Adaptive Changes in Endurance Athletes: A Review of Molecular, Echocardiographic and Electrocardiographic Findings

ar physical activity has a beneficial impact on the cardiovascular system. However, the intense and prolonged exertion typical of professional athletes and amateur marathon runners can lead to adaptive changes in the heart. These changes encompass both structural and functional modifications, which may have positive or negative effects on cardiac func- tion and contribute to the development of so-called “athlete’s heart.” Prolonged exercise induces adaptations at the molecular and cellular levels, including altered gene expression and remodeling of myocardial proteins. It may also cause transient elevations in biomark- ers such as N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin. Some athletes experience cardiac arrhythmias, including atrial fibrillation. Mor- phological changes, such as myocardial hypertrophy or chamber dilation, can be assessed using echocardiography. Studies have reported potentially benign valvular abnormalities, as well as cases of myocardial fibrosis and arrhythmias. Early diagnosis of cardiac condi- tions in marathon runners is essential for effective prevention and health monitoring. This article reviews the current data on cardiac changes in endurance athletes, based on the literature from the past decade. Keywords:athlete’s heart; biomarkers; myocardial regeneration; echocardiography; exercise; marathon runners; molecular mechanisms of adaptation; running 1. Introduction Regular physical activity offers numerous health benefits, including a positive impact on the cardiovascular system. However, the intense and prolonged

prevention and health monitoring. This article reviews the current data on cardiac changes in endurance athletes, based on the literature from the past decade. Keywords:athlete’s heart; biomarkers; myocardial regeneration; echocardiography; exercise; marathon runners; molecular mechanisms of adaptation; running 1. Introduction Regular physical activity offers numerous health benefits, including a positive impact on the cardiovascular system. However, the intense and prolonged exercise characteristic of professional athletes and amateur marathon runners or triathletes can lead to specific load-related adaptive changes in the heart. These changes involve both structural and functional modifications of the myocardium, which may have either beneficial or adverse effects on cardiac function, sometimes resulting in the development of so-called “athlete’s heart” [1–4]. Intense and sustained physical exertion induces not only macrostructural alterations in the heart but also adaptations at the molecular and cellular levels. In response to increased hemodynamic stress, changes in gene expression, activation of signaling pathways, and remodeling of myocardial proteins occur [5]. The changes can be classified as either reversible or irreversible. From a cardiolo- gist’s perspective, early detection of adverse irreversible changes is crucial. The current guidelines of the European Society of Cardiology (ESC) on sports cardiology and exercise Int. J. Mol. Sci.2025,26, 8329 https://doi.org/10.3390/ijms26178329

Int. J. Mol. Sci.2025,26, 8329 2 of 24 in individuals with cardiovascular disease recommend that a cardiological evaluation, conducted prior to initiating or continuing intensive training, should include a detailed medical history, physical examination, and a 12-lead resting electrocardiogram (ECG) to detect potentially dangerous arrhythmias or signs of myocardial hypertrophy. In equivocal cases or in individuals at higher risk (e.g., those with a positive family history, cardiac symptoms, or ECG abnormalities, further diagnostic evaluation is recommended. This includes transthoracic echocardiography, exercise testing, and 24 h Holter ECG monitor- ing. In selected athletes, particularly those involved in high-intensity endurance sports, advanced imaging techniques such as cardiac magnetic resonance (CMR) may be indicated to assess for myocardial fibrosis, benign structural changes, or to evaluate right ventricular function. The ESC guidelines also emphasize the importance of interpreting diagnostic findings within the context of physiological adaptations to training—referred to as “ath- lete’s heart”—which may mimic pathological changes, but are typically reversible and not associated with an increased risk of sudden cardiac death [6]. Intense exercise can cause a transient increase in biomarkers commonly used in clinical practice to assess cardiac function, such as N-terminal pro-brain natriuretic peptide (NT- proBNP) and high-sensitivity troponin [7,8]. These changes are more likely to reflect the body’s adaptation to significant and prolonged physical exertion rather than permanent cardiac damage. Although such changes are usually physiological and reversible, intense physical activity can lead to cardiac arrhythmias, such as atrial fibrillation (AF) or ventricular extrasystoles, particularly in older individuals who train intensively [9,10]. This type of physical stress also induces morphological remodeling of the heart, which can be as- sessed using echocardiography or cardiac CMR. Observed changes include myocardial hypertrophy, dilatation of cardiac chambers, and alterations in ejection fraction [11,12]. Studies indicate that endurance athletes may also develop valvular abnormalities. Physical activity appears to promote mild mitral and tricuspid regurgitation. In addition, athletes with pre-existing valvular conditions—such as bicuspid aortic valve—are also subject to evaluation [13]. Cases of right ventricular dysfunction in otherwise “healthy” athletes have been described in the literature. Other pathologies observed in asymptomatic endurance athletes include myocardial fibrosis,

