A Young Reed Pyeritz, MD, PhD in Sports Illustrated February 17, 1986

My friend, Reed Pyeritz, MD, PhD, passed from this world on August 10, 2026 at 5:45 AM. His daughter Abigail, wrote me on that day – “Dad died at 5:45 AM, just the time he would be getting back from a run in the old days.”

On August 28, 2026, 18 days after his death, my wife Camilla and I received a note from Reed. The back of the envelope said, “Dictated but not read” similar to what is often attached to a chart note. Reed had dictated his friends notes saying farewell and telling us know how much he enjoyed our times together.

I met Reed after I saw this picture in Sports Illustrated in 1986. Reed was interviewed on the death of Flo Hyman, the 1984 Olympic volleyball silver medalist in, who died from an aortic rupture due to undiagnosed Marfan syndrome. Reed was interviewed because he was THE world’s expert in Marfans.

Reed graduated from the University of Delaware in three years and obtained his MD and PhD at Harvard. He trained in internal medicine at the Brigham, and then did a fellowship in medical genetics at Johns Hopkins with the famed medical geneticist, Victor McKusick. Reed stayed at Hopkins but moved to Pittsburgh in the mid 1990s to join the staff of Allegheny General Hospital. I was at the University of Pittsburgh at the same time, so our families watched lots of Pittsburgh Steelers’ games together. Reed completed his career at the University of Pennsylvania where he had multiple roles including being the William Smilow Professor of Professor of Genetics, Chief of the Division of Medical Genetics, and one year as the Chair of the Faculty Senate.

We became friends because of his Sports Illustrated picture. Here’s that story.

When I was at Brown University in Providence, Rhode Island, I took care of a family distantly related to “Tarzan” Brown, the Narragansett Native American who won the Boston Marathon in 1936 and 1939. He was called “Tarzan” because he had a very defined, muscular physique. His real name was Ellison Myers Brown. I often was consulted by distance runners and their families because of my interest in the sport.

Tarzan was famous not only for winning Boston twice, but also for helping to name the Boston Marathon’s famous Heartbreak Hill. Tarzan had been leading the 1936 race up until the last and toughest of the Newton Hills, where he was caught by Johnny A. Kelly. Kelly had won in 1935 and is now referred to as “Johnny the Elder” to distinguish him from Johnny J. Kelly, “Johnny the Younger”. The Elder Kelly won Boston again in 1945. The Younger won Boston in 1957. At any rate, when Johnny the Elder caught up to Tarzan near the top of the last Newton hill, Johnny tapped Tarzan on the butt to signal “good race but I’m gonna pass now.” Tarzan sprung to life and took off to win. Johnny faded to fifth. Jerry Nason, the sports writer for the Boston Globe, wrote that Tarzan had broken Kelly’s heart on the hill, thus the name, Heartbreak Hill.

Tarzan’s relatives included several members with Marfan Syndrome, a genetic condition that affects connective tissue. So I called Reed, whom I knew only from the Sports Illustrated article and asked him if he would come to Providence to see my Marfan patients with me. Reed had to come to Boston in the near future, so I scheduled my patients appropriately, and we saw them together.

It was a very valuable experience. I cannot remember all he taught me in that one day, but I do remember:

- The fibrillin gene is a long gene with plenty of place for mutation, so approximately 14% of patients with Marfan appear to be spontaneous mutations. (We now think this rate of spontaneous mutations is higher – perhaps 25 percent.)

- The pectus excavatum in Marfan Syndrome is more frequently asymmetric than in other conditions.

- The ascending aorta dilates more than other areas of the aorta because it contains a lot of elastic fibers, which are affected in Marfan Syndrome. In fact, the ascending aorta is like an accessory pump expanding and then contracting, pushing blood forward with each beat.

- But the most important lesson was to be careful and thoughtful with these patients because a lot of different tissues can be affected. He related several stories of medical mis-adventurism. I still remember the story of one of his patients who had an apparent vaginal mass which someone biopsied. It was actually an extrusion of meningeal tissue from the spinal cord so the biopsy produced a hard-to-seal spinal fluid leak

After Reed’s visit, I would send my Marfan patients with dilated aortas to Hopkins, where Vince Gott, the cardiac surgeon, would repair them, and Reed would send patients to me in Providence when they lived in my area.

When Reed visited me in Providence in the late 1980s, Marfan pathophysiology seemed pretty simple: defects in the fibrillin gene led to the production of poor elastic tissue, which led to joint laxity, ectopia lentis and dilated aortas.

We now know that the pathophysiology is considerably more complex and that defects in the fibrillin gene, FNB1, affect more than just the quality of elastic tissue.(1) These defects disrupt the fibrillin microfibrils that connect elastic tissue to smooth muscle. But these defects also affect the regulation of Transforming Growth Factor (TGF) beta. TGF beta is sequestered within the fibrillin microfibrils. Defects in the fibrillin structure reduce control of TGF beta. Its release from sequestration accelerates elastic-fiber fragmentation, and medial degeneration of structures such as the aorta. The effect of this TGF beta dysregulation varies by tissue type. For example, the dysregulation in bone leads to longer bones typical of the Marfan Syndrome. We also now know that different defects in genes affecting the aorta alter the phenotype differently with some genetic defects more frequently associated with aortic rupture, for example.

Reed’s family had a celebration of life for Reed on Sunday, August 18 in Philadelphia. Several people spoke about Reed including physicians and folks from the Marfan Foundation. The Marfan Foundation has done wonders in improving survival for people with this condition. And the Marfan Foundation grew out of a group of patients that Reed had assembled at Hopkins.

People said great things about Reed at his celebration. But one thing I admired, and regret not saying, is how physically and mentally tough he was. He was a good triathlete in his youth, and ran the 1988 Boston Marathon in 2:51. But when older he had multiple medical problems, as many of us do: an open aortic valve replacement, amyloidosis, Parkinsonism, several orthopedic procedures, and yet he never complained. We travelled together in June 2025 on a cruise to Alaska, and he was always in the gym when I arrived.

And when it was his time to leave this planet, he wrote his friends thank you notes. I should have written him.

Here are the Rules:

1. Work with the best people you can - the Work with Winners or WWW Rule. The best simply know more and can teach you more. They make you better.

2. Take educational field trips to visit with experts or, even better, have the experts come to you and see your patients.

3. Be vigilant with your Marfan patients. The condition can affect many organs and provide many surprises.

4. Know the genetic defect in your Marfan and aortic patients. Different defects affect the aorta differently. Knowing the defect may help to decide when to intervene.

5. Make sure you thank the people who helped you because you might lose the chance.

References

1. https://www.openevidence.com/ask/b1aae5a6-5076-4c8b-a7f8-ba7538de63e9 (accessed August 28, 2026)

#ReedPyeritz; #MarfanSyndrome; #aorta; #aorticdisease; #TarzanBrown; #BostonMarathon; #JohnnyAKelly; #JohnnyJKelly

A Tibial Tubercle Tendon Xanthom in a Jogger with Heterozygous Familial Hypercholesterolemia. Cholesterol Deposits at Place of Stress in This Case the Tibial Tubercle Probably from the Stress of Jogging

I was asked to evaluate a 70 year old man with the following lipid levels:

Total cholesterol = 820 mg/dl – (That’s right eight hundred and twenty!)

HDL cholesterol = 85 mg/dl

Triglycerides = 86 mg/dl

LDL cholesterol = 711 mg/dl.

Repeat lipid levels revealed LDL-cholesterol (LDL-C) levels ranging from 430 to 495 on a statin, but the statin and doses were unclear.

Here is the differential diagnosis for such markedly elevated cholesterol levels.

#1 - Homozygous familial hypercholesterolemia (HoFH). HoFH is hyperlipidemia due to defects in any two genes affecting LDL catabolism. The genes that affect LDL catabolism are::

The LDL receptor (LDLR) gene;

The apolipoprotein B (apoB) gene;

The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene;

The Low-Density Lipoprotein Receptor Adaptor Protein 1 (LDLRAP1 gene.

Patients with HoFH have to inherit a gene with a defect affecting an LDL catabolism from each parent. I other words, each parent has to contribute to the condition. HoFH can be caused by defects in the:

The same defect in the same gene from each parent ;

Different defects in the same gene from each parent:

Defects in two different genes, one from each parent.

HoFH is diagnosed clinically by LDL-C levels above 400 mg/dl, tendon xanthomas in childhood, and elevated lipid levels in each parent consistent with the parents each having heterozygous familial hyperlipidemia (HeFH). (1) Be careful with this “each parent issue” because occasionally the husband is not the father, but the child clearly has HoFH. Also, rarely HoFH can be caused by two recessive genes in which case the parents’ lipid levels may be normal.

HoFH is impossible in the present case because his LDL-C levels (if untreated since childhood) would have killed this man in his teens or twenties if not sooner. I know of patients with HoFH who had coronary bypass surgery before age 10. So the lipid levels in this man have got to be due to something acquired and not inherited.

#2 - Hypothyroidism. The thyroid hormone is required for the synthesis of the LDL receptor so that marked hypothyroidism can cause marked hypercholesterolemia. I remember a woman admitted to our Coronary Care Unit with “hypertrophic cardiomyopathy” and an LDL-C of around 400 mg/dl. Her thyroid stimulating hormone (TSH) was markedly elevated indicating hypothyroidism. Both her cardiac hypertrophy and hypercholesterolemia were both caused by myxedema from hypothyroidism.

#3 – Nephrotic Syndrome – To be diagnosed with nephrotic syndrome, patients must leak at least three grams of protein per 24 hours into their urine through damaged renal glomeruli. There are multiple causes of nephrotic syndrome, but nonsteroidal medications can do it. I have seen several patients with markedly elevated LDL levels with nephrotic syndrome due to non-steroidal drugs. This entity can develop rapidly and may first manifest as an elevated LDL-C level.

When the kidney leaks large amounts of protein, the liver gets the message to “make more protein”. So, the liver makes more proteins including apolipoprotein B (ApoB). ApoB is sent into the circulation in the triglyceride-rich, very low density lipoprotein (VLDL) particle. Many clinicians know that nephrotic syndrome can elevated triglycerides by this mechanism, but some patients can delipidate the VLDL via the action of lipoprotein lipase (LPL) to produce LDL. I think this happens more frequently in active subjects because we and others have documented that exercise increases lipoprotein lipase (LPL) activity.(2) LPL is a major delipidator of VLDL.

The markedly elevated LDL-C levels due to nephrotic syndrome are worrisome, but not as worrisome as the genetic causes of elevated LDL-C because the increased LDL-C in nephrotic syndrome is recent and generally does not have sufficient time to inflict major vascular damage. Much of my first visit with such patients is to reassure them. Many of these patients think they are about to die because of their high LDL levels.

#4 – Ketogenic Diets – Many clinicians are unaware that the popular low carbohydrate, high protein/fat diets can produce marked elevations in LDL. I wrote about this in one of my pieces on sitosterolemia. (3) Sitosterolemia is an inherited condition in which patients over absorb the plant sterol, sitosterol.

Intestinal sterol absorption is regulated by two proteins. The Niemann-Pick C1-Like 1 (NPC1L1) protein regulates sterol absorption. Ezetimibe inhibits this protein thereby reducing cholesterol absorption and lowering LDL-C. The adenosine triphosphate (ATP) binding cassette transporters 5 & 8 (ABCG5 & ABCG8) regulate sterol excretion in the brush border of the intestine. They get rid of some of the absorb sterols like cholesterol and sitosterol. Defects in ABCG5 or 8 can produce sitosterolemia because the sitosterol is absorbed by NPC1L1, but not excreted.

So, why do only some people on a ketogenic diet develop high LDL-C levels?

Body weight may be a factor. Individuals with low body mass index (BMI) have higher markers of cholesterol absorption, whereas individuals with high BMI’s tend to have higher markers of cholesterol production. So, being leaner and eating a ketogenic diet may predispose an individual to developing high LDL levels from increased absorption.

The composition of the ketogenic diet probably affects the results. If whole eggs are a large component of the protein intake, the person, especially if thin, can absorb a lot of cholesterol to absorb from the yolk.

Genetics play a role. Dr. Ernie Schaefer from Boston Heart Labs reported a 51 year old woman with a body mass index of only 18.5 kg who used a ketogenic diet for depression and anxiety. Her LDL increased from 142 to 555 mg/ml on the diet.(4) Her beta-sitosterol level was also increased to 12.8 mg/dl (normal less than 15). She was found to have a pathologic variant in ABCG5, but she also had 2 variants of unknown significance in the gene for apolipoprotein B. A low cholesterol diet and ezetimibe decreased her LDL decreased to 159 mg/dl. Her sitosterol also decreased but did not normalize. Dr. Scheafer thinks that the combination of her ABCG defect, which increased cholesterol retention, and her high cholesterol diet produced the high LDL.

My patient was 5’7” tall and weighed 140 lbs. (BMI – 22). Eggs were a major component of his diet. Another woman I saw with hypercholesterolemia on a ketogenic diet was also not obese and was using the ketogenic diet to control migraines.

#5 – Sitosterolemia – As evidenced by Dr. Schaefer’s case above, defects in ABCG5 or 8 can produce both sitosterolemia and markedly elevated LDL-C levels on the right diet.

I treated my patient with a low egg diet and ezetimibe. I am awaiting repeat lipid levels.

Here are the Rules

- Ketogenic, high fat/protein, low carbohydrate diets can cause markedly elevated LDL-C levels as can genetic defects affecting LDL-C catabolism, hypothyroidism, the nephrotic syndrome and defects in the genes ABC5 & 8.

- Check lipid levels in patients on ketogenic diets to make sure they have not developed markedly elevated LDL-C levels.

- Treatment of patients with high LDL-C levels on ketogenic diets includes a diet low in cholesterol and ezetimibe to reduce cholesterol absorption. Statins can be added depending on the LDL-C response.

References

1. Ahmad Z, et. al. Update on familial hypercholesterolemia: An expert clinical consensus from the National Lipid Association.

J Clin Lipidol. 2026 Apr;20(4):708-737. PMID: 41741298

2. Thompson PD. What do muscles have to do with lipoproteins? Circulation. 1990 Apr;81(4):1428-30. PMID: 2317921

3. pauldthompsonmd.substack.com/p/can-a-guacamole-overdose-kill-you?utm_source=publication-search

4. Schaefer EJ, et.al. Marked Low Density Lipoprotein Cholesterol Elevation on a Ketogenic Diet, Cholesterol Absorption, Lean Mass, and Heterozygous Sitosterolemia; Case Report, Large Population Analysis, and Review. J Clin Lipidol. 2025 May-Jun;19(3):617-627. PMID: 40240243

#cholesterol; #LDL; #homozygoushyperlipidemia; #heterozygoushyperlipidemia; #hypothyroidism; #nephroticsyndrome; #ezetimibe; #sitosterolemia;

My first post for “500 Rules of Cardiology” on Substack was on August 15, 2023. The title was “Smile and Say ‘Hello’ to Everyone” because being cordial with one another can make medicine better and safer. If patients, trainees, and other clinicians know that you are friendly and approachable, they are more likely to ask questions and for advice, and the answers and advice may prevent a clinical care mistake.

I don’t think I have missed posting weekly since that August 15th three years ago. Please check out the old posts. I didn’t put them out there if I didn’t think they were useful.

Here are the three most frequently viewed post from the last three years. I have just put in the name of the post and not the full URL so as not to have the picture crowd into this article. If you want to read the post just add “https:” to the start of the stem.

#1 – “The Statin Rule of Six” explains how statins lower LDL the most per mg of drug at very low doses of the statin:

//pauldthompsonmd.substack.com/p/the-statin-rule-of-6

#2 – “My Wife’s Coronary Artery Calcification Score” discusses how to use coronary artery calcification scores to manage patients using my favorite wife’s results. (She ‘s also my only wife.}

//pauldthompsonmd.substack.com/p/my-wifes-coronary-artery-calcification

#3 – “Cholesterol and its Treatment” visually demonstrated the physiology of LDL metabolism and how I teach this to patients. It also shows what a perfectly tied bow tie looks like.

//pauldthompsonmd.substack.com/p/video-post-cholesterol-its-treatment

Here are my personal favorite posts from the past three years:

#1 – “Grave Concerns at the Boston Marathon” and its update discuss our group’s and others’ observations that lifelong endurance athletes have more coronary atherosclerosis than sedentary folks. Did you get the double entendre, “Grave Concerns…” ?

