Cardiology

Exercise and Fitness in the Prevention and Treatment of CAD

I. Coronary Artery Disease: What every physician needs to know.

  • For literally millions of adults in the U.S., interventions that have been shown to reduce the risk of initial and recurrent cardiovascular events, collectively referred to as primary and secondary prevention, include regular aerobic exercise and/or increased cardiorespiratory fitness, expressed as metabolic equivalents (METs; 1 MET = 3.5 mL O2/kg/min).

  • Prospective cohort studies and randomized, controlled trials of patients with established coronary artery disease (CAD) have now shown that increased physical activity is associated with a statistically significant mortality risk reduction, the magnitude of which is similar to that observed with low-dose aspirin, statins, β-blockers, and angiotensin-converting enzyme (ACE) inhibitors after myocardial infarction.

  • A recent systematic review and meta-analysis of 33 physical activity studies (n = 888,372 participants) reported risk reductions of 30% to 50% for cardiovascular mortality and 20% to 50% for all-cause mortality.

  • A number of recent studies have expressed exercise capacity or cardiorespiratory fitness in the context of survival benefit per MET achieved, irrespective of gender, body mass index, major risk factors, or other comorbid conditions (e.g., diabetes, metabolic syndrome). These observations are noteworthy in that each 1-MET increase in exercise capacity was associated with large (8% to 35%) improvements in survival time. Participants with an exercise capacity ≥ 8.0 METs generally had the most favorable health outcomes, whereas those who attained <5.0 METs had the poorest prognosis.

  • The least fit, least active, population subset (commonly referred to as "the bottom 20%") is generally reported to be 2 to 5 times more likely to die during follow-up compared with their more fit counterparts. Thus, it appears that this "high-risk" cohort may especially benefit from exercise counseling and interventions to improve survival time.

  • Walk training programs can result in a substantial increase in exercise capacity (peak METs), reduce body weight and fat stores, and facilitate cardiovascular risk reduction in persons with and without CAD. Workloads (i.e., speed and/or grade) should be progressively increased to account for a conditioning bradycardia.

  • If the current mantra "exercise is medicine" is embraced, exercise has indications and contraindications, and underdosing and overdosing are possible. Although considerable epidemiologic and clinical evidence suggests that structured exercise, increased lifestyle physical activity, or both, may help to protect against and treat aging-related chronic diseases, the absolute and relative risk of cardiovascular, metabolic, and musculoskeletal complications appear to increase transiently during physical activity. Thus, exercise may have a typical dose-response curve with a plateau in benefit or even adverse effects, in some individuals, at more extreme levels.

  • Patients on beta-blockers can, during moderate-to-vigorous exercise, still achieve the increase in metabolic rate necessary for favorable long-term adaptation and improvement. Thus, patients with CAD who are treated with beta-blockers can still derive the expected enhancement of cardiorespiratory fitness during exercise training, regardless of the type of beta-blocker that is prescribed.

  • Long exercise sessions can be broken into shorter periods of activity (e.g., three 10- or 15-minute exercise bouts), yielding similar physiologic improvements provided the total volume of training (kilocalorie expenditure) is comparable. For many elderly, deconditioned, or functionally limited patients (e.g., congestive heart failure), multiple short bouts of moderate-intensity physical exercise, repeated throughout the day, may be better tolerated (i.e., interval training, a work-rest approach) than a single long bout.

  • Despite the well-established benefits of regular physical activity, a national survey found that only about one third of patients reported being counseled about exercise during their most recent physician office visit. The fervor of the physicians' recommendation appears to be the single most powerful predictor of exercise-based cardiac rehabilitation participation.

II. Diagnostic Confirmation: Are you sure your patient has Coronary Artery Disease?

Despite advances in cardiac imaging, the gold standard to confirm obstructive coronary artery disease remains invasive coronary angiography. In addition to traditional angiography, intravascular ultrasound and optical coherence tomography are used to characterize the morphology of coronary plaque; fractional flow reserve provides physiologic assessment of the coronary stenosis.

