A review article was published in June 2012 in the journal Mayo Clinic Proceedings (O’Keefe et al., 2012) concerning potential adverse effects to cardiac health in the context of excessive endurance exercise (EEE). It received a significant amount of media attention due to its novel hypothesis, as it has long been held that endurance exercise results in positive health benefits to cardiac physiology. An examination of that hypothesis follows.
Excessive Endurance Exercise and Sudden Cardiac Death
The article begins with examining how vigorous exercise affects the incidence of sudden cardiac death (SCD), which is defined as natural death from a loss of consciousness due to an adverse cardiac event within an hour of the onset of symptoms. Cases of SCD during sporting events are, rather unfortunately, over-reported by the media, which could lead to readers being unnecessarily cautious about performing vigorous exercise, as they may conclude that vigorous exercise abnormally elevates risk of SCD. The research tells a rather different story, however: vigorous exercise is associated with a small and transient increase in risk of SCD, although habitual vigorous exercise greatly reduces this risk. For example, if an untrained (sedentary) individual performs vigorous exercise, cardiovascular (CV) stress will be high, and the relative risk of SCD during and shortly after that period of exercise increases by a factor of about 14 to 45 (Albert et al., 2000). This is one reason not to be negligent with the training period leading up to endurance events and, to this point, most marathon training plans have a person complete a minimum of six months of progressive training cycles to safely be able to finish the event, let alone race it. Nevertheless, the absolute risk of SCD during an episode of vigorous exertion for any given individual remains extremely low, at 1 in 1.51 million (Albert et al., 2000). Furthermore, with an increasing weekly frequency of high-intensity ET, the relative risk of SCD decreases quite dramatically, as shown by Table 2. The physiological basis for this phenomenon is well-established: with acute bouts of exercise, and especially in untrained individuals, increases in sympathetic nervous system (SNS) activity, which results in increased HR (the classic fight-or-flight response), and decreases in vagal activity (the vagus nerve decreases HR as part of the parasympathetic NS) lead to an acute increase in susceptibility to ventricular fibrillation (an oft-fatal arrhythmia caused by an uncontrolled twitching in the lower chambers of the heart), resulting in the transient increase in risk of SCD. However, chronic high-intensity ET increases vagal tone, resulting in increased cardiac electrical stability and in protection against ventricular fibrillation, thus reducing cardiac stress at any given workload and resulting in the dose-dependent relationship between increasing frequency of vigorous ET and decreasing risk of SCD seen in Table 2. The causes of SCD are quite varied, however, and include genetic mutations such as that resulting in hypertrophic cardiomyopathy, or lifestyle factors such as poor diet that can result in hypertension, among other potential causes. In fact, the most common cause of SCD in the older population stems from atherosclerosis, whereby the extent of coronary artery plaque occludes the passage of blood, resulting in myocardial ischaemia and inducing a potentially fatal arrhythmia (alternatively, the shear stress from vigorous exercise can result in the rupture of the fibrous cap that covers the atherogenic plaque, leading to the accumulation of platelets and resulting in a thrombus or an embolism that could occlude a major coronary artery). Thus, the incidence of SCD appears to be a function of genetics, lifestyle factors (smoking, diet), and environmental conditions (temperature, altitude). In all respects and cases, though, chronic exercise would appear to reduce the risk of SCD. The question that O’Keefe et al. are asking is whether EEE specifically may predispose an individual to a greater risk of SCD than a normal exercise regimen.
Excessive Endurance Exercise and Cardiac Fibrosis
The study then discusses research findings of cardiac fibrosis with excessive endurance exercise (EEE), citing several animal studies that employed particularly stressful exercise protocols to support their hypothesis. One of these protocols involved forcing rats to run on a treadmill for 60 minutes at approximately 90% of maximal heart rate (HRmax) for 5 days/week for 4 consecutive months (Benito et al., 2011). Such an exercise protocol resulted in the development of patchy myocardial fibrosis and diastolic dysfunction, increasing the susceptibility to atrial and ventricular arrhythmias. The study also found that the cardiac fibrosis was completely reversed within 8 weeks of detraining (see figure at right). It must also be noted that these training protocols employ an exercise “dose” that is arguably more strenuous than that of high-level amateur or elite athletes. As the lifespan of a rat is only 2-2.5 years, the exercise protocol employed in this study is akin to having humans training at the same frequency and intensity for 10 consecutive years. Moreover, the application of electrical shocks to the rats in order to encourage running lest they fall behind on the treadmill is, arguably, a protocol that could invoke great emotional stress. Such long-term, intensive exercise training without significant rest periods is more strenuous than most training programs of elite athletes. Case in point, many sports coaches highly recommend that athletes take a “transition period” of at least 2-3 weeks, if not a full month, after a sport season to fully recover from their efforts. Even after this transition period, elite athletes do not begin with high-frequency, high-intensity training: they start with “base” training, which is very low-intensity but high-volume training. The findings that detraining reverses the cardiac fibrosis completely within 8 weeks suggests that both the transition and base periods for elite athletes could have a similar effect in halting or reversing the development of cardiac fibrosis. This finding then appears to highlight the importance of taking pre-ordained rest periods on the order of atleast several weeks once per year to mitigate the development of cardiac fibrosis (Benito et al., 2011), although it remains to be seen whether transitioning from high-intensity to low-intensity exercise (instead of zero exercise as in detraining) would have the same effect in reversing cardiac fibrosis.
