Numerous epidemiologic studies have demonstrated a protective effect of exercise on coronary artery disease (CAD).5) A recent meta-analysis showed that a moderate-to-high level of leisure time physical activity was associated with a reduced risk of CAD. Specifically, vigorous and moderate exercise decreased the risk of CAD by 27% and 12%, respectively, compared with individuals with low or nil exercise activity.5) Possible contribution of exercise-induced blood pressure lowering, improved body composition, glucose tolerance, insulin sensitivity, and platelet function has been suggested.6)

Studies on stroke prevention and meta-analysis of the studies7-10) indicated that moderate- to high-intensity exercise was associated with a reduced stroke risk. This protective effect is not only confined to ischemic stroke, but also extends to reduction of hemorrhagic and, therefore, the total stroke risk.7) Overall, moderately active individuals had a 20% lower risk and highly active individuals had a 27% lower risk of stroke incidence or mortality than the low-active individuals.8) Considering the pooled relative risk from studies on CAD and stroke prevention, the protective effect on stroke seemed comparable or even greater than the effect on CAD.7)

Hypertension is a risk factor for both ischemic and hemorrhagic strokes, and there is a direct dose-response relationship between blood pressure and stroke risk. Physical activity lowers blood pressure, improves lipid profiles, and also improves endothelial function, which enhances vasodilation and vasomotor function in the vessels. In addition, physical activity can play an antithrombotic role by reducing blood viscosity, fibrinogen levels, and platelet aggregability, all of which might reduce cardiac and cerebral events.8)

There have been numerous epidemiologic studies on physical activity and cancer prevention.11) The available data indicate that physical activity has a different association with different types of cancers.11) Most studies focused on commonly occurring cancers (e.g., prostate, lung, colorectal for men, breast, lung, colorectal for women). The effect on the risk of colon cancer varied from 80% reduction to 60% increase. Overall, exercise was associated with a lower risk of colon cancer among both men and women. In addition, a dose-response relationship in cancer prevention was observed across levels of physical activity.11) In contrast, the available data show no clear association between physical activity and rectal cancer rates in men and women.11) It also appears that physically active women have a 20-30% reduced risk of breast cancer.12) Although exercise appears to be related with a lower risk of lung cancer, the confounding effect of smoking (passive smoking, depth of inhalation, use of filter tips etc) could not be completely controlled. There is no clear data supporting that physical activity decreases the risk of prostate cancer, with the median relative risk around 0.9. The data for other cancers, such as ovarian, testicular, pancreatic, kidney or bladder cancer, are limited. Although the beneficial effect of physical activity on the colon and breast cancers is obvious, the amount of exercise, the duration or frequency of exercise, as well as the dose-response relationship, is less clear.

A significant relationship between physical activity and reduction in mortality has been reported, with a mortality reduction reaching up to 20-40%.13-16) A clear dose-response relationship was established and a larger volume of physical activity was related with a lower all-cause mortality.14)15) This inverse dose-response relationship has been shown both in men and women, in younger and older subjects.16) However, fewer data are available about the relationship between components of exercise dose (duration, intensity, frequency) and the improvement in longevity.15)

Other beneficial effects of exercise include modification of cardiovascular risk profiles, such as control of hypertension, improved lipid profile, prevention of type 2 diabetes, benefit on the bone-mineral metabolism and body composition.17)

CAD is the most common cause of SCD in older subjects. Even in previously asymptomatic adults, coronary artery plaque disruption (rupture or erosion) with acute thrombotic occlusion can be found. However, the mechanism by which vigorous exercise precipitates cardiac events is not clearly defined. Exercise-related physiologic changes, such as elevated blood pressure, increased heart rate, coronary artery spasm in the affected artery segment, may contribute to the plaque disruption. Other contributing factors include deepening of the coronary fissures, as well as catecholamine-induced platelet activation and aggregation. Once myocardial blood flow is severely impaired in acute ischemia, ATP-sensitive potassium channels open and, together with hyperkalemia or cellular acidosis, lead to a markedly increased dispersion of repolarization and cell-to-cell conduction, which ultimately leads to ventricular fibrillation (VF).38)

The most prominent cellular electrophysiological alteration seen in failing heart is prolongation of the action potential duration. This is caused by down-regulation of the K⁺ currents and alteration in the inward Na⁺ and Ca⁺⁺ currents. This action potential prolongation occurs inhomogeneously throughout the transmural myocardium, and serves as a substrate for reentrant ventricular tachyarrhythmias.39)40) In addition, altered channel gating property of the RyR receptor, reduced sarcoplasmic reticulum (SR) Ca⁺⁺ ATPase function and increased Na-Ca exchange contribute to spontaneous Ca⁺⁺ leak, decreased SR Ca⁺⁺ contents, and reduced Ca⁺⁺ transient. These changes, in association with up-regulated Na-Ca exchange and reduced inward rectifier K⁺ current, lead to contractile dysfunction and development of delayed afterdepolarization.41)42) Upon sympathetic stimulation, spontaneous Ca⁺⁺ release and enhanced Na-Ca exchange, together with I_K1 reduction, results in greater propensity for developing delayed after-depolarization.43)