A. History Part I: Pattern Recognition:

Onset: Precipitated by exertion, emotional stress, or cold weather

Provocation or palliation: Improves with rest and sublingual nitroglycerin. No change with movement or palpation. Antacids and antiinflammatory agents do not improve symptoms

Quality: Pressure, heaviness, crushing pain

Radiation: From midsternum to neck/jaw, shoulders, left arm

Severity: Typically pain is not severe as patients modify their activities to stay comfortable; however, when symptoms arise, patients complain of moderate amount of discomfort resolving with rest + nitroglycerin

Timing: Progress over time from mild chest discomfort with moderate/heavy exertion (stable angina) to severe discomfort with minimal exertion or even at rest (unstable angina)

B. History Part 2: Prevalence:

Based upon data from the Framingham Heart Study, several traditional risk factors for coronary artery disease have been established:

  • Hypertension

  • Dyslipidemia (low HDL, elevated LDL)

  • Cigarette smoking

  • Diabetes mellitus

  • Family history of CAD

  • Advancing age

  • Male sex

  • Obesity/inactivity

C. History Part 3: Competing diagnoses that can mimic Coronary Artery Disease.

Musculoskeletal pain: Persistent, sharp pain, worse with inspiration and upper body movement. Reproducible with palpation. Does not worsen with exertion. Does not improve with nitroglycerin. Improves with antiinflammatory agents.

Pneumonia: Sudden onset of pleuritic-type chest pain associated with fevers and productive cough. No change with exertion. Does not improve with nitroglycerin. Usually there is fever, cough, and/or abnormal chest radiograph.

Pulmonary embolism: Sudden onset of pleuritic-type chest pain associated with dyspnea. May be associated with cough and/or hemoptysis. Usually there are identifiable risk factors for venous thromboembolism.

Pericarditis: Sudden onset, sharp, pleuritic-type chest pain, which improves when patient sits up and leans forward. Often associated with a friction rub on cardiac examination. Pathognomonic ECG changes involve widespread ST-elevation without reciprocal changes and P–R depression.

Aortic dissection: Sudden onset, severe tearing or ripping sensation in the chest or upper back. May be associated with unequal blood pressure in the upper extremities. Does not improve with nitroglycerin or antiinflammatory agents.

Esophagitis: Gradual onset, severe retrosternal burning chest pain radiating to the neck or throat. May improve with nitroglycerin if there is associated esophageal spasm. Improves with antacids. May worsen with nonsteroidal antiinflammatory agents.

Cholecystitis: Steady, severe pain located in the right upper quadrant radiating to the chest and right shoulder. Nausea, vomiting, and anorexia are associated. Worsens 1 hour after ingesting fatty foods. No change with exertion or nitroglycerin.

D. Physical Examination Findings.

Patients with chronic, stable coronary artery disease do not have any classic abnormal physical examination findings. The examination may, however, provide clues to the presence of atherosclerotic risk factors.

  • Hypertension: Fundoscopic (cotton-wool spots, hemorrhage, arteriovenous nicking) and cardiac (accentuated S2, presence of S4, and laterally displaced point of maximal impulse)

  • Dyslipidemia: Xanthelasma and corneal arcus

  • Diabetes mellitus: Retinopathy, neuropathy, foot ulcers

E. What diagnostic tests should be performed?

Stress tests

Exercise electrocardiogram

Patients with an intermediate pretest probability of obstructive CAD who are able to exercise to 85% of predicted maximal heart rate and without baseline ECG abnormalities (>1 mm ST depression at rest, preexcitation, LBBB, ventricular pacing).

Exercise echocardiogram

Patients with an intermediate pretest probability of obstructive CAD, who are able to exercise to 85% of predicted maximal heart rate, but with baseline ECG abnormalities or taking digoxin, to localize ischemia and/or to assess for viability. Advantages over stress nuclear MPI include: (1) less time, (2) able to assess for viability, (3) able to use intracardiac hemodynamics before and after stress, and (4) no radiation.

