: the volume, the composition (soft versus calcified), and how it changes over time. In an international multicentre study, deep-learning analysis of CCTA quantified plaque and stenosis and predicted risk in line with expert readers.¹⁵ It is an added cost layer, and insurance coverage is only starting to catch up, but for someone trying to track whether disease is progressing or regressing over years, it can turn a single snapshot into a trend line. That is its own future post.

What I’d Actually Do

If you are having symptoms, even vague ones like exercise intolerance or atypical chest tightness, and your standard workup keeps coming back normal, ask about CCTA. Specifically, and as a question, not a demand.

Try something like this:

“I would like to discuss coronary CT angiography. I understand stress testing looks for ischemia, but CCTA looks at the coronary anatomy directly. Given my persistent symptoms and normal functional testing, I want to understand whether I fit the group where current chest-pain guidelines support CCTA, or why another test is a better first step in my case.”

That sentence tells your clinician you have done your homework and frames the visit as a discussion. If they decline, it is reasonable to ask that the request and the reason for declining go into your chart. That is not adversarial. It is good documentation, and clinicians sometimes reconsider when the question and the answer are both on the record.

CCTA is not cheap. It uses IV contrast and can run two thousand dollars or more out of pocket. But weigh that against the alternative: a cascade of stress tests, nuclear imaging, and follow-up visits that may still not answer the anatomy question a single CCTA would. If your insurer requires pre-authorization, ask the office to start it. The 2021 Class I recommendation is the starting point for that conversation.

And if you carry any of the off-checklist risk factors, psoriasis, another autoimmune condition, a family history that does not fit the calculators, or you just know something is off and no one can explain it, keep asking. The system is built for the average patient. If you are not average, you have to be the one who brings the sharper question into the room.

I had every advantage. I am an emergency department nurse at Mayo Clinic. I have a graduate background in bioinformatics. I can cite the guideline and speak the language that makes a cardiologist pause. And it still took all of that to get the test ordered. Most clinicians can follow the logic when the question is framed clearly. Sometimes they just need a patient who knows enough to ask it.

Caption: The four-step script for the cardiology visit. The 2021 ACC/AHA Class I recommendation is the starting point, not a demand.

The Final Signal

• What the standard tests get right: a normal ECG, echo, Holter, or stress test is real information about rhythm, structure, and blood flow under stress. It is just incomplete.

• What CCTA adds: it answers a different question, what the coronary arteries actually look like, that functional testing can miss.

• The fair read on my cardiologist: he was not irrational for hesitating. The system was working from probability, and I was the outlier. The adversary in this story is probability-based medicine when you do not fit the model, not the person across the desk.

• What does not prove safety: a low hsCRP and good glucose control tell you about your blood and your metabolism. They do not prove the wall of your artery is quiet.

• What is still open: I went from zero plaque to an 80% blockage in eight years with none of the usual explanations. Was it accelerated plaque from an off-checklist driver, a silent thrombotic event that never announced itself, or something the small vessels would explain? I do not know yet. When your symptoms and your workup disagree, the next move is not panic or self-diagnosis. It is a sharper question, and those are the threads I pick up next.

Next in the series: I Was Doing Almost Everything Right. It Wasn’t Enough. The biohacker resume, the cracks I did not see, and the question that started a year-long investigation.

Would you push for a CCTA if your cardiologist said you did not need one? Have you ever had a “normal” workup that did not match how you felt? I want to hear your story.

References

1. Stone NJ, Smith SC Jr, Orringer CE, et al. Managing Atherosclerotic Cardiovascular Risk in Young Adults: JACC State-of-the-Art Review. J Am Coll Cardiol. 2022;79(8):819-836. PMID: 35210038 [Finding: Lays out the risk factors that predict early heart disease in young adults: smoking, hypertension, familial hypercholesterolemia, diabetes, and premature family history. Nick checked almost none of these boxes.]

2. Shamaki GR, Safiriyu I, Antia A, et al. Prevalence, predictors, and in-hospital outcomes of ST-elevation myocardial infarction among young adults without traditional cardiovascular risk factors in the United States. Am Heart J Plus. 2024;43:100408. PMID: 38882592 [Finding: Of 41,990 young STEMI patients, about 8 percent had none of the standard risk factors, and those patients had 2.6 times the adjusted odds of dying in the hospital. The risk-factor-free heart attack is rarer but deadlier.]

3. Grufman H, Schiopu A, Edsfeldt A, et al. Plasma levels of high-sensitive C-reactive protein do not correlate with inflammatory activity in carotid atherosclerotic plaques. J Intern Med. 2014;275(2):127-133. PMID: 24010553 [Finding: In 160 surgically removed carotid plaques, blood hsCRP showed no association with the inflammation actually inside the plaque tissue. The core evidence that a clean systemic marker does not prove a quiet artery wall.]

4. Patrick MT, Stuart PE, Zhang H, et al. Shared genetic risk factors and causal association between psoriasis and coronary artery disease. Nat Commun. 2022;13(1):6565. PMID: 36323703 [Finding: Found genetic loci shared by psoriasis and coronary artery disease, confirming the two are biologically linked through inflammatory signaling rather than coincidence. The Mendelian-randomization arm pointed to coronary disease causally raising psoriasis risk (OR 1.11).]

5. Karbach S, Croxford AL, Oelze M, et al. Interleukin 17 drives vascular inflammation, endothelial dysfunction, and arterial hypertension in psoriasis-like skin disease. Arterioscler Thromb Vasc Biol. 2014;34(12):2658-2668. PMID: 25341795 [Finding: In mice engineered to overexpress IL-17 in the skin, the psoriasis-driving molecule triggered systemic vascular dysfunction and oxidative stress. Mechanistic support that skin inflammation can damage arteries far from the skin.]

6. Díez-Díez M, Ramos-Neble BL, de la Barrera J, et al. Unidirectional association of clonal hematopoiesis with atherosclerosis development. Nat Med. 2024;30(10):2857-2866. PMID: 39215150 [Finding: In a 6-year human study, CHIP mutations raised the risk of developing new atherosclerosis, while existing atherosclerosis did not expand the mutant cells. The relationship runs one way: CHIP drives the disease, not the reverse.]

7. Mann J, Davies MJ. Mechanisms of progression in native coronary artery disease: role of healed plaque disruption. Heart. 1999;82(3):265-268. PMID: 10455072 [Finding: Healed plaque ruptures were found in 73 percent of severely narrowed segments versus only 16 percent of mildly narrowed ones. Evidence that coronary disease can advance in silent, stepwise jumps rather than steady creep.]

8. Schelbert EB, Cao JJ, Sigurdsson S, et al. Prevalence and prognosis of unrecognized myocardial infarction determined by cardiac magnetic resonance in older adults. JAMA. 2012;308(9):890-896. PMID: 22948699 [Finding: Cardiac MRI found silent heart attacks in 17 percent of older adults, outnumbering the recognized ones at 9.7 percent, and they still carried higher mortality. Silent infarcts are common and under-treated.]

9. Del Buono MG, Montone RA, Camilli M, et al. Coronary Microvascular Dysfunction Across the Spectrum of Cardiovascular Diseases: JACC State-of-the-Art Review. J Am Coll Cardiol. 2021;78(13):1352-1371. PMID: 34556322 [Finding: Reviews how disease in the heart’s smallest vessels can cause real ischemia and angina even when the large coronary arteries look normal on imaging. A distinct way to have something genuinely wrong with clean large-artery tests.]

10. SCOT-HEART Investigators, Newby DE, Adamson PD, et al. Coronary CT Angiography and 5-Year Risk of Myocardial Infarction. N Engl J Med. 2018;379(10):924-933. PMID: 30145934 [Finding: Adding CCTA to standard care cut 5-year coronary death or heart attack from 3.9 to 2.3 percent, a 41 percent relative reduction, without more invasive procedures. The benefit came from seeing plaque and starting prevention earlier.]

11. Williams MC, Wereski R, Tuck C, et al.; SCOT-HEART Investigators. Coronary CT angiography-guided management of patients with stable chest pain: 10-year outcomes from the SCOT-HEART randomised controlled trial in Scotland. Lancet. 2025;405(10475):329-337. PMID: 39863372 [Finding: At 10 years the CCTA-guided group still had fewer coronary deaths or heart attacks than standard care, 6.6 versus 8.2 percent. The early benefit held up long term.]

12. Gupta A, Lau E, Varshney R, et al. The Identification of Calcified Coronary Plaque Is Associated With Initiation and Continuation of Pharmacological and Lifestyle Preventive Therapies: A Systematic Review and Meta-Analysis. JACC Cardiovasc Imaging. 2017;10(8):833-842. PMID: 28797402 [Finding: Patients shown they had coronary calcium were far more likely to start preventive drugs: roughly 2.6 times the odds for aspirin and 2.9 for lipid-lowering therapy. Seeing the plaque changes behavior.]