//pauldthompsonmd.substack.com/p/update-on-grave-concerns-at-the-boston

//pauldthompsonmd.substack.com/p/update-on-grave-concerns-at-the-boston

#2 – “What Does Cross-Dressing Have to Do With Brugada Syndrome?” tells why Laotian men would go to bed dressed as women.

//pauldthompsonmd.substack.com/p/what-does-cross-dressing-have-to?utm_source=publication-search

#3 – “ What Do Mushrooms Have to Do With Statin Myopathy” discusses the statin content in mushrooms and how they can hurt some patients.

//pauldthompsonmd.substack.com/p/what-do-mushrooms-have-to-do-with

But I really like all the posts or I wouldn’t have posted them so check them out. I want to make sure you get your money’s work, which is not hard since it’s free?

Some Updates:

My Shameless Family Promotion #5 published on July 23, 2026 stated that my son Matthew’s first full length movie would premier at the Rhode Island Film Festival on August 8^th. Well, the film won the Best Feature Film Award and the lead actor, Justin Lim, won the award for best actor. What a relief. You’re only as happy as your least happy child. Thank you to those readers who came to the show. The movie is still in festivals and private showing so not yet publicly available.

My dear friend, Reed Pyreitz, MD, PhD, left this world on August 10^, 2026. Reed had been the William Smilow Professor of Medicine at the University of Pennsylvania Perelman School of Medicine and was a pioneering medical geneticist and THE expert on Marfan Syndrome. We bonded in the 1980’s when Reed came to my clinic at Brown University in Providence to see my patients with Marfan Syndrome and to teach me how to manage them. We traded patients for years. Camilla and I were lucky enough to take an Alaskan cruise with Reed and his wife, Jane, in June of 2025 so we have lots of warm memories and happy pictures with which to remember him.

#500 Rules of Cardiology; #ReedPyreitz; #HandlewithCare; #marfan; #marfansyndrome;

I grew up north of Boston. When I was about 9 years old my mother started taking care of a boy 3 years younger than I. This boy would come to our house after school and stay with us until his mother picked him up after her work. The boy’s father had died suddenly in 1950 when the son was in utero. The boy’s paternal aunt had also died suddenly at a young age. This boy was like a brother. He stayed with us for dinner when that was necessary. We played with my friends in the neighborhood together, but this boy could never keep up with us when we were running from one play area to another. We generally used the fields in the Route 128 cloverleaf as our baseball and football fields and would run from them to our driveway basketball court. My “almost brother” would always lag behind. We called him “hound dog” because he would always sniff out where we were and find us.

We were friends, but not extremely close. I had three older sisters who also helped take care of him, and I think I felt a little displaced by the new arrival. I think he also resented me because I was a better athlete even though he was physically bigger. We lost contact after I went to college until he called me in 1990. He was turning 40 and wanted to make sure he did not have what killed his father and aunt. He came to see me at the Miriam Hospital at Brown University. The nurse handed me his ECG before I entered the room. I knew immediately that he had hypertrophic cardiomyopathy (HCM). I treated him with beta-blockers, which he could not tolerate, and ultimately with verapamil. I left Brown in 1992 for a position at the University of Pittsburgh. One of my colleagues assumed his care when I left, but they never bonded.

In about 1994 I saw an article about automatic implantable cardioverter-defibrillators (AICDs). These devices were not widely available or used at that time, but were being implanted in some high-risk patients. They were developed by two cardiologists, Drs. Michael Mirowski and Morton Mower at the Sinai Hospital in Baltimore and Johns Hopkins Medical Center. (1) I wrote a letter my friend telling him that I thought he should have one implanted, and asked him to call me. He never called. I interpreted that as a “no thanks.”

I relocated from the University of Pittsburgh to Hartford Hospital In 1997. I still remember every detail of the August night in 1997 when his wife called to tell me that my almost brother had had a cardiac arrest and that the emergency personnel were at their home. He did not survive. At the wake, his wife told me that she found my letter on his desk.

Barry Maron, MD, and his son and colleague, Marty Maron, MD, have detailed the amazing progress we have made in preventing sudden cardiac deaths (SCD) in patients with HCM.(2) Barry has had a large role in that progress and was a early advocate of AICD placement in HCM patients.(3)

My childhood friend’s father and aunt were not diagnosed because HCM was not recognized during their lifetimes.

The British pathologist Robert Donald Teare is credited with discovering HCM even though there were case reports before his 1958 publication.(4) Teare was a pathologist at St. George’s Hospital in London. He described eight individuals with cardiac septal hypertrophy, seven of whom had died suddenly.

The National Institutes of Health (NIH) was the major site in the United States for the study of HCM in the early days after HCM was discovered. Eugene Braunwald and a cardiac surgeon, Andrew Glenn Morrow, encountered a patient with septal hypertrophy similar to Teare’s case in 1958 at the NIH. (4) The presence of a systolic murmur and a sub-valvular gradient suggested discrete subaortic stenosis from a membrane-like structure. But Morrow found only septal hypertrophy at the operation, and performed a septal myectomy, (the “Morrow Procedure”) to relieve the obstruction. The NIH became one of the major sites for the study and treatment of HCM. Amazingly, Braunwald diagnosed HCM in Dr. Morrow, who refused surgery and died suddenly in 1992. Several of Morrow’s offspring inherited the disease.

Barry Marron was at the NIH from 1972 until 1992 and participated in many of the early HCM studies. Barry also combined his personal interests in sports and HCM to write one of the earliest reports on sudden cardiac death (SCD) in athletes. (5) He and colleagues collected 29 athletes aged 13 to 30 years, 22 of whom died during or soon after exertion. All but one of the victims underwent necropsy. HCM was the cause of death in 14 of the athletes. The cases for this paper were collected from media reports and from reviews of the autopsy registry at the NIH and at the Armed Forces Institute of Pathology. Barry subsequently collected 1,866 sudden deaths in athletes of which 1049 (36%) were due to cardiovascular disease. (6) The most common causes of SCD were HCM (30%) and anomalous coronary artery origin (17%) especially when the deaths occurred during exertion.

These reports identifying HCM as the predominant cause of death among athletes have often been questioned because of possible ascertainment bias because some of the cases were found via the NIH registry of SCD, and the NIH was a major site of HCM clinical care and research.

A group in Great Britain, led by Professor Sanjay Sharma at Saint George’s Hospital, who is also the medical director of the London Marathon, reported that the predominant cause of SCD in athletes was not HCM but sudden arrhythmic death syndrome (SADS).(7) Among 128 adolescent athletes, 58% had an ostensibly normal heart and were thought to have died of SADS, whereas only 3% and 7% had HCM and idiopathic left ventricular hypertrophy (LVH), respectively. These cases were evaluated by expert cardiac pathologists, but all of the cases were referred to these specialized pathologists raising the possibility that the more obvious cases, such as obvious HCM were not referred.

Selection biases may also exist depending on the athlete populations studied, recreational young athletes or competitive young athletes.

A recent study examined the cause of SCD in 143 collegiate athletes.(8) Only half of the deaths were during exertion. The autopsy was unrevealing in 19% of the cases, implying that they were SADS deaths. LVH was present in 17% of the victims and HCM in 12.7% of the victims, making it possible that again, approximately 30% of the SCDs in college athletes could be HCM.

Consequently, it appears that HCM is still the predominant cause of SCD during exertions, but there are several issues worth noting.

The incidence rate of SCD in patients with diagnosed HCM has clearly decreased. The Marons attribute this to the development of newer medications that reduce cardiac obstruction, the widespread use of AICDs, and the increased use of ECG screening. (3) I agree, but I also think that ECG screening has changed the clinical profile of patients with HCM. Previously, HCM was detected primarily because of symptoms. Now, with widespread ECG screening, we are detecting asymptomatic individuals with mild disease, whose risk of SCD is likely less than that of those with symptomatic disease. Also, the use of ECG screening of athletes is probably identifying an even less risky subgroup because individuals with HCM and the cardiac capacity to be athletes, likely have less risk than symptomatic non-athletes.

And determining how we treat all individuals with HCM based on results from highly selected athletes is potentially dangerous. For example, a report described 76 elite athletes of whom 66% were National Collegiate Athletic Association (NCAA) Division I athletes and 34% were professionals.(9) All were allowed to return to competition after being diagnosed with such conditions as HCM and long QT syndrome. Their subsequent event rate was only one exertion-related and two non-exertion related adverse cardiac events over 6±7 years, but 63% of the athletes were found by screening and were asymptomatic when diagnosed. Interestingly, the three events all occurred in athletes who had been diagnosed after presenting with symptoms.

So, no Rules, but I have two concerns. One, is that screening asymptomatic athletes detects primarily low risk disease. Such screening might do more harm than good because these athletes were going to remain…asymptomatic. Two, is that recent recommendations, (10) that liberalize the restrictions on athletes with HCM are increasingly based on outcomes from asymptomatic individuals, who were found by screening. Such results may lead us to forget that HCM in symptomatic patients can be a very dangerous disease.

That is something I can’t forget.

REFERENCES

1. Maron BJ, Estes NAM, Rowin EJ, Maron MS, Reynolds MR. Development of the Implantable Cardioverter-Defibrillator: JACC Historical Breakthroughs in Perspective. J Am Coll Cardiol. 2023 Jul 25;82(4):353-373. PMID: 37468191

2. B J Maron ¹, W K Shen, M S Link, A E Epstein, A K Almquist, Maron BJ, Maron MS. Evidence Supporting Decrease in Sudden Deaths Due to Hypertrophic Cardiomyopathy: Athletes and Patients. JACC Adv. 2026 May;5(5):102735. PMID: 42206791

3. Maron BJ, Shen WK, Link MS, Epstein AE, Almquist AK, Daubert JP, Bardy GH, Favale S, Rea RF, Boriani G, Estes NA 3rd, Spirito P. Efficacy of implantable cardioverter-defibrillators for the prevention of sudden death in patients with hypertrophic cardiomyopathy. N Engl J Med. 2000 Feb 10;342(6):365-73. PMID: 10666426.

4. Thiene G, Calore C, De Gapari M, Basso C. Storytelling of Hypertrophic Cardiomyopathy Discovery. J Cardiovasc Dev Dis. 2024 Sep 28;11(10):300. PMCID: PMC11508572 PMID: 39452271

5. Maron BJ, Roberts WC, McAllister HA, Rosing DR, Epstein SE.mSudden death in young athletes. Circulation. 1980 Aug;62(2):218-29. PMID: 6446987

6. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980-2006. Circulation. 2009 Mar 3;119(8):1085-92. PMID: 19221222

7. Finocchiaro G, Radaelli D, D’Errico S, Papadakis M, Behr ER, Sharma S, Westaby J, Sheppard MN. Sudden Cardiac Death Among Adolescents in the United Kingdom. J Am Coll Cardiol. 2023 Mar 21;81(11):1007-1017. PMID: 36922085

8. Petek BJ et.al. Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-Year Study. Circulation. 2024 Jan 9;149(2):80-90. PMID: 37955565

9. Martinez KA, Bos JM, Baggish AL, Phelan DM, Tobert KE, Newman DB, Scherer E, Petek BJ, Ackerman MJ, Martinez MW. Return-to-Play for Elite Athletes With Genetic Heart Diseases Predisposing to Sudden Cardiac Death. J Am Coll Cardiol. 2023 Aug 22;82(8):661-670. PMID: 37587576

10.Ommen SR, et. al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2024 Jun 4;149(23):e1239-e1311. PMID: 38718139

#hypertrophiccardiomyopathy; #suddencardiacdeath; #barrymaron; #athletes; #cardiacrisksofexercise; #eugenebrauwald; #exercise; #exercisecompliations

This Beautiful Photo of Boston is by Jimmy Woo on Unsplash

I just learned that the first “Boston Sports Cardiology Summit” will be held on Friday and Saturday, September 25 and 26, 2026.

The cost is $499 until Sept 7 and $599 thereafter. There are lower fees for trainees. The course is affiliated with Harvard Medical School and offered by Massachusetts General Hospital (MGH). This continuing education initiative will also serve as the inaugural event for the Sports Cardiology Society .

I am not lecturing at the meeting, so have no vested interest in your attending, but I reviewed the agenda and it looks excellent. I also am not yet a member of the Sports Cardiology Society so again, no conflict. I did cover the inpatient cardiology and consult services with MGH residents and fellows part time for three years after I stopped being Chief of Cardiology at Hartford Hospital, but I no longer do that so have no conflicts there as well.

The details of the meeting are available here:

https://learn.hms.harvard.edu/programs/boston-sports-cardiology-summit

I learned of the meeting and Society when Matt Martinez, MD, at the Cleveland Clinic informed me that the Society had awarded me their Lifetime Achievement Award. I am honored, but hope they don’t have some clairvoyant knowledge why I should get this award now. Hopefully, everyone at a Sports Cardiology Society knows CPR.

Please share this with colleagues and trainees who may be interested.

Pericardial disease has always been tough to diagnose especially before portable echocardiography and cardiac MR were readily available.

One of my Rules from those days is “If They Have Peripheral Edema, Have Seen Three Cardiologists, and No One Knows What It Is, It’s Constrictive Pericarditis.” I will write about that later, but my recent week of service coverage brought up another rule that can be related to pericardial disease. The Rule is:

Don’t Make or Dismiss a Diagnosis Based on One Parameter –

We were asked to follow a young patient with an almost 2 cm pericardial effusion. She had had a prolonged hospital stay because of infection and renal failure requiring persistent dialysis. We were told she was not in pericardial tamponade because her echo did not show any right ventricular compromise. But the echo did show “stranding” consistent with the development of fibrous bands between the parietal and epicardial pericardium. I could not do a formal pulsus paradoxus measurement because we could not find a manual sphygmomanometer, but I thought she had pulse diminution with inspiration by palpation. Dr. E. William Hancock, a pericardial disease expert at Stanford when I was a fellow there, once told me that clinically important pulsus paradoxus could usually be felt by femoral pulse palpation. Dr. Hancock was worth listening to on pericardial disease because he was the first to define effusive constrictive pericarditis in 1971. (1) Effusive-constrictive pericarditis is rare and occurs when there is both visceral pericardial constriction and a tense fluid effusion. The key finding is that that the high right heart pressures fail to normalize after draining the fluid.

Because of Dr. Hancock’s comments on the peripheral pulse in tamponade, I was concerned our patient had pericardial tamponade because of her pulse decrease. I wanted to tap the effusion to exclude infection and because I thought others would also be concerned about tamponade later. The invasive cardiology team inquired if I was sure I wanted to do it because she was not in tamponade by echo. I told them my concerns and they agreed to proceed. I always request that the invasive cardiologists measure the pericardial pressure at the start and end of the tap, another Hancock teaching. The pericardial pressure was 22 mmHg at the start and decreased to 2 to 4 mmHg at the end of the case so she had been in tamponade.

Whew! I am glad I requested the tap. I am not presenting this as “Boy, was I smart,” but as “Boy, was I lucky.” My patient could have gotten seriously sick without that drainage.

I present this case because it emphasizes the importance of not making or excluding a diagnosis on the basis of one parameter. I encouraged the tap because she did not look “great” to me; she had a big effusion; and I thought I felt paradox on her peripheral pulse.

I do not know why her right ventricular chambers did not show collapse on the echo, as they should in tamponade, but it could be that the fibrous strands held the right-sided structures open. Dr. Sean McMahon, director of our cardiac echo lab, also mentioned that high right atrial and ventricular pressures can prevent diastolic collapse. Loculation of fluid can also cause restricted cardiac filling without right chamber collapse on echo.

I have one other pericardial case that I use when I tell trainees “not to make a decision on the basis of one parameter.”

I had just moved from Brown University to the University of Pittsburgh and was on the consult service. I was called emergently to the dialysis unit where a patient had had syncope and was in near arrest. Given that it was the dialysis unit, and renal failure can produce pericardial effusions and tamponade, I was pretty sure the patient was in tamponade, but he had absolutely no important pulsus paradox. I measured it myself because those were the days when manual sphygmomanometers were readily available. This was before widespread portable echocardiography so no echo was available. Also, I had been taught that tamponade was a clinical diagnosis based on a paradoxical pulse. I hesitated for a minute - the “new boy on the block” didn’t want to over-react and there was no paradoxical pulse, but the situation was desperate. So I asked for the pericardial needle and syringe and went ahead. I blindly (without echocardiography) used the old landmarks: slightly to the patient’s left of the xiphoid process, at a 30 degree angle, aiming for the left shoulder. When I popped through the pericardium, the bloody fluid was under such pressure that it pushed back the plunger in the syringe. The patient improved immediately.

