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Exercise and Coronary Artery Disease

Assessing Causes and Managing Risks

Joseph R. Libonati, PhD
Helene L. Glassberg, MD

Exercise and Sports Cardiology Series
Editor: Paul D. Thompson, MD

THE PHYSICIAN AND SPORTSMEDICINE - VOL 30 - NO. 11 - NOVEMBER 2002

In Brief: Exercise has many benefits, but it is not completely risk-free. Many factors can contribute to cardiac events during exercise, including coronary artery disease (CAD) and nonatherosclerotic causes such as anomalous coronary arteries, myocardial bridging, and vasculitis. Myocardial infarction and sudden cardiac death are the two major problems in older patients with CAD, but most exercise-related deaths in young patients result from hypertrophic cardiomyopathy and coronary artery anomalies. Preexercise screening that includes a careful history, medical examination, and, for some, exercise testing, can stratify risk and mitigate potential problems during exercise.

Compelling data show that physical activity reduces mortality from coronary heart disease (CAD), hypertension, diabetes, and some cancers.1 Despite its benefits, physical activity also carries risks. The absolute incidence of cardiovascular complications during physical activity in healthy individuals is low, but sudden death and myocardial infarction (MI) during physical exertion do occur in asymptomatic, presumably "fit" individuals. These cases attract widespread attention and arouse public concern about the cardiovascular risks of exercise. These risks are also a major concern for physicians who conduct preparticipation exams on patients.

CAD and Exercise

During acute aerobic exercise, total-body oxygen needs are met by increases in cardiac output and the arteriovenous oxygen difference.2 The coronary flow must rise to supply demand during exercise when oxygen requirements increases, because the myocardial arteriovenous difference is nearly maximal at rest. Myocardial ischemia occurs when there is a mismatch between coronary blood flow (supply) and myocardial oxygen demand. Coronary artery vasoconstriction also contributes to exercise-induced ischemia in patients with CAD.

Acute events. The extent of luminal stenosis, length of atherosclerotic plaques, development of coronary collaterals, amount of myocardial mass, degree of vascular autoregulatory function, and shape and stability of atheromas are important determinants of how coronary atherosclerosis affects flow.3,4 More recent data suggest that inflammation plays a significant role in determining the stability of an atherosclerotic plaque. Although the increased heart rate and consequent increased myocardial oxygen demand from exercise can generate myocardial ischemia and angina, increased myocardial oxygen demand alone is an unlikely cause of exercise-related acute cardiac events.

Coronary lesions associated with subsequent acute MI are often only minimal-to-moderate stenoses and are generally less than 70% of coronary artery diameter,5 suggesting that plaque rupture and coronary thrombosis produce most MIs. Plaque rupture is also important in the pathogenesis of exercise-induced MI.6 The fibrous cap determines the plaque's vulnerability to rupture, and disruption often occurs in a luminal wall area where normal endothelium and atherosclerotic surfaces join.3

Exercise. Plaque rupture can occur by one of several mechanisms, but all involve vascular endothelial function (table 1). In individuals with healthy coronary arteries, exercise induces coronary vasodilation. Paradoxically, in patients with CAD, exercise produces coronary artery vasoconstriction.7 Stresses on vulnerable plaque from acute hemodynamic responses to exercise are another possibility. The epicardial coronary arteries are forced to track the myocardium during contraction. Exercise increases heart rate,8 causing more frequent bending and twisting of coronary arteries. In addition, exercise decreases end-systolic volume and increases end-diastolic volume, magnifying the excursion of these arteries, and perhaps contributing to plaque cracking and rupture. Exercise also increases systolic blood pressure, adding to shear stress on the plaque surface.9

TABLE 1. Potential Mechanisms Related to the Rupture of Unstable Arterial Plaque
Cytokines and other inflammatory stimuli

Platelet aggregation

Coronary vasoregulation

Myocardial inotropy

Transmural mechanical forces

Myocardial systolic:diastolic ratio

Coronary artery flexing

Geometry of plaque

Shear stress

Oxidative stress

Intracoronary pressure

Exercise could also contribute to thrombosis and an acute cardiac event after plaque disruption. During acute exercise, plasma catecholamine concentrations increase proportionally to the work rate. In turn, increased catecholamine levels stimulate platelet aggregation10 and could contribute to thrombosis. Interestingly, platelet aggregation arising from exercise is most apt to occur in sedentary subjects because exercise elicits a greater hormone release in them than in trained subjects.10

Vasodilators, Exercise, and CAD

When considering vascular endothelial function, the nitric oxide (NO) system is an important factor in coronary event pathophysiology. Cardiac complications are less frequent in habitual exercisers, perhaps, in part, due to the upregulation of the NO system.