13. Gulati M, Levy PD, Mukherjee D, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain. Circulation. 2021;144(22):e368-e454. PMID: 34709879 [Finding: The current US guideline endorses CCTA as a first-line option for symptomatic patients without known coronary disease, using shared decision-making. The official basis for asking about the scan.]

14. Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of Anatomical versus Functional Testing for Coronary Artery Disease (PROMISE). N Engl J Med. 2015;372(14):1291-1300. PMID: 25773919 [Finding: In 10,003 stable chest-pain patients, an anatomy-first CCTA strategy did not beat functional testing on outcomes (3.3 versus 3.0 percent). The guardrail against scanning everyone, which is why the case for CCTA here is narrow and symptom-specific.]

15. Lin A, Manral N, McElhinney P, et al. Deep learning-enabled coronary CT angiography for plaque and stenosis quantification and cardiac risk prediction: an international multicentre study. Lancet Digit Health. 2022;4(4):e256-e265. PMID: 35337643 [Finding: A deep-learning tool measured plaque and stenosis on CCTA in about 51 seconds with agreement close to expert readers and intravascular ultrasound, and the volume it measured predicted future heart attacks. AI can turn a scan into a precise, trackable number.]

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X / @nickhansonrn · LinkedIn (linkedin.com/in/nickhanson)

Not medical advice.

I run 12-lead ECGs on patients every shift in the ER at Mayo Clinic. Mine came back textbook. So did my echo. So did my Holter. Every standard test said my heart was fine. Then I pushed for one more scan, and it found an 80% blockage in my right coronary artery.

Here is what unsettles me most: I passed the entire standard cardiac workup with a severe, flow-limiting blockage sitting in my artery the whole time. And the test that finally caught it, a CT coronary angiogram (CCTA) that looks straight inside the heart’s arteries, is the one the major guidelines (ACC, AHA, ESC, and NICE) had already moved to as the first test for stable chest pain like mine. Not a stress test. Not an echo. I still had to push to get it. That fight is its own story, and it is next week’s post.

Last week I walked through the study the keto community relied on to claim that sky-high LDL doesn’t cause plaque, and how the follow-up data got retracted for uncorrectable methodological problems. That post was about the science I trusted. This one is about the tests I trusted.

Because here’s the thing that haunts me most about my own case: even after the diet question came into focus, every standard cardiac test told me I was fine. The science was wrong about LDL being benign. And the screening system was blind to the damage it caused.

The Clean Sweep

In the weeks before I was diagnosed with an 80% blockage of my right coronary artery, I ran through a cardiac workup at a major academic medical center. I didn’t just pass. I aced it.

My 12-lead ECG showed normal sinus rhythm. I run these all day in the ER. I know what a clean tracing looks like, and mine was textbook. My echocardiogram came back with normal wall motion, normal ejection fraction, no structural abnormalities. My Holter monitor tracked my heart rhythm for 48 hours and came back unremarkable outside of a very minimal burden of PVCs (premature ventricular contractions), which are sometimes felt as skipped beats, or contractions, and are usually harmless if only seen in small numbers. My Apple Watch and Oura Ring had never flagged a single abnormal reading. Resting heart rate in the low 50s. Labs to look for things like lipoprotein(a), a genetic risk factor for heart disease, were negative. So were other less-tested markers like homocysteine. My inflammation was fine, with a rock-bottom CRP. And as mentioned in other posts, no insulin resistance per hemoglobin A1c testing and my own experimentation with a continuous glucose monitor.

Every test said I was fine. Every metric pointed to a healthy heart in a healthy 44-year-old.

A few weeks later, I was pulling over on an interstate after reading a critical result on my phone: severe, flow-limiting occlusion of my right coronary artery. An 80% blockage. The interventional cardiologist told me only a few blood cells at a time were squeezing past it. I was one bad day away from a heart attack.

How does that happen? How does someone pass every standard cardiac test and still have severe coronary artery disease?

The answer isn’t complicated. It’s just uncomfortable: those tests weren’t designed to find what was killing me.

What These Tests Actually Do (and Don’t)

A 12-lead ECG records the electrical activity of your heart over about 10 seconds. It’s a snapshot. It can detect arrhythmias, signs of an active heart attack, and sometimes evidence of a prior one. I use it dozens of times per shift. What it cannot do is see plaque inside your coronary arteries.

If the heart muscle is getting adequate blood flow at rest, the tracing looks normal. An artery can be 80 percent blocked and still deliver enough blood at rest to keep the electrical pattern clean.

Mahmoodzadeh et al. compared resting ECG findings against coronary angiography (the gold standard, where they thread a catheter in and look directly at the arteries) and found an overall sensitivity of just 51.5%.¹ In plain terms, that means the ECG missed nearly half of all real coronary disease cases. For the right coronary artery, the one that was 80% blocked in mine, the detection rate was just 25.8%.¹

The test most people think of as “checking your heart” catches a right coronary blockage about one in four times.

An echocardiogram uses ultrasound to look at your heart’s structure and function: chamber sizes, valve function, how the muscle is contracting. It’s the gold standard for structural heart disease. It is not a coronary artery test.

A resting echo looks at whether the heart muscle is moving properly. But if the coronary arteries are slowly narrowing and the muscle hasn’t yet been starved enough to sustain visible damage, the walls look fine. The ejection fraction (the percentage of blood the heart pumps out with each beat) looks fine. Everything looks fine. The echo can’t see the disease until the disease has already done serious damage.

My echo was pristine because my heart muscle was still being perfused, barely. The RCA was 80% blocked, but the remaining 20% was enough to keep the muscle alive and contracting normally at rest. The echo looked at the muscle and said “all good.” It never looked at the artery.

A Holter monitor records your heart rhythm continuously over 24 to 48 hours. It’s built to catch arrhythmias and rhythm abnormalities that might not show up on a 10-second ECG. It can also pick up signs of ischemia (when the heart muscle isn’t getting enough blood), but only if that ischemia happens to occur during the monitoring window.² Mine was unremarkable because during those 48 hours, my blockage wasn’t causing enough oxygen deprivation to trigger a detectable change. The disease was there. It just wasn’t declaring itself.

Caption: Each standard test answers a real question. None of them answers whether plaque is sitting inside a coronary artery.

Ischemia vs. Anatomy: The Blind Spot

This is the distinction that explains my case, and it’s the one most patients never hear.

All traditional cardiac testing (ECGs, echos, Holters, stress tests) is built around one question: Is the heart muscle getting enough blood right now? That’s called testing for ischemia. You stress the heart and look for signs that blood flow isn’t keeping up with demand.

But that’s not the same as asking: What do the arteries actually look like?

An 80% blockage can be compensated. The body can grow small detour vessels around the blockage, or the geometry of the narrowing might preserve enough flow. The stress test comes back normal. The plaque is still there.

Caption: Function tests ask whether the heart is struggling right now. Only anatomy tests show what the arteries actually look like. I passed the first question. I had not answered the second.

The resting-ECG numbers are bad enough. But even exercise stress testing (where you’re on a treadmill pushing your heart rate up) doesn’t close the gap. A 2012 systematic review of 34 studies by Banerjee et al. found that exercise testing is better at ruling coronary disease out than ruling it in, and that for a standard treadmill ECG, a normal result only modestly lowers the odds that real disease is there.³ A clean stress test can still sit on top of significant plaque. For the condition that kills more people than anything else on the planet, that should bother all of us.

And none of these tests can tell you anything about what kind of plaque you have, whether it’s calcified and stable, or soft and vulnerable to rupture. They detect the downstream consequence (ischemia) rather than the upstream cause (atherosclerosis). The entire traditional workup asks whether the heart is struggling right now. It never asks whether the arteries are diseased.

The Scale of What We’re Missing

Here’s where this stops being about my case and starts being about yours.

The PESA study imaged 4,184 asymptomatic adults aged 40 to 54 with no history of cardiovascular disease. These were bank employees in Madrid, middle-aged, apparently healthy people living normal lives.⁴

Sixty-three percent of them already had subclinical atherosclerosis, silent plaque building somewhere in their arteries. To be precise about what that means: PESA looked across several arterial beds, the carotids, the abdominal aorta, the leg arteries, and the coronaries, not the coronary arteries alone. The point isn’t that 63% had a hidden coronary blockage. It’s that by midlife, silent arterial disease was already the norm rather than the exception, in people a standard workup would have waved straight through. Among the men it was 71%, and even among the participants flagged as low 10-year risk by standard calculators, 58% already had disease.⁴

Patel et al. examined 398,978 patients without known coronary artery disease who were referred for elective coronary angiography, the invasive test where they thread a catheter in to look directly.⁵ Only 37.6% turned out to have obstructive disease. That doesn’t mean every prior test failed. It means the old pathway was a blunt instrument for deciding whose arteries were actually worth looking at directly.