The relationship of elevated concentrations of biomarkers for cardiac damage during and after EEE, including cardiac troponin (CT), creatine kinase MB (CKMB), and B-type natriuretic peptide (BNP), to the development of cardiac fibrosis is uncertain and subject to debate. Many have argued these elevations are entirely benign and transient increases that result in beneficial CV adaptations to EEE. O’Keefe et al. suggests that these serologic markers of cardiac damage could contribute to cardiac fibrosis and development of arrhythmias. However, three independent studies present uncertain results in this regard. Breuckmann et al. (2009) studied a cohort of 102 healthy male marathon runners aged 52-70 years and found that 12% of these runners demonstrated late gadolinium enhancement (LGE, see footnote) compared with only 4% of sedentary control subjects. The suggested cause for this increased incidence of LGE in marathoners was coronary microembolization, a process related to coronary artery disease (CAD) in which plaque rupture causes the lipid pool contained within the atheroma to be carried downstream, resulting in microembolization, localized inflammation, reduced blood flow, contractile dysfunction, and the development of cardiac fibrosis. This mechanism appears more likely in light of the high shear stress on epicardial arteries during vigorous exercise, which can increase plaque erosion and subsequent thrombus formation. Additionally, exercise has been shown to lead to platelet activation, leukocytosis, and increases in hematocrit, particularly under dehydration conditions where plasma water content is reduced (Kratz et al., 2006). Thus, this imbalance between prothrombotic and fibrinolytic factors after strenuous exercise may further contribute to intravascular microthrombus formation. An experimental model of sequential coronary microembolization in dogs eventually led to heart failure, suggesting that the biological mechanism of coronary microembolization may be a large part of the proarrhythmia substrate (Sabbah et al., 1991). Finally, a study by Baldesberger et al. (2007) demonstrated that former elite professional cyclists exhibited sinus node disease (SND) and arrhythmias at a rate of 15.5%, compared to only 2.5% in age-matched control subjects. This would appear to support the notion that EEE is pro-arrhythmogenic. However, and quite importantly, the authors noted that the use of illicit drugs could be an important contributing factor to this discrepancy, as the authors state that “The percentage of FAs [former athletes] in our study admitting the use of amphetamines or other drugs was amazingly high.” As a result, cardiac fibrosis and the development of potentially fatal arrhythmias may be more of a function of CAD and associated coronary microembolization’s than being a function of EEE alone. Moreover, using the seemingly increased incidence of arrhythmia’s in elite athletes to determine whether EEE causes adverse cardiac events can be misleading, as many elite athletes have used illicit performance-enhancing drugs that can alter the normal functioning of the heart.
Excessive Endurance Exercise and Right Ventricle Dysfunction
The guts of the hypothesis presented in this paper, however, appears to be the resultant decline in right ventricular (RV) function following EEE, evidenced by reductions in RV ejection fraction (RVEF) post-exercise. This phenomenon has a dose-response relationship, as evidenced by the graph on the left, whereby increasing exercise duration results in decreased RVEF. The significance of this RV dysfunction post-exercise is that it increases the potential for pro-arrhythmic effects, as the ventricular arrhythmias typically originate from a mildly dysfunctional RV and/or interventricular septum. In combination with patchy myocardial fibrosis, which favors reentry (the process where a cardiac impulse travels recurrently in a tight circle around the heart, resulting in sustained abnormal circuit rhythm, or arrhythmia), this can pose problems for individuals who do EEE training. Trivax et al. (2010) assessed the acute cardiac effects of marathon running in 25 middle-aged men and women, performing cardiovascular MRI and 24-hour ambulatory EKG both 4 weeks prior to, and immediately after, the marathon. The study found that marathon running causes dilatation of the RA and RV, a reduction in RVEF, and the release of CT and BNP. Importantly, their finding of RA and RV dilatation and subsequent RVEF reduction suggests the development of diastolic dysfunction from hours of sustained, near-maximal cardiac output and the accompanying increases in cardiac preload and afterload that over time can stretch the myocardium. In a similar vein, a study by La Gerche et al. (2012) assessed a cohort of 40 highly trained aerobic athletes after competing in marathon, half-ironman, full-ironman and alpine bicycle races, finding similar reductions in RVEF and increases in RV volumes. However, they also found that these changes returned to baseline levels within 1 week of the event, and that such RV structural remodeling was most prevalent in longer duration events. Among the 40 athletes studied, 5 (12.5%) presented with myocardial scarring as detected by LGE. Moreover, these were the athletes with the largest cumulative experience in competitive endurance events. The significance of this acute RV dysfunction with EEE is bolstered by the finding that among athletes with symptoms of ventricular arryhtmia (VA), 50% had RV structural abnormalities (O’Keefe et al., 2012). The potential for EEE to induce detrimental RV remodeling may thus be a significant factor in contributing to the potential adverse CV effects of EEE.