In a large multicenter ICD registry, ventricular tachyarrhythmias appeared to play a major role in the pathogenesis of SCD in HCM, while bradyarrhythmia-mediated events could not be excluded as a cause of SCD.44) As sinus tachycardia was often the initiating rhythm before development of ventricular tachyarrhythmias, high sympathetic drive seemed to be proarrhythmic in patients with HCM.45)

It has been shown that the histological features of HCM are a markedly disorganized myocardial architecture, medial hypertrophy with luminal narrowing of the intramural coronary arteries, and replacement fibrosis after bursts of myocardial ischemia or myocyte necrosis.46) This highly heterogeneous substrate may be prone to develop ventricular tachyarrhythmias during exercise, due to outflow tract obstruction, myocardial ischemia or sympathetic surge, as previously demonstrated.47-49)

Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy in which the right ventricular myocardium is progressively replaced by fat and fibrosis. SCD is frequently the first manifestation of the disease, and it occurs relatively frequently during exercise or stress. RV dilation, precordial repolarization abnormalities, and LV involvement have been associated with higher risk of sudden death.50)

Congenital coronary artery anomaly indicates either the left main coronary artery arising from the right aortic sinus/pulmonary artery, or the right coronary artery arising from the left aortic sinus. Overall, it is an important cause of sudden death in young athletes. Cardiac events occur mainly during intense exertion probably provoked by myocardial ischemia from angulation of the coronary ostium or compression of the coronary artery. Premonitory symptoms (syncope, chest pain) may occur shortly before the onset of sudden death. Echocardiography or stress electrocardiogram (ECG) with maximal exercise may not disclose this anomaly, and a careful history taking revealing the presence of syncope or chest pain during exercise is crucial in the pre-participation screening of competitive athletes.51)

Myocardial bridging is defined as a segment of a major epicardial coronary artery running intramurally through the myocardium, and is a common angiographic or autopsy finding. It is generally a benign congenital coronary artery anomaly, but it has been associated with angina, arrhythmia, depressed left ventricular (LV) function, myocardial stunning, and sudden death.52) Medical treatment with beta-blockers seems to be the first choice. However, intracoronary stents and surgery have been attempted in selected patients with refractory symptoms. Additional study is necessary to define the role of the myocardial bridge in the occurrence of sudden death, and to select the patients requiring invasive or surgical management.52)53)

Myocarditis accounts for about 10% of the SCD in the young population. Infection or exposure to toxic chemicals/radiation can cause myocardial inflammation, and SCD results from conduction abnormalities or malignant ventricular tachyarrhythmias.50)

The mitral valve prolapase (MVP) is a common echocardiographic abnormality, observed in about 3-4% of the general population. It is not a single disease entity, but a spectrum of different conditions, ranging from simple bowing of the mitral valve leaflet to redundant myxomatous leaflet and flail MV.54)55)

Although SCD frequently occurs during exercise, the MVP per se. may not be related with an increased risk of SCD. Instead, the risk of SCD is strongly associated with accompanying mitral regurgitation.54)55) The mechanism of SCD in patients with MVP is not clear. Ventricular tachyarrhythmias have been reported to occur more frequently in patients with MVP than in control subjects. However, this may be due to the presence of mitral regurgitation, not due to MVP itself. Therefore, the cause of SCD seems multifactorial, including ventricular tachyarrhythmias or atrioventricular block, hemodynamic dysfunction with severe hypotension, coronary artery spasm, hidden myocarditis or myocardial dysplasia.56)

The risk of SCD associated with ventricular preexcitation is less than 0.15% per year.57) The main mechanism of SCD seems to be atrial fibrillation conducting rapidly over an accessory pathway and degenerating into VF.58) Exercise is associated with an increased risk of VF. The approach to asymptomatic patients with ventricular preexcitation varies from simple observation to routine electrophysiological study and catheter ablation of the accessory pathway in patients with inducible atrial tachyarrhythmia.58) Considering the low risk of SCD in this aymptomatic population, the clinical decision should be individualized. Athletes with ventricular preexcitation should be evaluated for inducibility of supraventricular tachycardia and refractoriness of the accessory pathway before participation in competitive sports.69)

It has been well demonstrated that subgroups of patients with long QT syndrome (LQTS) are sensitive to sympathetic stimulation. Arrhythmic events are often associated with physical exercise, emotional stress or auditory stimulation in long QT type 1 or 2.59) Swimming is a relatively genotype-specific arrhythmogenic trigger for both type 1 of the long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). In contrast, type 2 LQTS patients are susceptible to auditory stimulation or alarm.59)60)