Caption: Two cohorts, one lesson: symptoms and functional tests are imperfect proxies for what is actually in the artery. (PESA, PMID 25882487; Patel, PMID 20220183.)

What Actually Looks at the Arteries

There are two tests that look directly at your coronary arteries for plaque.

Coronary artery calcium (CAC) scoring uses a non-contrast CT scan to quantify calcified (hardened) plaque in the coronary arteries. It’s fast, relatively cheap, and low radiation. A score of zero is associated with very low short-term cardiovascular risk.⁶

But a zero doesn’t mean your arteries are clean. Osborne-Grinter et al. analyzed data from the SCOT-HEART trial and found that among patients with a calcium score of zero, 14% still had non-obstructive disease and 2% had obstructive disease on CT angiography.⁷ Sama et al. confirmed in a 2024 meta-analysis that approximately 10% of asymptomatic patients with zero calcium scores have non-calcified plaque.⁸ The calcium score only sees hard plaque. It misses the soft plaque, the kind that can rupture. My own case makes the point: the majority of my RCA occlusion was not calcified. A calcium score alone might have missed it.

CT coronary angiography (CCTA) uses contrast dye and a CT scanner to create detailed images of the coronary arteries. It can see both calcified and non-calcified plaque, measure how much narrowing there is, and flag features that suggest higher-risk plaque. It is not a microscope, and it can’t tell you everything about a plaque’s biology, but compared with a calcium score it shows the artery itself: the narrowing, the calcified plaque, and the soft plaque a calcium scan can’t see. In patients evaluated for suspected coronary disease, the ACCURACY trial demonstrated 95% sensitivity and a 99% negative predictive value, meaning if the CCTA says your arteries are clean, they’re almost certainly clean.⁹

The outcomes data is now hard to argue with. The SCOT-HEART trial followed 4,146 patients for 10 years and found the group who got a CCTA had fewer non-fatal heart attacks: 4.3% versus 6.0%.¹⁰ The benefit didn’t come from more procedures. Revascularization rates were essentially identical, 15.2% versus 15.3%. The more plausible read is that when doctors could actually see the plaque, they acted on it: starting statins, escalating prevention, and patients took it more seriously. Preventive-therapy prescribing stayed higher in the CCTA group years later. Seeing the disease changed what people did about it. That’s a 10-year reduction in heart attacks that traces not to more stents, but to better information.

Caption: SCOT-HEART, 10-year outcomes. Seeing plaque on CCTA led to more prevention and fewer non-fatal heart attacks, not more stents. (PMID 39863372.)

A caveat, because the honest-broker version matters here: this is not an argument that everyone with chest discomfort needs a CT scan. When the question is “is my heart struggling under stress right now?”, a functional test can answer it, and the PROMISE trial found that for stable, low-to-intermediate-risk chest pain, an anatomy-first CCTA strategy did not produce better outcomes than functional testing.¹¹ The DISCHARGE trial found that for stable chest pain at intermediate risk, CT and invasive angiography led to similar rates of major cardiac events, with fewer procedure-related complications in the CT group.¹² The point isn’t that CCTA wins every time. It’s that anatomy and function are different questions, and a workup that answered everything except the anatomy question is exactly how someone like me gets reassured right up until the scan that changes everything.

The Guideline-Practice Gap

Here’s where I get angry. Not at my cardiologist. At the system.

In 2021, the ACC and AHA published updated chest pain guidelines that gave CCTA a Class 1 recommendation, the strongest category in medicine, the one reserved for situations where the benefit clearly outweighs the risk and the evidence is strong, as a first-line test for symptomatic patients at intermediate-to-high risk without known coronary artery disease.¹³ That was me: middle-aged, with symptoms, no prior cardiac history. In 2024, the European Society of Cardiology reached the same conclusion.¹⁴ The UK figured this out even earlier: NICE recommended CCTA as the first-line test for new, suspected cardiac chest pain back in 2016.¹⁵

So by the time I sat in a cardiology office, the major guideline societies had already pointed in the same direction: for a patient like me, the first look should be a CCTA. Not an EKG. Not an echo. Not a Holter. A CCTA.

I got an EKG, an echo, and a Holter first.

This is not about blaming individual doctors. My cardiologist is a skilled clinician, and the stepwise approach he used was the standard of care for decades. The problem is that the evidence moved, the guidelines moved, and everyday practice didn’t move with them. That happens in medicine more than any of us want to admit. And if it can happen at a major academic medical center, think about what’s happening in community cardiology practices and small rural towns without a cardiac CT scanner within 50 miles.

The barriers are real: reimbursement was low enough that CMS increased CCTA payment in 2025, there’s a widely reported shortage of physicians trained to read cardiac CT, and nuclear stress testing has massive installed infrastructure that institutions don’t abandon overnight. But none of those barriers change what the evidence says. And none of them should be invisible to the patient sitting in the exam room.

When the Symptoms Don’t Match the Textbook

The blind spots aren’t only in the machines. They’re in the assumptions about what a heart attack is supposed to look like. I’ve watched women come into the ER in the middle of a STEMI, an ST-elevation myocardial infarction, the kind where a coronary artery is usually fully blocked. AKA, a heart attack. And they walked in with none of the textbook signs. No crushing chest pain. Nothing radiating to the jaw or down the arm. No obvious shortness of breath. The complaint was that they felt dizzy. Or lightheaded. Or just wiped out and exhausted.

Here’s the part that should bother you, and it’s something I live every shift. When a patient reports chest pain, the response is fast and automatic: a 12-lead ECG within 10 minutes of walking through the door, because that tracing is how we catch a STEMI in progress. But if chest pain isn’t the complaint, that clock often never starts. No reported chest pain, no immediate ECG, and a heart attack that is actively happening can go unseen in the one room built to catch it.

This isn’t just my read from the floor. A registry analysis of more than a million heart attack patients found that 42% of women presented without chest pain, compared with 30.7% of men. And among the younger patients, the women who showed up without chest pain were more likely to die in the hospital than the men who showed up the same way.¹⁶ The pattern medicine is trained to recognize is the pattern that shows up more reliably in men.

None of this means every dizzy spell is a heart attack. It means “it doesn’t feel like the textbook” is not the same thing as “it isn’t my heart.”

What This Means For You

If you’re in your 30s, 40s, or 50s. If you’ve been told your cholesterol is “borderline” but not worth treating. If you’ve had vague chest symptoms that were chalked up to anxiety. If you’ve passed a standard cardiac workup and been told your heart looks great, consider what that workup actually tested.

A clean 12-lead means your heart’s electrical system is working. A clean echo means your heart muscle is contracting properly. A clean Holter means your rhythm was stable. None of those tests looked inside your coronary arteries for plaque.

If you have risk factors, things like elevated LDL, family history, or prior smoking, and you want to know whether plaque is forming, talk to your doctor about a coronary artery calcium score as a starting point. If there’s clinical suspicion or risk factors that warrant it, ask about a CCTA. And if your doctor suggests a stress test first, it’s worth asking: “The current ACC/AHA guidelines recommend CCTA as first-line for symptomatic patients without known CAD. Can we discuss whether that applies to me?”

You shouldn’t have to know that. But right now, you might need to.

I had every advantage: clinical vocabulary, ER experience, a cardiologist at Mayo Clinic. And it still took every ounce of that advantage to get the test that found my disease. But getting the test was only half the fight. The other half was getting my cardiologist to order it in the first place.

That’s next week’s post.

References

1. Mahmoodzadeh S, Moazenzadeh M, Rashidinejad H, Sheikhvatan M. Diagnostic performance of electrocardiography in the assessment of significant coronary artery disease and its anatomical size in comparison with coronary angiography. J Res Med Sci. 2011;16(6):750-755. PMID: 22091303 [Finding: Against angiography, a resting ECG had only 51.5 percent overall sensitivity for significant coronary disease, and just 25.8 percent for the right coronary artery. It misses roughly half of real disease.]

2. Stone PH. ST-segment analysis in ambulatory ECG (AECG or Holter) monitoring in patients with coronary artery disease: clinical significance and analytic techniques. Ann Noninvasive Electrocardiol. 2005;10(2):263-278. PMID: 15842439 [Finding: A review of how Holter ST-segment monitoring detects ischemia in coronary disease. Background support that a Holter only catches ischemia if it happens during the monitoring window.]