There are several limitations that have presented throughout these studies. Many of the studies featured in the review article used small sample sizes, and this could have distorted the true risk to CV health from EEE. However, the issue of small sample size, considering the relatively few people who participate in ultra-endurance events, may be difficult to address. The participants were also generally older in age, when it might be expected for cardiac abnormalities to occur more frequently. What’s more is that these studies did not take into account the multiple confounding variables likely to influence cardiac performance, such as variability in training levels, environmental conditions, type of exercise, motivation, and diet or presence of stimulants. Would a fatty, unhealthy diet result in increased risk for adverse CV effects with EEE, especially considering the suggested mechanism of coronary microembolization that is CAD-related? Would stimulant consumption spur development of cardiac fibrosis or contribute to the incidence of arrhythmia, considering that stimulants such as caffeine have been shown to elicit ventricular ectopies that can potentially (although not usually under normal circumstances) devolve into cardiac arrythmias?
All things considered, there seems to be mounting evidence that EEE does lead to cardiac fibrosis in a small percentage of individuals. The effect appears to be most pronounced during high-intensity, long-duration exercise bouts, such as a marathon or ironman, and not low or moderate intensity exercise. To mitigate any development of cardiac fibrosis, a significant rest period of about a month once per year, abstaining from any high-intensity exercise, would appear to be prudent. Fatty, sugary diets may be a primary culprit in the development of this fibrosis due to the suggested mechanism of coronary microembolization. The use of stimulants may contribute to the onset of arrhythmias during vigorous exercise. Hydration is important to prevent excessive coagulation of platelets that could occur with a decreased volume of blood plasma and subsequently lead to increased risk of thrombus formation. Finally, more research is needed to ascertain the role of multiple confounding factors in fibrosis development.
Abstracting to a Real-Life Example
The death of Micah True (photo at right) is an interesting "case study", albeit done posthumously. True, a long-time ultra distance runner who was featured in the popular running book Born to Run, could have exhibited signs indicating some truth to this hypothesis. The day of True's death, he went out for a 12-mile run in the Gila Wilderness in New Mexico. An intensive search culminated in finding his body near the side of a creek. The autopsy revealed that True's death was from idiopathic cardiomyopathy, or heart disease with an unknown cause, which doesn't necessarily reveal much. However, the day before his death, True had completed a 6-hour run. It may be the case that True suffered from acute RV dysfunction and patchy myocardial fibrosis from both his 6-hour EEE run the previous day as well as his decades of ultra-running experience. In combination with the presence of caffeine they found in his blood and mild dehydration, it's possible that True could have suffered from a fatal cardiac arrythmia.
Although the jury is most certainly still out on whether intense endurance exercise is bad for the heart, and it is more than likely that it is influenced by a consortium of confounding factors that are near to impossible to encompass in any single research or review paper, it is interesting that such a discussion even arises in the first place. Why do people participate in these intense, prolonged endurance activities nowadays? Why do millions of people toe the starting line in marathon's across the country each year? One can't help but wonder that, as a symptom of our societal push to increase productivity and working hours, we have relegated our exercise habits to a window of intense yet prolonged exercise. If instead of sitting in an office chair for most of the day, modern humans were instead on their feet, walking and expending energy at low levels of exertion, they would not be inclined to run 10 miles, bike 30 miles, or swim 2 miles before or after work. Case in point, it is rare for manual laborer's, who physically exert themselves for prolonged periods at low intensity, willingly submit to intense running or cycling sessions. Nontraditional standing desks may make an impact in this regard, but they have yet to become widely accepted.
Footnote 1. LGE, used in combination with CVMRI, is a technique for identifying areas of cardiac muscle that may have developed fibrosis. Gadolinium, the contrast agent, accumulates within the extracellular space, particularly in areas with increased myocardial collagen deposition that signify fibrosis development.
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Benito et al. (2011). Cardiac Arrhythmogenic Remodeling in a Rat Model of Long-Term Intensive Exercise Training. Circulation. 123:13-22. http://circ.ahajournals.org/content/123/1/13.full.pdf
Breuckmann et al. (2009). Myocardial Late Gadolinium Enhancement: Prevalence, Pattern, and Prognostic Relevance in Marathon Runners. Radiology. 251: 1. http://radiology.rsna.org/content/251/1/50.full.pdf)
Kratz et al. (2006). Effects of Marathon Running on Platelet Activation Markers: Direct Evidence for In Vivo Platelet Activation. American Journal of Clinical Pathology.125(2):1-5. http://www.medscape.com/viewarticle/523124_4
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La Gerche et al. (2012). Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes. ). European Heart Journal. 33(8): 998-1006. http://www.ncbi.nlm.nih.gov/pubmed/22160404
Sabbah et al. (1991). A canine model of chronic heart failure produced by multiple sequential coronary microembolizations. American Journal of Physiology. 260 (4 Pt 2): H1379-84. http://www.ncbi.nlm.nih.gov/pubmed/1826414
Trivax et al. (2010). Acute cardiac effects of marathon running. Journal of Applied Physiology. 108: 1148–1153. http://jap.physiology.org/content/108/5/1148.long