CPVT is an inherited disease characterized by a normal resting ECG, adrenergically-mediated bigemini premature ventricular contraction (PVC) and ventricular tachyarrhythmias. Mutation of the cardiac Ryanodine receptor 2 with impaired calcium-handling and delayed afterdepolarization was demonstrated to be the electrophysiological mechanism of fatal ventricular tachyarrhythmias.61)62)

Cardiac events in patients with short QT syndrome may occur during effort or loud noise, but this association appears to be weaker than in both LQTS and CPVT.63-65) The arrhythmogenic mechanism in patients with Brugada syndrome or early repolarization syndrome is strongly dependent on the vagal nerve activity, and exercise is less strictly prohibited compared with patients with LQTS, CPVT or HCM.66)

In Italy, a national pre-participation screening mandates annual evaluations that routinely include 12-lead ECG, in addition to medical history and physical examination. Wide implementation of the Italian screening model has been promoted by the endorsement of the European Society of Cardiology in 2005. Recent scientific evidence demonstrated this screening strategy to be useful for identification of HCM and other cardiomyopathies in asymptomatic athletes,67) and implementation of this program in Italy has been associated with substantial reduction in mortality due to cardiomyopathies.68) On the other hand, customary screening strategies for U.S. high school and college athletes is confined to medical history and physical examination at 2- to 4-year intervals.34) This is due to current lack of medical and financial resources, and more importantly, due to potentially deleterious effects to many athletes by virtue of false-positive test results that would lead to unnecessary further evaluation or disqualification.

To overcome this controversy, a new classification of the athlete ECG was proposed. ECG may be abnormal in up to 50% of athletes, which hinders the widespread use of ECG as part of the pre-participation screening. This new guideline classifies the changes seen on the athlete ECG into physiological (common and training-related) and pathological (uncommon and training-unrelated), to lower the traditionally high number of false-positive results and thus reducing unnecessary investigations69) (Table 4).

Guidelines from the AHA indicated that exercise testing is not necessary for all people beginning a moderate intensity physical activity program. The rationale is based on the extremely low rate of cardiovascular complications in asymptomatic persons while performing moderate-intensity physical activity, on the poor predictive value of exercise testing for acute cardiac events and on the high costs of mass exercise testing. Symptomatic subjects or those suffering from any cardiovascular disease, diabetes, other active chronic disease, or with any medical concern in general, should consult a physician prior to any substantive increase in physical activity, particularly vigorous-intensity activity.25)

Exercise-related cardiac events occur predominantly in subjects with underlying structural abnormalities. However, exercise may cause a deleterious effect in individuals without underlying cardiac diseases. Athlete's heart denotes exercise-related electrical and structural remodeling. Intense resistance training increases LV wall thickness and mass with little or no change in the LV diameter, while aerobic exercise is associated with asymmetric LV hypertrophy.70)71)

Clinical implications of the athlete's heart include differential diagnosis from hypertrophic/dilated/RV cardiomyopathy, or possible long-term consequences of the extreme LV remodeling. As exercise itself causes alteration in the cardiac chamber size and morphology resembling those of cardiomyopathies, differential diagnosis of the athlete's heart (i.e., a physiological adaptation) from cardiomyopathies has long been a diagnostic dilemma. Athletes with benign right ventricular outflow tract VT may show wall motion abnormalities mimicking ARVD. In addition, concern has been raised that uninterrupted training per se, might ultimately cause irreversible cardiac dilatation,71) systolic dysfunction,72) or even ventricular tachyarrhythmias.73) A recent report, however, demonstrated that even young Olympic athletes exposed to extreme endurance training over long periods of time (up to 17 years) did not show deterioration in LV function and morphology or any occurrence of cardiovascular events. These findings confirmed the concept that the athlete's heart is a physiological adaptation to exercise, not causing irreversible cardiac remodeling.74)

Commotio cordis refers to VF and SCD triggered by a blunt, non-penetrating, and often innocent-appearing blow to the chest wall, without visible damage to the ribs, sternum, or heart, in individuals without previous structural heart diseases. It is an important cause of exercise-related SCD in young athletes, accounting for 3% of all sudden deaths in young, competitive athletes.75) A direct blow to the chest walls falling on a critical time of the cardiac cycle (i.e., 10-20 msec on the upstroke of the T wave) can precipitate VF. The cellular mechanism of VF initiation appears to be multifactorial. Instantaneous increase in the left ventricular intra-cavitary pressure and opening of stretch-activated ion channels, including ATP-sensitive potassium channels, may result in inhomogeneous repolarization of the myocardium, thus creating the vulnerable substrate for VF.76)