3. Banerjee A, Newman DR, Van den Bruel A, Heneghan C. Diagnostic accuracy of exercise stress testing for coronary artery disease: a systematic review and meta-analysis of prospective studies. Int J Clin Pract. 2012;66(5):477-492. PMID: 22512607 [Finding: Across 34 studies, exercise testing was better at ruling coronary disease out than ruling it in, and a treadmill ECG was the weakest modality (positive likelihood ratio only 3.57). A clean stress test does not clear the arteries.]

4. Fernández-Friera L, Peñalvo JL, Fernández-Ortiz A, et al. Prevalence, vascular distribution, and multiterritorial extent of subclinical atherosclerosis in a middle-aged cohort: The PESA (Progression of Early Subclinical Atherosclerosis) Study. Circulation. 2015;131(24):2104-2113. PMID: 25882487 [Finding: Among 4,184 asymptomatic adults aged 40 to 54, 63 percent already had subclinical atherosclerosis (71 percent of men), and 58 percent of those rated low-risk by standard calculators had disease. Silent plaque is the midlife norm, not the exception.]

5. Patel MR, Peterson ED, Dai D, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med. 2010;362(10):886-895. PMID: 20220183 [Finding: Of 398,978 patients without known disease sent for elective invasive angiography, only 37.6 percent had obstructive coronary disease. The old workup was a blunt instrument for deciding whose arteries to look at.]

6. Greenland P, Blaha MJ, Budoff MJ, Erbel R, Watson KE. Coronary calcium score and cardiovascular risk. J Am Coll Cardiol. 2018;72(4):434-447. PMID: 30025580 [Finding: A review establishing the calcium score as a reproducible way to gauge cardiovascular risk and guide preventive treatment. The basis for a zero score signaling very low short-term risk.]

7. Osborne-Grinter M, Kwiecinski J, Doris M, et al. Association of coronary artery calcium score with qualitatively and quantitatively assessed adverse plaque on coronary CT angiography in the SCOT-HEART trial. Eur Heart J Cardiovasc Imaging. 2022;23(9):1210-1221. PMID: 34529050 [Finding: In SCOT-HEART, patients with a calcium score of zero still had non-obstructive disease in 14 percent and obstructive disease in 2 percent on CT angiography. A zero does not mean clean arteries.]

8. Sama C, Abdelhaleem A, Velu D, et al. Non-calcified plaque in asymptomatic patients with zero coronary artery calcium score: a systematic review and meta-analysis. J Cardiovasc Comput Tomogr. 2024;18(1):43-49. PMID: 37821352 [Finding: Pooling 14 studies and 37,808 patients, about 10 percent of asymptomatic people with a zero calcium score still had non-calcified (soft) plaque. The calcium score is blind to the plaque most likely to rupture.]

9. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64-multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY trial. J Am Coll Cardiol. 2008;52(21):1724-1732. PMID: 19007693 [Finding: The ACCURACY trial found 64-slice CT angiography had 95 percent sensitivity and a 99 percent negative predictive value for obstructive stenosis. If a CCTA reads clean, the arteries almost certainly are.]

10. Williams MC, Wereski R, Tuck C, et al. (SCOT-HEART Investigators). Coronary CT angiography-guided management of patients with stable chest pain: 10-year outcomes from the SCOT-HEART randomised controlled trial in Scotland. Lancet. 2025;405(10475):329-337. DOI: 10.1016/S0140-6736(24)02679-5 PMID: 39863372 [Finding: Over 10 years in 4,146 patients, CCTA-guided care cut non-fatal heart attacks (4.3 vs 6.0 percent) with near-identical revascularization rates. The gain came from more prevention, not more stents.]

11. Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of Anatomical versus Functional Testing for Coronary Artery Disease (PROMISE). N Engl J Med. 2015;372(14):1291-1300. DOI: 10.1056/NEJMoa1415516 PMID: 25773919 [Finding: In 10,003 patients with stable chest pain, an anatomy-first CCTA strategy produced no better outcomes than functional testing (3.3 vs 3.0 percent). Anatomy and function answer different questions; neither always wins.]

12. Maurovich-Horvat P, Bosserdt M, Kofoed KF, et al. CT or Invasive Coronary Angiography in Stable Chest Pain (DISCHARGE). N Engl J Med. 2022;386(17):1591-1602. DOI: 10.1056/NEJMoa2200963 PMID: 35240010 [Finding: In stable chest pain at intermediate risk, CT and invasive angiography gave similar major-event rates (2.1 vs 3.0 percent), but CT caused far fewer procedure-related complications (0.5 vs 1.9 percent).]

13. Gulati M, Levy PD, Mukherjee D, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain. Circulation. 2021. DOI: 10.1161/CIR.0000000000001029 PMID: 34709879 [Finding: The guideline that gave CCTA a Class 1 recommendation, the strongest tier, for intermediate-to-high-risk patients with chest pain and no known coronary disease. The standard I met when I was sent for an EKG and echo instead.]

14. 2024 ESC Guidelines for the Management of Chronic Coronary Syndromes. European Heart Journal. 2024;45(36):3415. PMID: 39210710 [Finding: The 2024 European guideline reached the same conclusion as the ACC and AHA, positioning CCTA as a first-line test for diagnosing obstructive coronary disease in suspected chronic coronary syndrome.]

15. National Institute for Health and Care Excellence. Chest pain of recent onset: assessment and diagnosis. Clinical guideline CG95. Published 2010, updated 2016. Available at: https://www.nice.org.uk/guidance/cg95. [Finding: The UK recommended 64-slice (or above) CT coronary angiography as the first-line test for new suspected cardiac chest pain, years ahead of the US guidelines.]

16. Canto JG, Rogers WJ, Goldberg RJ, et al. Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA. 2012;307(8):813-822. DOI: 10.1001/jama.2012.199 PMID: 22357832 [Finding: Across more than a million heart attack patients, 42 percent of women presented without chest pain versus 30.7 percent of men, and younger women without chest pain died in hospital more often than their male counterparts.]

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X / @nickhansonrn · LinkedIn (linkedin.com/in/nickhanson)

Not medical advice.

I want to tell you about one sentence in someone else’s paper, and why it stopped me cold.

Eric Topol put a new study in front of the cardiology crowd this week, a Nature Metabolism paper out of Northwestern. I read it the way I read most things, hunting for the line everyone else skims past. I found it. And the line that grabbed me was not the headline finding. It was a quiet mention of a molecule I have known, from two completely separate lives, for more than 25 years.

A quick word on who’s talking, because it matters here. I’m currently an ER nurse at Mayo, in an APRN-FNP program with a cardiology focus at Duke, and a published researcher in epigenetics and oncology. Before any of that, I spent 15 years as a CEO in the supplement industry. I did not just sell the products, I helped formulate them. And the molecule mentioned in this metformin paper, citrulline, was the workhorse ingredient in nearly every pre-workout “pump” formula on the shelf. It is the thing that is supposed to make your veins stand up at the gym and get blood and nutrients where you want them. I knew it as a marketing line long before I understood the biology underneath it.

Then I crossed over. Years of reading the literature on the inner lining of your blood vessels (the endothelium) and a short-lived gas it makes called nitric oxide, the molecule that tells an artery to relax and open. Citrulline feeds that pathway. So when I hit that sentence, I was sitting on a strange little seam. I knew this molecule as the guy who sold it, and as the guy who now reads the vascular biology for a living. That does not happen often, and it is why this one landed the way it did.

Here is the science, in plain terms.

For years the longevity world has worried about metformin, the old diabetes drug a lot of healthy people now take off-label, and whether it quietly cancels the benefits of exercise. The fear has a clean logic. Metformin slows one of the energy steps inside your mitochondria, the tiny power plants in your cells. Exercise works partly by training those same power plants to get better. So the worry was that the drug poisons your muscle mitochondria and steals your gains. I held that worry myself.

This new paper makes the crude version look wrong. The authors show metformin does its blood-sugar work mostly in the lining of the gut, not in muscle. And they say it plainly: a direct hit on muscle mitochondria is unlikely, because almost none of the drug ever reaches your muscle in the first place. That genuinely lowered a concern I had carried for a while.

But the paper does not let the drug off the hook. It moves the question.

Because here is the citrulline part. Metformin appears to suppress citrulline, and citrulline is made almost entirely in your gut, exactly where the metformin concentrates. Less citrulline can mean less nitric oxide, and less nitric oxide can mean less blood flow to a working muscle. The authors raise this themselves. Maybe the drug blunts some of exercise’s benefit not by harming muscle, but through a chain that runs from the gut, to citrulline, to nitric oxide, to blood flow. They even point out, with what reads like a wink, that citrulline is the dominant ingredient in pre-workout supplements.

