Paul D. Thompson, MD

I searched PubMed on January 19, 2021, using the terms “COVID” and “athletes” and got 675 hits. I repeated the search 6 days later and got 704 hits. When I added the term “cardiac”, I got 47 hits on January 20th and 71 hits on a search performed on January 25th.

That is an amazing number of publications on COVID-19 in athletes and an amazing increase in the number of publications in just a week. There must be a lot of assistant medical school professors headed to the associate professor level thanks to COVID-19 publications! But I am concerned that so many publications produced so quickly means that either new data are being produced rapidly or that the issues with COVID-19 in athletes are not settled.

I think the latter is most likely because many of the citations on COVID-19 in athletes are essentially opinion pieces. For example, in my latest cardiac search, the words 

 appeared in the title of 6 of the first 10 cited articles. So, what do we know?

Among 419 patients hospitalized in Wuhan, 19.7% had cardiac troponin (cTn) I values >99th percentile suggesting myocardial involvement. These patients had a worse prognosis.

Among 100 German patients studied by cardiac magnetic resonance imaging (cMRI) 64-92 days after their COVID-19 diagnosis, 78 had abnormal cMRI finding.

 These included 71 and 60 patients with cMRI elevations of T1 and T2 values, respectively, 32 with late gadolinium enhancement (LGE) suggestive of myocardial scarring, and 22 with evidence of pericardial involvement. HsTnT values were detected in 71 at the time of their cMRI.

The Sports Medicine community is concerned because myocarditis was the 3rd leading cause of sudden cardiac death (SCD) (after hypertrophic cardiomyopathy and anomalous coronary arteries) in Barry Maron’s collection of SCD in high school and college athletes. Myocarditis was responsible for 6% of the 1046 SCDs.

There are at least 3 studies that have looked at myocarditis using cMRI in athletes after COVID-19 infection. Among 26 Ohio State athletes studied 11-53 days after COVID diagnosis, none have ECG, echocardiographic or cTnI abnormalities on the day of imaging, but 12 (46%) had cMRI evidence of a myocardial scar and 2 met criteria for myocarditis (13%).

In a study from Vanderbilt University, researchers compared cMRI results in 59 of their athletes studied 10-162 days post COVID-19 diagnosis with 60 not infected athletic and 29 healthy non-athletic controls. The athletes had experienced no (22%) or mild (78%) COVID symptoms.

 Only 2 of the athletes (3%) had cMRI evidence of myocarditis, but two additional athletes had pericarditis or a new drop in their left ventricular ejection fraction. Moreover, there were mild increases in cMRI T1 and T2 values suggestive of myocardial involvement in 39% of the COVID athletes, 13% of the athletic controls, and 8% of the healthy normal subjects. This study was criticized for its small sample size.

In another study, clinicians from the U of Wisconsin performed a retrospective review of cMRI studies from 145 athletes consecutive athletes who had no (16%) mild (49%) moderated (28%) or undocumented (7%) symptoms.

 None were hospitalized. The athletes were studied 11-194 days after diagnosis. Only 2 athletes (1.4%) had findings of myocarditis. Also, 4 others had cTn elevations without cMRI findings. So do 13, 3, or 1.4% of previously healthy, college athletes develop myocarditis after COVID-19 infection?

We just do not know. Indeed, we know very little about myocarditis in athletes, a point I made in an editorial published at the very start of the epidemic.

 That editorial addressed viral myocarditis in general and not COVID-19 myocarditis because it predated the Wuhan cardiac report.

Concern about myocarditis has led some sports cardiology authorities to recommend routine cMRI screening of all athletes after COVID infection, even constantly asymptomatic athletes, before allowing return to exercise training and sports competition. That’s because these cMRI abnormalities in athletes after COVID raise the concern that many athletes are risk for SCD. But to my knowledge, there has not been a remarkable increase in SCD in athletes during the epidemic. This could be because athletes are not training and competing because COVID-19 myocarditis is not as deadly as we thought or because COVID-19 myocarditis is actually uncommon in athletes.