Nitric oxide production. NO is one of the most potent endothelial-derived vasodilators.11 NO has several other important actions,12-16 including stimulating the generation of second messengers, which causes calcium release from the endoplasmic reticulum.17 Intracellular calcium release stimulates constitutive nitric oxide synthase (NOS) to produce NO until calcium levels return to resting concentrations.18 Vascular tone is, in part, maintained by the basal, intermittent production of NO by NOS.19

Under normal physiologic conditions, shear stress and stretch are likely responsible for tonic, basal release of NO. Inhibitors of NO synthesis are known to cause vasoconstriction and hypertension,20 suggesting that continuous endothelial NO production helps maintain blood pressure. Studies21,22 reveal that cyclic strain can upregulate endothelial NOS and may partially explain the benefits of exercise on cardiovascular disease.

Nitric oxide and CAD. Impaired NO reactivity in atherosclerosis appears related to increased oxidative stress.23 Reactive oxygen species and subsequent oxidation of low-density lipoprotein may suppress the action of NO through several mechanisms. Particularly, the superoxide anion attenuates the biological activity of NO,24 and the deleterious effects are manifested with improved endothelial-mediated vasoreactivity when superoxide anion is removed by free-radical scavengers.23

Smooth-muscle proliferation is also important in the pathogenesis of atherosclerosis. The vascular endothelium is involved in cell growth, and mechanical removal of this layer is followed by proliferation of the intima.25,26 Balloon-induced endothelial injury has been shown to be inversely related to acetylcholine-induced vasodilation.27

The Vascular Endothelium and Habitual Exercise

The vascular endothelium plays a central role in both health and disease and responds to many different physiologic processes.

Fibrinolysis. The NO system is also regulated by the endothelium via the release of several factors, including tissue-type plasminogen activator (TPA) and plasminogen activator inhibitor (PAI-1). TPA binds to fibrin, converting plasminogen to plasmin and activating clot lysis. Thrombin, histamine, cytokines, and shear stress stimulate TPA release, and TPA receptors on endothelial cells localize plasminogen activation.28 PAI-1 acts to inhibit TPA in plasma and enhances thrombosis.29

The endothelium also regulates thrombosis through synthesis of von Willebrand factor, a glycoprotein that mediates platelet adhesion to injured vascular surfaces.28 Exercise training can improve the balance of the fibrinolytic system. Healthy, older patients who participated in 6 months of strenuous endurance exercise had significant improvement in hemostatic parameters, with increased TPA levels and reduced fibrinogen and PAI-1 concentrations.30

In addition to NO, other vasorelaxants such as prostacyclin and endothelium-derived hyperpolarizing factor are secreted from the vascular endothelium. Endothelial cells also secrete potent vasoconstrictors, including endothelin, endothelin-derived constricting factor, and angiotensin 2. The most abundantly produced prostaglandin, prostacyclin, relaxes smooth muscle and inhibits platelet aggregation. All of the prostanoids, including prostacyclin, can induce vasoconstriction.

Endothelial function. Most exercise-related acute cardiac events are likely due to endothelial dysfunction and atherosclerotic plaque rupture.6 Exercise-related events such as MI and sudden cardiac death are more frequent in habitually sedentary individuals than in physically active people. Consequently, regular physical activity may reduce the frequency of exercise-related events by improving endothelial function.31 Libonati et al32 documented improved endothelial function in physically active subjects, suggesting that NOS production is increased following exercise. Other studies10,33 revealed that exercise training or habitual physical activity may also improve platelet function, although the research focused on platelets directly rather than on the endothelial-platelet interaction.

Adverse Events During Exercise

Two major cardiac problems during exercise arise from CAD: sudden cardiac death and acute MI. Both events are primarily due to atherosclerosis and thus are predominantly adult occurrences. Exercise-related coronary events in younger subjects are extremely rare and most often arise from congenital coronary artery abnormalities.

Sudden cardiac death. In apparently healthy subjects, the absolute risk of sudden death during exercise is quite low (see "Cardiovascular Risks of Exercise: Avoiding Sudden Death and Myocardial Infarction," April 2001, page 33). Available studies34,35 estimate the exertional-related sudden death rate in previously healthy, middle-aged men to be about 6 to 7 per 100,000 exercisers per year. The risk of sudden death during exercise in young individuals is much lower, because they do not have advanced CAD, and congenital cardiovascular problems are rare.36 In both young and old patients, sudden death related to exercise is more common in men than in women. Despite the low absolute risk of sudden cardiac death, the rate is considerably greater during exercise than it is at rest.34,35,37,38

Myocardial infarction. Exercise is also a potent trigger of MI. Between 4% and 20% of MIs occur during or soon after exertion,39-41 and the incidence of MI during exertion is 2 to 6 times greater than at rest. The relative risk is greater in people who do not exercise regularly.39,40 Among sedentary people, the relative risk of MI during vigorous exercise was found to be several times higher than that during less strenuous activity.40 Among individuals who exercised five times per week, the relative risk was only 2.4 times greater than at other times.39

Prodromal symptoms. Many "healthy" patients who have cardiac-related events experience symptoms that they ignore. Nausea, dizziness, and even chest discomfort preceded sudden death in 20 of 28 marathoners, yet participants continued running despite these symptoms.42 Such findings make it imperative that clinicians advise their patients about symptoms and that patients recognize any prodromal symptoms during exercise.

