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Current Heart Failure Reports https://doi.org/10.1007/s11897-018-0385-9

BIOMARKERS OF HEART FAILURE (J GRODIN & W.H.W. TANG, SECTION EDITORS)

Biomarkers of Cardiac Stress and Injury in Athletes: What Do They Mean? Eoin Donnellan 1 & Dermot Phelan 1

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract Purpose of the Review Markers of myocardial stress, including troponin, creatine kinase, and brain natriuretic peptide are frequently elevated after endurance athletic pursuits. Here, we summarize the current literature pertaining to the potential mechanism of cardiac enzyme release in athletes and seek to determine the clinical implications of these findings. Recent Findings Recent studies have highlighted the potential adverse cardiac effects of long-term extreme endurance exercise. While troponin release occurs in a pattern distinct from ischemic damage, BNP release has been correlated with right ventricular dysfunction and is likely related to wall stress from prolonged increases in cardiac output. Higher intensity pre-race training regimes are associated with lower race-day enzyme release. Summary While the holistic benefits of regular moderate exercise are indisputable, recent studies have raised concerns about the potential risks of extreme endurance exercise. Release of serum biomarkers suggesting myocardial damage was first described in the 1970s, yet our understanding of the implications of these findings remains incomplete. The mechanisms of release are complex but appear to be primarily physiological phenomena rather than pathologic. Keywords Athletes . Cardiac injury . Endurance exercise . Myocardial damage

Introduction Regular physical activity significantly reduces cardiac morbidity and mortality [1, 2]. Current consensus guidelines recommend 150 min/week of moderate-intensity or 75 min/week of vigorous-intensity exercise for all adults in the USA [3]. While only approximately half of Americans meet these guidelines, there has been a recent dramatic increase in the popularity of long-distance, high-endurance activities such as marathons, triathlons, and long-distance cycles in recent years [4, 5]. The beneficial effects of exercise on cardiovascular health are manifold, and it plays major roles in primary as well as This article is part of the Topical Collection on Biomarkers of Heart Failure * Dermot Phelan [email protected] 1

Department of Cardiovascular Medicine, Cleveland Clinic, Desk J1-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA

secondary prevention of coronary artery disease (CAD). However, in recent years, several reports emanating from both the scientific community and media outlets have suggested that long-term, vigorous aerobic exercise may be as harmful as physical inactivity [6–9]. Several studies have demonstrated transient reduction in global myocardial function postendurance exercise, while the risk of atrial fibrillation and coronary calcification appears to be higher in these athletes [10•]. Cardiac biomarkers such as creatine kinase MB isoenzyme (CK-MB), cardiac troponin (cTn), and brain natriuretic peptide (BNP) are integral to the diagnosis of acute coronary syndromes (ACS) and congestive heart failure (CHF). Elevations in these biomarkers have been demonstrated after short- and long-distance exercise [11–13]. Increases in these biomarkers above the detection limit have been shown to increase the risk of death in multiple different disease states [14, 15]. However, the significance of elevations in these biomarkers in athletes in the absence of ACS or CHF remains uncertain. In this article, we will review the existing literature pertaining to these biomarkers in athletes.

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Beneficial Cardiovascular Effects of Exercise

Cardiac Biomarkers and Exercise

The cardiovascular benefits of exercise have been well described. In general, regular exercise increases cardiovascular functional capacity and reduces myocardial oxygen demand in healthy populations as well as those with CAD and CHF. The beneficial cardiovascular effects of exercise have been attributed to an array of hemodynamic, hormonal, metabolic, neurological, and respiratory factors [16–20]. From a metabolic standpoint, frequent exercise has been shown to positively impact carbohydrate and lipid metabolism including increasing high-density lipoprotein levels and reducing triglyceride levels, in addition to potentiating the positive effects of a low-cholesterol and low-saturated fat diet [21–24]. Moreover, exercise has been shown to increase insulin sensitivity, reduce inflammatory markers, increase nitric oxide synthesis, improve endothelial function, and enhance parasympathetic tone [25–29]. A curvilinear dose-response relationship exists between exercise and mortality with an increase from a sedentary to a mildly-active lifestyle producing dramatic mortality benefits and an increase from a moderately- to a vigorouslyactive lifestyle yielding diminishing returns [30].

