Atherosclerotic coronary artery disease (CAD) is the largest cause of CVD and is highly dependent on both genetic and lifestyle factors [
16]. Regular physical activity and exercise training are associated with a reduction of selected CVD risk factors, including lipid levels [
17], blood pressure [
18], and inflammation [
19]. Coronary artery atherosclerosis can be assessed using different imaging techniques (Table
1), of which computed tomography (CT) is the least costly, fastest and most widely used. The coronary artery calcification (CAC) score can be derived from CT images and is an excellent predictor of future cardiac events [
20]. Interestingly, Möhlenkamp et al. found a higher prevalence of CAC scores ≥ 100 Agatston units among 108 marathon runners (36%) compared to an age and risk factor-matched control group from the general population (22%).
Table 1
Imaging techniques to assess underlying atherosclerotic CAD and/or myocardial fibrosis in endurance athletes
CT | Coronary artery calcification (CAC) score | Transvenous endomyocardial biopsy—picrosirius red or Masson staining | Fibrillar collagen quantification |
CT coronary angiography | Plaque characteristics (i.e., plaque phenotype, plaque volume) | Cardiac MRI with gadolinium contrast infusion | Presence and volume of focal myocardial fibrosis |
IVUS | Atherosclerotic burden and plaque characteristics | Cardiac MRI with T1 mapping | Presence and volume of diffuse myocardial fibrosis |
OCT | Plaque lipid content, macrophage infiltration and thickness of fibrous cap | | |
Cardiac MRI | Plaque characteristics | | |
Recent studies have provided important novel insights regarding this widely cited observation. Aengevaeren et al. examined the association between lifelong volumes of physical activity and the prevalence and characteristics of coronary atherosclerosis in 284 male amateur athletes [
21••]. The most active athletes routinely exercised at volumes equal to four times current recommendations, whereas the least active athletes exercised at the current recommended volume. The most active athletes had a higher CAC prevalence than the least active athletes (68% versus 43%, odds ratio [OR]: 3.2, 95% CI: 1.6–6.6). However, the most active athletes also had a lower prevalence of mixed plaques (48% versus 69%; OR: 0.35, 95% CI: 0.15–0.85) and more often had only calcified plaques (38% versus 16%; OR = 3.57; 95% CI: 1.28–9.97) compared with the least active athletes. This observation has important clinical relevance as mixed plaques are associated with a higher probability of future cardiovascular events compared with calcified plaques (38% versus 6%) [
22]. Similar findings were reported in an English cohort of 152 veteran athletes and 92 sedentary controls [
23••]. Male athletes more often had atherosclerotic plaques (44% versus 22%;
p = 0.009) and a higher prevalence of CAC > 300 (11% versus 0%,
p = 0.009) compared to age and risk factor-matched sedentary controls. Again, veteran athletes predominantly had calcified plaques, whereas mixed plaques were more prevalent among controls. In aggregate, these data suggest that long-term exercise training is associated with accelerated coronary artery atherosclerosis, but that accelerated plaque calcification may outweigh the cardiovascular risks associated with increased CAC scores. Additional longitudinal studies are needed to confirm this hypothesis.
Lin et al. assessed changes in plaque characteristics among eight participants of the Race Across the USA (140 race days covering 3080 miles) [
24]. Four runners had no evidence of CAD on CT angiography before or after the race, but luminal stenosis and plaque volume (range: 4.8–94 mm
3) increased in four runners with coronary atherosclerosis present before the race. The change in plaque volume was mainly attributed to an increase in non-calcified plaque. However, concomitant increases in high sensitivity C reactive protein (CRP) were noted, suggesting that exercise-induced inflammation may contribute to accelerated plaque progression. Whether initial increases in non-calcified plaque volume may change to calcified volume during race recovery is unknown. Previous studies demonstrated that exercise increased parathyroid hormone [
25], decreased vitamin D3 [
26] and decreased magnesium levels [
27], all biomarkers of calcium-phosphate metabolism, which could affect vascular calcification [
28]. Future studies investigating the underlying mechanisms of accelerated coronary artery atherosclerosis in veteran athletes are needed and may provide insight into how to improve strategies to stabilize plaques in vulnerable patient populations.