I was shaken because I had almost not done the tap. I went downstairs and related my story to Jim Shaver, MD, the Chief of Cardiology at that time at Pitt. He proceeded to describe his observations that some patients with renal failure in tamponade did not have a paradoxical pulse.(2,3)

Here is how that works:

Inspiration increases blood return to the right ventricle. The right ventricle expands, shifts the septum leftward, and this compresses the left ventricle. This compression restricts left ventricle filling , which decreases left ventricular stroke volume. This reduces the systolic blood pressure (SBP). This is “pulsus paradoxus” or “paradoxical pulse” and it occurs to a slight degree (less than 10 mmHg), even in normal individuals without effusions. However in cardiac tamponade, the fluid in the tightly stretched pericardium compresses the ventricles. So, when inspiration fills the right ventricle, the leftward shift of the septum greatly reduces left ventricular filling and produces a large reduction in SBP (>10mm HG or >10% of SBP).

This septal shift cannot happen if the septum is thick and stiff from conditions such as long-standing hypertension, hypertrophic cardiomyopathy, or aortic stenosis. So, my dialysis patient with long-standing hypertension could not shift his septum to produce the paradox. I didn’t know that, but I am glad I did not forgo the tap just because the patient lacked a paradoxical pulse.

The Rule – Don’t Make or Dismiss a Diagnosis Based on One Parameter.

References:

1. Hancock EW. Subacute effusive-constrictive pericarditis. Circulation. 1971 Feb;43(2):183-92. PMID: 5540704

2. Shaver JA, Reddy PS, Curtiss EI, Ziady GM, Reddy SC. Noninvasive/invasive correlates of exaggerated ventricular interdependence in cardiac tamponade.J Cardiol. 2001;37 Suppl 1:71-6.PMID: 11433831

3. Reddy PS, Curtiss EI, O’Toole JD, Shaver JA. Cardiac tamponade: hemodynamic observations in man. Circulation. 1978 Aug;58(2):265-72. doi: 10.1161/01.cir.58.2.265.PMID: 668074

#cardiactamponade; #pericardialdisease; #pericardialeffusion: #jamesshavermd; #ErnestwHancock; #BillHancock; #JamesShaver; #effusiveconstrictivepericarditis

Sean McMahon, MD, reviewed this piece for me, but I am totally responsible for its final content.

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A recent post discussed Rules I used on my five days and nights of call the week before. The Rules I presented dealt with treating patients with congestive heart failure, the use of diuretics, and the importance of not worrying about what might happen.

I called it “Practicing at the Hospital of What’s Happening Now” in reference to Flip Wilson’s skit (The Church of What’s Happening Now) on his TV comedy show. One smart reader, whom I will not name because I don’t have his permission, wrote that Mark Twain said, “I have spent most of my life worrying about things that have never happened.” We sometimes do the same in medicine.

At any rate, here are two other Rules from my recent clinical week.

The Dye Don’t Lie – Our hospital, like most big city hospitals, is overflowing. There are patients on stretchers in the halls of the emergency department and the hospital. We often struggle with how to evaluate patients with chest discomfort. I usually try to get a regular, non-imaging exercise stress test as soon as possible. I am not trying to diagnose if they have coronary atherosclerosis; I am trying to decide if their discomfort represents cardiac ischemia and they have to stay in observation. We discussed the benefits of exercise tests over pharmacological testing, and why I prefer the exercise tests in “Say No To Drugs…For Cardiac Stress Testing”.(2)

When the discomfort is more suggestive of disease, I will often proceed right to angiography, preferably invasive. Since coronary access is now done via the radial artery, there is very little risk of serious bleeding. Invasive angiography is incredibly safe, and if there is no important disease, I free up a bed usually on that day. I also use CT angiography, but CT frequently overestimates the severity of the lesion because of calcium “bleeding”. That occurs when the density of the lesion’s calcium overestimates the stenosis. Such cases wind up needing an angiogram anyway. I do the invasive study because “the dye don’t lie.” It’s one test and done.

“Bilateral Pneumonia”, “Recurrent Pneumonia” and “Pneumonia in a Heart Failure Patient” need an NT-pro-BNP measurement. My team and I saw two patients last week who were labeled as having pneumonia and were treated with antibiotics. Both probably had only heart failure because both had markedly elevated NT-pro-BNP levels, and both had their cough and shortness of breath relieved by diuresis. One of these patients had been seen a week or so previously and treated for outpatient pneumonia. Heart failure can mimic pneumonia in symptoms and on the chest X-ray. Heart failure can also produce a temperature. In fact, Paul Dudley White, the famous Boston and Massachusetts General Hospital cardiologist lamented in 1940 that clinicians frequently did not know that heart failure patients can develop a fever. (2). So, inquire about heart failure symptoms in patients with “pneumonia” and get an NT-pro-BNP if heart failure is even a remote possibility.

Here are some corollaries:

1. Look at any sputum the patient can produce. The sputum of pneumonia should be colorful: yellow, green, or rusty orange. In contrast, the sputum of heart failure is white, although it may have light bloody steaking from alveolar ruptures especially if the onset is acute such as with an anterior wall myocardial infarction and acute heart failure. And the sputum of heart failure is not only usually white but also bubbly or frothy. It’s frothy because it contains a lot of surfactant because it originates in the alveoli. Surfactant reduces surface tension in the alveoli to keep them open. It also reduces surface tension in the sputum of heart failure patients to help you make the diagnosis.

2. Cardiac patients don’t have a cold unless they have a runny nose (coryza). Cardiac patients, and their doctors, are only allowed to diagnose a “cold” if the patient has coryza. Heart failure can mimic the cold or the flu and patients with heart failure often mistakenly diagnose themselves with a cold when they really have heart failure. So, the most important question to ask a cardiac patient who calls the office to inquire which cold remedy they can take is, “Do you have a runny nose?” It the answer is “no”, squeeze them into the schedule. They may need a NT-pro-BNP measurement to exclude heart failure.

3. Don’t Dismiss Heart Failure If The Patient Has a Normal Ejection Fraction – because more than half of folks over age 65 with heart failure have heart failure with a preserved ejection fraction. Many times when heart failure has been missed the clinician will say, “But their ejection fraction was normal.” As the population gets older, older heart failure with preserved ejection fraction will become more common.

References

1. https://pauldthompsonmd.substack.com/p/say-no-to-drugs-for-cardiac-stress

2. Kinsey, D. White, PD. Fever in Congestive Heart Failure. Arch Intern Med (Chic). 1940;65(1):163-170.

#coronaryangiography; #chestpain; #pneumonia; #heartfailure; #heartfailurepreservedejection; #HFpEF: #HRrEF

My son Matthew’s first full-length movie will be shown at the Rhode Island Film Festival in Providence, RI, on Saturday, August 8th at 7:30 PM. The showing is at the Avon Cinema, 260 Thayer Street. Matt wrote the script and directed the movie. I know he’s my son, but the movie is great with great actors. The picture above is of Peter Gerety and Justin H. Min, whom many of you will know. The story is about a marriage that ends before the gifts are unwrapped so they have to be returned or sold to settle the divorce. You will not be disappointed. Here is the link to buy tickets.

Link To Purchase Tickets

Paul

I just finished five days and nights of covering the in-hospital cardiology consult service for Hartford Hospital. My group provides consultation coverage for those patients who are uninsured or underinsured. These unfortunate folks are often admitted because they do not have the resources to take care of themselves appropriately. Yet, they are interesting both as patients and people.

With respect to “interesting patients”, I remember what my senior resident at Tufts New England Medical Center, John Stang, MD, taught me in 1973. John was an incredible resident and teacher. He was smart, funny and supportive. But when I once said to him, “John, this next patient isn’t very interesting,” he replied, “The patients are only as interesting as the doctor is smart.” He was right. All patients are interesting and can be educational if you look for it. John was almost too good as a resident, but we didn’t recognize that such compulsion and enthusiasm might be a problem. He was never without his tie, perfectly knotted even in the middle of the night. His handwriting was so perfect that it looked like it was from a typewriter that had cursive print. His notes were always witty. I remember one of his notes about a patient being transferred to Medicine from Urology, that started with, “Mr. Jones is being transferred from urology to medicine. I met him midstream, so to speak….” John became an outstanding educator at Ohio State, but suffered a bike accident, became addicted to opiates during recovery, lost his position, and committed suicide in 2008. One of John’s medical students published a moving memory of him. (1)

Here are the phrases and “Rules” I used most frequently during my recent five days on consult. I have picked out the ones that pertain to general medical care and managing congestive heart failure, but will hit some other of my rules in the subsequent post.

It’s hard to predict the future, especially in advance. This phrase is attributed to Yogi Berra, the New York Yankees catcher and American philosopher. Clinicians and patients are often worried about what a drug or treatment will do, but you never know what’s going to happen until it does.

Every patients is an experiment of one because you never know what’s going to happen.

The biggest mistake you can make in medicine is not paying attention. Because you cannot predict the future or the results from any intervention, you have to watch to see what happens. For example, sometimes it’s not totally clear if a patient needs additional diuresis or not. Sometimes, to help me decide, I give them a dose of intravenous furosemide and pay attention to the result. It they “pee like a race horse”, which is another medical term for “vigorous diuresis,” they probably needed more diuresis. If they don’t pee very much, they probably didn’t need the diuretic. I tell the trainees that furosemide is both diagnostic and therapeutic.

Don’t Be a Drip…per. The ability to see what happens within hours after the diuretic is the reason I prefer bolus diuretic dosing to diuretic drips. There is not much difference in clinical outcomes between boluses and drips in clinical studies, although drips do appear more effective in renal dysfunction. I prefer a bolus because I like to see what will happen.

There are two devils in medicine: the one you know and the one you can worry about. Many clinicians…and patients…worry too much about what can happen instead of what is currently happening, or has previously happened. The devil you know has a 100% chance of happening. The devil you worry about, may or may not happen. For example, Ms. Jones is reluctant to take a statin after her heart attack because she is worried about getting muscle problems with the statin. Well, she may get muscle problems, unlikely, but possible. Our studies suggest a 5-10% chance of the myalgia, (2) and if that myalgia devil does show up, we’ll stop the drug.

Worship at the Church of What’s-Happening-Now. There was a comedian named Flip Wilson who had a TV comedy show from 1970 to 1974. He would occasionally play a minister in “The Church of What’s Happening Now.” My trainees never get the connection, but I tell them that I practice “At the Hospital of What’s Happening Now”. Take care of what you know is happening now and worry less about what could happen later.

Set Ambitious Diuretic Goals. My trainees often set a goal for heart failure patients with volume overload of 2 liters per day. In contrast, if they have a lot of fluid overload, I set a goal of as much diuresis as I can get. Sure you can diurese too fast but early on in the admission when they are as big as a blimp, you rarely get into trouble. So, I do intravenous furosemide plus metolazone. Dual diuretic with metolazone really speeds up diuresis. We had one patient this week whom I insisted the team treat that way and he lost 20 kgs in four days. So be ambitious. If you overdo it, you can give them back some fluid.

Don’t Use Oral Diuretics in the Hospital. I have discussed this previously (3), but I always use intravenous diuretics to treat hospitalized heart failure patients. First, you know they are getting it, whereas if they have heart failure and especially if they have some intestinal edema, you don’t know how much they are absorbing. Second, the house staff often wants to switch to oral diuretics and watch the patient for a few days to see if it works. What a waste of a bed. There are no Golden Arches, the McDonald’s signature logo, in our hospital. Who knows if the diuretics will work when there “used to be gold in them thar hills”, but now there are Golden Arches.(3) The only way to know if the regimen will provide adequate diuresis at home is to send them home and see what happens.

Look at the Chloride Level to Assess Compliance. I have written about this previously. (4) Diuretics produce a hypochloremic, hypokalemic metabolic alkalosis. If a heart failure patient presents with fluid overload and a chloride much over 100 meq/L, they are probably not taking their diuretic. I also use chloride to monitor how effectively our diuresis is doing and when we should stop.

That Newton Guy Was Probably On to Something. I go slightly nuts when the trainees on morning round tell me that our hospitalized, fluid overloaded heart failure patient has “no peripheral edema. I usually start with, “Have you ever heard of Sir Isaac Newton and the theory of gravity.” The basic idea is that fluid goes to the point closest to the center of the earth.” I then explain that they should be checking for sacral edema, and that sacral edema is important because “If there’s fluid in the butt, there’s fluid in the gut”, and they won’t absorb oral medicines well.

The other thing that drives me nuts is when the residents touch the skin and say there is no fluid. To detect fluid requires a ten second hard push, not a touch.

I want to assure my former Senior Resident, John M. Stang, MD, that, thanks in part to him, all the patients that my team and I saw last week were interesting. Actually, they were fascinating.

That’s enough for now. I will address a few other Rules from last week in a subsequent post.

Please consider looking back through prior posts. I have been doing these once weekly since August 15, 2023, so there are a lot of “oldies but goodies”. Also, please pass along the site to your colleagues and friends who might enjoy the pieces. I present them to you, because I wish someone had taught them to me.

1. https://medicineandfaith.com/2017/11/14/memories-of-a-mentor/

2. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, Chipkin S, Pescatello LS, Simpson K, White CM, Thompson PD. Effect of statins on skeletal muscle function. Circulation. 2013 Jan 1;127(1):96-103. PMID: 23183941

3. https://pauldthompsonmd.substack.com/p/theres-gold-in-them-thar-hills

4. https://pauldthompsonmd.substack.com/p/pissing-away-the-chloride

#heartfailure; #diuretic; #volumeoverload; #johnstangmd; #medicalpractice #yogiberra

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I am a month away from my 79^th birthday. I do not exercise as long or as hard as I used to because of a hip fracture and replacement from a bicycle accident and because of my transcatheter aortic valve replacement (TAVR) which I discussed previously. (1)

But I spent the last two weeks on vacation at our lake house in Maine, where my favorite, and only, wife grew up. One day I got a little overenthusiastic given my age and health, and cycled 41.5 miles up 2,500 feet on the roads near the lake. I am slow, 12.1 miles per hour so I rode straight for three and a half hours. That was added on to 15 to 30 miles of cycling on each of the days before this bike ride. For two days after my long ride, I was absolutely exhausted. I had forgotten how severe the fatigue from too much exercise can be. This event reminded me of a rule:

Fatigue in endurance athletes is almost always due to overtraining.

I did not say “always”, but “almost always.” Sure, there can be other causes such as hypothyroidism, liver disease, viral infections, but if it is present at rest in an athlete or occurs with minimal exertion, it is usually simply “too-much-exercise” fatigue. This can occur from too much repeated exercise , so-called “overtraining”, or from an acute dose of too much exercise. Here are the common clinical scenarios.

1. Continued Hard Training After a New Personal Record (PR)

I recently advised the parent of a highly ranked American distance runner. The athlete had just run two personal record (PR) times in the mile of around 3 minutes and 52 seconds, but he then felt flu-like symptoms and was extremely tired. Over the next several weeks he felt sluggish and could not train well. I ordered the usual initial blood tests that I order for short-term fatigue in athletes: a basic metabolic panel, hematocrit, ferritin, and liver function tests. I primarily provided reassurance, but referred him to a sports cardiologist near the athlete’s home. This clinician agreed with a reduced training load and patience. The athlete subsequently returned to normal and ran a very fast 5,000 meter race about six weeks later.

Such fatigue, in my experience, generally occurs in good athletes who are driven to training hard. The episodes often present after a new PR. Athletic improvement requires working hard to reach a new level, relaxing a bit to consolidate the gains, and then pushing higher. My observation is that many athletes don’t back off to consolidate the gains after hitting a new PR, but push on even harder to get even better. This often results in extreme fatigue and a reduction in spirit and performance. Even if the athlete reduces their training somewhat after a new peak, it often isn’t enough because of the ”cumulative fatigue” from multiple prior hard workout sessions. Creating cumulative fatigue by stringing together multiple hard sessions can be a useful training technique, but too much for too long leads to reduced performance.

