May Strenuous Endurance Sports Activity Damage the Cardiovascular System of Healthy Athletes? A Narrative Review

tive effects of physical activity are countless, not only on the cardiovascular system but on health in general. However, some studies suggest a U-shape relationship between exercise volume and effects on the cardiovascular system. On the basis of this perspective, moderate-dose exercise would be bene cial compared to a sedentary lifestyle, while very high-dose physical activity would paradoxically be detrimental. We reviewed the available evidence on the potential adverse effects of very intense, prolonged exercise on the cardiovascular system, both acute and chronic, in healthy athletes without pre-existing cardiovascular conditions. We found that endurance sports activities may

of this perspective, moderate-dose exercise would be bene cial compared to a sedentary lifestyle, while very high-dose physical activity would paradoxically be detrimental. We reviewed the available evidence on the potential adverse effects of very intense, prolonged exercise on the cardiovascular system, both acute and chronic, in healthy athletes without pre-existing cardiovascular conditions. We found that endurance sports activities may cause reversible electrocardiographic changes, ventricular dysfunction, and troponin elevation with complete recovery within a few days. The theory that repeated bouts of acute stress on the heart may lead to chronic myocardial damage remains to be demonstrated. However, male veteran athletes with a long sports career show an increased prevalence of cardiovascular abnormalities such as electrical conduction delay, atrial brillation, myocardial brosis, and coronary calci cations compared to non-athletes. It must be underlined that the cause–effect relationship between such abnormalities and the exercise and, most importantly, the prognostic relevance of such ndings remains to be established. Keywords: athletes; atrial brillation; arrhythmias; cardiac magnetic resonance; electrocardiogram; ECG; exercise; long-QT; myocardial brosis; sports cardiology; troponin 1. Introduction The positive effects of physical activity, not just on the cardiovascular system but on health in general, are countless [1–3]. However, intense physical exercise may trigger malignant ventricular arrhythmias and promote disease progression in patients with un- derlying heart disease [4]. Whether strenuous and prolonged sports practice may carry short- and long-term adverse consequences to the heart is a matter of debate. According to one theory, a U-shaped relationship exists between dose of physical activity (pace, quan- tity, and frequency) and cardiovascular system effects. On the basis of this perspective, moderate-dose exercise would be bene cial compared to a sedentary lifestyle, but very high dose of physical activity would paradoxically be detrimental [5]. This review discusses the available evidence on the potential adverse effects of intense, prolonged endurance exercise on the cardiovascular system, both acute and chronic, in healthy athletes. The effects and risks of sports practice in individuals with pre-existing cardiovascular conditions are not addressed. J. Cardiovasc. Dev. Dis.2022,9, 347.

discusses the available evidence on the potential adverse effects of intense, prolonged endurance exercise on the cardiovascular system, both acute and chronic, in healthy athletes. The effects and risks of sports practice in individuals with pre-existing cardiovascular conditions are not addressed. J. Cardiovasc. Dev. Dis.2022,9, 347.

J. Cardiovasc. Dev. Dis.2022,9, 347 2 of 20 2. Acute Effects Prolonged strenuous exercise has profound acute effects on both structure and function of the heart. The right side of the heart is more sensitive to volume and pressure overload induced by exercise than the left side due to its thinner wall and lower resting pressure of the right chambers [6]. During exercise, the progressive increase in pulmonary vascular resistance leads to higher relative wall stress in the right ventricle (RV) when compared to the left ventricle (LV) [7]. This can cause an acute overload of the right heart that can lead to acute RV dysfunction, the occurrence of arrhythmias, and electrocardiographic (ECG) abnormalities. 2.1. Acute ECG Abnormalities Lord et al. [8] described 12-lead ECG ndings following a 100-mile ultra-marathon and demonstrated acute changes re ecting RV overload. Speci cally, they described an increase in the summated R wave in V1 and S wave in V5 (i.e., the Sokolow–Lyon criteria for RV hypertrophy) and in the elevation of the J point as well as in the prevalence of incomplete right bundle branch block and T-wave inversion. The echocardiographic assessment con rmed the RV overload following the race. The same authors showed that also the right precordial leads (V1R-V6R) show acute modi cations after an ultramarathon [9]. D'Ascenzi et al. [10] evaluated the acute ECG modi cations following endurance exercise (50 km ultramarathon). They found that ECG markers of right heart overload developed in a sizeable proportion of athletes, with a risen voltage of P wave, right atrial (RA) enlargement, increase in R-wave voltage in V1, and a rightward shift in the QRS axis as compared with pre-race data, which were more evident in athletes with the best performance during the race (Figure).J. Cardiovasc. Dev. Dis. 2022, 9, x FOR PEER REVIEW 2 of 21 and frequency) and cardiovascular system effects. On the basis of this perspective, mod- erate-dose exercise would be beneficial compared to a sedentary lifestyle, but very high dose of physical activity would paradoxically be detrimental [5]. This review discusses the available evidence on the potential adverse effects

