Thursday, April 14, 2016

The benefits of exercise exist on a U-curve

Few would dispute the idea that intense exercise, as a hormetic stressor, is beneficial for improving human health. From reducing blood pressure and cardiovascular disease mortality rates, to aiding in the prevention of body fat accumulation after or during diet-induced weight loss, and more, exercise has innumerable, virtually unquestionable benefits. However, the type, volume and intensity of said exercise matters a great deal.

Many people begin with the supposition that there are "cardio" based exercises, like running and swimming, and "strength" based exercises, such as resistance training, as in a gym, lifting weights, or partaking in Crossfit, which is all-the-rage now. Sticking with this concept, endurance exercises, such as running, biking and swimming, can be classified neatly in the "cardio" category, and have been quite popular since about the 1970s. In the last few decades, one of the most common themes I have seen in individuals who proactively decide to go from living a traditional American lifestyle, to engaging in healthy lifestyle behavior changes, has been that of deciding to "run the marathon."

As I have not yet spent much time overseas, I do not know whether this is strictly a Western phenomenon, but it seems to me that if someone in our neck of the woods learns that something is beneficial, well, by golly, a whole lot more of it must be that much better. Implicit in this notion is that if running is good for my heart, then participating in an ultra-endurance activity like the Boston marathon should make me IronGirl.

Sorry, no cigar. The benefits of [endurance] exercise exist on a U-curve.*

*This is not to suggest that the benefits of resistance exercise do not also exist on their own U-curve. They very well might. I have just not seen any corroborating data, with respect to that question.

Just because something is healthy at one level of intensity, or by a certain volume, does not mean that if you ramp it up a few notches, it will confer the same benefit, let alone even more. Now, we could sift through an endless array of decently well-controlled studies that exist in the peer-reviewed literature touting the benefits of exercise, many of which have looked exclusively or predominantly at endurance training. But I should like, instead, to take a gander at some of the fascinating data demonstrating what might happen if we intentionally ramp up the intensity and volume of endurance exercise in both humans and experimental animals, and look at a few n=1 case reports of people who have voluntarily done the same thing, under the presupposition that because running is healthy, running a lot must be even healthier.

A few years ago, I randomly stumbled across this experiment, by Benito, et al, conducted in Barcelona, and published in Circulation,[1] where they took male Wistar rats and exposed a group of them to intensive 4, 8 or 16 week exercise regimes, while a Sedentary group got to essentially kick back and relax, and then compared the effects of the intervention on the rats' hearts.

Significant functional and morphologic changes occurred in the hearts of those rats in the Exercise group, after 8 weeks of intense training, such that, upon close postmortem inspection, they had marked increases in interventricular septum and left ventricular wall thickness. Statistically significant increases in overall cardiac hypertrophy was noted in the Ex group. Evidence of both left ventricular systolic and diastolic dysfunction occurred by week 8 and 16, respectively, based on echocardiographic results. (RV diastolic dysfunction was claimed evident, but was apparently not statistically significant, and so did not make much of an appearance in the paper, from what I could tell.) In contrast, of course, the Sed group of rats did not show any signs of these significant pathological changes, throughout the duration of the 16 week experiment.

Perhaps the most interesting thing, to me, since hypertrophy of the myocardium as a result of intense and chronic over-exertion is an anticipated, or at least relatively expected, outcome, was when the researchers then looked at the effects of this exercise regimen on "chamber-specific ultrastructural remodeling." A.k.a. The development of myocardial fibrosis.

Here is what they found:

"There is widespread interstitial collagen deposition with disarray of myocardial architecture." Aside from being a clever way to say, "These rat hearts are fucked, and this kind of training is probably not a good idea," (at least for Wistar rats) these results suggest that the formation of these fibrotic lesions may present a substantially increased risk of potentially fatal dysrhythmia -- this could be one possible explanation for the all-too-common ultra-endurance athlete who drops dead at 35 from sudden cardiac related death. So, naturally, that's precisely what their team looked for next.

According to figure 6, researchers were able to induce polymorphic ventricular tachyarrhythmias via ventricular stimulation in the Ex rats:

Luckily -- again, if you are an unreasonably trained Wistar rat -- there is an upside to all this. A period of "de-training" post-intervention could reduce the cardiac remodeling seen in this experiment, which may indeed mitigate the detrimental effects of the overtraining seen, here. There are some pretty big questions implicit in this, however. Such as, will this detraining benefit continue to exist, if the intervention period is stretched further? At what point will the negative effects of the intervention persist? What are the mechanisms involved in producing these effects? As the authors state in their discussion: 

The biggest question of all, as many of you reading this will have already been screaming at me for the last ten minutes, assuming you've made it this far, is... Will it translate to humans?

Here is where things get really interesting.

In 2011, Wilson and colleagues published a paper in the Journal of Applied Physiology[2] examining 12 veteran endurance athletes, many of whom had either completed 100 marathons or spent over ten years continuously training at an olympic level. This is about as close as I can imagine coming to an ecological replication of the Benito experiment, if ever I've seen one.