indicate that endurance athletes may also develop valvular abnormalities. Physical activity appears to promote mild mitral and tricuspid regurgitation. In addition, athletes with pre-existing valvular conditions—such as bicuspid aortic valve—are also subject to evaluation [13]. Cases of right ventricular dysfunction in otherwise “healthy” athletes have been described in the literature. Other pathologies observed in asymptomatic endurance athletes include myocardial fibrosis, coronary artery atherosclerosis, and ar- rhythmias [14]. With the growing popularity of endurance sports, accurate assessment of the effects of intense physical activity on the heart is becoming increasingly important. This article reviews recent findings on cardiac adaptations to strenuous exercise, with particular em- phasis on structural, functional, electrophysiological, and molecular changes observed in endurance athletes, including marathon runners. While current physical activity guidelines highlight substantial health benefits from 150 min of moderate or 75 min of vigorous exercise per week, endurance athletes typically train 15 to 20 times beyond these recommendations [15,16]. Both the American Heart Association (AHA) and the ESC recommend cardiovascular screening before participation in competitive sports to identify high-risk individuals [17,18]. Studies also show that regular training and completing a first marathon at a slower pace may help reduce central blood pressure and arterial stiffness [14]. Early detection of cardiac problems in marathon runners is crucial for effective preven- tion and health monitoring. There is an urgent need to better understand the mechanisms underlying the changes observed in the athlete’s heart. Although marathon running is becoming increasingly popular—particularly among amateur athletes—data on the ef- fects of this form of exercise on the heart remain limited. Despite the growing number of studies, there are still no clear guidelines for monitoring the cardiovascular health of

Int. J. Mol. Sci.2025,26, 8329 3 of 24 marathon runners. This article presents recent findings on the molecular mechanisms as well as echocardiographic and ECG changes observed in endurance athletes. To prepare this manuscript, a comprehensive review of scientific databases—including ClinicalKey, PubMed, and EMBASE—was conducted, with a focus on publications from the last decade (2015–2025). 2. Impact of Exercise on Cardiac Pathogenesis In endurance sports such as marathon running, the structural dimensions of the ath- lete’s heart may resemble those observed in dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, and in some cases may even mimic hypertrophic car- diomyopathy [19–22]. Intense physical exertion can lead to adverse changes in cardiac function, such as accelerated development of coronary atherosclerosis, myocardial fibrosis, and right ventricular dysfunction [5,23]. After intense physical exertion, professional athletes may experience transient im- pairment of left ventricular function. Growing evidence suggests that due to differing compensatory mechanisms in the pulmonary and systemic circulation, exercise-induced cardiac overload affects and manifests in the right ventricle (RV) more prominently and earlier than in the left ventricle (LV) [24–27]. Systematic, intense training leads to moderate thickening of the left ventricular muscle and enlargement of the chamber, while maintaining normal systolic and diastolic function— a phenomenon known as the “athlete’s heart” [21,22]. This complex adaptation is a form of cardiac remodeling. Skeletal muscle contractions during intense running increase ve- nous return to the heart. During running, stroke volume (SV) increases due to enhanced ventricular filling in early diastole, although it may decrease in response to increasing pressure overload [28]. Simultaneously, during the middle phase of the run, heart rate (HR) increases to ensure adequate oxygen delivery to the working muscles. In the later part of the race, increased SV allows for a reduction in HR, thus adjusting cardiac output (CO) accordingly [29]. Changes in HR and SV together contribute to the overall increase in CO during exercise. Cardiac workload remains submaximal and relatively stable for most of the run duration [27,30–32]. This hemodynamic pattern is illustrated in Figure. The reduced resting heart rate commonly observed in endurance athletes is most likely due to

in HR, thus adjusting cardiac output (CO) accordingly [29]. Changes in HR and SV together contribute to the overall increase in CO during exercise. Cardiac workload remains submaximal and relatively stable for most of the run duration [27,30–32]. This hemodynamic pattern is illustrated in Figure. The reduced resting heart rate commonly observed in endurance athletes is most likely due to long-term, intense endurance training, which leads to enhanced vagal tone and reduced sympathetic activity in marathon runners [33]. Figure 1.Hemodynamic changes in the right heart during exercise: a schematic diagram.