So the concern did not disappear. It moved upstream. From the muscle, to the gut and the blood vessels. And to me that is the better question, because it is a sharper and more testable one. The human exercise data, for what it is worth, is real but mixed. Metformin has blunted fitness gains, muscle growth, and blood-vessel adaptation in some trials, while one careful study that biopsied actual human muscle found nothing happening there and told everyone to go look at other tissues, naming the gut.

Here is where I step away from the people who wrote the paper, and I want to be honest about the direction of it. The authors call citrulline supplementation “a straightforward and scalable solution.” I will not go that far. Nobody has run the trial. Nobody has tested whether citrulline actually offsets this specific blunting, in the people taking this specific drug. So I hold it where the evidence sits, an interesting and untested hypothesis, not a protocol. Being more careful than the people who ran the study is not me being contrarian. It is the entire job.

I will tell you my own piece of it, because it is fair to. I use citrulline myself. Not because of this paper, and not because you should, but because I have nitric-oxide-pathway quirks written into my own genes and I watch my blood pressure closely enough to see what moves it. That is a personal experiment with a sample size of one, run by someone who reads the literature and had to get a stent placed in his heart at age 44 despite being metabolically fit and otherwise healthy. It is a disclosure, not a recommendation.

What gets me is where this points. A molecule I once sold as a vanity ingredient turns up, decades later, in a serious metabolism paper, sitting at the center of the blood-vessel biology my own heart already forced me to care about. That is the thread my cardiovascular series was walking toward anyway: the living lining of the artery, the nitric oxide it makes, and eventually the genetics underneath all of it. This paper just put a familiar face on it, a week early, with Topol’s hand on the door.

Here is the part I would leave you with, and it is not really about citrulline. A good paper rarely settles a question. The best ones relocate it to better ground. The skill worth practicing is not being right the first time. It is noticing, out loud and without flinching, when the ground has shifted under something you used to believe.

This is the short version. The full research note is at calibratedsignal.com: every paper, the complete evidence breakdown, and the narrated audio, all in one place. I run one of these evidence-first investigations every week. To get the next one the day
it lands, instead of whenever an algorithm decides to show it to you, put it in your own inbox.

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)Thanks for reading Calibrated Signal! Subscribe for free to receive new posts and support my work.

I help run codes in the emergency department.

I have done CPR on people whose hearts stopped before anyone understood what went wrong. I have felt ribs crack beneath my hands. I have packaged people up and rushed them to the cath lab when we could get a rhythm back, and I have watched families fall apart in the corner of the room when we couldn’t. That is where I work.

I am not a weekend warrior typing hot takes from a laptop. I am writing this on my lunch break from a job where I help keep people alive, because the science here matters to me, and because a year ago I found out I was far closer to being the patient on that table than I ever understood.

That is why I care about this study. Not because I dislike keto. Not because I want to win an argument online. I care because I believed a version of the story it was used to tell: that rising LDL was not a real concern as long as my metabolic markers were clean.

I had the clean markers. I had a clean coronary CT angiogram at 36. I had the reassuring podcasts and the confidence that came with them.

Eight years later, I had a severe, flow-limiting blockage in my right coronary artery.

So after my stent, I went back to the papers. Not the blog posts. Not the podcast clips. Not the threads from people who had never run a code or watched an artery win. The actual papers.

THE BOTTOM LINE

A 2024 study of 80 people on keto with extremely high LDL found no more total coronary plaque than matched controls. It was used everywhere to argue that high LDL is harmless if you are lean and metabolically healthy. The study could not actually support that claim. It was cross-sectional, it never reported the soft-plaque breakdown it had the technology to measure, and it could not test whether high ApoB matters because everyone in it already had high ApoB.

The 2025 follow-up did measure soft plaque over a year, and it grew. That follow-up was then retracted in 2026, at the request of the authors and the editors, after a methodological problem surfaced.

Here is what I am not saying: I am not saying keto is the villain, and I am not claiming one diet explains my own blockage. What I am saying is narrower and better supported. There is no good evidence that extreme LDL and ApoB elevations on a ketogenic diet are safe just because someone is lean, active, and metabolically healthy. The causal link between ApoB and atherosclerosis is one of the most established findings in cardiovascular medicine, and one underpowered study with a retracted follow-up does not move it.

Vocabulary that matters

A few terms show up throughout. Worth knowing before we go further.

• ApoB (apolipoprotein B): one ApoB molecule rides on each atherogenic particle, so ApoB is essentially a count of the cholesterol-carrying particles most able to lodge in an artery wall. Often a better risk marker than LDL-C.

• LMHR (lean mass hyper-responder): the phenotype at the center of this debate. Lean, active, metabolically healthy people whose LDL shoots up dramatically on a low-carb or ketogenic diet.

• Soft plaque (non-calcified plaque): the live, lipid-rich plaque that can rupture without warning. Measured here as non-calcified plaque volume (NCPV).

• PAV (percent atheroma volume): the share of the artery wall taken up by plaque. A summary number that can move differently than raw soft-plaque volume.

• CCTA (coronary CT angiography): the scan that can actually see plaque inside the artery wall and tell soft plaque apart from calcified plaque.

How I Got Here

I did not come to keto through influencer culture at first. I came through the back door, in 2017, while studying mitochondrial theories of cancer and the Warburg effect. It was a year after a completely clean coronary CT angiogram at 36, and the metabolic argument sounded genuinely compelling. Restrict glucose. Shift fuel use. Improve insulin sensitivity. Lower inflammation. It sounded mechanistic, not magical.

At the same time I was being pulled deeper into the biohacking world because of my background. I had spent 15 years as a CEO in the health and wellness industry. I knew the products, the claims, the conferences, the personalities, and the way a plausible mechanism can turn into a movement. The low-carb, ketogenic, and eventually carnivore-light message fit neatly into all of it.

So I needed to know whether the science I had built my diet around actually said what I thought it said. Because while I was trusting those conclusions, my right coronary artery was quietly closing. My hsCRP was 0.45, no sign of systemic inflammation. No insulin resistance by labs or a continuous glucose monitor. No Lp(a) issue. By every metric the keto and carnivore community uses to wave away an LDL of 160, I should have been the safe case.

I was not the safe case. I was one bad day away from a heart attack at 44.

The 2024 KETO Trial: What It Actually Showed

In August 2024, the KETO trial ¹ made waves. Eighty people on ketogenic diets with a mean LDL-C of 272 mg/dL, more than double the usual recommended level, showed no more total coronary plaque than matched controls with a mean LDL-C of 123. The keto community celebrated. Case closed. LDL does not matter.

Not so fast.

The study was cross-sectional. It compared two groups at one moment in time. It did not follow anyone for 10 or 20 years, it did not count heart attacks, and it did not prove that decades of high ApoB exposure are benign in lean, insulin-sensitive people. And most importantly for my story, it did not give readers the clean soft-plaque answer they thought it gave them.

Caption: What the claim needed the study to show, what the study actually measured, and the gap between them. The 2024 trial could not answer the question we all really wanted to know the answer to - which is: “is soft plaque growing in my artery”.

Why Soft Plaque Is the Whole Game

The 2024 study reported total plaque scores and coronary calcium. It did not give readers the full breakdown of the plaque phenotype, and that distinction matters more than almost anything else here.

Calcified plaque is usually older, more organized disease. It is not “good,” and it is not harmless. It is still evidence that atherosclerosis has been happening. But the plaque that scares me most as an ER nurse is the softer, non-calcified, lower-attenuation plaque that can build silently in the artery wall and rupture without warning. That is the plaque that turns a podcast debate into a family standing in the corner of a resuscitation room, and yes, it happens to people in their 40s and 50s, as I see in the emergency department and nearly experienced myself.

The 2024 trial had the imaging technology to look at it. CCTA can tell soft plaque apart from calcified plaque. But the primary analysis did not report the full soft-versus-calcified breakdown in the way readers needed, which is a notable omission for data they already had.

Caption: Soft, non-calcified plaque sits under a thin cap over a lipid-rich core and is more rupture-prone. Calcified plaque is generally more stable, though still a sign of disease. A total-plaque or calcium number can hide which kind you have.

That omission is not a cosmetic detail. In the SCOT-HEART analysis, low-attenuation non-calcified plaque on CCTA was the strongest predictor of fatal or nonfatal heart attack, outperforming standard risk scores and even challenging the primacy of stenosis severity alone. ¹⁰

This is the study I had in the back of my mind when my LDL hit 160 and I did not blink. It was also there when I felt gnawing chest tightness and mid-back discomfort that I wrote off as anxiety, disc issues, or years of heavy lifting. When my doctor suggested I consider a statin, I politely declined. In my mind, mild-to-moderate LDL elevation was acceptable, because every podcast I listened to told me that metabolically healthy people did not need to worry about LDL the way everyone else did.