race (Figure).J. Cardiovasc. Dev. Dis. 2022, 9, x FOR PEER REVIEW 2 of 21 and frequency) and cardiovascular system effects. On the basis of this perspective, mod- erate-dose exercise would be beneficial compared to a sedentary lifestyle, but very high dose of physical activity would paradoxically be detrimental [5]. This review discusses the available evidence on the potential adverse effects of in- tense, prolonged endurance exercise on the cardiovascular system, both acute and chronic, in healthy athletes. The effects and risks of sports practice in individuals with pre- existing cardiovascular conditions are not addressed. 2. Acute Effects Prolonged strenuous exercise has profound acute effects on both structure and func- tion of the heart. The right side of the heart is more sensitive to volume and pressure overload induced by exercise than the left side due to its thinner wall and lower resting pressure of the right chambers [6]. During exercise, the progressive increase in pulmonary vascular resistance leads to higher relative wall stress in the right ventricle (RV) when compared to the left ventricle (LV) [7]. This can cause an acute overload of the right heart that can lead to acute RV dysfunction, the occurrence of arrhythmias, and electrocardio- graphic (ECG) abnormalities. 2.1. Acute ECG Abnormalities Lord et al. [8] described 12-lead ECG findings following a 100-mile ultra-marathon and demonstrated acute changes reflecting RV overload. Specifically, they described an increase in the summated R wave in V1 and S wave in V5 (i.e., the Sokolow–Lyon criteria for RV hypertrophy) and in the elevation of the J point as well as in the prevalence of incomplete right bundle branch block and T-wave inversion. The echocardiographic as- sessment confirmed the RV overload following the race. The same authors showed that also the right precordial leads (V1R-V6R) show acute modifications after an ultramara- thon [9]. D’Ascenzi et al. [10] evaluated the acute ECG modifications following endurance ex- ercise (50 km ultramarathon). They found that ECG markers of right heart overload de- veloped in a sizeable proportion of athletes, with a risen voltage of P wave, right atrial (RA) enlargement, increase in R-wave voltage

right precordial leads (V1R-V6R) show acute modifications after an ultramara- thon [9]. D’Ascenzi et al. [10] evaluated the acute ECG modifications following endurance ex- ercise (50 km ultramarathon). They found that ECG markers of right heart overload de- veloped in a sizeable proportion of athletes, with a risen voltage of P wave, right atrial (RA) enlargement, increase in R-wave voltage in V1, and a rightward shift in the QRS axis as compared with pre-race data, which were more evident in athletes with the best per- formance during the race (Figure 1). Figure 1. Acute ECG changes reflecting right heart overload. ECG of a top-level competitive athlete the day before (A) and immediately after (B) running a 50 km ultramarathon. After the race, the ECG showed higher P-wave voltages and a rightward shift in the QRS axis. Adapted from D’As- cenzi et al. [10]. Figure 1. Acute ECG changes re ecting right heart overload. ECG of a top-level competitive athlete the day before (A) and immediately after (B) running a 50 km ultramarathon. After the race, the ECG showed higher P-wave voltages and a rightward shift in the QRS axis. Adapted from D'Ascenzi et al. [10]. In a group of 10 athletes running a mountain marathon, a post-race prolongation of the signal-averaged P-wave duration was observed [11]. This ECG sign was accompanied by the elevation of several in ammatory markers, as well as atrial natriuretic peptide and high-sensitivity troponin, and the authors hypothesized that atrial in ammation might underline the prolongation of the intra-atrial conduction times. In summary, the studies agree that following an ultramarathon run, the ECG shows modi cations re ecting the right heart overload.

