June 26, 2013

There's a lot controversy surrounding the relationship between endurance exercise and heart disease. Smart people debate the issue of causality, the dosage of exercise needed to provoke disease, and many other confounding factors. But one thing we can all agree on is that there's something interesting going on with the biology.

Consider the exercise paradox: regular exercise is critical for good health. It does all sorts of things for the body and mind. But it is also clear that certain individuals who are exposed to high levels of exercise develop disease of both the heart muscle and electrical system.

The thing that's most interesting, at least to me, is the unpredictability of these ill effects. Some get it and some don't. Why is this? You know it's not as simple as just cumulative dose of exercise. There's more than that.

A study presented at EUROPACE 2013 sheds some light on the question of individual susceptibility to exercise. It's a science-intensive study, and I am a regular doctor, not a biologist. Please afford me some leeway in staying broad. The study concerns the disease arrhythmogenic right ventricular dysplasia (ARVD).

A Few Facts About ARVD:

Arrhythmogenic right ventricular dysplasia is a form of cardiomyopathy where fibrous and fatty tissue replaces normal myocardium, primarily in the RV. Disruption of the architecture of cell-cell coupling sets up a milieu favorable for arrhythmia. In Europe and to a certain extent in the US, ARVD is a not-infrequent cause of sudden death in young athletes.

What makes this disease especially interesting is its genetics. Mutations in the genes that code for connecting proteins, called desmosomes, are the culprit. These defects are passed down in an autosomal dominant pattern, but the genotype is variably expressed with incomplete penetrance. This means some patients might suffer early ventricular arrhythmia while others with the same genetic material live into old age. In other words, the genotype has many phenotypes.

Here's the kicker: It has been hypothesized that endurance exercise (remember the ARVD-association with athletes) might induce an ARVD-like disease (phenotype) in genetically susceptible individuals.

The Study:

Researchers from Birmingham, UK and colleagues in Muenster and Aachen, Germany used genetically modified mice to look at the interaction between exercise and heart disease. They knew that many patients with ARVD harbor mutations in the domain of the desmoglein 2 (DSG2) gene. They were able to genetically engineer mice lacking parts of the DSG2 gene. Those mice with two copies of the deletion (homozygous) developed profound ARVD, whereas those mice with one copy (heterozygous) did not manifest disease.

The question then was whether heavy physical exercise could provoke a disease state in genotypically susceptible mice. So they made heterozygous mice swim. Training sessions were done six days a week for up to 90 minutes per day. The research team then looked at both structure and electrical findings in the exercised mice and compared the swimming mice with their wild-type littermates.

The exercised and genetically susceptible (heterozygous—one copy of mutation) developed dilated RVs and had easily provoked ventricular arrhythmias. There were no such findings in the wild-type littermates.

This simple but elegant experiment led the researchers to conclude that endurance training revealed an ARVD-like phenotype in otherwise-healthy and morphologically inconspicuous mice. During the slide presentation they suggested that these data support the idea that endurance training may be dangerous for carriers of mutations in junctional proteins.

My take:

As an athlete and doctor to many endurance athletes with mysterious heart disease, these findings pique my interest. Look further than just the specific disease ARVD. Look at the concept of modifying one's phenotype. Recall that in the study, exercising mice had genetic susceptibility to the disease, but no disease was manifest. The mice looked normal and did not develop changes of cardiomyopathy until exposed to endurance exercise.

Why can't we broadly apply this concept to the endurance-exercise–heart-disease story? We know some—but not all—athletes develop arrhythmias like AF. And we know AF, like ARVD, has strong genetic ties. Take the athlete who harbors a yet-described partial gene defect for AF. He has no signs of disease. His nonathletic brothers and sisters do not have AF. But he's an exerciser, and might it be that the exercise unmasked or induced the disease?

It's the same story with focal cardiomyopathy. We know from post–marathon and Ironman studies that athletes sustain enzyme elevations and transient functional impairments of the RV and LV. These defects resolve in most athletes, but some develop persistent scarring. The easy explanation is that those few athletes who develop scar had the highest dosage of exercise. But you know it's more than just dose of exercise and random chance. It's something about the athlete's genetic make-up.

Mark my words on this one: When we learn more about the genetic basis of disease, the personal genome if you will, we will better understand susceptibility not just to exercise, but to many other of life's exposures. Why do some smokers avoid cancer? Why do some heavy drinkers never develop cirrhosis? Why does an occasional mean person live to old age?

The answer will be found in the genes.


Vloumidi E, Fortmueller L, Sakhtivel S, et al. Arrhythmogenic right ventricular cardiomyopathy-like phenotype induced by endurance training in heterozygous desmoglein-2 mutant mice. EUROPACE 2013; June 23, 2013; Athens, Greece. Abstract 83.


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