2. Post Marathon or Extreme Exertion Fatigue

Many runners go through fatigue and even mild depression after running a hard marathon. A marathon is 26.2 miles, and running it hard is fatiguing even if you are well trained. The adage used to be one day of easy training for every mile of hard racing, but again, many athletes don’t back off. Also, the marathon seems to cause more dysphoria than expected. Some of the dysphoria is the physical fatigue, but good runners don’t do marathons often. Some runners feel as if they missed an opportunity if they didn’t run as fast as they had hoped. That missed opportunity, and having to wait for another chance, causes dysphoria in some people.

Many marathoners are upset with themselves over the dysphoria. I have discussed dysphoria and depression after a cardiac event in the post on how the “head bone is connected to the heart bone”.(2). I call it my “wounded wolf” lecture and it goes something like this:

I tell patients that some depression after a cardiac event (or a marathon or overtraining) is often a normal phenomenon, and is similar to what a wolf does if it gets gored while hunting caribou. The injured wolf retreats to its den and lays low to save calories to heal the wounds because failure to heal the wounds means that the wolf will never successfully hunt caribou again. Dysphoria and laying low is a way to facilitate your body recovering from injury or too much exertion.

I think this analogy often makes sense to patients and athletes, and helps them understand that the dysphoria is usually transient.

Even in non-athlete populations, fatigue at rest is not usually due to heart disease. In this group, sleep apnea is possible, but depression is a frequent cause of fatigue at rest in non-athletes and should be included in the differential diagnosis.

With athletes who I think have over-training fatigue, I often tell them of what Frank Shorter, the 1972 Olympic Marathon winner, said after he retired. When asked if he missed competing, he said something like, “I don’t miss being dead tired all the time.”

Three runners have won the Olympic Marathon twice. Abebe Bikila from Ethiopia won running barefoot in1960 in Rome and again with shoes in 1964 in Tokyo. The Tokyo win was 40 days after his emergency appendectomy. Waldemar Cierpinski from East Germany beat Frank Shorter by 50 seconds in Montreal in 1976. Cierpinski won again in 1980 in Moscow, when the US and other Western countries boycotted the Games to protest Russia’s involvement in Afghanistan. Eliud Kipchoge from Kenya won in 2016 in Rio and in 2020 in Tokyo.

Cierpinski should be removed from the list and replaced by Frank because Cierpinski was listed as one of the East German athletes who used performance enhancing drugs when those records became available to Western journalists after the fall of the Berlin Wall. Frank won in Munich in 1972 and would have won again in Montreal if Cierpinski hadn’t cheated.

I know Frank Shorter from 1988 when we both worked as commentators for NBC’s coverage of the Seoul Olympics. I was at those Olympics in part because I informed my agent at the time, the late Art Kaminsky (1946-2013), that someone at those games was likely to be caught using the anabolic steroid stanozolol. Kaminsky passed this information on to NBC and they hired me as their “Sports Medicine Analyst” for the Games. Kaminsky was a prominent New York City television “talent agent”, who came to represent me (when I had hair) because his wife and my wife were college roommates at Tufts. I knew a lot about stanozolol because it was considered a “safe” anabolic steroid. We had used stanozolol in our studies comparing the effect of oral versus injectable testosterone on cholesterol levels. We documented that the oral stanozolol decreased high density lipoprotein cholesterol (HDL-C) levels by 33% within a week of starting the drug, whereas injectable testosterone had little effect on HDL-C. We have discussed this in a prior post, (3), but oral drugs go directly to the liver post-absorption via the portal circulation so have larger effects on liver products such as HDL Stanozolol was widely used by athletes because it was considered undetectable; it broke down rapidly in the GC-mass spectroscopy detection equipment.

Don Catlin, MD (1938-2024) ran the Olympic Drug Testing Lab for the 1984 Olympics in Los Angeles, and measured drug levels in some of our anabolic steroid studies (4-6). I knew that Don had developed a technique to stabilize stanozolol during testing so that it was detectable. This was not widely known among athletes so I suggested to Art that someone would likely be detected with the drug in Seoul. Amazingly, stanozolol was detected in the urine sample from Ben Johnson, the Canadian who had “won” the 100 meter race. That earned me my first appearance on the Today Show with Bryant Gumble.

I personally learned of over-training fatigue in 1976 after finishing 16^th in the Boston Marathon. I was a cardiology fellow at Stanford. I decided I was going to become a better runner by training harder. So, I decided to increase my training mileage from about 80 miles to 100 miles weekly. Shortly after increasing my mileage, I was in cardiology clinic with Bill Hancock, MD, an excellent clinician and pericardial disease expert. After clinic Bill took me aside and told me that I had done a terrible job, and seemed lethargic. I apologized and promised to do better, but I knew the reason. I was exhausted by the mileage and felt tired all the time.

I knew I wasn’t going to be a very good runner for the reasons presented earlier (7) so I focused on being a cardiologist.

I think most clinicians don’t appreciate how exhausting the training can be for a highly competitive endurance athlete. The fatigue can be extreme and debilitating.

So, when evaluating athletes with fatigue, I remember the Rule:

Start with a dose of decreased training before the million dollar workup. With a history of hard training as described above, almost all athletes get better in several weeks with reduced training. If they don’t get better, then I re-examine the issue and spend the big bucks for all the testing.

1. https://pauldthompsonmd.substack.com/p/biking-75-miles-to-my-tavr

2. https://pauldthompsonmd.substack.com/p/the-head-bone-is-connected-to-the

3. https://pauldthompsonmd.substack.com/p/a-young-fit-man-with-low-hdl-is-on

4. Thompson PD, Zmuda JM, Catlin DH. Use of anabolic steroids among adolescents.N Engl J Med. 1993 Sep 16;329(12):888-9. PMID: 8355760

5. Thompson PD, Sadaniantz A, Cullinane EM, Bodziony KS, Catlin DH, Torek-Both G, Douglas PS. Left ventricular function is not impaired in weight-lifters who use anabolic steroids. J Am Coll Cardiol. 1992 Feb;19(2):278-82.PMID: 1531057

6. Zmuda JM, Fahrenbach MC, Younkin BT, Bausserman LL, Terry RB, Catlin DH, Thompson PD. The effect of testosterone aromatization on high-density lipoprotein cholesterol level and postheparin lipolytic activity. Metabolism. 1993 Apr;42(4):446-50 PMID: 8487666

7. https://pauldthompsonmd.substack.com/p/whats-the-boston-marathon-got-to

#fatigue; #marathon; #exercise; #stanozolol; #WaldemarCierpinski; #FrankShorter; #overtraining; #depression; #AbebeBikila; #EliudKipchoge

The unnamed athlete’s story presented above was published with permission.

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I had a transcatheter aortic valve replacement (TAVR) with an Edwards Lifesciences valve for symptomatic aortic valve stenosis. I had had severe aortic stenosis by echocardiography for at least two years, but I was asymptomatic and capable of riding my bike up to 75 miles in the western Connecticut hills with no symptoms. But when symptoms appeared, I got the valve fixed as detailed in 500 Rules of Cardiology. (1)

My last blog stated:

“It is especially important now for clinicians to continue to critically evaluate common medical wisdom because so many studies of new drugs and devices are designed and funded by the manufacturers, and then published in journals supported by the same companies. I say that despite being a clinician who is eternally grateful to industry for the wonderful drugs and devices they have invented. It’s just that sometimes the enthusiasm exceeds the evidence.

I don’t like criticizing industry because they have given us so many great drugs and devices to help our patients, but within a week of my blog, an article in Medpage reignited my concern that we clinicians are being manipulated to do what pharmaceutical and device companies want, and not always what’s best for patients.

The Medpage article on Jun 26, 2026, entitled “Aortic Stenosis Patients Still Tripped Up by Diagnosis Issues on the Path to AVR” stated that according to a national registry: “U.S. patients flagged with moderate or severe AS, based on an initial echocardiogram, ended up getting all their confirmatory diagnostic assessments within 30 days in 61.4% of cases in 2024, up from 54.2% in 2023 (P=0.001), per the American Heart Association’s Target: Aortic Stenosis registry. Among those with a class I indication for aortic valve replacement (AVR), the goal of timely treatment was achieved by 84.7% in 2024, no significant change from 82.2% the year before. This meant that nearly one in six eligible individuals did not get AVR within 90 days….”

This delay was described as a “gap in care”. These data were presented at the New York Valves conference and simultaneously published in Circulation. The MedPage article also stated that “There’s been a small but ‘alarming’ bump in aortic stenosis (AS) deaths among people ages 45 to 74 in recent years, according to nationwide trends” and that “… prior studies have suggested increased wait-time mortality during periods of rapid adoption of TAVR, which has been thought to explain the overall uptick in AS deaths in recent years.”

Wow. That is scary. We clinicians are allowing a gap in care, and an “increase in mortality” and an “uptick in AS deaths”. We better start hustling these patients to surgery or TAVR faster. But when you check the article on wait-time, it refers to patients with symptomatic severe aortic stenosis.(2) Symptomatic severe aortic stenosis is a different animal than asymptomatic severe aortic stenosis. And when you look up articles on the uptick in AS deaths, the change is extremely small and not significant. The increase in one study was 1.75%. The cause is unclear.(3) It is unusual to see an increase with the appearance of a new, effective, non-surgical treatment such as TAVR. (3) It’s possible (but not discussed) that the increase could be related to more frequent and earlier use of TAVR procedures in asymptomatic AS patients because the procedure is so much less invasive than surgical repair.

But who has the time to look up the reference articles? Clinicians should be able to trust what is written in medical journals and in lay literature for clinicians. The MedPage article is not wrong, just…slanted. I looked up the references because I delayed my TAVR until I had symptoms. I also try to delay interventions in my truly asymptomatic patients because if I can delay the procedure several years, it might just be enough to enable them to be “one and done” and not require a redo. So, that is my bias. But I think that many of these articles push clinicians to earlier, and more, interventions. Who wants to be wrong? Doing something is better than doing nothing, or is it? Early may be the right approach but many times the justifying data are absent. For example, those studies showing clinical benefit from TAVR in asymptomatic patients obtained their clinical benefit primarily by reducing heart failure admissions and not by reducing deaths, strokes, or the stuff we really care about.

The Circulation manuscript does not list who funds the AHA’s registry but Google AI says that Edwards Lifesciences funds it. Hmmm.

And then there are the physician financial incentives.

I have a relative with Parkinson’s who developed atrial fibrillation. He was referred to a cardiologist who refused (yes, refused) to treat him with a novel anticoagulant because of the Parkinson’s, and told him that without an atrial occlusion device he would have a stroke. My relative was scheduled for the device, a procedure which the cardiologist just happened to perform. My relative was so frightened by the cardiologist’s refusal to discuss other options, that he called me. My relative has never fallen and does non-contact, Parkinson’s boxing therapy weekly. Neither I nor my electrophysiologist colleagues thought my relative had an absolute contraindication to a novel oral anticoagulant. My relative changed cardiologists.

So, the Rule is: Surround yourself by expert clinicians whose opinion and recommendations you can trust. I feel fortunate to have my cardiology colleagues at Hartford Healthcare because our clinicians are largely salaried, and the culture is to do what is right for the patient.

None of us can know everything so we have to depend on others. But pay enough attention to the medical literature so that you can make some evaluation on your own and recognize when others may be slanting their opinion. Just another example of “Trust but Verify”.

1. https://pauldthompsonmd.substack.com/p/biking-75-miles-to-my-tavr

2. Albasam O, et. al. Increasing Wait-Time Mortality for Severe Aortic Stenosis: A Population-Level Study of the Transition in Practice From Surgical Aortic Valve Replacement to Transcatheter Aortic Valve Replacement. Circ Cardiovasc Interv. 2020 Nov;13(11) PMID: 33167700

3. https://www.tctmd.com/news/concerning-trends-seen-aortic-stenosis-related-mortality-cdc-wonder

#medicalcare; #TAVR; #EdwardsLifesciences; #aorticstenois; #heartvalve; #atrialocclusion; #atrialfibrillation; #conflictofinterest

Graph of Subscribers to 500 Rules of Cardiology

On June 22, 2026 500 Rules of Cardiology reached 7,000 subscribers. That’s a lot of people, and I don’t take writing for you all lightly. I try to write about clinically important issues, in a way that makes reading the pieces interesting.

I acknowledge that my blog’s title, 500 Rules of Cardiology, is presumptuous, but I want to assure you that these “Rules” are what I think is correct, and that I do have some medical credibility. I have written over 500 peer-reviewed manuscripts, which have made some contribution to the literature. For example:

We were early (1) in addressing the cardiac dangers of exercise in 1979. The story behind that is that a runner died in a local running road race when I was training in cardiology at Stanford. I was discussing the death at work in the Stanford Heart Disease Prevention Program. Mike Stern, MD was an endocrinologist there and mentioned that he had collected several newspaper reports of similar events. Kevin Duncan, a medical student from Kansas, and I expanded that collection, collected data from the victims’ families and physicians, and published the results in JAMA. (1) That report was important because at that time, Dr. Thomas Bassler, a charming California pathologist and one of the founders of the American Medical Jogging Association, had created the medical myth that running a marathon conferred immunity to atherosclerotic cardiovascular disease (ASCVD). He did this by writing letters to the editors of major journals and by citing his prior letters on this hypothesis as documentation of its veracity. PubMed lists 66 publications to TJ Bassler, most of which fit that description.

Our original paper led to our being among the first, if not the first, to quantify the risk of vigorous exercise. That project collected jogging deaths in the state of Rhode Island, a state with one medical examiner’s office. This was run by Bill Sturner, MD (1934-2016). (2) Bill was able to collect data on all the deaths during jogging in the state because sudden deaths require an evaluation. We used state data on the frequency of jogging to estimate a yearly death rate during jogging of one death per 15,200 ostensibly healthy joggers. This absolute risk was low, but the relative risk of death during jogging was seven times higher than the risk during more sedentary activities. This study predated David Siscovick’s classic 1984 New England Journal of Medicine (NEJM) publication of cardiac arrests in Seattle, which also showed an increased risk of arrest during exercise and a yearly risk of one death per 18,000 joggers.(3) It was reassuring to obtain similar death rates from two sides of the country.

The interest in the risk of exercise continues and now includes a NEJM Reviews article on increased coronary atherosclerosis, myocardial fibrosis, right ventricular enlargement, atrial fibrillation (Afib), and aortic size in life-long endurance athletes. (4) But reports on the side-effects of too much exercise, have not come easily. Our first article on increased rates of Afib in life-long athletes was doubted and rejected by the major journals until I finally published it in the British Journal of Sports Medicine, (5) a good, but lesser known journal.

We also published one of the first reports of a cardiac events with cocaine use at a time when the cardiac risks of cocaine were underappreciated. Our report was that of a 21-year-old male who was given cocaine as a wedding present, and suffered an inferior wall MI on his wedding night despite having normal coronaries. (6) We also contributed three of the seven cardiac cases reported by my Tufts medical school classmate, the late Jeff Isner (1947-2001), in his seminal NEJM report on cocaine heart disease. (7) My three cases came from another collection Bill Sturner and I were compiling in Rhode Island.

With Peter Herbert, MD, I had 11 years of NIH funding to examine how exercise training affects high density lipoprotein (HDL) metabolism. We did, what are to my knowledge, the only studies on HDL catabolism in distance runners using radioactive iodine to track the HDL proteins. Peter taught me how to purify HDL, labelled it with ¹²⁵I and inject it back into me and some of my running friends to measure HDL catabolism. These runners were not just your average joggers; three of the five subjects in our first study (8), including me, had qualified for the USA Olympic Marathon Trials. We documented that HDL levels were increased in the athletes, primarily because of reduced HDL catabolism. We thought that the reduced catabolism was likely due to reduced levels of triglycerides in the HDL particles, which prolong the particles’ survival. (9)

I have discussed our studies on statin myopathy in several prior blogs.(10-17) We were early to this topic and made some contributions, especially with the STOMP study. (18)

This summary is not bragging or to tell you to blindly trust what I post here, because all of my research projects have taught me one thing – trust, but verify. What I write in the blog is what I think is right, but I remember using procainamide to treat premature ventricular contractions and atrial fibrillation. We thought we were doing the right thing, but we were probably killing people. Several of our “contributions” contradicted current wisdom such as: Exercise is totally protective against ASCVD, you cannot do too much exercise, cocaine is safe, and statins have no muscle side effects without large creatine kinase elevations.