J. Cardiovasc. Dev. Dis.2022,9, 347 3 of 20 2.2. Acute Atrial Dysfunction Atrial dilatation is typical of the athlete's heart, but the atrial function is usually normal [12–15]. However, acute strenuous exercise may acutely impair atrial function. The high degree of stress on the myocardial structure during endurance sports has an impact, especially on the right heart cavities; however, some evidence suggests that the left atrium (LA) may also be affected. After a marathon, a reduction in LA diastolic and systolic peak deformation was demonstrated through myocardial speckle-tracking echocardiography in 17 healthy adult men [16]. The mechanism seemed to be secondary to impairment of the LV diastolic relaxation. Sanz-de la Garza et al. [17] analyzed the acute effects of a trail race of three lengths (14, 35, and 56 Km). They found that the RA reservoir and contractile function decreased after the longest race. The medium distance impacted the RA reservoir but not the contractile function, while athletes who had run the shorter distance did not exhibit modi cations in the RA function. A similar trend was observed for the LA that was affected to a lesser degree than the RA. The authors also found high interindividual variability in atrial response to exercise among athletes running the same distance. Chen et al. [18] evaluated atrial function by feature-tracking cardiac magnetic resonance (CMR) after a triathlon completion: they found that LA global longitudinal strain, but not RA, decreased after exercise. Different results were obtained by Cavigli et al. [19], who studied the echocardio- graphic and electrocardiographic changes of a group of 68 master athletes ( 40 years old) participating in a 50 km ultra-marathon. They found that mean biatrial size and func- tion were within normal values and did not differ after the race compared with pre-race values. These data disproved the hypothesis of an acute atrial dysfunction induced by ultra-endurance exercise, although reporting of mean values only did not allow assessing whether post-race differences were observed, at least in a subgroup of athletes. In summary, discrepancies exist among different studies concerning the acute effects of intense exercise on atrial function.

after the race compared with pre-race values. These data disproved the hypothesis of an acute atrial dysfunction induced by ultra-endurance exercise, although reporting of mean values only did not allow assessing whether post-race differences were observed, at least in a subgroup of athletes. In summary, discrepancies exist among different studies concerning the acute effects of intense exercise on atrial function. Even if prolonged exercise can cause acute atrial dysfunction, preliminary evidence suggests that this is a transient and reversible effect [20]. 2.3. Acute Ventricular Dysfunction Exercise causes an increase in cardiac output due to higher heart rate and cardiac contractility. A noted hypothesis, however, presumes that maintaining a high cardiac workload for a prolonged time may result in a transient cardiac dysfunction, i.e., a form of exercise-induced “cardiac fatigue” [21]. Saltin and Stenberg described this phenomenon for the rst time in 1964 by reporting that the stroke volume decreased after 3 h of exer- cise in four athletes [22]. The short-term effect of prolonged endurance exercise on LV function was analyzed in a meta-analysis of 23 studies published in 2002: reduction in LV ejection fraction with exercise was reported more frequently in untrained subjects performing moderate duration physical activity (>3h) and in trained athletes performing ultra-endurance races (>10.5 h). Recovery of LV ejection fraction to previous values is typically described after 48 h [?]3 . In 2015, a meta-analysis that included studies using advanced imaging techniques found that prolonged exercise reduces LV global longitudi- nal strain and twisting [24] . Alexoius et al. studied the acute effects of exhaustive 25 km open-sea swimming on LV function and morphology in a group of 20 elite male swimmers (22.3 4.1 years). The result was that prolonged exhaustive swimming was associated with depressed LV function, as suggested by reduced stroke volume, ejection fraction, and LV fractional shortening. According to the authors, increased afterload would justify this nding [25] . In contrast, a third meta-analysis also published in 2015 [26] found that prolonged endurance exercise does not have an impact on LV function. LV ejection fraction, strain, strain rates, rotation, rotation rates, and torsion

LV function, as suggested by reduced stroke volume, ejection fraction, and LV fractional shortening. According to the authors, increased afterload would justify this nding [25] . In contrast, a third meta-analysis also published in 2015 [26] found that prolonged endurance exercise does not have an impact on LV function. LV ejection fraction, strain, strain rates, rotation, rotation rates, and torsion were also unaltered in a cohort of non-elite male runners after the London marathon [27], and in a cohort of master amateur athletes running a 50 km ultramarathon [28]. Gajda et al. demonstrated that prolonged