Cardiovascular risks of exercise testing. The risks depend primarily on which group is undergoing the test. Based on population studies43-45 and other data, the estimated risk of death is 1 per 10,000 tests, for MI it is 4 per 10,000, and for hospital admission it is 5 per 10,000. These event rates can be used to gauge exercise testing in the usual clinical setting among typical patients.46 The absolute figures for any facility will depend primarily on the patient mix.

Exercise-related events in CAD patients. Risk-benefit data exist for exercise training in patients with CAD. A meta-analysis47 revealed that participation in cardiac rehabilitation exercise programs reduced total mortality 20%, CV mortality 22%, and fatal reinfarctions 25% over 3 years but produced no significant difference in the 1-year rate of recurrent nonfatal infarctions. Animal models suggest that exercise training reduces ventricular fibrillation48 and increases myocardial ischemic tolerance.49

Nevertheless, risks are associated with vigorous exercise programs in patients with CAD.50 Two studies51,52 of rehabilitation programs and patient statistics suggest that cardiac arrest is 2 to 7 times more frequent than MI in patients with known disease. In contrast, the ratio of sudden death to MI in apparently healthy subjects is approximately 1:7,41 and the difference may reflect myocardial scarring in cardiac patients that increases the risk of ventricular fibrillation.

Nonatherosclerotic causes. Atherosclerotic CAD is the predominant cause of exercise-related MI and sudden cardiac death in adults, but not in young subjects. Of all patients with acute MI, 4% to 7% do not have atherosclerotic CAD.53-54 Nonatherosclerotic causes include anomalous coronary arteries, myocardial bridging, coronary artery vasculitis, infectious diseases, and structural and therapy-induced conditions (table 2).55-71

TABLE 2. Nonatherosclerotic Causes of Coronary Artery Disease55-71
Anomalous Coronary Artery Origin and Course
Myocardial bridging ("tunneled" epicardial arteries)
Ostial obstruction
Passage between pulmonary artery and aorta
Coronary Artery Vasculitis (Arteritis)
Polyarteritis nodosa
Systemic lupus erythematosus:
    Immune complex-mediated endothelial injury
    Thrombosis from antiphospholipid antibodies
    Premature accelerated atherosclerosis from
    glucocorticosteroid therapy
Infectious Disease-Derived Arteritis
Infective endocarditis
Salmonellosis
Syphilis
Kawasaki disease
Other Causes
Radiation therapy-induced coronary stenosis
Heart transplant-associated coronary arteriopathy
Coronary artery aneurysm
Metabolic disorders (eg, homocystinuria, amyloidosis)

Preexercise Screening and Evaluation for CAD

The major purpose of preparticipation cardiovascular screening is to identify persons with known cardiovascular disease, symptoms of cardiovascular disease, and risk factors.72,73 Screening also identifies people with known cardiovascular disease who should not participate in an exercise program or who should begin their regimen in a medically supervised program, as well as patients with other special needs.74,75

Screening tools. Even simple screening instruments such as the Physical Activity Readiness Questionnaire (PAR-Q, see below) can identify those at risk.76 Although the risks of MI and sudden death in exertion are low, it is reasonable to assume that cardiovascular screening, particularly in older individuals, will diminish adverse cardiovascular events during exercise.

The extent and practicality of preparticipation screening is an important consideration. For instance, exercise testing as a screening tool for all asymptomatic persons may lead to a high rate of false-positive findings77 and unnecessary diagnostic procedures. Moreover, exercise testing alone may not be capable of detecting individuals at risk for an acute adverse event. As a cautionary measure, an extremely thorough and mandatory screening process may also unnecessarily prohibit patients from participating in an exercise program and may discourage them from exercise and physical activity.

The American Heart Association (AHA) and the American College of Sports Medicine (ACSM) recommend two practical tools for preparticipation screening.73 The PAR-Q is a simple, self-administered questionnaire that addresses questions concerning symptoms that may suggest angina pectoris. If patients answer "yes" to one or more questions, they are encouraged to contact their physician before beginning an exercise program. The AHA and the ACSM Preexercise Screening Questionnaire is slightly more complex than the PAR-Q73 and uses history, symptoms, and risk factors (including age) to assess a patient's risk of a cardiovascular event. At-risk individuals are then encouraged to contact their healthcare provider before participation. High-risk individuals who wish to begin moderate-to-vigorous exercise are encouraged to begin in a supervised program.