A biomarker is defined as a “characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention” [38]. Cardiac biomarkers, such as CK-MB, cTn, and BNP, complement cardiac imaging in the diagnosis of various conditions, including ACS, CHF, and valvular heart disease. In general, a useful biomarker is one that reflects disease severity, changes with disease progression, identifies those in whom symptoms are likely to develop, and can be reliably and reproducibly measured [39]. Exercise also results in elevations in cardiac biomarkers. However, the mechanism of release and prognostic significance of these elevations remains uncertain.

Potential Deleterious Effects of Exercise Several hazardous cardiovascular effects of endurance exercise have also been reported. In particular, arrhythmias have been reported more frequently in endurance athletes. One study showed a fivefold increase in the relative risk of AF in athletes compared to the general population [31]. Furthermore, higher coronary artery calcium scores along with increased atherosclerotic plaque burden have also been demonstrated in masters athletes compared with agematched controls [32, 33]. A U-shaped relationship between exercise and mortality has been described. A Danish study found that light joggers had lower mortality rates than non-joggers, and mortality rates in moderate and strenuous joggers were similar to those of non-joggers [9]. Finally, increased myocardial fibrosis has been observed in small studies of endurance athletes, with the amount of fibrosis correlating with the intensity and duration of exercise [13, 34]. Interestingly, myocardial fibrosis in athletes appears to be concentrated where the RV inserts into the septum, a location which is typically observed in hypertrophic cardiomyopathy patients but rarely observed in those with CAD [35]. Reversible post-exercise reductions in left and right ventricular function have also been described, with the right ventricle affected to a greater extent than the left ventricle [36, 37]. The long-term implications of these findings remain ill-defined.

CK-MB CK is a dimeric protein that is found as three principle isoenzymes: muscle (MM), heart (MB), and brain (BB) [40]. CK is a reliable marker of skeletal muscle damage. Exercise-induced increases in CK range from asymptomatic elevations to fulminant rhabdomyolysis. The association between CK levels and endurance training and competition in well-conditioned athletes was described as early as 1980. One study of 15 participants in the 1979 Boston marathon measured CK levels before, 24 h after, and 4 weeks following the marathon. CK levels were elevated throughout the study, and an inverse relationship was described between CK levels and finishing times [41]. A further study from the same group assessed CK-MB levels in 108 well-trained marathon runners after competition and found that the peak levels of these enzymes in asymptomatic runners were similar to those reported in patients during acute myocardial infarction (MI). Subsequent to this, the group obtained skeletal muscle biopsies from the lateral gastrocnemius muscle in 25 well-trained runners and 10 controls and measured the concentration of the MB isoenzyme. They found that the MB isoenzyme accounted for 8.9 ± 1.3% of total CK activity per gram of total protein in the skeletal muscle of runners and 3.3 ± 0.7% in the control group, while the total concentration of CK did not differ between the two groups [42]. To help explain this finding, another group conducted electron microscopy of gastrocnemius samples obtained from 40 male marathon runners and 12 control male non-runners. They found a higher concentration of pluripotent satellite cells, which can produce the MB isoenzyme and indicate a regenerative response in the well-trained athletes compared to the sedentary controls [43]. Therefore, the observed CK-MB release was likely skeletal muscle in origin and is not specific to the heart in this context. A more recent study from Korea measured CK isoenzyme levels in 32 male runners during and after a 200 km run. They measured CK levels before the race, at 100 km, 150 km, and 200 km as well as 24 h after the race and found only minute elevations in the

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MB and BB isoenzymes but profound elevations in the MM isoform [44]. This finding may relate to the fact that these are more highly trained individuals competing at lower intensity levels compared to most marathon runners.