Although there are a few inherent limitations in its use, such as it "relies on the signal intensity difference between fibrotic and normal myocardial tissue, and hence a region of 'normal' nulled myocardium is needed as a reference to detect abnormalities,"[3] Wilson, et al, used late gadolinium enhancement imaging (LGE) to detect patterns of myocardial fibrosis in the study participants. 50% of them had diffuse patterns of myocardial fibrosis. These are people who are supposed to be healthier than all of us, especially due in large part to their exceptional athleticism. In spite of it, they actually appear to be worse off, at least with respect to the health of their heart muscle! (Age is a factor for some of the athletes studied in this trial, but age-matched controls were examined, and the age-confounder was set aside as an important contributor.)

The study was of course a small one, and so generalizability may be a factor of consideration. But think about it, though. This is not supposed to be representative of the population at large, but of a small subset of elite athletes. Therefore, the sample may in fact be sufficient to generalize, at least to other extreme endurance athletes. And remember, all 12 of these individuals were "otherwise healthy" at the outset of the study. None of them were smokers, as far as they were willing to admit to on the inclusion data. (Though, being that they were all males, translating these data to females may prove challenging. Gosh, we could really use some more data on female athletes...)

Although I found this study fascinating because it was almost like a real-life corroboration of Benito and colleagues animal study, this is not the end of the line for similar research in human beings. Oh, no. There's actually quite a bit more, following this same line of logic:

In 2012, Dr. James O'Keefe, et al, published a review in Mayo Clinic Proceedings[4] suggesting that, although the hypothesis warrants further research for substantiation, there is good human and animal data to suggest, at least on a preliminary basis, that excessive endurance exercise (EEE) may predispose susceptible individuals to adverse cardiovascular events, including arrhythmia and extensive myocardial fibrosis.

In a 2011 issue of the European Heart Journal[5], La Gerche, et al, describe their study of 40 endurance athletes, after the completion of a marathon, and suggest that "although short-term recovery appears complete, chronic structural changes and reduced right ventricular function are evident in some of the most practiced athletes..."

In 2010, Wilson, et al, published a study in the European Journal of Applied Physiology[6] demonstrating that long-term, high intensity endurance activity is strongly associated with maladaptive changes in cardiac morphology and electrical conductivity, among other physiologic and pathophysiologic alterations, even connecting it to implications with respect to brain function.

In 2013, Doutreleau, et al[7] showed that such chronic and excessive endurance training could have negative consequences on the conduction pathways in the heart, presumably through this remodeling and fibrotic changes in the myocardium. In their study, they report two cases of type II second-degree atrioventricular block in well-trained, otherwise healthy, middle-aged adult athletes.

Although merely a case report, and not a study, per se, in 2012, in the Journal of Athletic Training[8], Poussem, et al, describe a highly-trained, 30 year old cyclist with "nonsustained ventricular tachycardia originating from the left ventricle on a stress test associated with myocardial fibrosis of the left ventricle as shown with magnetic resonance imaging." The unique thing about this case report was that most often these findings are seen after sudden cardiac death (SCD), on autopsy. Presumably, the diagnosis in this instance is being relegated to an effect of intense, unrelenting endurance exercise, but, there are probably too many confounding variables in this particular instance to be able to say one way or another. It is particularly interesting, however, that it happens to line up quite nicely with the rest of the data, thus far. (Was the cyclist in this case a recreational drug user? Could that have caused or contributed to the pathology seen, here?) Still...

In 2008, published in the British Journal of Sports Medicine,[9] professor Whyte and colleagues ask the question whether exercise may or may not have been the cause of the idiopathic left ventricular hypertrophy and idiopathic interstitial myocardial fibrosis found during the autopsy of an "experienced, highly trained" marathon runner, who died suddenly while running.

Published in the British Journal of Sports Medicine back in 2007[10], Mitchell M. Lindsay and Francis G. Dunn conducted the first experiment, to my knowledge, demonstrating that, in veteran endurance athletes with left ventricular hypertrophy, there is "biochemical evidence of disruption of the collagen equilibrium favoring fibrosis... suggest[ing] that fibrosis occurs as part of the hypertrophic process in veteran athletes."

In 2011, La Gerche published another trial[11], this time with 39 endurance athletes and 14 controls, looking for evidence that intense exercise might be putting an exorbitant load on the right ventricle of the heart. Despite some inherent limitations, which they carefully outline in the paper, the following is what they found after careful analysis of the data:

On top of all the myocardial fibrosis business, there are other potential risks that have been outlined in the literature, since Benito and others' work. For instance, just this year, M Sanz de la Garza, et al, published a study in the Scandinavian Journal of Medicine and Science in Sports[12] looking to examine the potential impact of intense endurance training on multiple thrombotic risk factors, and claim that excessive endurance exercise may actually increase the chances of pulmonary embolism, through the development of deep vein thromboses (DVT), or clots in the legs. Unlike the mechanisms that may be involved in the development of cardiac morphologic changes via collagen recruitment in cardiomyocytes, etc., these are likely to be due to extraneous complications from overexercising; including dehydration, inflammation and, as they put it in the abstract of the paper, "hemoconcentration."

