Abstract
ctivity is recommended for the prevention of primary and secondary cardio- vascular (CV) disease as it is linked to a number of health benefits, especially CV. However, recent research suggests that high-volume, long-term endurance exercise may hasten rather than slow the coronary atherosclerosis progression. This contentious theory has generated a great discussion and is still a major source of doubt when it comes to the clinical treatment of coronary artery disease (CAD) in athletes. CAD is the primary cause of sudden cardiac death in athletes over 35 years.
research suggests that high-volume, long-term endurance exercise may hasten rather than slow the coronary atherosclerosis progression. This contentious theory has generated a great discussion and is still a major source of doubt when it comes to the clinical treatment of coronary artery disease (CAD) in athletes. CAD is the primary cause of sudden cardiac death in athletes over 35 years. Thus, recent studies evaluated the prevalence of CAD in athletes and its clinical and prognostic implications. Indeed, many studies have shown a relationship between endurance sports and higher volumes of coronary calcified plaque as determined by computed tomography. However, the pre- cise pathogenetic substrate for the existence of an increased coronary calcification burden among endurance athletes remains unclear. Moreover, the idea that coronary plaques in elite athletes present a benign morphology has been cast into doubt by some recent studies showing potential association with adverse cardiovascular events. This review aims to analyze the association between physical activity and CAD, explaining possible underlying mechanisms of atherosclerotic progression and non- ischemic coronary lesions, focusing primarily on clinical and prognostic implications, multimodal evaluation, and management of CAD in endurance athletes. Keywords:coronary artery disease; chronic coronary syndrome; elite athletes; endurance athletes; coronary plaque 1. Introduction Exercise training and physical activity (PA) are crucial approaches for lowering the risk of cardiovascular (CV) events. Elite endurance athletes often surpass the recommended weekly threshold of 150 min of moderate exercise or 75 min of intense exercise by the current guidelines for CV prevention [1]. However, a reverse J-shaped dose–response association between cumulative exercise exposure and CV morbidity has been reported in multiple cases over the years, indicating that there may be a threshold beyond which there is a loss of some of the previously noted exercise-related advantages [2,3]. Indeed, the possible harmful effects of lifetime high-intensity endurance exercise on the heart are a topic of long-standing discussion [4]. J. Clin. Med.2024,13, 5144.
J. Clin. Med.2024,13, 5144 2 of 26 In athletes older than 35, coronary artery disease (CAD) is the leading cause of sudden cardiac death (SCD), with clinical manifestations occurring in only 12–36% of the individu- als [5,6]. Indeed, there is evidence that athletes are not immune to the formation of coronary artery plaques, which challenges our knowledge of the relationship between exercise and coronary health, emphasizing the relevance of a careful CV evaluation in athletes [7,8]. High-volume, high-intensity exercise training may actually raise the incidence and severity of subclinical coronary atherosclerosis, according to a number of recent research[ . Notably, examination of the athletes’ plaque morphology revealed less mixed plaques and more frequently calcified plaques, indicating a more benign atherosclerotic pattern [9]. However, it is mostly unclear which is the underlying mechanism of atherosclerosis in elite athletes. Furthermore, it is still uncertain the clinical implications and the best management strategy for CAD in athletes. Therefore, the aim of this narrative review is to explain current knowledge about the association between exercise and CAD, explaining potential underlying mechanisms of atherosclerosis and coronary plaque characteristics in athletes and focusing on their clinical and prognostic implications. There are also discussed other potential causes of exercise-induced ischemia and methods for the evaluation of athletes with suspected CAD, highlighting the challenges in the management of these patients. 2. Materials and Methods We conducted a comprehensive literature search for data on articles published from 1990 to 2024 in PubMed, PMC, SportDiscus, and Cochrane reporting exercise-related issues related to coronary diseases. The main search terms were coronary artery disease in athletes, coronary plaque, coronary artery calcification in athletes, exercise-induced ischemia, endurance sports, coronary artery anomalies, myocardial bridge, and coronary artery dissection. To conduct further investigation, we additionally searched through the publications’ references that were collected. Clinical investigations, expert consensus, guidelines, case series, case reports, and narrative and systematic reviews constituted most of the articles that were considered. The search and result description were arranged into the following primary sections: exercise and coronary artery disease, a long-standing paradox; features of coronary atherosclerosis in endurance athletes; special subgroups of