It is especially important now for clinicians to continue to critically evaluate common medical wisdom because so many studies of new drugs and devices are designed and funded by the manufacturers, and then published in journals supported by the same companies. I say that despite being a clinician who is eternally grateful to industry for the wonderful drugs and devices they have invented. It’s just that sometimes the enthusiasm exceeds the evidence.

So my experiences have taught me to question what I, and others, think is true. As you 7,000+ subscribers read what I write and what I think is true, I hope that you will also “Trust but Verify.”

Please continue to read this blog and encourage your friends and colleagues to do so as well. I would like to reach 8,000 subscribers. But verify my thoughts with your own experiences. If the principles I suggest work, add them to your own Rules. But be careful because … rules are made to be broken.

1. Thompson PD, Stern MP, Williams P, Duncan K, Haskell WL, Wood PD. Death during jogging or running. A study of 18 cases. JAMA. 1979 Sep 21;242(12):1265-7.PMID: 480538

2. Thompson PD, Funk EJ, Carleton RA, Sturner WQ. Incidence of death during jogging in Rhode Island from 1975 through 1980. JAMA. 1982 May 14;247(18):2535-8.PMID: 6978411

3. Siscovick DS, Weiss NS, Fletcher RH, Lasky T. The incidence of primary cardiac arrest during vigorous exercise. N Engl J Med. 1984 Oct 4;311(14):874-7. PMID: 6472399

4. Thompson PD, Eijsvogels TMH, Kim JH. Can the Heart Get an Overuse Sports Injury? NEJM Evid. 2023 Jan;2(1): PMID: 38320102

5. Sorokin AV, Araujo CG, Zweibel S, Thompson PD. Atrial fibrillation in endurance-trained athletes. Br. J Sports Med. 2011 Mar;45(3):185-8. PMID: 19654095

6. J S Schachne, B H Roberts, P D Thompson. Coronary-artery spasm and myocardial infarction associated with cocaine use. N Engl J Med. 1984 Jun 21;310(25):1665-6. PMID: 6727939

7. Isner JM, Estes NA 3rd, Thompson PD, Costanzo-Nordin MR, Subramanian R, Miller G, Katsas G, Sweeney K, Sturner WQ. Acute cardiac events temporally related to cocaine abuse. N Engl J Med. 1986 Dec 4;315(23):1438-43. PMID: 3785295

8. Herbert PN, Bernier DN, Cullinane EM, Edelstein L, Kantor MA, Thompson PD. High-density lipoprotein metabolism in runners and sedentary men. JAMA. 1984 Aug 24-31;252(8):1034-7.PMID: 6748208

9. Thompson PD, Cullinane EM, Sady SP, Flynn MM, Chenevert CB, Herbert PN. High density lipoprotein metabolism in endurance athletes and sedentary men. Circulation. 1991 Jul;84(1):140-52. PMID: 2060090

10. https://pauldthompsonmd.substack.com/p/whats-the-boston-marathon-got-to

11. https://pauldthompsonmd.substack.com/p/statins-increase-exercise-induced

12. https://pauldthompsonmd.substack.com/p/finally-a-proper-study-of-exercise

13. https://pauldthompsonmd.substack.com/p/the-risks-and-benefit-of-statin-treatment

14. https://pauldthompsonmd.substack.com/p/stomp-the-effects-of-statins-on-muscle

15. https://pauldthompsonmd.substack.com/p/its-bogus-to-use-n-of-1-studies-to

16. https://pauldthompsonmd.substack.com/p/some-patients-will-take-anything

17. https://pauldthompsonmd.substack.com/p/what-do-mushrooms-have-to-do-with

18. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, Chipkin S, Pescatello LS, Simpson K, White CM, Thompson PD. Effect of statins on skeletal muscle function. Circulation. 2013 Jan 1;127(1):96-103. PMID: 23183941

#exercise; #exercisecomplications; #cocaine; #atrialfibrillation; #myocardialfibrosis; #rightventricule; #aorticsize; #athletes; #HDL; #runners

Reproduced from Ramasinghe C, Xu B. Journal of Agriculture and Food Research 25 (2026)

Eight out of my last 11 posts have discussed statin associated muscle symptoms (SAMS) and the debate as to whether or not SAMS exists and its incidence. This post addresses a subject where there is no debate; that statins can produce Statin Associated Auto Immune Myopathy (SAAIM). This is extremely rare, except in some ethnic groups, but all clinicians should know of SAAIM and how to manage it because failure to recognize and treat SAAIM can lead to severe disability…wheelchair type disability.

Let’s start with a train of emails between me and a very capable clinical cardiologist.

Email to me - August 17, 2020: I have a patient who has been on high intensity statin since 2013 for an LAD stent. 3 weeks ago she told me she has had diffuse muscle aches since December. I stopped the statin and checked her CPK which was elevated at 5,600 (my note- normal is less than 200 U/L).. After 3 weeks she only feels partially better. I was going to give her another 2-3 weeks. If she was still symptomatic I was going to consider a rheum consult for muscle biopsy. Thanks

My Reply - August 17, 2020: She may have Statin Associated Auto Immune Myopathy (SAAIM). These patients develop auto anti-bodies against HMG Co-A reductase. Andy Mammen’s group at the NIH and Johns Hopkins, found a protein in a lot of patients with unexplained myopathy, 63% of whom had been on statins. (1) He later documented that it was an anti-statin antibody. (2) (My note - it is actually an antibody against HMG CoA reductase.) If she had garden variety statin myalgia/myopathy she should have gotten better after a week or two off statins. Most patients with usual statin myopathy get better fast. The persistent symptoms and the persistently highly elevated CK makes SAAIM a possible diagnosis. Get another CK right away and order HMG CoA reductase antibodies. They are available in Quest. If the CK is still up and antibodies are positive, CALL (I mean CALL) a rheumatologist because she may need immunosuppression with steroids, methotrexate, etc. This is a bad disease that can cripple people and does not usually stop on its own. Dr. Mammen published a short summary in the NEJM.(3)

Follow-up email - Sept 2, 2020: Just to give an update. Her CPK had doubled and HMG CoA reductase antibodies were positive at 93. I had her see a rheumatologist who started steroids. Thanks for your help again.

Now a Discussion and the Rules

SAMS does not usually have markedly elevated CK levels. Although CK levels can increase in garden variety SAMS, the increase is usually small and the CK rarely exceeds 10 times the upper normal limits. Large CK increases in patients on statins, when they do occur, are usually transient and often occur after more-than-usual exercise. Garden variety SAMS also does not cause muscle weakness. SAMS patients may complain of weakness, but we did not find weakness on formal testing in our studies. Weakness in a SAMS patient should make you worry.

Most SAMS improves markedly or resolves completely within one to two weeks after stopping the statin. In contrast, SAAIM persists despite drug cessation. SAAIM is caused by antibodies against hydroxy-methyl-glutaryl CoA (HMG CoA) reductase, the rate limiting enzyme in cholesterol-mevalonate pathway. Statins inhibit HMG CoA reductase. Somehow that statin causes the immune system to develop antibodies against the statins’ target enzyme. SAAIM may persist after stopping the statin because of “satellite cells.” Satellite cells are pluripotential cells that repair injured skeletal muscle and contain lots of HMG CoA reductase to make cholesterol to make cell membranes during the repair. This constant supply of HMG CoA reductase perpetuates the inflammation/injury until the patient is treated with immunosuppression.

Another possibility is that statins in the environment continue the inflammation process. There is a lot of lovastatin in fungi, like Chinese Red Rice Yeast, which most clinicians know contains lovastatin and thereby lowers cholesterol. But umbrella mushrooms (Pleurotus ostreatus), the mushrooms at salad bars Pre-COVID, also contain statins. Umbrella mushrooms are 9% lovastatin by dry weight. (4) Dr. Mammen’s initial reports on the myopathy included some patients who were never on statins, and he suspects that their disease was induced by environmental statins.

SAAIM is rare, but is now recognized more frequently because a blood test for HMG CoA reductase antibodies is available. The condition was also probably frequently missed. I remember a patient referred to me from New York probably 25 years ago, who had persistent myositis after being treated with statins. I did not think the statins were causative primarily because the patient’s visit predated recognition of SAAIM. There are also probably mild cases that are missed, so it is probably smart to obtain the antibody test if a patient has symptoms atypical for garden variety SAMS and an elevated CK.

SAAIM is rare and estimated to occur in only 0.002% of statin treated patients .(5) That’s 2 in 100,000 statin-treated patients, but there are exceptions. An incidence of 0.3% (3 in a 1000) has been reported among native Americans in Arizona. Andy and colleagues also reported an incidence of 0.3% among patients at the Gallup Indian Medical Center in New Mexico. (5) This rate is about 150 times that for the general population. Such observations suggest that clinicians should have a higher threshold for stating statins in this native American group and a higher suspicion of SAAIM if SAMS appears.

I searched PubMed using “statin associated autoimmune myositis” AND “native Americans” to see if there were articles on the SAAIM incidence in other native American tribes outside of the Southwest, but I found no citations. Dr. Google Ai said that the incidence was increased only in Southwestern tribes, but buyer beware.

There is a genetic predilection for SAAIM. The class II human leukocyte antigen (HLA) DR 11 is present in 70% of patients with SAAIM but in only 18% of comparison subjects.(5) The prevalence of this genotype in native Americans in the Southwest and in other areas is unknown, but genetic differences are likely responsible for the higher incidence in this population group.

I wonder if the dry Southwestern climate might have predisposed Southwestern tribes to develop SAAIM. Fungi grow in wet, dark areas, which is not the Southwest. So maybe failure to be exposed to fungi during childhood contributes to developing an immune response later. Alternatively, perhaps native Americans living in the Southwest with a genetic predilection for SAAIM were able to thrive and reproduce because they were not exposed to statin-producing fungi, whereas this genetic predilection was eliminate from humans living elsewhere because of their frequent exposure to the antigen from statin-producing fungi. All of this is pure speculation on my part.

I do think knowing about statins from mushrooms and fungi is useful. I use it to remind statin-averse patients that statins have a “natural” origin. I used to tell patients that lovastatin was made by a bunch of fungi living in a vat and working for Merck.

The Rules:

1. SAMS does not usually have markedly elevated CK levels.

2. SAMS does not usually cause muscle weakness.

3. SAMS should improve markedly or resolves completely within one to two weeks after stopping the statin.

4. Untreated SAAIM can lead to wheel-chair-requiring disability.

5. Order an anti-HMG Co A reductase antibody level if a “SAMS” patient has persistently elevated CK levels or weakness, or does not improve promptly with statin cessation because patients with SAAIM often require immunosuppression to stop the disease

6. CALL the rheumatologist to get the patient seen promptly once the diagnosis is made.

7. Advise against mushroom consumption in patients with SAAIM.

8. Have a higher threshold for starting statins in native Americans from the Southwest and have a higher suspicion for SAAIM in individuals with this ancestry.

9. Remind statin-wary patients that lovastatin, one of the first commercially available statins, was made by fungi working for Merck.

References

1. Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL. A novel autoantibody recognizing 200-kd and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum. 2010;62(9):2757-2766.

2. Mammen AL, Chung T, Christopher-Stine L, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum. 2011;63(3):713-721.

3. Mammen AL. Statin-associated autoimmune myopathy. N Engl J Med. 2016;374(7):664-669.

4. Ramasinghe C, Xu B. New insight into occurrence, quantification and bioactivities of lovastatin from natural resources (mushroom, red yeast rice and tea). Journal of Agriculture and Food Research 25 (2026) 102621

5. Wei J, Ketner E, Mammen AL. Increased risk of statin-associated autoimmune myopathy among American Indians. Arthritis Rheumatol. 2022 Sep;74(9):1602-1603.PMID: 35333459

#statinmyopathy; #statinmuscles; #andrewmammen; #statinassociatedautoimmunemyositis; #statinsideeffects; #nativeamericans; #navajo; hmgcoareductaseantibodies; #hmgcoreductase; #myopathy; #fungi; #Merck; #lovastatin; #AndrewMammen

The Cover of the Book Beth and I Edited on SAMS

Seven out of the eight most recent posts have dealt with statin-associated muscle symptoms (SAMS), but we are not yet finished with SAMS.

This post addresses how I manage muscle complaints in patients on statins. My opinion is based on clinical experience dealing with a lot of statin-intolerant patients and on my being the principle investigator on two, and a participating investigator on two more, NIH grants to our SAMS group at Hartford HealthCare.

Here’s my approach.

1. I take a history to see if the symptoms sound statin-related. The Taylor and Rosenson, National Lipid Association’s SAMS Clinical Index Score (1) with caveats (2) is a useful starting point. Like the Score, I am less suspicious if the symptoms are unilateral, associated with recent exercise, and occur in small muscle groups. I am more suspicious if the symptoms occurred after statin dose escalation.

2. I make sure the patient is not weak. Our studies demonstrate that weakness is rare with statin complaints. If the patient is weak, they might have Statin-Associated Autoimmune Myopathy (SAAIM), which can lead to serious, irreversible muscle damage.(3) We will discuss this important entity in a future post.

3. I look for other drugs that could have contributed to the statin becoming symptomatic, especially gemfibrozil and the -mycin antibiotics.

4. I measure creatine kinase (CK) levels. High CK levels are also an indicator of SAAIM. Most patient with SAMS do not have abnormal CK levels, but average CK levels are often slightly higher in true SAMS. We found this is the “SAMS verification phase” of our Co-enzyme Q10 grant discussed below. (4)

5. I stop the statin and monitor the response. Rapid resolution of symptoms within one-two weeks suggests that the statin is the culprit.

6. I reevaluate to make sure that the patient needs the statin. I don’t think statins should be in the water. Deciding if the patient needs the statin is always a difficult decision for me, because I do think statins benefit most patients, but some patients suffering with statins have no family history, no elevation in lipoprotein and no diabetes or prediabetes, so I wonder if they are really benefitting from lipid lowering. Coronary artery calcification scores imply a low 10-year risk of atherosclerotic cardiovascular disease (ASCVD), (5) but are not useful in the young because calcified disease has not had time to develop. But sometimes I am referred older patients with SAMS and a zero CAC. Such folks are unlikely to benefit from lipid-lowering so I cure the SAMS by stopping the statin.

7. I try another statin. My experience is that patients with SAMS get similar complaints with other statins. The exception may be pitavastatin, which is often, for unclear reasons, tolerated, but it is sometimes hard to get and sometimes not covered by insurance despite being generic.

8. If the symptoms went away with statin cessation, and the patient is willing, I try a lower dose of the statin. I have discussed previously that you get the largest LDL-C reduction per mg of statin at very low statin doses. (6) The longer-acting statins, atorvastatin and rosuvastatin, do not have to be given daily. We gave rosuvastatin, 5 or 10 mg, but primarily 5 mg, twice weekly to 40 of my clinic patients with possible statin myalgia and documented a 27% LDL-C reduction after only 4 weeks of treatment.(7). To my knowledge this only occurs with the longer acting statins.

9. I use ezetimibe 10 mg daily, either alone or preferably combined with a low-dose statin. I have discussed that doubling the dose of a statin produces only a 6% additional reduction in LDL-C whereas ezetimibe produces a 20% average LDL-C reduction if the patient is not on a statin and a 24% reduction if they are on a statin. (6) The larger percent reduction on a statin is probably due to the fact that the statin has already reduced the LDL-C, so the ezetimibe contribution is a larger percent of a similar reduction, or because statins increased intestinal cholesterol absorption. Many patients can reach their LDL-C goal with low dose or intermittent statin plus ezetimibe. Ezetimibe can also be given twice or thrice weekly because it also has a long half-life.

Some think that ezetimibe doesn’t work if the patient is already on a low-cholesterol diet. According to Dr. Google AI, the average American man or woman consumes about 348 and 242 mg of cholesterol daily whereas your liver excretes about 1000 mg daily in the bile. So, there is still plenty of intestinal cholesterol available for ezetimibe, even when the patient is not consuming much cholesterol.