Int. J. Mol. Sci.2025,26, 8329 4 of 24 Endurance effort significantly increases myocardial oxygen demand and SV. In the early phase of exertion, there is a rapid increase in HR due to the withdrawal of tonic vagal influence and activation of the sympathetic nervous system. This results in the release of adrenaline and noradrenaline into the circulation. These catecholamines increase myocardial contractility and heart rate, leading to elevated SV. During prolonged endurance activity, features of transient cardiac dysfunction may emerge, with an average drop in left ventricular ejection fraction (LVEF) of up to 2% after endurance exercise. This is observed in untrained individuals as well as ultra-endurance athletes [34–36]. Repeated contractions of muscle fibers during intense physical exertion induce both mechanical and metabolic stress, associated with mitochondrial dysfunction and a shift in the adenosine diphosphate to adenosine triphosphate ratio. This leads to damage of the sarcolemma and extracellular matrix, mitochondrial swelling, dilation of T-tubules, and fragmentation of the sarcoplasmic reticulum, resulting in increased cell membrane permeability and release of muscle proteins into the circulation. Additionally, disturbances in calcium homeostasis, oxidative stress, and inflammation contribute to the progression of muscle injury. In response to this condition, increased levels of inflammatory mediators such as interleukins (IL)—IL-1β, IL-6, IL-8, IL-1ra, and IL-10—are observed, which are characteristic of endurance-exercise-induced muscle damage [37,38]. 2.1. Molecular Changes and Biomarkers Studies indicate that intense physical exertion, particularly during long-distance running, can acutely stress the cardiovascular system. Elevated levels of biomarkers of myocardial injury and hemodynamic dysfunction are commonly observed. Increased concentrations of markers such as cardiac troponins, creatine kinase-MB fraction (CK-MB), NT-proBNP, and mid-regional pro-adrenomedullin (MR-proADM) suggest transient or chronic cardiac stress, and even cardiomyocyte injury [39,40]. To assess myocardial microdamage after intense exertion, biomarkers of cell necrosis— such as troponin I (TnI) and creatine kinase (CK)—have been used, as well as markers of cardiac overload, such as NT-proBNP and MR-proADM, and indicators of endogenous stress such as copeptin [38–41]. Other markers have also been identified, such as copeptin (a marker of endogenous stress) and pro-inflammatory cytokines like IL-6 and tumor necrosis factor (TNF-α), which increase after

necrosis— such as troponin I (TnI) and creatine kinase (CK)—have been used, as well as markers of cardiac overload, such as NT-proBNP and MR-proADM, and indicators of endogenous stress such as copeptin [38–41]. Other markers have also been identified, such as copeptin (a marker of endogenous stress) and pro-inflammatory cytokines like IL-6 and tumor necrosis factor (TNF-α), which increase after intense physical exertion and may play a role in the pathogenesis of myocarditis, cardiac arrhythmias, and fibrosis [41–45]. The underlying mechanisms of these changes include necrosis of both myocardial and skeletal muscle cells as well as cardiac overload, which may ultimately lead to perma- nent structural changes in the cardiovascular system [27]. In endurance sports, elevated concentrations of myocardial injury biomarkers—such as NT-proBNP and troponin—and signs of cardiac dysfunction are commonly observed. These changes may contribute to subclinical myocarditis and cardiac remodeling, increasing the risk of arrhythmias. The concentrations of cardiac injury markers—including cardiac troponin, CK-MB, and NT- proBNP—significantly increase both during and after marathon running [46]. CK-MB, a classical marker of myocardial injury, may be elevated in up to 8% of athletes, particularly affecting the RV [47]. After running, a clear increase in blood levels of troponin T (cTnT)—a protein primar- ily found in the thin myofilaments of myocardial fibers—is observed, suggesting reversible myocardial injury and transient cardiac dysfunction. In amateur marathon runners, an increase in cTnT levels and transient myocardial injury occurs more frequently than in professionals [46,48]. Intense physical exertion may lead to a temporary increase in car- diomyocyte sarcolemma permeability, due to mechanical stress, excessive reactive oxygen species (ROS) production, acid–base imbalance, and passive transport of cardiac troponins