So, ultimately, what does this mean? Does this mean that I think cardio is uniformly "bad" and that you should stop partaking entirely? Do I think any and all forms of endurance training are unhealthy?

Uh... No. Wait, that wasn't good enough. Can I get a hell no, instead?

Look at the one consistency in all these data. Everyone studied (including the rodents!) were pushed -- or, rather, pushed themselves, in the vast majority of cases -- to the breaking point. There is an unimaginable difference between running a weak 2 miles per day and running 11 miles per day, at 80% of your purported maximum heart rate.

Will some regular, light endurance training destroy your heart? No! Will training at intensities similar to ultra-endurance triathletes destroy your heart? It's a little too soon to tell, but, it appears quite possible... so, again, what's "the answer?"

My recommendation would be to avoid participating in multiple marathons. Otherwise, I would be equally as concerned about the health of your heart muscle, if you remain seated on your love seat like a lazy slob eating Sun Chips all day, delicious though they are.

As I have said twice now, there is an undoubted U-curve associated with the benefits of [endurance] exercise. Too little is not good; way too much is also bad. My final recommendation? Adopt the Goldilocks principle of "just right" and you'll be good to go. But, whatever you do, please choose to move, rather than be a slug. "Eat less, move more" doesn't have to be "right" for me to know that exercise in appropriate amounts is incredibly beneficial and health promoting. The lesson in this post is more about what happens if you push it to an extreme on the spectrum -- and to suggest that, as with most things, there may be a sweet spot, somewhere in the middle, where a balanced approach confers the best results.

(Me? I'll stick with picking up heavy things and putting them back down, and the occasional sprint or HIIT session, here and there... but my rationale for that will have to wait. I've already kept you plenty long enough.)


1. Benito, B., Gay-Jordi, G., Serrano-Mollar, A., Guasch, E., Shi, Y., Tardif, J. C., ... & Mont, L. (2011). Cardiac arrhythmogenic remodeling in a rat model of long-term intensive exercise training. Circulation, 123(1), 13-22.
2.Wilson, M., O'Hanlon, R., Prasad, S., Deighan, A., MacMillan, P., Oxborough, D., ... & George, K. (2011). Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes. Journal of Applied Physiology, 110(6), 1622-1626.
3. Karamitsos, T. D., & Neubauer, S. (2013). Detecting diffuse myocardial fibrosis with CMR: the future has only just begun. JACC: Cardiovascular Imaging, 6(6), 684-686.
4. O'Keefe, J. H., Patil, H. R., Lavie, C. J., Magalski, A., Vogel, R. A., & McCullough, P. A. (2012, June). Potential adverse cardiovascular effects from excessive endurance exercise. In Mayo Clinic Proceedings (Vol. 87, No. 6, pp. 587-595). Elsevier.
5. La Gerche, A., Burns, A. T., Mooney, D. J., Inder, W. J., Taylor, A. J., Bogaert, J., ... & Prior, D. L. (2011). Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes. European heart journal, ehr397.
6. Wilson, M., O’hanlon, R., Basavarajaiah, S., George, K., Green, D., Ainslie, P., ... & Nevill, A. (2010). Cardiovascular function and the veteran athlete. European journal of applied physiology, 110(3), 459-478.
7. Doutreleau, S., Pistea, C., Lonsdorfer, E., & Charloux, A. (2013). Exercise-induced second-degree atrioventricular block in endurance athletes. Medicine and science in sports and exercise, 45(3), 411-414.
8. Poussel, M., Djaballah, K., Laroppe, J., Brembilla-Perrot, B., Marie, P. Y., & Chenuel, B. (2012). Left ventricle fibrosis associated with nonsustained ventricular tachycardia in an elite athlete: is exercise responsible? a case report. Journal of athletic training, 47(2), 224.
9. Whyte, G., Sheppard, M., George, K., Shave, R., Wilson, M., Prasad, S., ... & Sharma, S. (2008). Post-mortem evidence of idiopathic left ventricular hypertrophy and idiopathic interstitial myocardial fibrosis: is exercise the cause?. British journal of sports medicine, 42(4), 304-305.
10. Lindsay, M. M., & Dunn, F. G. (2007). Biochemical evidence of myocardial fibrosis in veteran endurance athletes. British journal of sports medicine, 41(7), 447-452.
11. La Gerche, A., Heidbuchel, H., Burns, A. T., Mooney, D. J., Taylor, A. J., Pfluger, H. B., ... & Prior, D. L. (2011). Disproportionate exercise load and remodeling of the athlete’s right ventricle. Med Sci Sports Exerc, 43(6), 974-981.
12. Sanz de la Garza, M., Lopez, A., & Sitges, M. (2016). Multiple pulmonary embolisms in a male marathon athlete: Is intense endurance exercise a real thrombogenic risk?. Scandinavian Journal of Medicine & Science in Sports.