10.If the statins are not tolerated, I consider bempedoic acid (BA) or Nexletol. Bempedoic acid has been documented to reduce ASCVD events in statin-intolerant subjects in the CLEAR Outcomes Trial.(8) Bempedoic acid works at a step in the stain pathway above hydroxy-methyl-glutaryl Co A reductase where statins work. Bempedoic acid does not appear to cause muscle effects. I previously discussed why this make sense. (9) To summarize that post, bempedoic acid is orally administered as a pro-drug. It has to be activated in the liver by a long-chain fatty acid reductase. This enzyme is present primarily in the liver with some in the kidney. If bempedoic acid slips by hepatic first pass metabolism and gets to skeletal muscle, the muscle does not have the enzyme to activate the drug.

I generally tell that metabolism story to patients because I think it helps them believe that the drug will not reproduce SAMS.

BA does have some baggage. It interferes with the renal excretion of creatinine and uric acid. The creatinine increase produces pseudo kidney impairment because the creatinine returns to baseline with drug cessation, but this creatinine increase often frightens patients and unaware clinicians. The CLEAR-Outcomes study documented that BA reduces cardiac events, (8) I was on that study’s executive committee and helped write the manuscript. I argued that we should not label the increase in creatinine “kidney injury” because it was not truly kidney injury. My objection failed. The increase in uric acid is more clinically significant because this can provoke gout so I do not use the drug in patients with a history of gout unless their uric acid is very low with treatment. Another issue with bempedoic acid is that some insurance companies won’t cover it or require a large copay.

11. I try red rice yeast (RRY) with or without ezetimibe. We participated in a study that failed to show that RRY was better tolerated than pravastatin in SAMS patients, (10) but RRY does contain a lot of lovastatin and does reduce LDL-C to a variable degree depending on the formulation. The use of RRY is discouraged by most authorities because it may contain citrinin, a renal toxin, if the citrinin is not removed by the manufacturers. The effect on LDL-C also varies by the batch of the product, which is another issue. But RRY does lower LDL-C and is often tolerated by those who do not like standard prescriptions. The usual over-the-counter dose is 1200 mg daily.

12.If the patient is willing, I might try colesevelam to reduce LDL. A packet of colesevelam before dinner can produce about a 17% reduction in LDL-C. Combined with ezetimibe, you can approach a 35% reduction. Bile-acid sequestrants are now out of favor because significant LDL-C reduction previously required large doses of the drug. For example, in the Lipid Research Clinics Primary Prevention Trial, we gave patients six packets of cholestyramine daily…the so-called “six pack.” But each molecule of cholestyramine had only one binding site for a molecule of bile acid. Colesevalam is engineered so that one molecule binds six molecules of bile acid/bile salt. Thus the six pack is now the one pack.

So, why before dinner? Dinner is usually the fattiest meal of the day and fat stimulates cholecystokinin, which stimulates contraction of the gall bladder to deliver bile to the gut. Thus, you get a bigger reduction if the drug is given near the fatty meal because it encounters more bile.

13.If the above does not work, I start the patient on a PCSK9 inhibitor, either the every-other-week monoclonal antibodies, Alirocumab or evolocumab, or the twice yearly mRNA inhibitor, inclisiran.

14.Sometimes I recommend Coenzyme Q10 (CoQ10)

Clinicians frequently ask me if Coenzyme Q10 (CoA10) works for patients with SAMS. CoQ10 is an important enzyme in mitochondrial function. Statins interfere with CoQ10 synthesis because CoQ10 is, like cholesterol, a product of the mevalonate synthetic pathway. CoQ10 blood levels decrease during statin therapy, but I had thought that this was due to the fact that CoQ10 is carried in lower density lipoproteins.(11) So, the decrease in CoQ10 could be due to the statin reducing the LDL or/and because statins had reduced CoQ10 production. I began to question my opinion that lower CoQ10 levels were due to lower LDL levels when I learned that blood CoQ10 did not decrease with bile-sequestrant resins or with PCSK9 inhibitors. There were some studies that suggested that CoQ10 did reverse symptoms in some SAMS patients, but these studies did not document that the patients’ symptoms were due to the statin before treatment. I have written about my skepticism. (11)

So, we did an NIH-funded Co-Q10 study, but we made sure we were only treating patients with SAMS. We randomized 120 of my patients, whom I thought had SAMS, to two, two-month preliminary trials of simvastatin 20 or placebo separated by a 4-week washout. (4) In other words, before entering the CoQ10 study, potential subjects were treated with placebo or simvastatin for two months and then switched to the other treatment. Only subjects who felt pain only on the statin were allowed into the CoQ10 protocol. Only 35.8% of my patients, whom I thought had SAMS, developed pain only on the statin. Another 17.5% experienced pain on both treatments; 29.2% felt pain only on placebo, and 17.5% did not develop any symptoms. With this approach only verified SAMS patients were entered into the CoQ10 Trial.

I believe we designed the CoQ10 treatment protocol well. We used CoQ10 purchased from Tishcon Corp, a CoQ10 producer recognized in the CoQ10 research community. We loaded the patients with 600 mg of CoQ10 for two weeks before placing them on 600 mg daily therapy. The usual CoQ10 dose is 200 mg daily. We used the high CoQ10 dose of 600 mg daily, to avoid criticisms from the supplement community that we underdosed the subjects.

Serum CoQ10 levels increased from 1.3 ± 0.4 to 5.2 ± 2.3 mcg/mL with simvastatin plus CoQ10 treatment, and decreased slightly with simvastatin plus placebo treatment (1.3 ± 0.3 to 0.8 ± 0.2) (p < 0.05). Pain scores for severity and interference with daily activities increased with simvastatin therapy, but did not differ whether or not the subjects were treated with CoQ10 or not. There was no change in muscle strength or exercise performance measured as VO2max with simvastatin with or without CoQ10. CoQ10 also did not affect the time to pain onset. We concluded that CoQ10 did not prevent or reduce SAMS.

An interesting observation is that those patients who had verified SAMS (n=43) from our verification study had higher creatine kinase (CK) levels on simvastatin that those who were not verified (n=77), 152±80 vs 117±68 U/L, respectively, p<0.05. That observation just confirms my belief that SAMS is real in some patients.

Even though we did not find a CoQ10 effect, I have had patients who swear by it. So if patients suggest it or want to try it or a have a friend who recommended it, I encourage them to do it. I especially do this in those patients who are fans of over-the-counter (OTC) remedies, the ones who will “take anything except what I write on a prescription pad,” and in whom I wonder if their symptoms are due to SAMS. My standard line is, “Our studies suggest that CoQ10 does not work, but I have had some patients who swear by it. It just might work for you.” The usual dose is 200 mg of the OTC brands, but they are often expensive. Sometimes it works, possibly because it was the patient’s idea, but I don’t really care how it works. My goal is to get patients who need statins to take them.

1. Taylor BA, Sanchez RJ, Jacobson TA, Chibedi-De-Roche D, Manvelian G, Baccara-Dinet MT, Khan I, Rosenson RS. Application of the Statin-Associated Muscle Symptoms-Clinical Index to a Randomized Trial on Statin Myopathy. J Am Coll Cardiol. 2017 Sep 26;70(13):1680-1681. PMID: 28935043

2. https://pauldthompsonmd.substack.com/p/nothing-cures-statin-muscle-complaints

3. Mammen AL. Statin-Associated Autoimmune Myopathy. N Engl J Med. 2016 Feb 18;374(7):664-9 PMID: 26886523

4. Taylor BA, Lorson L, White CM, Thompson PD. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis. 2015 Feb;238(2):329-35. PMID: 25545331

5. https://pauldthompsonmd.substack.com/p/you-got-a-ticket-to-ride

6. https://pauldthompsonmd.substack.com/p/the-statin-rule-of-6

7. Gadarla M, Kearns AK, Thompson PD. Efficacy of rosuvastatin (5 mg and 10 mg) twice a week in patients intolerant to daily statins. Am J Cardiol. 2008 Jun 15;101(12):1747-8. PMID: 18549851

8. https://pauldthompsonmd.substack.com/p/bempedoic-acid-for-patients-with

9. Nissen SE, … Thompson PD,… et.al Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023 Apr 13;388(15):1353-1364. PMID: 36876740

10.Halbert SC, … Thompson PD, Rader DJ, Becker DJ. Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance. Am J Cardiol. 2010 Jan 15;105(2):198-204. PMID: 20102918

11.Zaleski AL, Taylor BA, Thompson PD. Coenzyme Q10 as Treatment for Statin-Associated Muscle Symptoms-A Good Idea, but . Adv Nutr. 2018 Jul 1;9(4):519S-523S. PMID: 30032220

#statinsideeffects; #skeletalmuscle; #statins; #exercise; #statinmyopathy #exercisemuscleinjury; #atorvastatin; #SAMS; #clinicaltrials #coq10

1970 - Ball State, Muncie, Indiana - L to Rt - David Costill, PhD, George Branan, MD, Ken Sparks, PhD, Craig Turner, Richard Bowers, PhD, Paul Thompson. Robert Gregor, PhD is the muscle biopsy subject.

I have had multiple patients who refused to take statins for various reasons, but who tolerated them just fine after they had a cardiovascular event. I distinctly remember my first patient to whom this happened. He was a man with genetic hyperlipidemia, whom I saw in the late 1990’s before Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9is) were available. He tried several statins under my direction but had different problems with all of them. He subsequently suffered an anterior wall myocardial infarction followed by heart failure, but he survived and is doing well. And now he has no trouble taking a high dose statin with ezetimibe. He is not my only patient with a similar story. I encourage appropriate patients to take statins, but have found that you cannot force the issue if they are not willing. Thus, the rule: Nothing Cures Statin Muscle Complaints Like a Heart Attack

Such a rule suggests that I don’t believe that Statin Associated Muscle Symptoms (SAMS) are real, but that is not true. I am convinced they exist as discussed in my May 26, 2026 post on our STOMP or STatins effect On Muscle Function and Performance study. (1) STOMP demonstrated that muscle complaints occurred in 4.6% of placebo-treated subjects and in 9.4% % of subjects treated for six months with atorvastatin 80 mg daily, the highest approved dose (P = 0·054).

But treatment in STOMP lasted only six month. I received several emails after the May 26, 2026 post from patients whose muscle complaints developed years after the start of treatment.

One was from Dave Costill, PhD, an internationally known exercise physiologist at Ball State in Muncie, Indiana. I spent the summer of 1970 with Dave as a research assistant and subject for studies of muscle glycogen metabolism in distance runners. I am reminded of my research subject role when I feel the small scars on my thigh where I had seven muscle biopsies performed in eight days. The picture is of Bob Gregor, PhD, getting one of his biopsies. The research protocol went like this:

• Get a lateral quadriceps muscle biopsy;

• Run ten miles;

• Get another biopsy right after the run;

• Repeat the ten mile run and muscle biopsy for two more days;

• Don’t run for 3 days and eat a high carbohydrate diet ;

• Get another biopsy on day eight.

The study showed that the running/carbohydrate protocol increased muscle glycogen (“glycogen loading”) probably by increasing glycogen synthetase activity. (2) That summer was my introduction to exercise physiology research and solidified my interest in exercise and ultimately cardiology. Dr. Costill subsequently established Ball State as one of THE powerhouses in exercise science. I have always been grateful to him for his impact on my career. I am also grateful for my seven muscle biopsies in eight days because whenever I had to do muscle biopsies for our statin muscle studies, I always told people, “A muscle biopsy is no big deal. I had six in three days.”

I still hear from Dr. Costill, who turned 90 on April 1, 2026. Dr. Costill continues to exercise by swimming almost daily. After my May 26, 2026 post, he wrote:

“My experience - 30 years with statins. Last 2-3 years developed extreme leg muscle fatigue, while doing common work around home and when having to stand for long periods. I also got muscle cramps at almost the same time each day during workouts. That happened consistently over last two years. Symptoms always seem to go away after about 20 minutes of rest. Those symptoms seem to have disappeared since I stopped taking statins about a week ago. I am hesitant to blame these improvements on a placebo effect, especially the cramping problem. I plan to continue the vacation from statins for another week and then get a blood value.”

There were several other notes which confirm my clinical experience that some patients develop muscle symptoms years after starting a statin. That observation is contrary to the only validated score to help decide if symptoms are due to a statin.(3) That scale was developed by Robert Rosenson, MD, Beth Taylor (now Parker), PhD and other and is as follows:

The National Lipid Association’s Statin Myalgia Clinical Index Score

Pain Characteristics

Regional Distribution

• Symmetric hip flexors/thigh aching 3 Points

• Symmetric calf aching 2 Points

• Symmetric upper body aching 2 Points

• Nonspecific, asymmetric, intermittent 1 Point

Symptom Onset After Starting the Statin

• < 4 weeks 3 Points

• 4-12 weeks 2 Points

• >12 weeks 1 Point

Improvement with Statin Discontinuation

• < 2 weeks 2 Points

• 2-4 weeks 1 Point

• No Improvement 0 Points

Statin Rechallenge

• Symptoms Reappear < 4 weeks 3 Points

• Symptoms Reappear 4-12 weeks 1 Point

The total is used to predict the possibility that the symptoms are SAMS as follows:

• 9-10 Points - Probably SAMS

• 7-8 Points - Possibly SAMS

• < 7 Points - Unlikely SAMS

This score is valuable in evaluating when muscle complaints are likely due to the statin, but the problem is that these criteria were “validated” using the STOMP data. STOMP lasted only six months and to qualify as medication associated muscle symptoms in STOMP, a subject had to develop new onset muscle symptoms unassociated with exercise, have the symptoms resolved within two weeks of drug cessation, and have the symptoms return within four weeks of restarting the drug. Using STOMP as validation probably biases the timeline for the development of symptoms to mimic the STOMP criteria.

This also emphasizes one of STOMP’s biggest issues – it was a brief treatment protocol given that statins are “life-long” drugs.

Another problem with STOMP is that we tried to objectively measure pain, which is a subjective symptom.

The STOMP study population was also young. We recruited men and women into three, equal-sized age groups, 20-39, 40 to 54 and over 55 years old. Muscle symptoms were more frequent in older subjects. The average age of the subject groups was 43.6 years for the atorvastatin group and 44.6 years for the placebo subjects, but the age of the subjects with qualifying muscle discomfort was 52.5 years for the atorvastatin and 58.9 years for the placebo subjects. STOMP would have probably had more complaints if we had studied older subjects.

My overall conclusion is that statins cause muscle symptoms. These occur in at least 5% of patients, probably more, but not all symptoms in patients on statins are due to the statin.

Here are the Rules:

- Statins cause muscle symptoms in at least 5% of patients, probably more.

- A cardiac event can often cure statin associated complaints.

- Statin associated muscle symptoms can appear years after starting statin treatment.

I am going to stop here to keep the postings brief. I am getting tired of writing about statins, but think we have three to go to address: the management of SAMS, the possible mechanisms, and the importance of not missing statin-induced necrotizing myositis.

1. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, Chipkin S, Pescatello LS, Simpson K, White CM, Thompson PD. Effect of statins on skeletal muscle function. Circulation. 2013 Jan 1;127(1):96-103. PMID: 23183941

2. Costill DL, Bowers R, Branam G, Sparks K. Muscle glycogen utilization during prolonged exercise on successive days. J Appl Physiol. 1971 Dec;31(6):834-8. PMID: 5123660

3. Taylor BA, Sanchez RJ, Jacobson TA, Chibedi-De-Roche D, Manvelian G, Baccara-Dinet MT, Khan I, Rosenson RS. Application of the Statin-Associated Muscle Symptoms-Clinical Index to a Randomized Trial on Statin Myopathy. J Am Coll Cardiol. 2017 Sep 26;70(13):1680-1681. PMID: 28935043

#Statins; #statinsideeffects; #statinmyopathy; #skeletalmuscle; #rhabdomyolysis; #statins; #exercise; #statinmyopathy #exercisemuscleinjury; #atorvastatin; #SAMS; #davidcostill; #robertrosenson; #bethtaylor

My last several posts have summarized some of our studies on Statin Associated Muscle Symptoms (SAMS). Our studies show that statins produce muscle symptoms including myalgia and cramps in about 5% of subjects treated with the highest doses of these drugs for short term periods. Consequently, I think some of these patients, not all, actually have what I call SIMS for Statin Induced Muscle Symptoms, but we’ll keep it simple and continue to use SAMS for Statin Associated Muscle Symptoms.