Increased myocardial fibrosis
Exercise-induced increases in cardiac biomarkers, such as troponin, a marker of cardiomyocyte damage, and B-type natriuretic peptide (BNP), a marker of myocardial stress, are common in athletes after endurance exercise [
29]. Recent studies explored the impact of endurance exercise on novel cardiac biomarkers, such as galectin-3, a marker of myocardial fibrosis, [
30] and soluble suppression of tumorigenicity-2 (sST2), a marker of extracellular matrix remodeling and fibrosis [
31]. Resting levels of galectin-3 were higher in athletes (
n = 21) compared to controls (
n = 21), whereas significant increases were observed following a 30-km run (12.8 ± 3.4 to 19.9 ± 3.9 ng/ml,
p < 0.001) [
30]. Similarly, sST2 concentrations increased following a marathon (34.2 to 54.2 ng/ml,
p < 0.001), with 68 of 79 athletes (86%) demonstrating a concentration above the upper reference limit. Complete normalization of sST2 levels occurred within 48 h [
31]. Increases in cardiac biomarkers are modest and transient, but the clinical implications of these elevations are unknown. Accordingly, long-term exercise training/competition with repetitive exposure to prolonged vigorous exercise may increase cardiac fibrosis.
Cardiomyocyte damage leads to myocardial fibrosis, which is characterized by collagen infiltration in the extracellular matrix. The presence and magnitude of myocardial fibrosis can be determined via microscopic analysis of cardiac muscle obtained by postmortem biopsy or via cardiac magnetic resonance imaging (MRI; Table
1). Previous studies using MRI in athletes reported that the prevalence of myocardial fibrosis varied substantially (0% to 50%) between study populations [
13,
32]. A systematic review found evidence of myocardial fibrosis in 30 of 509 scanned athletes (5.9%) [
33•]. Myocardial fibrosis patterns were heterogeneous, and most frequently located near the interventricular septum and the right ventricular insertion points. The presence of myocardial fibrosis was strongly associated with the cumulative exercise dose. In contrast to studies from Germany [
34] and the USA [
35]. Bohm et al. found no difference in left and right ventricular function parameters between 33 competitive elite male master endurance athletes and 33 controls matched for age, height, and weight, [
34], and myocardial fibrosis was observed in only 1 athlete. Abdullah et al. compared left ventricular characteristics across groups of long-term exercisers (< 2/2–3/4–5/6–7 exercise sessions/week) and found a stepwise improvement of cardiac structure and function with increasing doses of physical activity [
35]. Among the 92 study participants, delayed gadolinium enhancement was observed in only 1 exerciser in the 2–3 sessions/week group. These studies suggest that myocardial fibrosis is a rare finding among endurance athletes. The discrepancy in prevalence rates may be due to the age and training status of the study population or to survival bias. On the other hand, Wilson et al. used delayed gadolinium enhancement on cardiovascular MRI to describe diverse patterns of myocardial fibrosis in 6 of 12 highly trained veteran endurance athletes [
36]. Additional prospective studies are needed to confirm the association between exercise dose and incident myocardial fibrosis.
Whereas previous studies predominantly employed gadolinium infusion to determine focal fibrosis, T1 mapping is increasingly used to quantitate diffuse fibrosis (Table
1). Gormeli et al. found that athletes had significantly higher left ventricular (LV) native T1 values (1230 ± 39 ms versus 1174 ± 36 ms,
p < 0.001) and interventricular septum (IVS) native T1 values (1268 ± 48 ms versus 1180 ± 27 ms,
p < 0.001) compared to matched sedentary controls [
37]. Furthermore, native T1 values of the LV (
p < 0.05) and IVS (
p < 0.05) were significantly higher in athletes that trained ≥ 5 years as compared to those training < 5 years, and the highest values of LV end diastolic volume and IVS wall thickness were found in those athletes who had trained the longest. These data suggest that more training results in greater cardiac remodeling, but potentially also more diffuse myocardial fibrosis.
The clinical consequences of myocardial fibrosis in athletes are largely unexplored. A German study found that coronary revascularization was more common in athletes with, than without, fibrosis, 25% versus 1%, respectively [
12]. Schnell et al. reported a case series of serious cardiac complications in Belgian athletes with isolated subepicardial fibrosis, such as non-sustained ventricular arrhythmias, symptomatic ventricular tachycardia, and progressive LV dysfunction [
34]. British veteran athletes with myocardial fibrosis demonstrated normal cardiac function, but co-localized regional cardiac dysfunction was found in fibrotic areas, substantiated by evidence of an attenuated cardiac strain and base to apex gradient [
38]. These observations suggest that the presence of myocardial fibrosis requires appropriate clinical follow-up to evaluate the possibility of future adverse cardiovascular outcomes.