J. Cardiovasc. Dev. Dis.2022,9, 347 4 of 20 intense swimming did not affect biventricular function in 14 swimmers (13–67 years) par- ticipating in an ultramarathon, swimming for 500 km (in 5 km intervals) [29]. As previously discussed, the RV function may be more profoundly affected than the LV by cardiac fatigue, secondary to an increase in volume and pulmonary systolic pressure [30,31]. A meta-analysis of 14 studies examining RV function following an event of at least 90 min duration found that parameters of RV function tend to worsen after exercise with no signi cant difference according to exercise time > or <6 h [26]. In contrast, in 35 runners participating in the London marathon (aged 18–50 years), no signi cant changes were found after the race in RV function [16]. In the same way, among 68 master athletes participating in a 50 km ultramarathon, mean RV dimensions and functions did not change after the race. In only four athletes, a reduction of RV strain, not accompanied by other signs of dysfunction, was observed [28]. In summary, discrepancies exist in the literature about the acute effects of prolonged exercise on ventricular function. These differences may be linked to different methods, study samples, and exercise duration. It is likely that only intense prolonged exercise may lead to transient ventricular dysfunction in a subset of athletes. All studies agree that ventricular “fatigue” is a transient phenomenon with complete recovery of ventricular function [7]. The theory that repeated bouts of transient myocardial dysfunction may eventually lead to permanent damage (so-called “exercise-induced cardiomyopathy”) is discussed below. 2.4. Atrial and Ventricular Ectopic Beats At present, there is no evidence that athletes show an increase in the ectopic atrial burden compared to their sedentary counterparts [32] or that endurance exercise acutely triggers atrial ectopic beats [19,33]. These recently published ndings are relevant because an increased atrial ectopic activity is one of the potential mechanisms of the increased prevalence of atrial brillation (AF) in athletes (see below). The ventricular ectopic burden does not seem to differ between athletes and non- athletes [34–37], with only one study reporting a

that endurance exercise acutely triggers atrial ectopic beats [19,33]. These recently published ndings are relevant because an increased atrial ectopic activity is one of the potential mechanisms of the increased prevalence of atrial brillation (AF) in athletes (see below). The ventricular ectopic burden does not seem to differ between athletes and non- athletes [34–37], with only one study reporting a higher prevalence of complex ventricu- lar arrhythmias at 24 h Holter monitoring ECG in 40 young endurance athletes than in 40 sedentary individuals [38]. Recent investigations compared the prevalence and deter- minants of ventricular ectopic beats on 24 h Holter monitoring among young [39] and middle-aged endurance athletes [40], nding no differences compared with non-athletes. Most athletes showed no or very few premature ventricular beats during the 24 h recording. Zorzi et al. [41] described the ECG changes of a group of athletes after an endurance (48 km) and ultra-endurance (120 km) high-altitude race. They used a portable single-lead ECG device and recorded a 1 min tracking before and immediately after the run. After the race, the athletes showed a higher heart rate, a similar QRS duration, and a longer QTc interval duration. The number of athletes showing at least one premature ventricular beat increased signi cantly after the race from 0.5% to 3.3%. However, most participants did not show any arrhythmia after strenuous exercise (Figure). Cavigli et al. recorded the heart rhythm during a 50 km ultramarathon and found that 24% showed PVBs, but in only a minority of them, the PVBs were distinctively exercise induced (i.e., 7%). In agreement, other studies have reported no signi cant effect of a marathon race on ventricular arrhythmias in male endurance athletes [42,43]. Hence, current evidence does not support the perspective that sports activity increases the burden of atrial or ventricular arrhythmias in healthy individuals. Similarly, no increase in the incidence of atrial or ventricular ectopic beats is observed in most athletes, even during and after a prolonged period of exercise.

sports activity increases the burden of atrial or ventricular arrhythmias in healthy individuals. Similarly, no increase in the incidence of atrial or ventricular ectopic beats is observed in most athletes, even during and after a prolonged period of exercise.

This review discusses the potential adverse effects of intense, prolonged exercise on the cardiovascular system in healthy athletes.