So, if STOMP (the effects of STatins On Muscle Function and Performance) (1) demonstrated an increase in SIMS in statin-treated subjects, albeit with a p value of 0.054, plus small increases in creatine kinase (CK) levels, why is there such persistent doubt that SAMS are real and caused by statins?

I think that “N-of-1” statin studies are a big contributor. “N-of-1” trials use an individual subject with SAMS as his/her own control and treat these subjects with multiple periods of statin or placebo. I know of three N-of-1 statin studies (and four publications), but they all have the same flaw.

The first statin N-of-1 study randomized eight patients with possible SAMS to three, three-week trials of their offending statin or placebo, separated by a three-week washout phase.(REF) All patients had developed myalgia within three weeks of starting their statin, which justified the brief treatment periods. Subjects were unable to distinguish when they were on the statin or placebo.

The second N-of-1 statin trial was first published as a letter. It randomized 60 SAMS patients to one-month trials of atorvastatin 20, placebo, or no pill at all over a year. (3) All patients had previously developed symptoms within two weeks of starting statin therapy. Symptom intensity was 8.0 on no pills, 15.4 on placebo and 16.3 on statin treatment. This demonstrated that even a placebo alone caused more symptoms than no pill at all and that statin or placebo treatment were indistinguishable. The results from this letter were subsequently published as the SAMPSON trial or the Self-Assessment Method for Statin side effects or Nocebo. (4)

The third N-of-1 SAMS study is StatinWISE or the Statin Web-based Investigations of Side Effects.(5) StatinWISE randomized 200 participants to 6 x 2-month treatment periods of atorvastatin 20 mg daily or placebo. Nine percent of the statin and 7% of the placebo subjects stopped the trial because of intolerable muscle symptoms, a non-significant difference. Unfortunately, only 151 of the 200 randomized subjects completed at least one pair of statin/placebo trials.

So, all three trials support the notion that SIMS and SAMS are bogus and not real. What’s my problem?

Most people think that research and science are like Lady Justice balancing the scales, but most studies find what they are designed to find. These N-of-1 trials were designed to confirm the suspicion that most SAMS complaints are not related to the statins. I agree that many, maybe most, but not all, SAMS are not caused by the statin. But these trials do not document that statin muscle symptoms do not exist because they did not document that these patients had SAMS before the study. Consequently, what these trials show is that many patients with SAMS do not have muscle symptoms due to the statin. These N-of-1 studies do not disprove the existence of SIMS because they didn’t document that the subjects had SIMS in the first place.

We have advocated verifying the presence of SIMS before enrolling subjects in SIMS/SAMS studies.

In our NIH-funded study of the effectiveness of Co-Enzyme Q10 (CoQ10) for treating SAMS, we randomized 120 of my patients, whom I thought had SAMS, to two, two-month preliminary trials of simvastatin 20 or placebo separated by a four-week washout. (6) In other words, before entering the CoQ10 study, potential subjects were treated with placebo or simvastatin 20 for two months and then switched to the other treatment. Only subjects who felt pain only on the statin were allowed into the CoQ10 protocol. Remarkably only 35.8% of my patients, whom I thought had SAMS, developed pain only on the statin. Another 17.5% experienced pain on both treatments; 29.2% felt pain only on placebo, and 17.5% did not develop any symptoms. With this approach only verified SAMS patients were entered into the CoQ10 Trial, which, by the way, did not work, but I’ll address that in another post.

Amgen’s GAUSS-3 Trial used our design to determine if 491 patients had verifiable SAMS before assigning subjects to injections with the PCSK-9 inhibitor, evolocumab, or placebo. (7) GAUSS-3 found results similar to ours: 42.6% had verified myalgia, 9.8% had pain on statin and placebo, 26.5% had pain only on placebo, and 17.3% did not develop pain.

What is striking in GAUSS-3 is that 42.6% had pain on atorvastatin only vs. 26.5% on placebo, a highly significant difference. Our CoQ10 study and GAUSS-3 were designed to evaluate specific therapies for SAMS. Both studies showed that many SAMS complaints are not SAMS, but GAUSS-3 confirmed that muscle symptoms are much more likely on a statin than on placebo.

So, these N-of-1 studies are useful in encouraging statin use, because they document that symptoms in many patients are probably not produced by the statin. But let me shout: THESE STUDIES DO NOT DISPROVE THE EXISTENCE OF SIMS, because they did not prove that the subjects had SIMS before the study.

Harlan Krumholz, MD, is a cardiologist at Yale, a respected clinician and clinical epidemiologist, and present editor of the Journal of the American College of Cardiology (JACC). He recently lamented the number of statin-worthy patients who do not take statins, and attributed much of this to the “nacebo effect”, which is the expectation of harm from a drug, the opposite of expecting benefit or the placebo effect.(8) To support his argument he cites the SAMPSON study (which I have addressed) and also results from the ASCOT-LLA or the Anglo-Scandinavian Cardiac Outcomes Trial - Lipid-Lowering Arm.

Dr.. Krumholz does not argue that SAMS does not exist, but he does suggest that we should address this by combating disinformation. I agree, but I do think we have to realize and accept that not all of these patients are just “making it up.” I have addressed SAMPSON above. As for ASCOTT-LLA, here is the letter that Beth Taylor, PhD and I submitted to Lancet . It was not accepted.

“Gupta and colleagues examined the frequency of muscle-related adverse events (MAEs) during the blinded and open-label, follow-up phases of ASCOT–LLA. (8) Only 2.03% of subjects per year treated with atorvastatin 10 mg daily and 2.00% of patients on placebo reported MAEs during ASCOT-LLA, but 1.26% of statin users and 1.00% of non-statin users reported MAEs during open-label follow-up, a relative risk of 1.41 with confidence intervals of 1.10–1.79 (P = 0.006). The authors use these results to support their hypothesis that MAEs on statins are primarily due to patient and physician concern that such symptoms may occur, the “nocebo” effect. But if there is a nocebo effect, why did the rate of muscle complaints go down from 2.03 to 1.26% when subjects knew they were on a statin? A nocebo effect should increase the rate of complaints. The 1.26% number did exceed the rate in folks not on statins in follow-up (1.00%), but why do the authors dismiss the possibility that this 26% higher rate represents real statin MAEs? Subjects who developed SAMS during the blinded phase were less likely to take statins during follow-up so the real rate of MAEs could have been higher than the 1.26% per year. How a nocebo effect can reduce reports of complaints needs to be explained.”

OK, enough. Here are the Rules:

1. N-of-1 statin studies do not prove that statin initiated muscle symptoms are Bogus.

2. N-of-1 statin studies do document that statins are not the cause of symptoms in many patients with statin-associated muscle complaints.

3. Even experienced clinicians (myself included) are not very good at deciding whose symptoms are caused by the statins.

One last comment. My clinical experience is that when I strong-arm or persuade a reluctant patient onto a statin, they are almost certain to get a “statin-related” complaint.

1. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, Chipkin S, Pescatello LS, Simpson K, White CM, Thompson PD. Effect of statins on skeletal muscle function. Circulation. 2013 Jan 1;127(1):96-103. PMID: 23183941

2. Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon JL. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160(5):301–310. doi: 10.7326/M13–1921 [doi].

3. Wood FA, Howard JP, Finegold JA, et. al. N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects. N Engl J Med. 2020 Nov 26;383(22):2182-2184. PMID: 33196154.

4. Howard JP, Wood FA, Finegold JA, et. al.Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment. .J Am Coll Cardiol. 2021 Sep 21;78(12):1210-1222. PMID: 34531021

5. Herrett E, Williamson E, Beaumont D, et al. Study protocol for statin web-based investigation of side effects (StatinWISE): A series of randomised controlled N-of-1 trials comparing atorvastatin and placebo in UK primary care. BMJ Open. 2017;7(12):e016604–2017–016604.

6. Taylor BA, Lorson L, White CM, Thompson PD. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis. 2015 Feb;238(2):329-35. PMID: 25545331

7. Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA. 2016;315(15):1580–1590. PMID: 27039291

8. Krumholz, HM. Time to Move Beyond the Statin Nocebo Effect. J Am Coll Cardiol. 2026 May 19;87(19):2549-2551.PMID: 42153682

9. Gupta A, Thompson D, Whitehouse A, et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet. 2017 May 2. PMID: 28476288

#Statins; #statinsideeffects; #statinmyopathy; #skeletalmuscle; #rhabdomyolysis; #statins; #exercise; #statinmyopathy #exercisemuscleinjury; #atorvastatin; #SAMS; #clinicaltrials #coq10 #harlankrumholz

My last post discussed the debate as to whether or not statins cause muscle side effects. (1) This debate is between excellent researchers, who perform large, randomized controlled clinical trials of statins (the Cholesterol Treatment Trialists’ [CTT] Collaboration), and clinicians, who primarily treat patients.

Whereas clinicians generally believe that statins can produce muscle symptoms without altering creatine kinase (CK) levels, clinical trialists doubt that this occurs. But our review of 44 clinical trials suggests that the clinical trials rarely specifically queried about muscle symptoms.(2) I have likened this to the US military’s previous approach to gay personnel: Don’t Ask, Don’t Tell. The opinion that statins did not cause muscle symptoms was so prevalent that the preferred term became “statin-associated muscle symptoms” (SAMS) and not statin “produced or caused” muscle symptoms. You could not get a paper on statins and muscle symptoms published without hedging the cause of the symptoms.

So, we designed STOMP or the Effects of STatins On Muscle Function and Performance study. STOMP was NIH-funded. (3) Three sites (and their principal investigators) participated: Hartford Hospital (me) , the University of Massachusetts, Amherst (the late Priscilla Clarkson, PhD), and the University of Connecticut, Storrs (Linda Pescatello, PhD). Beth Parker, PhD, now Beth Taylor, who worked with me at Hartford was the overall study leader, but many others made critical contributions including Michael White, PhD, Professor of Pharmacy at the University of Connecticut, who supervise the packaging of the statins and the identical placebo.

STOMP randomized 463 statin-naïve subjects to 80 mg of atorvastatin or placebo for six months. A total of 202 atorvastatin and 217 placebo subjects completed the study. We measured maximal, treadmill oxygen uptake, 14 measures of leg and muscle strength using a dynamometer, and CK levels at baseline and at the end of the study. Subjects were called every two weeks to inquiry about the presence of muscle symptoms.

Medication associated muscle symptoms required that a subject develop new onset muscle symptoms unassociated with exercise, that the symptoms resolved within two weeks of drug cessation, and that the symptoms returned within four weeks of restarting the drug.

There were no differences in muscle strength or exercise performance between the patient groups. More patients in the statin group (9·4%) met the study definition of myalgia vs the placebo group (4·6%) (P = 0.054). Average CK increased 21 U/L (P<0.001) with statin therapy. CK increased from pretreatment values to 6 months more often with atorvastatin (131 of 202, 64.9%) than with placebo treatment (87 of 217, 40.1%) (P<0.001) (4). Also, 24 atorvastatin subjects increased their CK >2x baseline levels compared to 12 placebo subjects (P = 0.02). (4) Greater increases in CK with atorvastatin did not deleteriously impact skeletal muscle performance or predict myalgia. No subject demonstrated a persistent CK greater than 10 times upper limits of normal, the accepted diagnosis of rhabdomyolysis at the time.

We concluded that statins produced muscle symptoms in approximately 5% of subjects and that statins produced a small increase in CK, an indicator of muscle injury, in more subjects than did placebo. Except for the myalgia, which was always mild and would probably not have affected statin compliance, there were no clinically detectable effects on muscle performance.

Statins are clearly well-tolerated by most patients and have been used widely without defined negative effects on skeletal muscle in the vast majority of patients. I remember Eugene Braunwald, MD, who died on April 22, 2026 at age 96, stating that he started lovastatin as soon as it was available (in 1988) and had used it all the rest of his life. I don’t know many middle-aged cardiologists who don’t take a statin. Nevertheless, it is interesting to question if these muscle outcomes have some role in statins’ ability to produce diabetes, for example, since the major disposal site for glucose is skeletal muscle. Also, I have seen some patients who I think did develop muscle weakness with statins.

To our knowledge, STOMP is the only randomized clinical trial that has carefully measured the effect of statins on exercise performance and skeletal muscle strength.

But to no surprise, the Oxford clinical trials group discounted these results. We had preplanned to exclude from analysis the 29 statin and 19 placebo patients who discontinued participation because of time, relocation, or non-muscle symptoms. The Oxford group reanalyzed our data, including these dropouts.(5) This produced myalgia rates of 8.2% for patients on atorvastatin and 4.2% for patients on placebo (p=0.08). We had not used this approach because we sought to determine symptoms in subjects actually taking the drug. I suggested that the Oxford group should perform a larger STOMP-like RCCT to make sure they are right in concluding that statin myalgia does not exist.

The Cholesterol Treatment Trialists’ (CTT) Collaboration has recently published an update on statin side-effects, which is slightly more accepting of the possibility of statin myalgia.(6) That publication states in the introduction:

“The main established adverse effect of statin therapy is myopathy, which occurs in rare cases (approximately one case per 10 000 person-years), or, in a more severe form, rhabdomyolysis (approximately 2–3 cases per 100,000 person-years), as indicated by muscle symptoms and related biochemical changes (eg, multi-fold rises in creatine kinase concentrations). In addition, statin therapy causes a small absolute increase (about 1%) in less severe muscle symptoms, although this excess is largely confined to the first year of treatment.”

I could be wrong, but STOMP suggests that the prevalence of “less severe muscle symptoms” is five times higher than that. The CCT group’s conclusions are again based on largely, “Don’t Ask, Don’t Tell” studies. Also, remember that “less severe symptoms” are the symptoms occurring in someone other than yourself.

I think the Rule is that statins cause muscle symptoms in about 5% of subjects treated with the maximum doses.

References:

1. https://pauldthompsonmd.substack.com/p/the-risks-and-benefit-of-statin-treatment

2. Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J. 2014 Jul;168(1):6-15. PMID: 24952854

3. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, Chipkin S, Pescatello LS, Simpson K, White CM, Thompson PD. Effect of statins on skeletal muscle function. Circulation. 2013 Jan 1;127(1):96-103. PMID: 23183941

4. Ballard KD, Taylor BA, Thompson PD. Statin-associated muscle injury. Eur J Prev Cardiol. 2015 Sep;22(9):1161. doi: 10.1177/2047487315586096. Epub 2015 May 6.PMID: 25948131

5. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388: 2532–61. PMID: 27616593

6. Cholesterol Treatment Trialists’ (CTT) Collaboration. Assessment of adverse effects attributed to statin therapy in product labels: a meta-analysis of double-blind randomised controlled trials. Electronic address: ctt@ndph.ox.ac.uk, et al. Lancet. 2026.PMID: 41655587

#Statins; #statinsideeffects; #statinmyopathy; #skeletalmuscle; #rhabdomyolysis; #statins; #exercise; #statinmyopathy #exercisemuscleinjury; #atorvastatin; #SAMS; #clinicaltrials

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This is the fourth post in a series on how statins affect skeletal muscle. The previous three were published on Substack on April 14 (1) , April 21 (2), and April 28, 2026.(3)

This Substack post introduces our randomized controlled trial on how statins affect muscle symptoms and performance; the results will be in a future post.

Lovastatin was approved by the FDA on August 31, 1987 and released By Merck as Mevacor, the first commercially available statin, shortly thereafter. Lovastatin was known to increase creatine kinase (CK) levels when approved, but shortly thereafter it was documented that statins could also cause clinically important rhabdomyolysis. The first report was a letter in the New England Journal of Medicine reporting rhabdomyolysis in four of six cardiac transplant patients, all of whom were being treated with lovastatin because of severe hypercholesterolemia.(4) The four with rhabdomyolysis were also treated with cyclosporine, and two were treated with gemfibrozil. Both of these drugs are now known to increase the risk of statin muscle injury.

The authors speculated that the rhabdomyolysis was due to the interaction of cyclosporine with the statin. Cyclosporine interferes with cytochrome 450 (CYP) 3A4, the enzyme which catabolizes many of the statins. Reducing CYP 460 3A4 activity would increase lovastatin blood levels. Cyclosporine also interferes with organic anion trans-porter (OATP) 1B1, which transport statins out of cell. Reducing OATP 1B1 activity would increase cellular lovastatin levels.