That belief did not survive contact with my angiogram.

The Follow-Up That Flipped the Narrative

In 2025, the same research group published longitudinal data on 100 participants. ² This time they used AI-guided quantitative plaque analysis, and this time the soft plaque was measured directly. The signal was impossible to miss.

Non-calcified plaque volume increased by a median of 18.9 mm³ in a single year. In their published reply to criticism, the authors stated this represented a 42.8% relative increase. ⁴

In one year. In lean, metabolically healthy people. In the exact phenotype being described online as protected.

There was also a deeper design problem. There was no proper longitudinal control group receiving the same serial CCTA scans, so the study could not tell us how that progression compared with matched people who did not have keto-induced extreme LDL and ApoB elevations. Without that comparison, you cannot fully contextualize how alarming the progression is, because the study was not built to let you. That is not a footnote. That is a limitation that should have been front and center.

That soft plaque was building in my arteries at a rate I could not feel, could not catch with standard screening, and did not know to look for, because the study that should have raised the alarm was busy telling a different story.

Then It Got Retracted

Here is where most people sharing this research on social media have not caught up.

The 2025 paper was retracted in 2026. ³ Not corrected. Not amended. Retracted. And it is worth being precise about how that happened, because it is more interesting than the usual version. The retraction was made at the request of both the authors and the editors. After publication, a methodological problem with how the imaging had been analyzed came to light, and all parties agreed the errors were too great to fix with a correction. To their credit, the authors raised the concern and requested the retraction themselves.

That honesty is real, and I will give it full weight. But the practical reality stands: the paper that produced the headline “Plaque Predicts Plaque, ApoB Does Not” is now marked as unreliable by the journal, and it is still being shared as if it were not. The claim escaped into the bloodstream long before the retraction caught up to it.

The Attempted Rehabilitation

In January 2026, Budoff and colleagues posted a preprint on medRxiv, a reanalysis of the same cohort using different plaque-quantification methods. ⁵ This is the team returning to the same data with different analytical software.

I want to be precise about what this is. A medRxiv preprint is a manuscript posted publicly before peer review. It has not been vetted by independent reviewers, and it has not been accepted by a journal. It is a draft. And there is a deeper issue: going back to the same dataset with different tools after the original analysis was retracted is a post hoc reanalysis. It may eventually hold up, and it may not. But the bar for credibility here should be higher, not lower, and that bar is peer review, which this preprint has not cleared.

The “ApoB Doesn’t Predict Plaque” Problem

The 2025 study’s marquee claim, that ApoB does not predict plaque progression, is the one most likely to get someone in trouble. Here is what actually happened.

Soft plaque grew in nearly everyone in the study. Median non-calcified plaque volume went up 18.9 mm³. PAV went up 0.8%. The plaque increased. That part is not in dispute.

What the authors found is that within their cohort, the people with higher ApoB did not progress faster than those with lower ApoB. From that, they concluded ApoB does not drive plaque in this population.

The problem? Every single person in the study already had massively elevated ApoB. The median was 178 mg/dL, with an interquartile range of 149 to 214. For context, a desirable ApoB is generally put around 90 mg/dL or lower, and the ESC/EAS guidelines push the target down to 65 to 80 mg/dL for higher-risk patients. ⁹ So the “lower ApoB” group in this study was still running levels most lipidologists would flag as high risk.

Caption: Every participant was already deep in the high-ApoB zone, clustered roughly between 149 and 214 mg/dL, with no normal-ApoB comparison group. When everyone is already high, the study cannot detect whether high ApoB is dangerous.

This is a textbook restriction-of-range problem. If you took 100 people who all smoke two packs a day and tracked them for a year, you probably would not find a clean dose-response relationship between cigarettes and lung damage either. Not because cigarettes are safe, but because there is no meaningful variation in the exposure. Everyone is already deep in the danger zone.

To actually prove ApoB does not drive plaque, you would need a control group with normal ApoB getting the same scans over the same period. They do not have that. What they have is 100 people with uniformly high ApoB all progressing at roughly similar rates, which is exactly what you would expect if ApoB is causal and everyone is above the threshold that matters.

And this is not a fringe position. The causal relationship between ApoB-containing lipoproteins and atherosclerosis is one of the most established in cardiovascular medicine, confirmed by Mendelian randomization and decades of evidence across study designs. ⁶ A 2019 Mendelian randomization study of more than 654,000 participants found that coronary heart disease risk tracks ApoB particle number, not LDL-C or triglycerides independently. ⁷ And in September 2024, the National Lipid Association published an expert consensus confirming ApoB’s superiority over LDL-C for risk assessment. ⁸ When LDL-C and ApoB disagree, risk tracks with ApoB. That is the consensus of the field, not one person’s opinion.

There Is Also a Survivorship Problem

To be in this study, you had to be alive, still on keto, and willing to participate. Anyone who developed cardiovascular disease and stopped the diet was less likely to show up in the data. Anyone who died definitely did not.

I know what that looks like from the other side of it. I have helped run codes on people who never got the chance to become a follow-up data point. They are not sharing their n=1 online. They are not in the keto success stories. They are not in the cohort. Some of them are in the cemetery. That is what survivorship bias looks like when it stops being a statistics term.

One Transparency Note

It is also worth being transparent about who produced this work. At least one author is affiliated with an advocacy foundation in the low-carbohydrate space, and several of the authors are public proponents of the diet being studied, some with paid subscription platforms built around that message. That creates a potential financial conflict of interest.

To be clear, a conflict of interest does not prove bias, and it does not make the data wrong. Plenty of conflicted research holds up fine, and in this case the authors themselves requested the retraction once the problem came to light. A conflict is simply a transparency flag, and a reason to read the evidence with more care, not less, especially when a headline conclusion happens to line up with the authors’ public position.

The Calibrated Claim Audit

Two claims are really on trial in this post. Here is where each one stands.

ClaimMechanismEvidenceMy readHigh LDL/ApoB on keto is harmless if you are a lean “hyper-responder”Unestablished. No pathway explains why an ApoB particle would behave differently hereWeak. One cross-sectional study, a retracted follow-up, restriction of range, survivorship biasNot supported by the evidence that existsApoB-containing particles cause atherosclerosisVery strongVery strong. Mendelian randomization (654,000+), RCTs, imaging, NLA and ESC/EAS consensusHigh confidence

Commercial distortion risk: Moderate to high. The LMHR claim is advanced largely by advocates with affiliated foundations and, in some cases, paid platforms in the low-carb space. That does not make the claim wrong, but it changes how carefully I read the evidence.

Let Me Be Clear

I am not here to tell everyone to abandon ketogenic diets. Keto is a tool. It has legitimate evidence in epilepsy, it helps some people lose weight, and it may have specific uses in certain metabolic and neurologic contexts. Context matters.

But “context matters” is not the same thing as “LDL does not matter.”

The problem is not keto. The problem is using metabolic health as a permission slip to ignore ApoB. The problem is telling lean, active, insulin-sensitive people that an LDL of 160, 200, or 270 is background noise because their triglycerides look good, their inflammation is low, and their glucose monitor is boring.

That claim is not harmless. I believed a version of it. I had the clean labs, the clean glucose data, the low inflammation, and a clean coronary scan at 36. Eight years later, I had a severe, flow-limiting blockage in my right coronary artery. A clean scan at 36 did not buy me lifetime immunity from what eight more years of biology could do.

What I’d Do If I Were You

If your LDL is elevated and rising, and you are leaning on one underpowered study whose follow-up was retracted to tell you everything is fine, you owe it to yourself to dig deeper.

Ask your clinician about ApoB testing. Ask whether your particle burden fits the story you have been told. Ask whether a calcium score is enough for your situation, or whether a CCTA with plaque characterization would answer a different question. And do not wait for crushing chest pain. I did not have crushing chest pain. I had nagging chest tightness, mid-back discomfort, and less pep in my workouts. That was enough for my artery to already be in trouble.

If your doctor is telling you your LDL deserves attention, think very carefully before using a podcast or a retracted study as the reason to ignore them.

What Happened to Me

After my stent, the interventional cardiologist who treated me came to see me in recovery. His message was blunt: get your LDL as low as you can. I took him seriously. My LDL is now dramatically lower, and a follow-up CTCA last month showed an open stent and regression of soft plaque.

Did I become vegan? No. Do I still eat steak? Yes. But I gave up keto, I gave up carnivore-light, and I stopped treating LDL like a harmless side effect of being metabolically healthy. Right now my plumbing is not getting worse. It is clearing.

