30 hours of continuous running, the heart may beat 250,000 times and produce 27,000 liters of blood flow. This is an astonishing level of work, and unlike the skeletal muscles, there is no rest at the end of the race, as the heart has to continue beating. Does the heart cope easily with this activity or, like the muscles of your legs, is it vulnerable to fatigue, and might there even be some cellular damage (that in the legs may produce soreness for days)?

Consequently, we could also ask the question, “Does the stress of ultramarathon running result in cardiac fatigue and damage?” We address these two areas in the next subsections based on data collected at a number of endurance events, including the Western States Endurance Run (WSER) in 2007-2009 and the Comrades Marathon in 2004.

The acute impact of ultramarathon running on heart health

While there is a large body of evidence demonstrating the benefits of regular physical exercise upon cardiovascular health, the majority of these datacome from moderate-duration (<1 hr), moderate-intensity exercise programs. This is markedly different from the cardiovascular challenge faced by ultramarathon runners. We have examined a number of different endurance races and have shown evidence for postrace impairment in both diastolic (relaxation) and systolic (pumping) cardiac function (George et al. 2005; Scott et al. 2009; Oxborough et al. 2011).

Figure 1. Example of transmitral blood-flow velocity Doppler recording before and after completion of an ultramarathon. Note the marked reduction in early transmitral filling velocity (E) and the enhanced late (A) filling velocity postexercise; such changes may indicate impaired diastolic function or transient “stiffening” of the left ventricle.

This postexercise reduction in cardiac function has been termed “cardiac fatigue” and is characterized by decrements in a number of echocardiographic indices of function. Using echocardiography to assess cardiac function prior to and immediately following completion of exercise, investigators have shown a reduction in early transmitral filling of the left ventricle and a compensatory increase in late ventricular filling (see figure 1 on the previous page).

These data are suggestive of an impaired diastolic function, meaning that the left ventricle is unable to relax as well as it could prior to the completion of the endurance event or that blood returning to the heart is reduced. Global markers of systolic function such as ejection fraction and/or stroke volume also appear to be acutely impaired following ultramarathons; this is likely related to an impaired filling during the diastolic period but is also a direct effect of prolonged exercise upon the heart muscle itself. Using more advanced ultrasound techniques such as tissue Doppler and deformation imaging, we have shown reduced myocardial function in individual regions of the heart following the Comrades and WSER Ultramarathons (George et al. 2005; Scott et al. 2009; Oxborough et al. 2011) (see figure 2).

Figure 2. Radial strain (deformation) before (top) and after (bottom) completion of the Comrades Marathon. Note the reduction in strain in the septal segments following completion of the race. Reduced strain reflects an impaired ability of the cardiac muscle to deform, and hence overall function is reduced.

Exercise-induced cardiac fatigue appears to be related to exercise duration, with the greatest effect being observed following the longest, most challenging events. Using meta-analysis techniques to collate data from a large number of studies, we concluded that exercise >2 hours leads to an acute reduction in diastolic function, whereas the exercise duration needs to be extended to ~6 hours before significant changes are observed in systolic function (Middleton et al. 2006). Furthermore, it appears that overall training status is also an important mediator in the onset of cardiac fatigue. Highly trained athletes need to exercise for longer durations before reductions in systolic function become evident.

Although the majority of work in this area has focused on the left side of the heart, recent work has started to examine the right ventricle as well. Interestingly, the right ventricle may be more prone to cardiac fatigue than the left (La Gerche et al. 2008), and there appears to be an interaction between the left and right ventricles (Oxborough et al. 2011), suggesting that a common mechanism is likely responsible for the postexercise reduction in function in both the left and right sides of the heart.

Early studies examining cardiac fatigue were largely descriptive in nature; however, since the concept of exercise-induced cardiac fatigue has been accepted within the literature, authors have moved their focus to the potential mechanism that might explain this phenomenon. During endurance exercise, physiologic homeostasis is challenged; core temperature rises, catecholamines (epinephrine and norepinephrine) are persistently elevated, and the work of the heart increases significantly. It is possible that all of these changes to the physiological environment, in isolation or collectively, may compromise cardiac muscle function and explain cardiac fatigue.