Int. J. Mol. Sci.2025,26, 8329 5 of 24 from the intracellular space to the extracellular compartment. As a result of stretching and mechanical load, the cell membrane may undergo transient damage, leading to cTn release into circulation. This phenomenon is especially pronounced during prolonged and high-intensity exertion [49]. Although the elevation in troponin levels is often transient and reversible, it can be misleading, as it may suggest an acute coronary syndrome in asymptomatic individuals. However, in athletes, increased troponin levels most often result from reversible increases in cardiomyocyte membrane permeability rather than necrosis [50]. Oxidative stress and electrolyte disturbances associated with intense endurance exercise may increase membrane permeability, elevating troponin concentrations in the blood [51]. Studies show that elevated NT-proBNP levels correlate with the duration and intensity of exercise, as well as with volume and pressure overload parameters. This may indicate ventricular overload—especially of the RV—and a neurohormonal adaptive response of the heart. NT-proBNP may increase 5- to 10-fold after exercise in those participating in endurance events [48,52]. High-intensity physical exertion selectively activates the NF-κB pathway, a protein complex regulated by TNF-αand p38 MAPK, which belongs to the class of stress-sensitive kinases. These pathways are involved in immune responses, cell cycle control, and the regulation of various cellular processes. Their activation plays an important role in myocar- dial remodeling by promoting fibrosis, which may represent a mechanism leading to AF in endurance athletes [53]. Endurance athletes demonstrate elevated levels of plasma markers of collagen synthe- sis and degradation, including tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), carboxy-terminal telopeptide of type I collagen (CITP), carboxy-terminal propeptide of type I procollagen (PICP), galectin-3 (Gal-3), and circulating profibrotic microRNA-21. The highest TIMP-1 concentrations correlate with left ventricular hypertrophy. A significant increase in plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) is also observed. This molecule plays a key role in inflammatory cell adhesion and leukocyte migration through the vascular endothelium. A study conducted in white runners partici- pating in high-intensity training found that sVCAM-1 may serve as a useful biomarker for assessing and monitoring adverse structural and functional changes in the left atrium

of soluble vascular cell adhesion molecule-1 (sVCAM-1) is also observed. This molecule plays a key role in inflammatory cell adhesion and leukocyte migration through the vascular endothelium. A study conducted in white runners partici- pating in high-intensity training found that sVCAM-1 may serve as a useful biomarker for assessing and monitoring adverse structural and functional changes in the left atrium (LA), with levels positively correlating with LA volume [34,47,52,54]. Gal-3 is a marker of myocardial remodeling and fibrosis, released in response to mechanical stretching of cardiomyocytes and inflammatory processes induced by activated macrophages. Our study showed that physical exertion leads to a transient increase in Gal-3 levels in amateur athletes. Notably, a greater post-race increase in Gal-3 concentration was observed in participants with lower LVEF and reduced RV contractility, suggesting that exercise-induced cardiac fibrosis may lead to transient left ventricular dysfunction. Moreover, myocardial ischemia may initiate an inflammatory response that promotes macrophage infiltration and consequently contributes to the development of myocardial fibrosis [55–58]. The study observed leukocytosis, neutrophilia, and elevated levels of muscle damage markers, pro- and anti-inflammatory cytokines (IL-6, IL-8, IL-10, TNF-α, MIP-1), as well as myokines and growth factors such as decorin, growth differentiation factor 15 (GDF15), brain neurotrophic factor (BDNF), follistatin, and fibroblast growth factor 21 (FGF-21) directly after the race. Simultaneously, decreased levels of myostatin, musclin, IL-15, and apelin were noted, which persisted up to 72 h post-exercise. Plasma lactate dehydrogenase activity correlated with levels of inflammatory cytokines (IL-10 and TNF-α) but showed no relationship with the myokine response [59].

