Exercise-Induced Cardiac Troponin Elevations: From Underlying Mechanisms to Clinical Relevance

Abstract

Serological assessment of cardiac troponins (cTn) is the gold standard to assess myocardial injury in clinical practice. A greater magnitude of acutely or chronically elevated cTn concentrations is associated with lower event-free survival in patients and the general population. Exercise training is known to improve cardiovascular function and promote longevity, but exercise can produce an acute rise in cTn concentrations, which may exceed the upper reference limit in a substantial number of individuals. Whether exercise-induced cTn elevations are attributable to a physiological or pathological response and if they are clinically relevant has been debated for decades. Thus far, exercise-induced cTn elevations have been viewed as the only benign form of cTn elevations. However, recent studies report intriguing findings that shed new light on the underlying mechanisms and clinical relevance of exercise-induced cTn elevations. We will review the biochemical characteristics of cTn assays, key factors determining the magnitude of postexercise cTn concentrations, the release kinetics, underlying mechanisms causing and contributing to exercise-induced cTn release, and the clinical relevance of exercise-induced cTn elevations. We will also explain the association with cardiac function, correlates with (subclinical) cardiovascular diseases and exercise-induced cTn elevations predictive value for future cardiovascular events. Last, we will provide recommendations for interpretation of these findings and provide direction for future research in this field.

Keywords: apoptosis; athletes; cardiomegaly, exercise-induced; heart; heart injuries; necrosis.

Figure 1.

The cTn complex plays an essential role in cardiomyocyte contraction. When an action potential reaches the cardiomyocyte, calcium enters the cell, leading to a conformational change after binding of calcium ions to the TnC subunit. Hence, the myosin binding sites are exposed, allowing the myosin head to bind to the actin filaments and facilitating cardiomyocyte contraction. Note that the majority of cTn complexes are bound to the actin filament but are also present in an early releasable pool. cTn indicates cardiac troponin.

Figure 2.

Factors driving the magnitude of exercise-induced troponin release. There is great variability in the effect of each factor on postexercise troponin concentrations across studies and all factors have limited predictive value (r²<35%). Exercise intensity and duration appear to have the largest impact on postexercise concentrations, likely reflecting overall cardiac workload.

Figure 3.

Proposed pattern of exercise-induced elevations of cTn concentrations. A, Schematic illustration of the kinetics of cTn concentrations after a bout of endurance exercise. Changes of cTn concentrations during exercise are unclear (dashed line), but cumulative data show that cTn concentrations continue to rise after exercise cessation, with peak values reached between 2 and 6 hours after exercise. Complete normalization occurs within 24 to 72 hours after exercise. The 99th percentile or upper reference limit of normal (URL) is shown in red. B, Waterfall plot of individual (n=151) postmarathon cTnI concentrations, highlighting the large interindividual variation across athletes performing a similar endurance exercise bout. Data are pooled from participants of the Boston and Eindhoven marathons. Values in both plots are expressed as a multiple of the URL of the cTn assay. cTn indicates cardiac troponin.

Figure 4.

A schematic overview of the potential underlying mechanisms of exercise-induced cTn release. An increased cardiomyocyte sarcolemmal permeability attributable to cell wounds, release of extracellular blebs, and increased exocytosis rates can be considered as reversible cardiac damage, resulting in a physiological increase of cardiac troponin concentrations. Similarly, an increased cardiomyocyte turnover may transiently increase cardiac troponin concentrations. A higher rate of apoptosis and especially necrosis should be classified as (micro)damage to the cardiomyocyte, representing a pathological response to exercise, which may have long-term health consequences. cTn indicates cardiac troponin.

Figure 5.

Hazard ratios of postexercise troponin I > upper reference limit of normal for mortality and MACEs, and mortality and MACE separately, based on data from Aengevaeren et al. Troponin I was measured ≈10 minutes after 30 to 55 km of walking in 725 older long-distance walkers who experienced 62 events, 29 deaths, and 33 MACEs, during 43 [23–77] months follow-up. MACE indicates major adverse cardiovascular event.