An increase in core temperature as observed during prolonged endurance exercise results in significant fluid loss via sweat. In an attempt to improve heat dissipation, blood is redistributed to the peripheral circulation and the sweat glands are stimulated. This redistribution of blood and loss of fluid means that the blood volume returning to the heart during resting recovery may be lower than at rest prior to the onset of exercise. If less blood volume is returning to the heart, this will reduce filling of the ventricles (preload) and thus explain the differences in transmitral filling observed in early cardiac-fatigue studies. Data collected by Hart and colleagues (Hart et al. 2007) used postural manipulation to examine the influence of changes in preload before and after a marathon and demonstrated that altered preload does indeed explain some of the postexercise differences in diastolic function.

In order to maintain the enhanced cardiac function required to meet the metabolic demands of exercise, catecholamines are released to increase heart rate and enhance cardiac contractility. Although acute exposure to catecholamines enhances cardiac function, prolonged exposure may result in a desensitization of

the beta receptors in the heart and ultimately lower overall cardiac function. This is widely reported in the clinical setting of heart failure when catecholamines are chronically elevated. Using pharmacological challenges to explore the effect of prolonged exercise upon the beta receptors in the heart, two groups (Eysmann et al. 1996; Hart et al. 2006) have shown that exercise-induced elevations in catecholamines result in desensitized beta receptors following prolonged bouts of endurance exercise. Interestingly, this mechanism seems to be specifically related to the changes in systolic function rather than diastolic function.

The next and potentially most concerning mechanism that may explain the onset of cardiac fatigue is exercise-induced cardiac injury. It is theoretically possible that the change in physiological environment associated with prolonged exercise (such as increased core temperature, decreased pH, and enhanced mechanical stress) could cause direct damage to the cardiac muscle cells. Early studies from the 1980s demonstrated an appearance of creatine kinase- MB (CK-MB) following marathon running indicative of myocardial damage (Siegel et al. 1985; Apple et al. 1984). However, the specificity of CK-MB was later questioned, as it demonstrated significant cross-reactivity with skeletal-muscle damage. Notwithstanding, later studies using highly specific ERB eck, SEES CB op cardiac troponin assays have y ae ae y further supported the concept – of exercise-induced cardiac damage. We have shown that 47 percent of endurance athletes experience significant elevation in cardiac troponin postexercise (Shave et al. 2007) and that 36 percent of London Marathon runners complete the race with a circulating concentration of cardiac troponin that is above the clinical cutoff for acute myocardial infarction (AMI) (Shave et al. 2005). However, similar to the change in cardiac function following prolonged exercise, the elevation in cardiac biomarkers is transient in nature. This transient release is fundamentally different from that seen

© Joe McCladdie

following an AMI in that the magnitude of release is much lower and the duration of release much shorter. More recently, using serial assessments of biomarkers during prolonged exercise, we have shown that cardiac troponin is released in everyone during marathon running (Middleton et al. 2008) and that it is also released in some individuals following short-duration exercise (Shave et al. 2010). Accordingly, while the earlier studies suggested that prolonged exercise such as ultramarathons may stimulate the release of cardiac-specific markers of damage, we believe that this release is likely not of serious concern and may reflect the start of positive cardiac remodeling. It is still unclear, however, whether the release of cardiac biomarkers is directly related to the change in cardiac function following prolonged exercise. Some studies have presented significant correlations between changes in both left (Neilan et al. 2006) and right (La Gerche et al. 2008) ventricular function, while others have reported no relationship, so further work is needed. Similarly, further work is required to examine the long-term consequences of repeated bouts of exercise-induced cardiac fatigue and whether exercise-induced reductions in cardiac function impede performance.

In summary, while there is mounting evidence of an immediate vulnerability of the heart to acute ultramarathon running, it seems that this insult is small in absolute terms, very transitory, and of seemingly no known clinical significance. While the reporting of exercise-induced cardiac fatigue and damage is commonplace, we do not know the current mechanisms underpinning each of these processes; it is highly likely that this is simply a physiological response to the extreme cardiac work undertaken. Despite current data, it would seem that the heart is still more resilient than skeletal muscles when performing ultramarathon running.