Int. J. Mol. Sci.2025,26, 8329 6 of 24 Endurance exercise triggers an initial pro-inflammatory response in which neutrophils and pro-inflammatory M1 macrophages play a key role. This is followed by a compen- satory anti-inflammatory response mediated by M2 macrophages and T cells, including regulatory T lymphocytes (Tregs) and CD8+ cells. This process leads to a temporary state of immunosuppression [37,60]. Studies have shown that IL-6 stimulates myogenic differentiation in both C2C12 myoblast cell lines and primary human myoblasts. It also promotes protein synthesis in C2C12 myotubes and the proliferation of murine myoblasts and human satellite cells. Animal model studies have highlighted the role of IL-6 in activating M2 macrophages, which promote angiogenesis and tissue regeneration processes, as well as enhance cell proliferation [61–63]. Follistatin exhibits myogenic properties resulting from its direct inhibition of myostatin binding to the activin type IIb receptor and suppression of Smad3 protein phosphoryla- tion. This leads to increased protein synthesis via the mTOR/S6K/S6RP signaling cascade, supporting skeletal muscle mass development. Follistatin may correlate with BDNF levels, a factor essential for activation and proliferation of muscle satellite cells after injury. Lit- erature reviews indicate that BDNF acts on the myocardium by inhibiting cardiomyocyte apoptosis and mitochondrial dysfunction, supporting angiogenesis, enhancing cardiomy- ocyte contractility, and regulating calcium homeostasis through tropomyosin receptor kinase B (TrkB) signaling pathways [64–67]. Mitochondrial and endoplasmic reticulum dysfunction induce FGF-21 expression in skeletal muscles. FGF-21 regulates PI3K-AKT signaling, activates activating transcription factor 4 (ATF4) in muscles, and participates in the elimination of damaged mitochondria through mitophagy, as well as in muscle fiber type switching. In this way, it affects both muscle mass and function. Additionally, FGF-21 demonstrates similar metabolic properties to IL-6 in skeletal muscles. A negative correlation was observed between the FGF-21 response and levels of decorin and apelin, suggesting that stronger FGF-21 activation may counteract the post-exercise decline of these proteins [66,68,69]. Myostatin binds to activin type I and II receptors, leading to phosphorylation and activation of SMAD family proteins. The SMAD-2/3 complex binds to SMAD-4, initiating the transcription of genes responsible for protein catabolism. Additionally, myostatin is involved in protein degradation

and levels of decorin and apelin, suggesting that stronger FGF-21 activation may counteract the post-exercise decline of these proteins [66,68,69]. Myostatin binds to activin type I and II receptors, leading to phosphorylation and activation of SMAD family proteins. The SMAD-2/3 complex binds to SMAD-4, initiating the transcription of genes responsible for protein catabolism. Additionally, myostatin is involved in protein degradation via the ubiquitin–proteasome system and autophagy. Exercise-induced inflammatory mediators such as IL-10 and IL-8 showed correlations with changes in musclin levels—a protein with a region homologous to the natriuretic peptide family. Musclin likely supports skeletal muscle oxidative capacity by stimulating mitochondrial biogenesis [66,70–73]. Suppression of tumorigenicity 2 (ST2) belongs to IL-1 receptor family and functions as a receptor for the IL-33 cytokine. IL-33 is secreted by cardiac fibroblasts in response to cell injury and acts by binding to the membrane-bound form of the ST2 receptor (ST2L) on cardiomyocytes. The IL-33/ST2 axis is activated in the heart in response to mechan- ical overload or injury, leading to the inhibition of myocardial fibrosis and hypertrophy. Marathon running causes a significant increase in sST2 concentration, with higher levels observed in runners with better performance. It has been shown that male sex, exercise intensity, and greater body weight loss during the marathon are directly associated with sST2 levels [74,75]. Beyond biomarker changes, recent studies have elucidated key molecular signaling pathways that mediate exercise-induced cardiac remodeling. Physiological hypertrophy is largely driven by IGF-1/PI3K–Akt–mTOR activation, whereas pathological remodeling in- volves Ang II and endothelin-1 signaling through MAPK and calcineurin/NFAT pathways, promoting fibrosis and apoptosis. In parallel, activation of TGF-β/SMAD signaling con-

This article reviews cardiac changes in endurance athletes based on recent literature.