What Would Change My Mind

I am angry about this, but I am not closed-minded. I hold this position with conviction, and I hold it loosely. Three pieces of evidence would update it:

• Long-term hard-outcome data on the LMHR phenotype. Decade-scale prospective data showing equivalent or lower cardiovascular event rates in lean mass hyper-responders versus matched controls. Not one-year imaging. Not cross-sectional snapshots. Real endpoints over 10 to 20 years. The hypothesis has not met this bar.

• A mechanism for why ApoB behaves differently in this phenotype. Not “their metabolism is different.” A specific molecular pathway showing why an ApoB particle in an LMHR person fails to lodge in the artery wall and trigger the cascade it triggers in everyone else. The lipid energy model explains why the LDL is high. It does not explain why that LDL would not do what high LDL always does.

• Mendelian randomization showing LDL-lowering variants do not reduce risk in this phenotype. The cleanest possible test. It has not been done.

If any of those emerged, I would update, publicly, on this site. The path to changing my position is open. It just runs through evidence I have not seen yet.

The Final Signal

• What the claim gets right: total plaque and calcium did not differ in the cross-sectional snapshot, and the LMHR phenotype is a real, interesting metabolic pattern.

• What it gets wrong: it treats a cross-sectional study with no soft-plaque breakdown, a retracted follow-up, and severe restriction of range as proof that high ApoB is safe. It is not.

• What I changed: I stopped treating a rising LDL as background noise, got my ApoB and LDL down hard, and my soft plaque is now regressing.

• What would change my mind: the three specific tests above. None has been met.

• What’s next: if no standard test caught my blockage, which test actually would have? That is the next post.

A Note on Convergence

In April 2026, Peter Attia and Tom Dayspring published a much deeper lipidology version of this same critique (“There is no safe gamble with high LDL cholesterol”). Their angle is technical. Mine is personal and clinical. They are asking whether the lean mass hyper-responder hypothesis has the evidence to overturn the ApoB-causality consensus. I am asking what happens when a real person believes that hypothesis before the evidence is ready. Different angles, same practical conclusion. That is how a field’s consensus actually moves, and we are watching it happen.

What’s Next

Here is the part that still haunts me. My 12-lead ECG was clean. My echocardiogram was normal. My Holter monitor was unremarkable. My labs looked reassuring. My wearable data looked great. Every standard cardiac test said I was fine. I still needed a stent.

So next week I am going to walk through exactly why standard cardiac screening missed a severe, flow-limiting blockage, and what I would ask for now if I were sitting across from a primary care clinician with new chest tightness, mid-back discomfort, or that hard-to-describe sense that my workouts had lost their usual pep. That question might save someone’s life.

References

1. Budoff MJ, et al. “Carbohydrate Restriction-Induced Elevations in LDL-Cholesterol and Atherosclerosis: The KETO Trial.” JACC Advances. 2024;3(8):101109. PMID: 39372369 · doi:10.1016/j.jacadv.2024.101109 [Finding: In 80 lean keto eaters with LDL-C of 190 or higher versus matched controls near 123, total coronary plaque burden did not differ between groups. This is a cross-sectional snapshot, not proof that the high LDL is safe over time.]

2. Soto-Mota A, Norwitz NG, et al. “Longitudinal Data From the KETO-CTA Study: Plaque Predicts Plaque, ApoB Does Not.” JACC Advances. 2025;4(7):101686. PMID: 40192608 [RETRACTED] [Finding: Over one year in 100 keto eaters, non-calcified plaque rose a median of 18.9 mm³ while baseline plaque, not ApoB or LDL, predicted who progressed. This paper has since been retracted.]

3. Retraction: “Longitudinal Data From the KETO-CTA Study: Plaque Predicts Plaque, ApoB Does Not.” JACC Advances. 2026;5(5):102824. PMID: 42206798 · doi:10.1016/j.jacadv.2026.102824 [Finding: The retraction notice for reference 2, issued at the request of both the authors and the editors over methodology concerns judged too significant to fix with a correction.]

4. Soto-Mota A, et al. “Reply: The Keto CTA Study.” JACC Advances. 2025;4(7):101862. PMID: 40450909 [Finding: The authors confirm the 18.9 mm³ plaque rise was a 42.8 percent relative increase, a figure they omitted from the original paper and call a sincere oversight. This is the source of the 42.8 percent number.]

5. Budoff MJ, et al. “The Impact of Sustained LDL-C Elevation on Plaque Changes.” medRxiv. Posted January 2026. [PREPRINT, NOT PEER-REVIEWED] [Finding: A post hoc reanalysis of the same KETO-CTA cohort using different plaque-quantification methods, posted publicly before peer review. As a preprint, it has not cleared independent review or journal acceptance.]

6. Ference BA, et al. “Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies.” European Heart Journal. 2017;38(32):2459-2472. PMID: 28444290 [Finding: The European Atherosclerosis Society consensus concluding that LDL causes atherosclerotic disease, drawing on genetic, epidemiologic, and trial evidence across more than two million people. The relationship is dose-dependent.]

7. Ference BA, et al. “Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease.” JAMA. 2019;321(4):364-373. PMID: 30694319 [Finding: In 654,783 participants, the drop in coronary heart disease risk tracked the absolute change in ApoB particle number, not LDL-C or triglycerides on their own. ApoB is the unit that matters.]

8. Soffer DE, et al. “Role of apolipoprotein B in the clinical management of cardiovascular risk in adults: An Expert Clinical Consensus from the National Lipid Association.” J Clin Lipidol. 2024;18(5):e647-e663. PMID: 39256087 [Finding: The National Lipid Association consensus holding that ApoB adds risk information beyond a standard lipid panel. When LDL-C and ApoB disagree, risk follows ApoB.]

9. Mach F, et al. “2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.” European Heart Journal. 2020;41(1):111-188. PMID: 31504418 [Finding: For very-high-risk patients these guidelines set an LDL-C goal below 55 mg/dL plus at least a 50 percent reduction from baseline. The target the keto cohort sits far above.]

10. Williams MC, et al. “Low-Attenuation Noncalcified Plaque on Coronary Computed Tomography Angiography Predicts Myocardial Infarction: Results From the Multicenter SCOT-HEART Trial.” Circulation. 2020;141(18):1452-1462. PMID: 32174130 · doi:10.1161/CIRCULATIONAHA.119.044720 [Finding: Low-attenuation soft plaque was the strongest predictor of heart attack, beating calcium score and stenosis severity. A burden above 4 percent carried roughly five times the risk.]

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Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X / @nickhansonrn · LinkedIn (linkedin.com/in/nickhanson)

Not medical advice.

I was merging onto a busy interstate when my phone buzzed. A notification from Mayo Clinic. The first line read: “Critical result: severe, flow-limiting occlusion of the right coronary artery.”

I pulled the car over. I knew exactly what those words meant. I run codes in the Mayo Clinic emergency department, so I have watched up close what a blocked coronary artery does to a person. I had just found out I could be the next one on the table.

The scan that caught it was a coronary CT angiogram (CCTA), a CT that uses contrast dye to look straight at the arteries feeding the heart. It sees both the hard, calcified plaque and the soft plaque that ruptures without warning and kills you. I had gone through three weeks of normal tests and had to argue my cardiologist into ordering it. Good thing I did.

My name is Nick Hanson. I’m a former health and wellness industry CEO turned clinician-scientist. I’ve been from the boardroom, to the bench, to the bedside. This is the story of how I ended up with a chunk of metal in my coronary artery, why I’m angry about it, and why I started Calibrated Signal.

I was 44 years old. Former athlete, lifelong exerciser, non-smoker, non-drinker. I had a master’s in bioinformatics from a joint program between the University of Minnesota, Mayo Clinic, IBM, and Cray Computers. I had published cancer epigenetics research. I’d spent 15 years as a health and wellness industry CEO. I had a curated and optimized multi-supplement stack, a sauna, an ice bath, and a low-carb high-fat diet that the biohacking world swore was optimal.

None of it mattered. I had an 80% coronary blockage and was one bad day away from a heart attack that could have killed me. A literal ticking time bomb. And my first feeling wasn’t fear. It was anger. I had done everything I was told was right, and it had quietly failed me anyway.

The Diagnostic Fight

A month before that scan, I was sitting across from my Mayo Clinic cardiologist with a complaint of vague chest tightness. It would come on without warning, not necessarily tied to exercise. Sometimes it actually got better when I worked out. I had a history of mild anxiety and some disc degeneration in my spine, so I acknowledged it could be either of those. But it had been getting worse over the past few months, and something felt off.