The effect of training on heart size and function in the ultramarathon athlete

The effect of exercise training on heart size and function has been of interest to medics, scientists, and athletes for hundreds, if not thousands, of years. It has, however, only recently been possible to measure (or estimate) cardiac chamber size, wall thickness, and mass with the advent of noninvasive imaging techniques. Tools such as echocardiography and cardiac magnetic-resonance imaging allow real-time and highly accurate assessment of the left ventricular cavity as well as the thickness of the muscle walls that surround the left ventricle. By using simple modeling, the left ventricular cavity and wall size can be used to calculate left ventricular mass and thus be used to define any hypertrophic (muscle growth) response to training. It is thought that chronic endurance training can increase left ventricular mass predominantly by an enlargement of the left ventricular cavity volume (when measured at the end of filling or end-diastole). In addition to small increases in wall thickness around the cavity, an “eccentric” or balanced hypertrophy of left ventricular mass is said to occur that is nearly always accompanied by normal or improved resting left ventricular function (George et al. 1991). This eccentric hypertrophy has been reported in many individual studies and a compilation of studies in a meta-analysis (Pluim et al. 2000). This adaptation to endurance-exercise training, along with a lower resting heart rate, is highly reproducible and is considered “textbook” knowledge.

Of interest to scientists and clinicians is the concept of the upper normal limit of possible cardiac adaptation to a healthy or physiological stimulus like exercise training (George and Spence et al. 2011). Knowledge of the upper limits of left ventricular cavity size and left ventricular wall thickness, in particular, is important to help diagnostically differentiate the normal “athletic heart” from some cardiac diseases such as dilated cardiomyopathy (chamber size increase) and hypertrophic cardiomyopathy (wall thickness increase). While not common in athletes, these disease states can, if present, increase the risk of sudden cardiac death during vigorous exercise. The death of young athletes, from any sport, on the field of play is devastating and catastrophic and can often have far-reaching implications for the sport. In many countries (Italy, for example) and many specific sports, cardiac preparticipation screening is undertaken in an effort to find those athletes with cardiac disease (likely genetic/inherited) and remove them from intense and competitive participation. Any screening process is importantly underpinned by clear knowledge of what is normal and what level of cardiac growth or hypertrophy is possible with exercise training.

It has been stated in many scientific papers that the upper limit of cardiac adaptation, or hypertrophy, occurs in endurance-trained athletes (Naylor et al. 2008) and more specifically in cyclists, rowers and cross-country skiers (Pelliccia et al. 1999). In a recent analysis of many individual studies, the left ventricular cavity of an endurance athlete was on average about 55 millimeters and the left ventricular wall thickness was around 10 millimeters. The magnitude of the data from past studies and the concept that cyclists, rowers, and skiers have the biggest hearts was challenged by a study of ultramarathon runners in Japan (Nagashima et al. 2003). In 291 male Japanese ultra-endurance runners Nagashima et al. (2003) reported a mean left ventricular cavity dimension of 61 millimeters, with 11 percent of those tested having a cavity size greater than 70 millimeters. Further, maximal left ventricular wall thickness was reported at 19 millimeters. Both of these ranges are considerably larger than previously suggested (Pluim et al. 2000) (see figure 3 on page 50). Clearly, the consequence of this information is that many more ultramarathon runners would show extreme heart dimensions whose size overlaps considerably with pathologies noted previously (dilated cardiomyopathy and hypertrophic cardiomyopathy). This will place the clinician in a very difficult diagnostic dilemma and could well lead to significant worry and even removal of athletes from training and competition. False positive screening outcomes could

Pluim et al. (2000), meta-analysis of Nagashima et al. (2003), 291 Japanese endurance athletes ultramarathon runners

Figure 3. A comparison of left ventricular dimensions between (a) mean values for endurance athletes reported in a meta-analysis, and (b) maximal values for ultramarathons. (ST=septal wall thickness; LVD=left ventricular dimension)

lead to loss of earnings and psychological trauma as well as potentially harming overall cardiac health because of the withdrawal from physical activity.