Troponin Troponin is a tadpole-shaped complex consisting of three subunits—troponin T (TnT), troponin C (TnC), and troponin I (TnI)—and is a highly sensitive marker of myocardial damage [45]. The release of cTn during ACS occurs in a biphasic manner. The initial rise is thought to represent the release of cytosolic cTn due to increased membrane permeability, while the subsequent rise is attributed to the release of bound cTn [46]. In general, the release of cTn can be divided into three categories: primary ischemic cardiac injury, resulting from plaque rupture and vessel occlusion; secondary ischemic cardiac injury which is due to a mismatch between myocardial oxygen supply and demand; and nonischemic cardiac injury occurring as a result of blunt trauma, penetrating trauma, or myocarditis [47–49]. Exercise-induced elevations in cTn have been described in a variety of settings, including triathlons, foot races, endurance cycling, and ultra-endurance races [36, 50–52]. A meta-analysis of 26 studies examining post-exercise TnT and TnI elevations in participants in endurance activities demonstrated that post-exercise cTn levels exceeded the assay’s lower limit in roughly half of the participants and that there was a higher incidence of cTn elevation after foot races than after cycling or triathlons. Furthermore, this meta-analysis demonstrated that there was an inverse relationship between exercise duration and peak cTn concentrations, with shorter, higher intensity activities being associated with more pronounced elevations [45]. Numerous theories have been proposed to explain these exercise-induced increases in cTn. One theory is that exercise results in increased myocyte permeability as a result of mechanical stress, free radical production, or disturbances in pH with a consequent release of cytosolic cTn [53, 54]. Another theory suggests that exercise stimulates stretch-responsive integrins which mediate the transport of cTn out of viable myocytes [55]. An understandable concern is that exercise results in myocardial cell necrosis and subsequent cTn release. Of clinical utility in differentiating cTn release postendurance exercise compared to an acute MI relates to differential kinetics of release. A study by Tian et al. evaluated hsTnT in 26 athletes at multiple time-points after a 90 min constant load treadmill run [56]. Peak hs-TnT release was observed 3 to 4 h post-exercise with a rapid reduction to baseline. Interestingly, the magnitude and duration of hs-TnT release were greater in adolescent athletes compared to adult athletes. This may be related to increased reactive oxidative stress in the immature heart or slower recovery of renal function in

adolescent athletes after renal insult from prolonged exercise. A further study examined the kinetics of TnT release in 9 welltrained men during and after a treadmill marathon using serial blood draws. All participants had increased TnT between 60 and 120 min and TnT returned to baseline in all subjects within 1 h of race completion. However, all but one participant had a subsequent release of TnT within 24 h of race completion, and five of the nine subjects had an elevated TnT 24 h after completion [57]. While the duration of release of cTn has varied between studies of athletes, it is characterized by an early peak and rapid return to baseline in cTn levels. This contrasts substantially to the pattern seen in myocardial infarction where the peak occurs usually at about 24 h with prolonged elevation in levels for at least 4–7 days (Fig. 1). The pattern of release of hs-TnI compared to hs-TnT also suggests a different mechanism of release of cTn in endurance sports compared to myocardial necrosis. A study of 22 healthy volunteers completing a 30-km running trial investigated the release kinetics of high-sensitivity troponin I (hs-cTnI) and T (hs-cTnT) before, immediately after, and 2 and 5 h after the trial. They found that maximum hs-cTnT levels were reached at 2 h after exercise, while peak hs-cTnI concentration occurred 5 h after exercise. This pattern is different to acute MI where peak hs-cTnI levels are reached prior to peak hs-cTnT levels [58•]. The clinical implications of exercise-induced cTn release remain ill-defined. While a number of studies have shown reduction in LV function, this has not been shown to correlate with cTn release [36, 37]. However, there has been some correlation seen with reduction in RV function. Neilan et al. performed echocardiography and measured TnT concentrations in 60 non-elite participants within 20 min of completion of the 2004 and 2005 Boston marathons and found that more than 60% of participants had a TnT level > 0.01 ng/mL, while 40% had TnT concentrations at or above the decision limit for acute MI (≥ 0.03 ng/mL) [37]. This increase in TnT was found to correlate with post-race diastolic dysfunction, higher pulmonary pressures, and RV dysfunction. Mousavi et al. reported a correlation between TnT concentration and post-

Fig. 1 Pattern of serum troponin concentration after acute coronary syndrome (dark line) compared to endurance exercise (broken line)

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marathon RV systolic and biventricular diastolic dysfunction. However, MRI performed 1 week after marathon completion did not show any evidence of persistent dysfunction or myocardial fibrosis [59]. Shave et al. proposed an algorithm in 2010 for the proposed management of patients with suspected ACS after prolonged exercise which remains relevant today (Fig. 2) [45].