After this NEJM letter, it was widely accepted that statins could cause muscle injury with elevated CK levels and even frank rhabdomyolysis in certain clinical situations, but a controversial and important paper in 2002 expanded the scope of possible statin muscle side effects. This paper was written by Paul Phillips, MD, an invasive cardiologist in San Diego.

The report included four patients who had muscle symptoms on statins, but did not have CK increases. The patients were entered into a small, clinical trial in “a community hospital research center.” The patients were placed on statin or placebo, but were blinded as to what they were on. The outcome measures were the ability to identify statin use, muscle function and muscle biopsy results.

All four blinded subjects were able to identify statin use because of symptoms. Strength was tested by hip flexion and abduction, and decreased when on statins. Muscle biopsies showed evidence of mitochondrial dysfunction which reversed in three patients who had repeat biopsies off of the statin.

This paper was highly controversial and contributed to a 20+-year debate, that is still ongoing, as to whether or not statins could cause muscle symptoms without increases in CK levels. Clinicians, such as me, are convinced that they can whereas clinical trialists, led by Sir Rory Collins and the Oxford University statin research group, were convinced – on the basis of their clinical trials results – that statins could not cause symptoms without CK increases.

At times, this discussion became quite contentious. I remember a formal debate I participated in at an American Heart Association meeting where I debated Professor Jonathan Tolbert. Professor Tolbert was one of the primary developers of statins when he worked for Merck, and later worked with the Oxford Group on their clinical trials of statins. It was an honor to be asked to debate such a respected expert. After the debate, in which I think I did extremely well, I introduced myself to one of the senior members of the group, not Dr. Tolbert, and said something like, “We should have no hard feelings because reasonable people can disagree,” to which he replied with British frost, “Well, I do not want to be reasonable.”

I understand his position. The Oxford group does industry-supported clinical trials. Their trial results have important public health implications. They want these drugs used as widely as possible because statins at modest doses reduce atherosclerotic cardiovascular events by about 35% no matter what the population. That is called the “relative risk reduction” or RRR because it compares the risk reduction in that population with what happened in the same population without the statin. For example, if a drug reduced the number of heart attacks in a group of patients from 2 in 1000 to 1 in 1000, that would be a 50% absolute risk reduction, even though only one person benefitted. The more important number is the absolute risk reduction or the ARR. The ARR in the example would be one fewer heart attack in 1000 people or a 0.001% ARR. Another way to look at this is called the number needed to treat (NNTT) in order to prevent an event. In this example, the NNTT is 1000 to save one heart event.

This is a critical concept in the argument about statins. Statins are life-saving drugs but they are most beneficial in patients with the greatest risk of having a problem if not treated.

This concept is often left out of the statin debate.

But I digress. I understand the position of those who want to ignore possible statin side effects, but ignoring possible side effects has side effects of its own:

1. Clinicians come to disregard the patients’ complaints, which contributes to bad medical care.

2. Patients with complaints are dissatisfied with their clinicians who are ignoring their complaints.

3. Researchers seeking to study the complaints are not funded, so solutions and treatments are not developed.

So, my colleagues and I decided to examine why the statin randomized controlled clinical trials (RCCT) did not find any sign of muscle complaints. I, along with two of our best-ever cardiac hospitalists, Harsha Ganga and John Slim, did a systematic search and review of published databases to identify RCCT of statin therapy. We identified 1,012 published articles related to statin RCCT of which 42 qualified for analysis. CK values were reported only if above 10 times (X) the upper normal limit (UNL) in 15 trials, above 5 X UNL in 5 trials, and above 3 X in 22 trials. Four trials reported average CK values which increased in three trials. Muscle problems were reported in 26 trials and tended to be slightly higher in the statin group (12.7 vs 12.4%, P = .06). Remarkably, we found that only one of the trials reported that they specifically queried about muscle symptoms. We thought it sounded like, “Don’t ask, Don’t tell.”

We decided to do our own RCCT to examine the effects of statins on skeletal muscle symptoms and performance. We performed the Effect of Statins on Skeletal Muscle Function and Performance (STOMP) (6) Our study was not big enough to examine benefit, but we wanted to determine the frequency of muscle complaints and whether statins affected exercise performance. STOMP was NIH funded. The results will be in a future post.

Here are the key Rules so far:

- Medications, e.g. statins, prevent more disease events when given to a population of people at high risk of getting the disease.

- In order to know the possible benefit of a preventive treatment, you need to know not only the relative risk reduction (RRR), but also the absolute risk reduction (ARR) and the number of people you need to treat (NNTT) to eliminate one event.

- All medical treatments are a risk/benefit decision so that the other key measurement in deciding if to treat someone is the number of people you would need to treat to harm someone and the severity of possible harm.

References

1. https://pauldthompsonmd.substack.com/p/whats-the-boston-marathon-got-to

2. https://pauldthompsonmd.substack.com/p/statins-increase-exercise-induced

3. https://pauldthompsonmd.substack.com/p/finally-a-proper-study-of-exercise

4. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, Vladutiu GD, England JD. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002 Oct 1;137(7):581-5. PMID: 12353945

5. Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J. 2014 Jul;168(1):6-15. PMID: 24952854

6. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, Chipkin S, Pescatello LS, Simpson K, White CM, Thompson PD. Effect of statins on skeletal muscle function. Circulation. 2013 Jan 1;127(1):96-103. PMID: 23183941

#skeletalmuscle; #rhabdomyolysis; #statins; #exercise; #statinmyopathy #exercisemuscleinjury; #lovastatin; #clinicaltrials

Drawing Reproduced from the Web in commemoration of Dr. Braunwals’s Receiving the 2002 King Faisal Prize in Medicine

Dr. Eugene Brauwald died on April 22, 2026 at age 96. His contributions to cardiology are extraordinary. This article was first posted on January 20, 2026, but is repeated now in his memory of all he taught us.

Somewhere during my medical training, someone told me that if you really want to improve medical care, you should be a good teacher because teaching magnifies your effect. Dr. Thomas Lee’s book on Eugene Braunwald (1) states that when Braunwald took over as Chief of Medicine at the Brigham, he considered getting the right residency director as one of his most important tasks.

His reasoning? Having a strong residency director would create a competitive residency that would attracted the best residents, who would provide better care. The best of the best residents could subsequently be recruited to join the faculty. Having a strong residency program also makes an institution more attractive to attendings who like to teach.

One of the most important effects of teaching, is that the teacher gets smarter. I always say that “Teaching Teaches the Teacher” or T- 4. Dr. Braunwald also knew that his trainees would go elsewhere across the country and if the residents were well-trained, they would enhance the Brigham’s reputation. It’s an upward spiral. Dr. Braunwald recruited Marshall Wolff, who became a beloved leader of the Brigham residency program.

Good teachers make a place better. I am not referring only to teaching medical students and trainees. Constantly teaching nurses and other clinicians if done with respect and absolutely no condescension can improve clinical quality. A teaching environment also attracts job candidates to such an institution.

I once worked where we had lots of applicants for our advanced practice nurse (APRN) positions, despite not paying top dollar. I asked one of our APRN’s why she worked there when she could get more pay at just about any other hospital. She replied that her plan was to work there for a couple of years because the teaching/training was so good. She would then be more desirable at other places.

Teaching does not have to be formal or scheduled. Simply telling the staff, “I’m going to do this because …” makes the people we work with smarter. I start my clinical consult notes with, “Thank you for asking me to evaluate Mr. Jones. I made the following recommendations for the following reasons”. The goal is to make my consult notes educational, but does it work? I think so. When I first started the lipid management clinic at Hartford Hospital in 1997 approximately 5% of patients sent to me for hypercholesterolemia were hypothyroid. So, my first line would be: “I started Mr. Jones on thyroxine 25 mcg daily because his TSH is elevated indicating that he is hypothyroid. Hypothyroidism decreases LDL receptor activity, which reduces the clearance of LDL-cholesterol and increases LDL blood levels.”

After 29 years of such letters, almost no patient sent to me with hyperlipidemia is hypothyroid. I know that my notes are not totally responsible, but they might have contributed. I often lament that our present electronic medical notes almost never include the clinician’s reasoning for their recommendations. It’s a lost opportunity to improve medical care.

You do not have to practice at a teaching hospital to teach. Teaching the nurses and others around you is critically important. It makes their jobs more interesting, but also means that they can help you avoid oversights. And smart staff can also make suggestions to other doctors in the practice to help improve overall medical care.

Dr. Braunwald got it right, as he so often has. Being a good teacher and using every possible opportunity to teach creates an upward spiral for you, your clinical care and knowledge, and your institution. Good teachers should get more credit for the unmeasurable good they do to improve medical care.

1. Lee TH. Eugene Braunwald and the Rise of Modern Medicine. Harvard University Press, Cambridge, MA. 2013.

#teaching #medicalteaching #braunwald

Reproduced from Shutterstock by Subscription

The last several posts discussed statins and exercise-induced muscle injury. Several readers thought that I was a statin opponent, and cancelled their subscriptions. I never miss taking my statin, but much of my recent career has been examining the possible side-effects of statins on skeletal muscle. We’ll return to that theme in a couple of weeks to discuss what I think is the only randomized clinical trial (mine) designed to examine the effects of statins on skeletal muscle symptoms and performance.

Today I am going to repeat the piece on Professor Peter Schwartz and his work on Long QT Syndrome. That’s because Prof. Schwartz is presenting Cardiovascular Grand Rounds today (May 5, 2026) at Hartford Health Care. I cannot attend in person because Camilla and I are in Spain taking Spanish lessons, but those of you who can attend are in for a treat from a legend.

Here’s the post.

Many cardiologists, and especially electrophysiologists, know the name, Peter J. Schwartz, from Milan, Italy. Professor (Prof.) Schwartz is known for his work on Long QT Syndrome (LQTS) and sudden cardiac death (SCD), but he has also made significant contributions to related areas of cardiovascular medicine. I first knew of his work from his studies using a canine model to examine the role of exercise training in reducing SCD.(1) That model placed a reversible snare around the left anterior descending artery in dogs. The snare could be tightened to produce ischemia during exercise, and often ventricular fibrillation (VF). Prof. Schwartz and colleagues showed that the possibility of VF was markedly reduced after exercise training and that the VF risk returned after the dogs were detrained. They attributed this increased VF resistance to enhanced vagal tone.

These studies are important to those of us interested in the risks and benefits of exercise, but Prof. Schwartz’s greatest contributions are his studies of LQTS. Prof. Schwartz has recounted his 50 years in this field. (2). Here is a summary of that article. I have reviewed Dr. Schwartz’ career previously in PracticeUpdate, but that newsletter is no longer published.(3)

Prof. Schwartz’s paper starts with the lines, “This is not a review article on the long QT syndrome (LQTS). It is the account of a privilege. “ The privilege is to take care of the patients with LQTS. What a great reminder that it remains a privilege to practice medicine and to try to help patients.

Prof. Schwartz states that “It all started on 14 October 1970, during the most popular TV quiz program in Italy, shown in prime time and watched by millions”. During that show, a 19-year old, female contestant with a history of fainting during exertional and emotional stress responded to a question by collapsing and dying. She had previously been admitted to another hospital in Milan where her ECG was considered normal, but Prof. Schwartz later reviewed that ECG and found that the QT was markedly prolonged.

The autopsy of the quiz contestant was unrevealing, but the victim’s 9-year-old sister had similar symptoms so the mother had the sister admitted to the University of Milan Hospital. Prof. Schwartz was starting his clinical career, and was responsible for four clinical beds in the department of internal medicine. Fortunately, the daughter was admitted to one of his beds. Her ECG showed marked QT prolongation, but none of the senior physicians were impressed because at that time textbooks considered the QT interval as essentially useless information. As Prof. Schwartz writes, “That was my epiphany for the realization that textbooks can, and often should, be challenged.” The girl was scheduled for an exercise test, but became nervous when she saw the testing equipment and developed T-wave alternans, a harbinger of ventricular fibrillation. The test was cancelled.

Prof. Schwarz was able to implicate the prolonged QT as the cause through library research. This was well before PubMed and other computer search engines. Medical researchers used Index Medicus to search for relevant articles, and then had to physically find the article in the stacks of articles. Prof. Schwartz found the cases of prolonged QT reported by Jervell and Lange-Nielsen in deaf children and by Romano and Ward in patients with normal hearing. Almost all of the life-threatening cardiac events in these cases occurred during activities with increased sympathetic activity. Prof. Schwartz also wanted to know if T-wave alternans was related to LQTS. So, he reviewed every issue of Index Medicus from 1920 to 1970 to look for other cases with T-wave alternans. He found only seven cases of T-wave alternans that were not associated with LQTS

Prof. Schwartz, during his initial years of clinical work, was also performing basic research on single-fiber recordings from cardiac sympathetic nerves. He used this laboratory to demonstrate that in animal models, left stellate ganglion stimulation increased cardiac sympathetic tone, prolonged the QT and produce T-wave alternans.

He started his patient on beta-blockers because he recognized that his patient’s and many of the reported events in the literature occurred during physical and emotional stress. His patient subsequently experienced a stress-related event demonstrating that beta-blockade alone was insufficient so she underwent left stellate ganglion ablation in 1973. She did well, and Prof. Schwartz was the best man at her wedding. She died in an automobile accident in 2018.

Prof. Schwartz became interested in what had happened to the other LQTS patients reported in the literature. As he says, “Shyness was never my weakness and I started asking anyone who had published even a single case of LQTS what happened to the patient after the publication … luckily, I kept all my LQTS correspondence.” He wrote to Prof. Anton Jervell, of Jervell and Lange-Nielsen Syndrome fame. Jervell was in his 70’s at the time. Several of these letters are included in Prof. Schwartz’s publication. Prof. Schwarz ultimately collected 203 patients. In 1977, he met Arthur Moss, MD, from the University of Rochester, who had performed the first left stellate ganglion ablation in 1971. Dr. Moss was interested in the cases that Prof. Schwartz had accumulated and suggested that they form the International Registry for LQTS. This registry has been instrumental in developing strong pedigrees for genetic studies.

One of the more interesting genetic studies came out of Prof. Schwartz’s collaboration with colleagues in South Africa. They used a South African family to examine why family members with identical LQTS genetic defect had markedly different clinical outcomes. They uncovered several “modifier genes”. Most of these modifiers worsened the phenotype but one reduced the severity of the syndrome by altering the ubiquitin pathway. The ubiquitin pathway catabolizes normal and abnormal proteins, including ion channels. The asymptomatic, genotype positive family members had a gene that inhibits ion channel catabolism so that the normal ion channels persisted longer on the cell membrane. This prevented the abnormal depolarization that would have occurred if the normal ion channels had been catabolized more rapidly.

An amazing coincidence in the South African story is that one of the founders of this family with LQTS was a man who had immigrated to South Africa from the Netherlands in 1690 to work for the Company of the Indies. That man’s name was Pieter Swart, the Dutch equivalent of Peter Schwartz.

Maybe destiny is more than genes?

So, what are the rules:

- You can have a lot of success by picking an area that fascinates you and pursuing it.

- Listen to, but don’t always believe, the experts. If Prof. Schwartz had accepted that the QT was not important, his career would have never happened.

- Don’t be shy. Prof. Schwartz’s international registry started because he was willing to ask others, who were older and more famous, to share their cases.

For the interested, the genetics of LQTS has been reviewed.(5)

1. S S Hull Jr ¹, E Vanoli, P B Adamson, R L Verrier, R D Foreman, P J Schwartz. Exercise training confers anticipatory protection from sudden death during acute myocardial ischemia. Circulation. . 1994 Feb;89(2):548-52. PMID: 8313542

2. Schwartz, PJ. 1970-2020: 50 years of research on the long QT syndrome-from almost zero knowledge to precision medicine. Eur Heart J. 2021 Mar 14;42(11):1063-1072. PMID: 33057695

3. https://www.practiceupdate.com/content/do-you-want-to-read-a-great-mystery-story-about-lqts/123156/65/2/3

4. Schwartz PJ, Crotti L, George AL. Modifier genes for sudden cardiac death. Eur Heart J 2018;39:3925–3931.

5. Schwartz PJ, Ackerman MJ, Antzelevitch C, Bezzina C, Borggrefe M, Cuneo B, Wilde AAM. Inherited cardiac arrhythmias. Nat Rev Dis Prim. 2020;6:58. PMID: 32678103

#LQTS #PeterJSchwartz #suddencardiacdeath #electrophysiology #cardiology #QTinteval