Nagashima and colleagues produced provocative data that required verification or challenging as well as extending the data collections in relevant directions (Nagashima et al. 2003). Specifically, Nagashima and colleagues studied only male Japanese ultramarathon runners and did not report data for cardiac function. In deciding to replicate and challenge this work, we also sought to extend it by studying male and female ultramarathon runners at the WSER. Further, with developing heart-imaging technology, we studied cardiac function to help address whether the hearts of the athletes presented a healthy physiological adaptation.

Over a period of three years (2007-2009), we recruited 165 ultramarathon runners at the WSER. Some of these data have been reported in a short report (George and Warburton et al. 2011). All participants self-reported to be healthy and were tested at registration prior to the race. Age, training history, body size, resting heart rate, and resting blood pressure were recorded (table 1 on page 51) before completing a noninvasive heart scan (see figure 4 on page 52). Compared with men, women were slightly younger and had less training experience, smaller body sizes, and lower blood pressures.

With the athletes lying on their left side, we completed a standard heart scan that allowed us to estimate left ventricular cavity size, maximal left ventricular wall thickness, and total left ventricular mass. We also calculated a left ventricuTable 1. WSER participant training history, physical characteristics, and comparison between men and women. Data are mean+SD with [range].

Whole Cohort Men Women ea Cl

N 165 126 39 =

Age (yr) 4449 45+10 4247 0.032 24-76] 24-76] 26-60]

Competitive 16+11 17+11 12+9 0.034

weaining yt) 2-48] 2-48] 2-34]

Distance training 59+21 57415 59+22 0.626

miles Week) 15-120] 30-100] 15-120]

Marathons and 46453 47453 39450 0.428

ultramarathons 3-500] 3-500] 3-300]

completed (n)

Height (m) 1.75+0.10 1.79+0.08 1.65+0.07 0.000 1.47-1.97] 1.54-1.97] 1.47-1.76]

Body mass (kg) 70.9412.1 75.5+9.4 56.147.3 0.000 41.0-100.5] 52.0-100.5] 41.0-72.4]

BSA (m?) 1.86+0.20 1.94+0.15 1.61+0.13 0.000 1.35-2.19] 1.51-2.19] 1.35-1.83]

Resting heart rate 58+9 59+9 58+9 0.827

(beats/min) 38-83] 39-83] 38-80]

Resting SBP 117+10 118+10 112+8 0.002

mig) 90-148] 90-148] 98-140]

Resting DBP 76+8 7748 7347 0.015

mig) 48-90] 48-90] 54-86]

BSA=body surface area, SBP=systolic blood pressure, DBP=diastolic blood pressure

lar mass index after individual differences in body size were taken into account.

In addition, we assessed the contractile and relaxation function of the heart by studying the speed of movement of the heart wall during systole (contraction) and diastole (relaxation). We also measured peak blood-flow velocities during the early and later phases of left ventricular filling. The ratio of these velocities (E/A) is often reported as an index of left ventricular filling. For all data we calculated an average for the entire group as well for the male and female runners. Further, we reported minimum and maximum values.

Figure 4. An exemplar figure of a noninvasive echocardiogram scan.

Data for cardiac structure and function are shown in table 2 on page 53. A number of interesting factors emerge. First, the average cardiac dimensions, as well as maximum data for chamber dimension and wall thickness, were very similar to the previous meta-analysis of many different endurance athlete groups (Pluim et al. 2000). These data do not reflect or substantiate the extreme levels of cardiac hypertrophy seen in some Japanese ultramarathon runners (Nagashima et al. 2003). Second, despite the fact that ultramarathon runners do have an enlarged heart compared with sedentary control data (see, for example, Pluim et al. 2000), cardiac functions during contraction and relaxation were entirely normal, again suggesting a healthy physiological cardiac adaptation in these athletes. Finally, while absolute cardiac dimensions were higher in the male compared with the female ultramarathon runners, it is worth noting that this difference was lost when data (such as left ventricular mass) were normalized for individual differences in body size. Bigger men have bigger hearts! Cardiac function was not different between men and women.