Screening as policy. Cardiovascular screening of all new health club members is a prudent policy for facilities that have exercise equipment. Currently, preexercise screening is performed only sporadically.78 All exercise facilities must incorporate prescreening exercise health appraisals into their policies of operation. Prescreening is important for educating new members about the signs and symptoms of cardiovascular disease during exercise. Increasing public awareness might help individuals terminate exercise before an event. Without preexercise screening, it is impossible to determine whether a person may be at risk during exercise.73

Part of the responsibility for preparticipation health screening falls on the prospective participant. Individuals who have symptoms of or known cardiovascular disease, yet neglect to obtain the recommended medical evaluation, or those who fail to complete the health appraisal questionnaire, may be excluded from exercise at a health facility or athletic competition.

Risk Stratification and the Individual Patient

After an appropriate medical consultation, individuals can be classified for exercise training (table 3).73,74 Other issues also need to be considered. Comorbidities such as insulin-dependent diabetes mellitus, morbid obesity, severe pulmonary disease, complicated pregnancy, or debilitating neurologic or orthopedic conditions may constitute a contraindication to exercise or warrant closer supervision. Additional details may be found elsewhere.72

TABLE 3. Classification for Exercise Training for Patients With Coronary Artery Disease, Based on AHA and ACSM Standards
Class and Description (Subclass) Population Exercise Recommendations
A. Apparently healthy(A-1)



(A-2)

(A-3)		 Young patients



Older persons

Patients with <2 CV risk factors
and normal exercise tests		 Can engage in moderate and
vigorous exercise without exercise
testing or prior medical exam

May participate in moderate activity
without prior medical exam or
symptom-limited exercise test
B. Known stable CAD, low risk
for vigorous exercise but
slightly higher than for
apparently healthy persons		 Clinically stable patients with CAD,
valvular heart disease, congenital
heart disease, cardiomyopathy,
or exercise test abnormalities
that do not meet class C criteria		 Should have medical exam and a
maximal exercise test before
participating in moderate or vigorous
exercise; data from a medical
exam done within 1 yr acceptable
unless clinical status has changed
C. Moderate-to-high risk of
cardiac complications during
exercise, or those who are
unable to self-regulate activity
or understand the
recommended activity level		 Persons with CAD, acquired valvular
disease, congenital heart disease, cardio-
myopathy, exercise test abnormalities not
directly related to ischemia, previous
ventricular fibrillation or cardiac arrest not
occurring with acute ischemic event or
cardiac procedure, complex ventricular
arrhythmias that are uncontrolled at mild-
to-moderate work intensity with medication,
3-vessel or left main CAD, or ejection
fraction <30%		 Same as for class B
D. Unstable disease with
activity restriction		 Patients with unstable ischemia, uncompensated
heart failure, uncontrolled arrhythmias, severe
and symptomatic aortic stenosis, HCM or
cardiomyopathy from recent myocarditis,
severe pulmonary hypertension, or other
conditions that could be aggravated by
exercise (eg, resting systolic BP >200 or
resting diastolic BP >110 mm Hg, active
or suspected pericarditis)		 No activity recommended for
conditioning
AHA = American Heart Association; ACSM = American College of Sports Medicine; CV = cardiovascular; CAD = coronary artery disease;
HCM = hypertrophic cardiomyopathy; BP = blood pressure

Although the overall risk of cardiac events during physical exertion is elevated, the increase is small. However, an individual's risk may be high. To advise patients appropriately, therefore, physicians should understand the risks of exercise, have a strategy for identifying those at risk, and know the proper exercise modalities to minimize risk. In turn, patients should be familiar with their exercise tolerance, self-monitor during exercise, and heed individual warning symptoms.

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This article was adapted from the recently published book: Thompson PD (ed): Exercise and Sports Cardiology, New York City, McGraw-Hill Medical Publishing, 2001 (to order: 1-800-262-4729 [ISBN:0-07-134773-9]).

Dr Libonati is an assistant professor in the department of kinesiology at Temple University in Philadelphia. Dr Glassberg is an assistant professor of cardiology at Temple University School of Medicine in Philadelphia. Address correspondence to Joseph R. Libonati, PhD, 122 Pearson Hall, Temple University, Philadelphia, PA 19122-6096; address e-mail to jlibonat@astro.temple.edu.

Disclosure information: Drs Libonati and Glassberg disclose no significant relationship with any manufacturer of any commerical product mentioned in this article. No drug is mentioned in this article for an unlabeled use.

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