Some investigators are collecting cMRI results on athletes in an attempt to determine how many have myocardial changes. Such a registry is important, but not the key point. The key point is how many athletes experience SCD during exercise after COVID-19 infection.

What do I think? I think that athletes have a lot of cMRI abnormalities, but similar changes may occur with other viral infections. I suspect that COVID 19 myocarditis is not as dangerous as first suspect, at least not in previously healthy athletes. Such considerations prompted the American College of Cardiology’s Sports and Exercise Subsection to recommend less testing in athletes before return to play unless they were hospitalized, very sick or have ongoing symptoms.

 In the interim I fear we are restricting and frightening too many athletes and families. We have to be honest about what we do and do not know. Right now, we know little about myocarditis in athletes, COVID or otherwise.

1. Shi S, Qin M, Shen B, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in wuhan, china. 

. 2020;5(7):802-810. doi: 10.1001/jamacardio.2020.0950 [doi].

2. Puntmann VO, Carerj ML, Wieters I, et al. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19). 

. 2020;5(11):1265-1273. doi: 10.1001/jamacardio.2020.3557 [doi].

3. 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. 

. 2009;119(8):1085-1092. doi: 10.1161/CIRCULATIONAHA.108.804617 [doi].

4. Rajpal S, Tong MS, Borchers J, et al. Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection. 

. 2021;6(1):116-118. doi: 10.1001/jamacardio.2020.4916 [doi].

5. Clark DE, Parikh A, Dendy JM, et al. COVID-19 myocardial pathology evaluation in AthleTEs with cardiac magnetic resonance (COMPETE CMR). 

. 2020. doi: 10.1161/CIRCULATIONAHA.120.052573 [doi].

6. Starekova J, Bluemke DA, Bradham WS, et al. Evaluation for myocarditis in competitive student athletes recovering from coronavirus disease 2019 with cardiac magnetic resonance imaging. 

. 2021. doi: 10.1001/jamacardio.2020.7444 [doi].

7. Thompson PD, Dec GW. We need better data on how to manage myocarditis in athletes. 

. 2020:2047487320915545. doi: 10.1177/2047487320915545 [doi].

8. Kim JH, Levine BD, Phelan D, et al. Coronavirus disease 2019 and the athletic heart: Emerging perspectives on pathology, risks, and return to play. 

. 2020. doi: 10.1001/jamacardio.2020.5890 [doi].

Articles

With studies and editorials being published on the topic at a historic rate, Dr. Paul Thompson offers perspective on what clinicians know about the incidence of COVID-19-related myocarditis in athletes. 

How Frequent and Dangerous is COVID-19 Myocarditis?

A new clinical trial (1) and the accompanying clinical commentary (2) suggest that digoxin may be coming back from the dead.

The Rate control Therapy Evaluation in permanent Atrial Fibrillation trial (RATE–AF) was an open-label, but endpoint-blinded study that assigned 160 patients, aged 60 or older with permanent atrial fibrillation (AF) to treatment with either digoxin or bisoprolol.

 Patients had New York Heart Association Class II or greater heart failure.

The primary outcome was quality of life (QOL) assessed by questionnaire at 6 and 12 months; there were 17-20 secondary endpoints. Neither QOL nor 16 of 17 secondary parameters were different at 6 months, although more digoxin-treated patients improved their European Heart Rhythm Association symptom classification score 2 or more classes (53 vs 9%, 

At 12 months, 8 of 20 secondary outcomes improved more with digoxin than with bisoprolol, including NTproBNP (960 vs 1250 pg/mL in the two groups, respectively). Serious adverse events occurred in 37 of the bisoprolol, but in only 15 of the digoxin patients. Heart rates did not differ.

 with these results! I had never totally abandoned digoxin, partly because when I was trained in the 1970s, digoxin was 

 drug for AF rate control. But I constantly doubted my continued use. That’s because a series of cross-sectional studies showed worse clinical outcomes in acute MI patients treated with digoxin.