We can conclude that cardiac adaptation in American ultramarathon runners was not as extreme as reported recently in Japanese ultramarathon runners (Nagashima et al. 2003). In addition, all athletes studied had normal left ventricular systolic and diastolic function. Taken together, this significantly reduces the poTable 2. Cardiac dimensions, left ventricle function, and comparison between men and women. Data are mean+SD with [range].

Normal Normal

Data Data ((itsa)} (women)

LV chamber 5.20.4 53404 4.9403 0.000 49 46 dimension [4.2-6.2] 46-62] [4.2-5.5]

Wall thick- 1.10.2 11402 1,040.1 0.000 09 08 ness (cm) 0.61.4] 0.8-1.4] 0.6-1.2]

LV mass (g) 210457 225454 161429 +~—«-0.000-—Ss=:‘174 136

105-378] 123-378] 105-236]

LVmass/ 82416 83417 79413 0.164 NA NA BSA’* 45-133] 45-133] [59-112]

(g/m?#3)

E/A 1.444037 1.414038 1.534033 0.078 129 1.29

0.72-2.84] 0.72-2.84] — [0.99-2.30]

E’ (m/s) 0.11+0.02 0.1140.02 0.12+0.02 0.118 0.12 0.12 0.06-0.18] 0.06-0.18] — [0.07-0.15]

S’ (m/s) 0.09+0.02 0.09+0.02 0.09+0.01 0.582 0.09 0.09 0.06-0.14] 0.06-0.14] [0.07-0.13]

LV=left ventricular, BsSA=body surface area, E=early diastolic filling velocity, A=atrial diastolic filling velocity, E’=early diastolic tissue velocity, S’=systolic tissue velocity. Normal mean data for men from Pluim et al. (2000) and for women from Whyte et al. (2004). Normal functional data are from combined data for men and women from Alam et al. (1999) as there is little sex-based difference. NA = not available.

tential for a diagnostic dilemma in any cardiovascular screening process in any ultramarathon runner. The reason why the current data differ from the Nagashima paper remains uncertain and is likely complex. Both studies recruited athletes across a broad age range (into the 70s), and while we report data for women as well, this does not alter the key differences in maximal dimensions reported for men in both studies. A genetic contribution to the larger cardiac dimensions in Japan cannot be ruled out and may require further study. It is possible that the use of only single-dimension measures (called M-mode) in the Japanese study may have led to occasional cases of overestimation of cardiac dimensions. We used a combination of imaging modes to try to accurately represent cardiac structure and function. Whether the extreme cardiac dimensions in some Japanese athletes were

© Michael Lebowitz/Long Run Pictures

representative of a cardiac pathology with altered function was not determined but should be followed up.

The final insight from the current data is that while absolute cardiac dimensions were greater in men, when these data were normalized for body size, sex differences were considerably reduced. Alongside similar functional data, this would suggest that cardiac adaptation to ultramarathon training is similar in male and female athletes when body-size differences are accounted for.

Conclusions

The study of the heart of ultramarathon runners is vitally important to help us understand the physiological adaptation to training that underpins changes in performance. Clearly, the heart of the ultramarathon runner is adaptable and vulnerable, like the hearts of most individuals. Prolonged exercise such as ultramarathons results in a transient (24- to 36-hour) reduction in left and right ventricular function. Such “cardiac fatigue” may be partially explained by changes

in blood volume and desensitization of beta receptors and occurs simultaneously with the release of markers of cardiac damage. Although clear evidence for the existence of cardiac fatigue is now available, the long-term consequences of repeated periods of cardiac fatigue alongside the release of cardiac biomarkers is not known. Furthermore, whether cardiac fatigue affects exercise performance is also still in question.

We determined the upper limits of cardiac adaptation ina large number of North American ultramarathon runners. In agreement with a previous meta-analysis, we observed cardiac dimensions very similar to other studies of endurance athletes but not at the extreme levels seen in a Japanese study of ultramarathon runners. Combined with data that observed normal resting cardiac function, we conclude that ultramarathon training results in a larger heart, but this adaptation is healthy and likely important to support the blood-flow demands of training and competition.

Overall, we can conclude that while the cardiovascular stress of ultramarathon training and competition is considerable, the hearts of these athletes are remarkably adaptable and resilient.

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