BNP B-type natriuretic peptide (BNP) is an endogenous peptide predominantly released from the heart in response to ventricular wall stress and exhibits multiple beneficial functions including vasodilation, diuresis, and natriuresis [60]. Several studies have shown an inverse relationship between BNP concentration and lower exercise capacity as measured by peak oxygen consumption (peak VO2) in patients with cardiac and pulmonary disease [61–63]. A more recent study assessed 10 asymptomatic patients with a baseline BNP < 100 ng/L undergoing cardiopulmonary exercise testing and also demonstrated this inverse relationship between myocardial BNP release and peak oxygen consumption [64]. La Gerche et al. studied BNP concentration and echocardiographic parameters in 27 athletes participating in

an ultra-endurance triathlon a week before and a week after the race. They found that BNP rose significantly in every athlete after the race (mean 12.2 vs. 42.5 ng/L) and that LV ejection fraction (EF) was unchanged. However, new regional wall motion abnormalities were evident in seven athletes, and RV function was reduced in the entire cohort [36]. A further study examined BNP concentration and echocardiography in 40 athletes before, immediately after, and 1 week after an endurance (3–11 h duration) race. Mean BNP levels rose significantly after the race (13.1 ± 14 vs. 25.4 ± 21.4 ng/L, p = 0.003) and correlated with reductions in RVEF (r = 0.52, p = 0.001) but not LVEF [13]. These findings are consistent with those of Neilan et al. who measured N-terminal pro-BNP (NT-proBNP) levels in 60 nonelite participants before and after the 2004 and 2005 Boston Marathons. NT-proBNP increased from a mean of 63 to 131 pg/mL (p < 0.001), and this increase correlated directly with post-race diastolic dysfunction, increased pulmonary pressures, and RV dysfunction (RV mid strain, r = − 0.70, p < 0.001) and inversely with training mileage (r = − 0.72, p < 0.001). Athletes who trained more than 45 mi/week had lower post-race NT-proBNP levels (106 vs. 182 pg/mL, p < 0.001) and less RV dysfunction (25 ± 4% vs. 16 ± 5%, p < 0.001) compared with those who trained less than

Fig. 2 Algorithm outlining proposed management of patients with suspected ACS after prolonged exercise. Reproduced with permission from Shave et al. [45]

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35 mi/week [37]. A study of 39 endurance athletes found that RV end-systolic stress was lower than LV end-systolic stress at rest (143 ± 44 vs 252 ± 49 kdyn/cm, p < 0.001) but increased to a much greater extent during strenuous exercise (125 vs. 14%, p < 0.001) [65]. Intensity of exercise likely plays a role in the degree of BNP release. There was no change in serum BNP levels in athletic controls (n = 82) or athletes with cardiovascular risk factors (n = 54) after the Nijmegen Marches which consists of four consecutive days of walking exercise 30–50 km/day [66].

References Papers of particular interest, published recently, have been highlighted as: • Of importance 1.

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Although the beneficial effects of exercise remain indisputable, the potential deleterious effects of endurance activities have been highlighted in the media and scientific community in recent years. In this review article, we explored the mechanisms and clinical implications of changes in traditional cardiac biomarkers, such as CK-MB, cTn, and BNP with exercise. While CK is found in skeletal muscle predominantly in the MM isoform, exercise-induced elevations in the cardiac predominant MB isoform have been described [42]. However, these elevations have been attributed to CK-MB release from pluripotent satellite cells evident in recovering skeletal muscle of well-conditioned athletes [43]. Exercise-induced elevations in cTn have been shown to correlate with transient RV systolic and biventricular diastolic dysfunction. However, the pattern of release is dramatically different to that observed in ACS and is likely physiologic rather than pathologic [59]. Finally, elevations in BNP after exercise correspond to transient reductions in RVEF and increased pulmonary pressures and diastolic dysfunction reflective of the increased wall stress associated with exercise [36, 37]. Furthermore, an inverse relationship has been shown between extent of training and these transient myocardial changes. To date, there have been no studies showing long-term sequelae of these exercise-induced changes in cardiac biomarkers and echocardiographic evidence of damage. Indeed, the existing literature supports the idea that the benefits of exercise far outweigh the risks. Thus, physicians should endeavor to promote moderate exercise training for most of their patients.

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Conflict of Interest Eoin Donnellan and Dermot Phelan declare no conflicts of interest. 13. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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