These studies and the accompanying editorials left the drug for dead. I vaguely remember one academic electrophysiologist editorializing that use of digoxin was essentially malpractice. I dismissed these results and editorials by arguing that patients who received digoxin did so because they were sicker and developed AF. The TREAT-AF study, however, was a controlled study that showed increased mortality in digoxin treated patients, but this was not a true randomized controlled clinical trial because it used propensity matching to create the control group.

I stuck with digoxin over the years—not for everybody, but for those AF patients whose rates were difficult to control. Most patients with atrial arrhythmias can be controlled with beta-blockers or calcium channel blockers alone, but some with AF, and many with atrial flutter, require either high drug doses or an additional agent.

Beta-blockers block adrenergic stimulation, which is actually not great at rest and increases with exertion. In contrast, digoxin increases vagal tone, meaning that its greatest effect is on resting heart rate—when vagal tone is greatest. Consequently, combining digoxin with moderate doses of beta-blockers provides both resting and exercise AF rate control.

Also, one of the biggest hassles I get with beta-blockers is that the nurses hold the drug because the patient is hypotensive. Actually, most often the patient is hypotensive because their AF rate is too fast. Fast heart rates decrease filling time, leading to low stroke volumes and low systolic pressures.

Slowing the heart rate often cures the hypotension, but I have become hoarse trying to change nurses’ minds on this issue. Digoxin has saved my voice because it does not get held anywhere near as frequently as beta- or calcium channel blockers, but I always get pushback from the new cardiology fellows when I suggest using digoxin. This resistance usually dissipates after they see how well it works.

So, here are my suggestions for using digoxin effectively:

Always load the patient. Digoxin like many anti-arrhythmics does almost nothing without fully loading the patient. I load small-bodied patients with 0.25 mg IV x 3 doses given every hour or even faster if rate control requires faster dosing. I load large patients with 0.25 mg IV x 4 doses every hour. I look at the patient to decide who is small and who is large. I load outpatients using similar doses given orally.

Start hospitalized patients with intravenous digoxin so that whether it will work is prompt and obvious.

Do not worry about renal function when loading patients. Renal function affects digoxin clearance and therefore the replacement dose but not the loading dose. Normally, one-third of digoxin is cleared with normal kidney function so the maintenance dose is usually 0.25 mg or one-third of the loading dose. Lower maintenance doses are required with decreased renal function.

Do not use digoxin levels to evaluate the drug’s effectiveness. Digoxin level tells you only if the patient has taken the drug and if the blood concentration exceeds a safe level and you need to cut the dose. Increase the dose if the heart rate is not controlled and the dig level is not excessive.

I think that many inexpensive, useful drugs get abandoned because there is no industry push to use them. Others are victims of poor study designs, often industry-sponsored trials designed to make the generic drug look bad. None of the AF guidelines list digoxin as first-line therapy because there are no true RCCTs of digoxin.

 RATE-AF is not a perfect RCCT because it was open-labeled but hopefully it will prompt a closer look at this 235-year-old drug.

Kotecha D, Bunting KV , Gill, SK, et al. 

Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life: The RATE-AF Randomized Clinical Trial

Curfman G. Digitalis Glycosides for Heart Rate Control in Atrial Fibrillation. JAMA. 2020 Dec 22;324(24):2508

In this column, Dr. Paul Thompson offers his perspective on the use of digoxin and explains why he has maintained use in certain patient populations despite its waning popularity in recent years.

Paul D. Thompson, MD: Is Digoxin Back from the Dead?

I was never in the military not because I had dangerous heel spurs—thank goodness—but because I had a medical school deferment. I do know enough about the military, however, to know that you can follow a person’s military career from the services ribbons mounted on the left chest of his/her dress uniform. These service ribbons provide us much more information than a person’s “name, rank and serial number”.