searched through the publications’ references that were collected. Clinical investigations, expert consensus, guidelines, case series, case reports, and narrative and systematic reviews constituted most of the articles that were considered. The search and result description were arranged into the following primary sections: exercise and coronary artery disease, a long-standing paradox; features of coronary atherosclerosis in endurance athletes; special subgroups of coronary anomalies and lesions in elite athletes; management of athletes with suspected coronary artery disease; conclusions. 3. Exercise and Coronary Artery Disease, a Long-Standing Paradox 3.1. Benefits of PA and Cardiac Adaptation or “Maladaptation” PA is recommended for primary and secondary CV disease prevention and is linked to several beneficial effects. A mere 15 min of PA daily is linked to a 14% decrease in all mortality causes. Conversely, a population-attributable proportion of 12% of CV disease mortality is caused by inadequate PA. Since atherosclerotic disease accounts for more than 44% of CV deaths, exercise is consequently one of the best ways to lower the risk of major CV events [14,15]. Therefore, the current European Society of Cardiology (ESC) guidelines on sports cardiology and exercise in patients with CV disease recommend at least 150 min per week of moderate-intensity or 75 min per week of vigorous-intensity aerobic exercise in healthy individuals [16]. Exercise seems to be cardioprotective, partially driven by the positive impact on several atherosclerotic risk factors such as high blood pressure (BP), dyslipidemia, obesity, and diabetes [17]. However, it has advantageous benefits on the heart muscle and endothelial function as well. Molecular mediator generation, variations in the neurohormonal release, and maintaining oxidant/antioxidant equilibrium are only a few of the many underlying positive effects on the endothelium. Furthermore, regular exercise causes the vascular endothelium to exhibit anti-inflammatory properties and releases myokines from the skeletal muscle, enhancing vascular homeostasis and vasodilator capability through nitric oxide production [18,19]. Additionally, exercise promotes angiogenesis, enhancing oxygen
J. Clin. Med.2024,13, 5144 3 of 26 delivery and decreasing adhesion molecules involved in the inflammatory atherosclerotic process [19]. Competitive athletes, who maintain lifetime extremely high levels of PA usually outlive sedentary and normally active individuals [20]. They also acquire advantageous adaptive CV characteristics such as increased myocardial and vascular compliance and heart remodeling [21,22]. Sports that need endurance are those that require long-term, intense, high-dynamic exercise, such as running or cycling, while strength training requires explosive muscle power, such as weightlifting. On the other hand, mixed sports, such as ball and team sports (like soccer or basketball), involve alternating stages of dynamic and/or static effort and recovery [23,24]. Static activity creates pressure stress on the left ventricle, whereas dynamic exercise largely applies a volume load. Training in sports with a high degree of dynamic component causes athletes to significantly increase their absolute left ventricular (LV) mass and chamber size (a condition known as eccentric hypertrophy). Conversely, with strength training, repeated bursts cause a considerable rise in blood pressure and heart rate, which increases LV mass but does not expand the size of the chamber (concentric hypertrophy) [23,24]. During competitions, there can be a significant increase in pulmonary artery pressure by up to 70% and important and constantly elevated cardiac output as a consequence of the elevated diastolic filling and ventricular emptying [25]. Despite these determinants, power output also plays a crucial role in determining the performance of athletes across various sports during competition [26]. Moreover, elite athletes have less important ventricular dilatation, but greater left atrial size and LV hypertrophy as compared to young athletes. However, LV ejection fraction (LVEF) remains preserved from a functional standpoint, but the stroke volume and diastolic function parameters increase [9]. Nonetheless, there is ongoing discussion on the health status of those who significantly exceed the minimum recommendations. Indeed, in the case of excessive exercise, defined as more than 150 min per week of moderate-intensity or 75 min per week of vigorous-intensity aerobic exercise, there is a potential for the CV system to become “maladapted”, which would put athletes at higher risk of CV
ongoing discussion on the health status of those who significantly exceed the minimum recommendations. Indeed, in the case of excessive exercise, defined as more than 150 min per week of moderate-intensity or 75 min per week of vigorous-intensity aerobic exercise, there is a potential for the CV system to become “maladapted”, which would put athletes at higher risk of CV and all-cause mortality [27]. Whether physically de- manding sports activities have a negative impact on the heart over time is a long-standing debate. According to one theory, there is a reverse J-shaped relationship between the effects on the CV system and the intensity/frequency of PA [28]. It is suggested that although moderate exercise would be beneficial in comparison to a sedentary lifestyle, extremely intense PA would be detrimental to CV health [28,29]. Indeed, excessive exercise volumes have been linked to cardiac dysfunctional adaptation leading to atrial fibrillation, myocar- dial fibrosis, exercise-induced cardiac biomarker release, and accelerated coronary artery calcification. Furthermore, excessive PA may raise the risk of myocardial infarction (MI) and SCD, particularly in cases where it is undertaken by untrained individuals [30]. Therefore, athletes are not exempt from CAD. Unexpectedly, new research suggests that high-volume, long-term endurance exercise could accelerate rather than slow the progression of coronary atherosclerosis [9–13]. This causes controversy because the primary cause of exercise- related SCD in elite athletes is atherosclerosis [31]. Plaque rupture and its consequences, including demand ischemia resulting in ventricular arrhythmia or ventricular arrhythmia from a previous scar, are the mechanisms of SCD in elite athletes with underlying CAD [32]. However, the underlying mechanisms of atherosclerosis and plaque formation in athletes remain still unclear. 3.2. Coronary Artery Disease in Elite Athletes There is currently enough data to suggest the existence of a minor but significant risk of atherosclerotic CAD among endurance athletes despite the well-established and indisputable health advantages of regular physical training. Indeed, it has been shown that there is a paradoxical relationship between long-term marathon running involvement and increasing calcified coronary plaque volume as determined by computed tomography coronary angiography (CCTA). Even in athletes with low atherosclerotic risk profiles, as