We ran everything. A comprehensive lab panel came back mostly normal. My hsCRP, a marker for chronic inflammation, was rock bottom at 0.45. Homocysteine normal. HbA1c looked great, no insulin resistance. I wore a continuous glucose monitor for a few weeks with zero concern. No issues with Lp(a) (a common culprit for atherosclerosis that is primarily determined through genetics). The only flag was my LDL (low-density lipoprotein, the cholesterol particle most tied to artery plaque) at 160, moderately elevated and slightly higher than it had trended most of my adult life. But many of the popular biohacking physicians and low-carb/high fat keto and carnivore advocates said mildly high LDL was of little concern in the absence of insulin resistance or chronic inflammation. I had neither.

My 12-lead ECG also came back normal sinus rhythm. I run these all day in the ER. It looked perfect.

He asked about wearable data as he could see the Apple Watch on my wrist and Oura Ring on my finger, neither of which had ever flagged high heart rates and showed excellent resting heart rate in the low 50s. The cardiologist seemed reassured.

I pushed back. I wanted to go deeper.

He was hesitant. Eight years earlier, at 36, I’d had a complete cardiac workup that included a 100% clean CCTA, one that found zero calcified or non-calcified plaque. With that history, and everything in front of him now reading normal, he saw little reason to keep digging. He did agree to add a Holter monitor to track my heart rhythm for a couple of days, something I hadn’t needed in 2016, because I’d started having some palpitations.

The Holter came back normal too. Zero concerns. (Here’s why those tests missed my 80% blockage.)

At follow-up he told me I could chalk this up to referred pain from my spinal disc issues triggering low-level anxiety. He pointed out that sometimes in the medical profession, when you know too much, your mind can run. I could see his point. I deal with heart attacks every day in the ER. It’s easy to let your mind go down that path.

But I had this gnawing feeling that something wasn’t right. I didn’t have the same pep in my workouts. I was getting tired sooner than normal. So I basically begged him to order a CCTA so I could eliminate my “heart attack anxiety” once and for all. If that came back clean, I’d stop chasing tests.

He was reluctant. A clean CCTA eight years ago made it hard to justify. But my LDL had been creeping up since I’d changed my diet, and he wasn’t a fan of the high-fat approach to begin with. He agreed. I agreed to reconsider a statin depending on the result.

The Result

A severe occlusion of my right coronary artery was not the result either of us expected. Mild atherosclerosis was also discovered in my left main and left coronary arteries. The right was labeled severe and flow-limiting. My heart was being starved of blood, and I was a walking time bomb that hadn’t detonated yet.

Within days I was scheduled for a stent with one of Mayo’s top interventional cardiologists. The procedure went as planned. Afterward, the interventionist handed me before-and-after images and told me that only a few blood cells at a time could squeeze past the occlusion.

Caption: My right coronary artery, before the stent and after. Real angiographic evidence, not a diagram.

That was all that was keeping the rest of my heart alive. He said I was one bad day away from a heart attack that could have been deadly.

The Reckoning

I spent the next month in a strange state of relief and anger. Relief that I wasn’t crazy. Relief that I’d fought for the test. Anger that I thought I was doing everything right.

Here’s the part that keeps me up at night. I didn’t stumble onto a ketogenic diet from some Instagram influencer. I found it while researching the Warburg effect and mitochondrial theory of cancer during my time publishing epigenetics research.¹ The Warburg effect describes how cancer cells preferentially use glucose for energy even when oxygen is available.² It’s a real metabolic phenomenon, and the hypothesis that restricting glucose could starve cancer cells had legitimate scientific interest behind it. I became a proponent of low-carb approaches based on what I thought the metabolic science supported.

Turns out the science I trusted didn’t account for what was happening inside my coronary arteries.

By every metric the keto and carnivore community uses to dismiss LDL concerns, I should have been fine. Rock-bottom inflammation. No insulin resistance. Perfect metabolic markers. The biggest thing I had changed was my diet. I had adopted a high-fat ketogenic and, at times, carnivore approach, and my LDL had quietly climbed during that period. I’m not pretending that one dietary change explains the entire biology of an 80% RCA occlusion. But it was the signal I had been taught to downplay, and it is the signal I now wish I had taken more seriously. The damage had been accumulating inside arteries that only the test I argued for could see.

Had I not been a published scientist and ER nurse who knows how to talk to doctors, I would not have gotten that scan. That blockage would still be there, or it would be decaying along with my body in a cemetery somewhere. That’s not dramatic. That’s the math.

The Connection I Didn’t See Coming

Before the cardiac event, before the ER, I spent three years at the Hormel Institute, a cancer research center run jointly by the University of Minnesota and Mayo Clinic. I worked in a cell signaling lab focused on epigenetic mechanisms of drug resistance in melanoma. My research centered on H3K27, a histone marker involved in how cancer cells evade treatment.

I didn’t choose that research topic. You don’t get to pick your PI’s focus when you’re a grad student. I spent years learning that particular piece of molecular machinery without any idea where it would lead.

H3K27 turned out to be tied to the same machinery behind modern biological aging clocks. Those clocks, the ones researchers like Steve Horvath built to measure how fast humans age, read DNA methylation. And the regions they watch most closely are the very ones kept silent by H3K27, the mark I’d spent years studying. I had no way of knowing that at the time. Nobody in my lab was thinking about aging. We were thinking about melanoma and brain cancer.

That connection, the realization that my cancer research mapped directly onto the longevity science I’d end up writing about, wasn’t planned or engineered. It was uncanny, accidental, and it changed how I understood my own career. The boardroom taught me how health products are marketed. The bench taught me how biology actually works at the molecular level. The bedside taught me what happens when patients don’t have the information they need. And a stent at 44 taught me that even someone with all three of those perspectives can still get it wrong.

That is why this site does not stop at cholesterol, scans, or stents. My heart was the event that forced the question, but the deeper question is biological aging.

What Calibrated Signal Is

After the stent, I decided to apply the same evidence-based lens I learned in cancer research to every aspect of my health. Calibrate every claim against the real data. Keep the signal. Throw out the noise, no matter how popular it is or who’s promoting it. That’s where the name comes from.

I read the full papers. Not abstracts, not summaries of summaries. The methods sections, the results tables, the supplementary data most people never open. My bioinformatics training means I can evaluate study design and statistics at a level most content creators skip entirely. My 15 years inside the supplement industry means I know which claims are evidence and which are marketing dressed up as science. I’ve formulated the products, managed the manufacturing, negotiated with the raw material suppliers. I know what’s in most bottles and what isn’t.

When the evidence supports something, I’ll tell you clearly. When it doesn’t, I’ll tell you that too. When we don’t know yet, I’ll say so. I would rather be honest than comfortable.

I don’t take sponsors. I don’t accept money to feature products. When I link to something, I’ll disclose the relationship, compare it to the alternatives, and let you decide. The information here is free and always will be.

Everyone deserves the same information I had when I argued for the test that saved my life. That’s it. That’s the mission.

What’s Next

Next week I’m going to tear apart the study that the keto and carnivore community points to when they tell you elevated LDL doesn’t matter if your metabolic markers are clean. I believed that study. I built my diet around it. And while my coronary artery was quietly closing, every biomarker it told me to watch said I was fine.

That post is personal. This one was the story. That one is the science.

And if you know someone who’s been told their LDL is “nothing to worry about” because their inflammation markers are low, restack this so it reaches them.

References

1. Grigore F, Yang H, Hanson ND, et al. “BRAF inhibition in melanoma is associated with the dysregulation of histone methylation and histone methyltransferases.” Neoplasia. 2020;22(9):376-389. PMID: 32629178 · doi:10.1016/j.neo.2020.06.006 [Finding: My own lab paper. It showed how BRAF inhibition in melanoma dysregulates histone methylation, including the H3K27 mark that later turned out to underpin modern biological aging clocks.]

2. Seyfried TN, Shelton LM. “Cancer as a metabolic disease.” Nutrition & Metabolism. 2010;7:7. PMID: 20181022 · doi:10.1186/1743-7075-7-7 [Finding: A review arguing cancer is fundamentally a metabolic disease, with impaired mitochondria forcing the Warburg shift to glycolysis. A hypothesis paper, not experimental proof, and one of the ideas that pulled me toward low-carb eating.]

Coming soon: Calibrated Age, a tool that scores any longevity intervention against the biology of aging and built out by a propriety bioinformatics pipeline. Subscribers hear about it first.

Nick Hanson, MS, RN, CEN
Mayo Clinic Board Certified Emergency Nurse
MS Bioinformatics & Computational Biology
Published Epigenetics and Oncology Scientist
PhD Candidate in Bioinformatics at University of Minnesota
APRN-FNP Candidate at Duke University
Former Health & Wellness Industry CEO (15+ years)
Certified Personal Trainer (ISSA)

Follow: X / @nickhansonrn · LinkedIn (linkedin.com/in/nickhanson)

Not medical advice.

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