I am lucky enough to spend one week a month rounding with trainees in Boston. I recently observed an excellent MD/PhD resident interview a new patient. We left that patient’s room with a complete past and present medical history, but we also left not knowing 

 the patient was. He was in a hospital gown so we had literally, and now figuratively, taken away his clothes and his personal identity.

I call finding out who a patient is, what they do, and where they live “giving them back their clothes”. It is really giving them back their personal identity, and it’s critically important. Not because it’s politically correct, but because if patients know that you are as interested in them as you are in their disease, they are more likely to ask questions, reveal their wants and worries, and participate fully in their care by taking their medicines and following your advice. And me? I get to develop relationships with patients and learn about their lives, something that brought most of us into medicine in the first place.

In this column, titled "Give Them Back Their Clothes", Dr. Paul Thompson reflects on the importance of creating a personal connection with patients as part of their care routine and the impact it can have on patients. 

Compassion in Medicine: Give Them Back Their Clothes

“Diagnostic anchoring” refers to clinicians’ tendency to make a diagnosis and to avoid considering the alternatives. I have had several patients referred to me over my career with the diagnosis of hypertrophic cardiomyopathy (HCM), who turned out to have cardiac amyloidosis. Amyloidosis and other diseases that produce left ventricular hypertrophy (LVH) are called “HCM phenocopies” because they copy the HCM phenotype but do not have the genotype.

Recognizing HCM phenocopies, and not succumbing to diagnostic anchoring, is now critically important because there are new treatments for some HCM phenocopies that can prevent progression and even initiate regression of the non-HCM disease. The following is a compilation of what I knew about this topic plus material presented in a web-based lecture on November 20, 2020, entitled “Highlighting Hypertrophic Cardiomyopathy and Fabry Cardiac Disease”.

The differential diagnosis of a thick heart includes classical HCM, long-standing poorly treated hypertension, cardiac amyloidosis, alpha-galactosidase A (a-GSA) deficiency or Fabry disease, lysosomal associated membrane protein–2 deficiency (LAMP-2) also called Danon or LAMP-2 disease, and hydroxychloroquine (HCQ) treatment.

HCM is the most frequent cause of thick hearts and affects 1/250 individuals.HCM is autosomal dominant and not sex-linked. It typically produces more septal than other wall hypertrophy. Indeed, HCM was historically called asymmetric septal hypertrophy or ASH. Clinicians should consider diagnoses other than HCM if there is no family history of HCM, when the disease onset is late in life, and when there is symmetric LVH or LVH that does not include the septum. But be careful because if anything typifies HCM, it is its variability. HCM can produce apical and symmetrical LVH, appear late in life, and occur in non-inherited patterns. One notorious example of a non-inherited pattern involved a cluster of HCM patients due to sperm-donation from an undiagnosed HCM carrier! 

Long-standing, poorly treated hypertension (HBP) can cause LVH, but this is now a rare HCM mimic because HBP is usually diagnosed and treated before the LVH is extreme.

Cardiac amyloidosis is presently recognized more frequently as causing thick hearts because of increased awareness of the disease and the use of non-echo imaging techniques such as magnetic resonance imaging (cMRI) and technetium 99 pyrophosphate scanning. Amyloidosis comes in three varieties.

 Deposition of antibody light chains produces AL amyloidosis. These light chains are produced by clonal plasma cells so it is treated as a variant of multiple myeloma. Inherited transthyretin (TTR) amyloidosis is due to mutations in the TTR gene. A gene mutation is present in approximately 3% of African Americans, but mutations occur in other populations including the Irish. 

There is also a non-inherited or “wild type” (wt) TTR amyloidosis. TTR amyloidosis is more frequent in men, especially old men, despite not being sex-linked. TTR amyloidosis produces orthopedic issues such as biceps tendon ruptures, carpal tunnel symptoms, spinal stenosis, and palmar tendon nodules, which may appear years before the cardiac amyloidosis becomes obvious. Amyloidosis should also be considered in patients with LVH and peripheral neuropathy since amyloid also invades peripheral nerves. It is important to diagnose TTR amyloidosis because new treatments such as tafamidis can help preserve functional capacity and reduce cardiovascular mortality.