minor but significant risk of atherosclerotic CAD among endurance athletes despite the well-established and indisputable health advantages of regular physical training. Indeed, it has been shown that there is a paradoxical relationship between long-term marathon running involvement and increasing calcified coronary plaque volume as determined by computed tomography coronary angiography (CCTA). Even in athletes with low atherosclerotic risk profiles, as
J. Clin. Med.2024,13, 5144 4 of 26 determined by the widely used risk score algorithms, this connection appears to exist regardless of the existence of CV risk factors [10]. There is growing evidence showing that male elite athletes, when compared to age and atherosclerotic risk-matched controls, have higher coronary artery calcium (CAC) scores and a higher prevalence of coronary atherosclerosis on CCTA [9,10]. For example, in the Measuring Athlete’s Risk of Cardiovascular Events (MARC) study, 318 middle-aged male athletes who could exercise to high workloads (318±48 Watts) were included, most of them having a low European Society of Cardiology Systematic Coronary Risk Evaluation (SCORE) risk. In 60 (16%) of them, there was an occult CAD defined asCAC > 100or coronary narrowing by more than 50% on CCTA in athletes withCAC < 100[33]. Another important study on CAD is the one conducted by Merghani et which enrolled 152 com- petitive runners and cyclists (age = 55±9 years) and 92 age-matched, normally active controls [9]. The controls did not have a family history of premature CAD (<40 years), a prior diagnosis of CAD, or other common CV risk factors. Compared to sedentary indi- viduals, male athletes had a higher incidence of atherosclerotic plaques of any luminal irregularity (44.3% vs. 22.2%;p= 0.009), and only male athletes had luminal stenosis of at least 50% (7.5%) and a CAC > 300 (11.3%). In addition, controls had mixed-morphology coronary plaques, while male athletes had mostly calcified plaques. This suggested that distinct pathophysiological mechanisms may be at play for the development of plaque in sedentary athletes [9]. To better understand how common subclinical atherosclerosis is connected to CV risk factors and how it affects myocardial damage and outcomes, Mohlenkamp et al. conducted a study enrolling experienced recreational marathon runners. There were 108 apparently healthy individuals who were 50 years of age or older, had run at least five full-length marathons (42.195 km) in the three years before, and had no history of established cardiac disease, compared to age- and Framingham risk score (FRS)-matched controls. Despite the significantly lower FRS, 36% of the runners had a CAC score
marathon runners. There were 108 apparently healthy individuals who were 50 years of age or older, had run at least five full-length marathons (42.195 km) in the three years before, and had no history of established cardiac disease, compared to age- and Framingham risk score (FRS)-matched controls. Despite the significantly lower FRS, 36% of the runners had a CAC score (CACS) > 100, which was comparable to age-matched controls. However, in contrast to FRS-matched controls, marathon runners had greater rates of CAC (median CAC: 36 vs. 12,p= 0.02) [10]. In addition, Tsiflikas et al. also examined male marathoners over 45 years of age and found that half of them had CAD, with 24% having plaques in the proximal coronary segments [34]. However, the connection between activity and CACS is still up for debate. In the Boston MASTER study, previous tobacco use and a family history of early atheroscle- rosis disease were shown to be the most common concerns among approximately 65% of elite athletes who had at least one documented CV risk factor. They demonstrated that there was little correlation between CAD and any aspect of previous exercise exposure and that CAD seemed to be connected with classic atherosclerotic risk factors, such as dyslipidemia and hypertension [35]. On the contrary, DeFina et al. examined 21,758 men and discovered that, in compar- ison to less physically active groups, extremely active men with >3000 metabolic equiv- alent of task (MET)-min·wk −1 of activity had an 11% greater risk of CAC > 100 AU [13]. Furthermore, 284 middle-aged males who played competitive or recreational sports in a different study conducted by Aengevaeren et al. had CCTA examinations and CAC measurements. To determine MET minutes per week, exercise volumes were multiplied with MET ratings. The movement of the participants was classified as being <1000, 1000 to 2000, or>2000 MET-min/week. The authors conclude that high levels of exercise are linked to an increased incidence of atherosclerotic and CAC plaque, as well as a propensity for calcified rather than mixed plaque [11]. These results were considered benign and non-alarming since calcified plaques are less likely to
The movement of the participants was classified as being <1000, 1000 to 2000, or>2000 MET-min/week. The authors conclude that high levels of exercise are linked to an increased incidence of atherosclerotic and CAC plaque, as well as a propensity for calcified rather than mixed plaque [11]. These results were considered benign and non-alarming since calcified plaques are less likely to rupture and more stable than mixed and non-calcified plaques [36]. Nevertheless, the clinical and prognostic implications remain still speculative, as discussed later.