Interestingly, 20% of patients with wtTTR have asymmetric septal hypertrophy making wtTTR a worthy HCM phenocopy. 

Patients whose LVH is due to HCM and especially those whose LVH is due to HBP should have impressive voltage criteria for LVH whereas patients with amyloidosis have either normal or decreased LV voltage. But a history of HBP that has been mysteriously cured and no longer requires anti-HBP drugs suggests new peripheral neuropathy another symptom of amyloidosis.

Fabry disease is another treatable cause of thick hearts. Fabry is X-linked and results from a decrease in lysosomal a-GSA activity resulting in the accumulation of glycosphingolipids in lysosomes. About 0.03% of the population carries the Fabry gene. It usually produces concentric LVH with LGE of the posterior wall and, in contrast to HCM, spares the septum.

Fabry also can produce ascending aortic enlargement and aortic insufficiency. Fabry should be considered with late-onset LVH especially if there is aortic enlargement. The disease is more common and severe in men, because of the X-linked inheritance. This inheritance pattern means that men can be diagnosed by measuring serum a-GSA activity because they don’t produce any, but that women must have gene analysis to detect the genetic defect. Fabry also causes AV conduction disease. Even though Fabry usually causes diffuse LVH, it can produce septal hypertrophy ASH and even systolic anterior motion of the mitral valve so Fabry should be excluded in all thick hearts. Both enzyme replacement therapy and migalastat, which helps chaperone a-GSA to lysosomes, reduce LVH in Fabry.

Danon or LAMP-2 disease is another rare, X-linked lysosomal glycogen storage disease. It usually presents in children who also have muscle weakness and intellectual disability.

Finally, HCQ can also produce a lysosomal storage disorder that mimics HCM becauseHCQ inhibits lysosomal function.

 HCQ is no longer recommended for COVID-19 treatment but is still used to treat rheumatoid arthritis and other inflammatory diseases, so should be considered as a cause of LVH in patients treated with this drug.

We are all taught to make a differential diagnosis for every patient’s condition, but this is especially important with thick-hearted patients to avoid missing a treatable disease.

1. Maron BJ, Lesser JR, Schiller NB, Harris KM, Brown C, Rehm HL. Implications of hypertrophic cardiomyopathy transmitted by sperm donation. 

. 2009;302(15):1681-1684. doi: 10.1001/jama.2009.1507 [doi].

2. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. 

. 2019;73(22):2872-2891. doi: S0735-1097(19)34729-1 [pii].

3. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. 

. 2018;379(11):1007-1016. doi: 10.1056/NEJMoa1805689 [doi].

4. Germain DP, Hughes DA, Nicholls K, et al. Treatment of Fabry disease with the pharmacologic chaperone migalastat. 

. 2016;375(6):545-555. doi: 10.1056/NEJMoa1510198 [doi].

5. Yogasundaram H, Putko BN, Tien J, et al. Hydroxychloroquine-induced cardiomyopathy: Case report, pathophysiology, diagnosis, and treatment. 

. 2014;30(12):1706-1715. doi: 10.1016/j.cjca.2014.08.016 [doi].

Dr. Paul Thompson reflects on the diagnosis and treatment of hypertrophic cardiomyopathy and other comorbid conditions, in this column, titled "Don’t Be Thick Headed With Thick Hearts". 

Paul D. Thompson, MD

Articles

How Frequent and Dangerous is COVID-19 Myocarditis?

Paul D. Thompson, MD: Is Digoxin Back from the Dead?

Compassion in Medicine: Give Them Back Their Clothes

Paul D. Thompson, MD: Don’t Be Thick Headed With Thick Hearts