J. Clin. Med.2024,13, 5144 5 of 26 3.3. Clinical and Prognostic Implications—A Long-Standing Debate Whether a high CACS and subclinical CAD in athletes have detrimental clinical and prognostic effects is still a controversy. Athletes who engage in lifelong, high-intensity PA may have a worse prognosis. Indeed, nearly 900 sudden sports-related deaths were recorded in a prospective national study carried out in France between 2005 and 2010, the majority of which (95%) were caused by CAD and largely involved young male athletes [5]. Athletes with pre-existing CAD may be more susceptible to myocardial infarction during periods of strenuous PA. Therefore, the focus of these patients’ therapy should be on assessing their risk of inducible ischemia. It has been demonstrated before that although athletes with raised CACS typically have calcified plaque morphology, which lowers risk, it is widely known that those with elevated CACS have a much higher risk of severe cardiac events compared to those with a CACS of 0. In fact, a CACS of 400 is linked to an estimated 34% chance of major adverse cardiac events (MACE), whereas a CACS of 0 relates to a 2.1% risk. In particular, those with CACS > 1000 seem to be at extremely high risk of both CV disease and all-cause death [37]. In accordance, zero CACS was less common in the Mohlenkamp et al. trial than it was in the MARC study (28.7% vs. 47.5%,p< 0.001). Additionally, it was revealed that CV events almost entirely occurred in those with a CACS greater than 100 AU, which was more common than in MARC (36.1% vs. 16.4%,p< 0.001) [10,33]. A very important prognostic piece of information was provided by the previously reported study by Mohlenkamp et al. In their study, the presence of myocardial injury was independently predicted by CAC percentile levels, as demonstrated by the fact that 12% of the runners had ischemic-type late-gadolinium enhancement (LGE) on the cardiac magnetic resonance (CMR). Follow-up data on CV events (21 months) were also included in the study. Out of the 38 athletes with CAC > 100, 4 athletes had coronary events (2 aborted cardiac arrests
injury was independently predicted by CAC percentile levels, as demonstrated by the fact that 12% of the runners had ischemic-type late-gadolinium enhancement (LGE) on the cardiac magnetic resonance (CMR). Follow-up data on CV events (21 months) were also included in the study. Out of the 38 athletes with CAC > 100, 4 athletes had coronary events (2 aborted cardiac arrests after PA, 1 acute myocardial infarction, and 1 surgical revascularization for CAD revealed by additional testing), and 3 of these athletes had LGE. However, there were no cardiac deaths reported in the study. These findings imply that subendocardial fibrosis in elite athletes could be a sign of micro-emboli, coronary spasm, and subclinical myocardial infarction due to demand ischemia. Remarkably, no participant withCAC = 0 experienced events. In contrast, cardiac events occurred in 8% and 14% of the athletes with CAC 100–400 and >400, respectively [10]. However, the study’s cross-sectional study methodology works well for identifying correlations but is not appropriate for determining causal links between exposures and clinical characteristics. While it is plausible to conclude that aging endurance athletes would have remarkably high levels of CAC, the underlying mechanisms are still unknown. Although inviting information, drawing the premature conclusion that intense exercise is the key mechanistic factor causing CAC is still premature. These results do not advocate for a decrease in PA because a lower level of exercise can be linked to the advancement of atherosclerosis. In fact, in 2013, Delaney and colleagues classified Multi-Ethnic Study of Atherosclerosis (MESA) study participants who underwent a follow-up CCTA scan based on their level of PA and showing that a lower level of PA was found to be highly associated with the progression of coronary calcification in athletes who already had it at baseline [38]. On the contrary, other research suggested that physical exercise is not linked to an increased risk of CV events, even in the presence of a high CACS. Indeed, Gao et al. supported earlier research showing a link between the general population’s elevated risk of CV events and the advancement of CAC. However, they noted that the risk was
Description
The review discusses coronary artery disease risks in elite endurance athletes and the implications of high-volume exercise.