Exercise MPI

Patients with an intermediate pretest probability of obstructive CAD, who are able to exercise 85% of predicted maximal heart rate, but with baseline ECG abnormalities or taking digoxin to localize ischemia and/or to assess for viability. Advantages over stress echocardiography include: (1) higher sensitivity and (2) better assessment in patients with prior infarct.

Dobutamine echocardiogram

Patients with an intermediate pretest probability of obstructive CAD, with baseline ECG abnormalities or taking digoxin, who are unable to exercise to 85% of predicted maximal heart rate. Advantages over vasodilator stress testing include: (1) safety in patients with bronchospasm or chronic obstructive pulmonary disease and (2) easily reversed with beta-blocker therapy.

Vasodilator stress testing

Patients with an intermediate pretest probability of obstructive CAD, with baseline ECG abnormalities or taking digoxin, who are unable to exercise to 85% of predicted maximal heart rate. Preferred test in patients with recent acute coronary syndrome, hemodynamic instability, or electrical instability when compared with dobutamine.

Cardiopulmonary stress test

By measurement of gas exchange, this test provides accurate information about the ability to use oxygen and to determine functional capacity. Allows for the assessment of exercise capacity, response to heart failure therapy in patients being evaluated for cardiac transplantation, differentiates between cardiac and pulmonary causes of exercise-induced dyspnea or impaired exercise capacity, and can help predict preoperative risk. Key variables include: VO2 peak (METs); respiratory exchange ratio (RER; VCO2/VO2); the ventilatory-derived anaerobic threshold; carbon dioxide production (VCO2); minute ventilation (VE); and the VE/VCO2 slope.

Coronary CT angiogram (CCTA)

In low-to-intermediate risk patients presenting with acute chest pain syndrome with a nonischemic electrocardiogram and negative biomarkers, CCTA can rule out obstructive coronary artery disease. In intermediate risk patients with inconclusive or discordant stress testing (ischemic ECG with normal imaging or vice-versa), CCTA can exclude obstructive coronary disease. Furthermore, CCTA is useful in determining bypass graft patency. CCTA is not useful in high-risk patients, patients with known CAD, or in patients with prior percutaneous coronary intervention.

Invasive cardiac angiography

Indications for invasive coronary angiography include:

  • ST elevation myocardial infarction

  • Non-ST elevation myocardial infarction <72 hours

  • Intermediate- or high-risk patients presenting with chest pain or acute coronary syndrome

  • CCS class III to IV angina on optimal medical therapy

  • High-risk criteria on stress testing regardless of angina severity

  • Unexplained left ventricular systolic dysfunction

  • Patients who cannot undergo stress testing with high suspicion of coronary disease

  • Patients whose occupation involves safety of others (pilots, bus drivers, etc.) with abnormal stress test

What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

In adults without documented coronary artery disease or diabetes mellitus who are undergoing evaluation for CAD, determination of Framingham risk is appropriate to estimate 10-year risk of myocardial infarction. To calculate Framingham risk, physicians need age, gender, total cholesterol, HDL cholesterol, smoking status, and systolic blood pressure. Obtaining a cholesterol panel is needed to make this assessment.

III. Management.

Structured exercise training sessions should include a preliminary aerobic warm-up (approximately 10 minutes), a continuous or accumulated conditioning phase (≥ 20 to 30 minutes or multiple 10- to 15-minute moderate-to-vigorous intensity exercise bouts), and a cool-down (5 to 10 minutes), followed by stretching activities. The most effective exercises for the conditioning phase include walking, jogging, stationary or outdoor cycling, swimming, rowing, stair-climbing, and combined arm-leg ergometry.

To promote and maintain health, adults need moderate-intensity aerobic (endurance) physical activity for a minimum of 30 minutes on 5 days each week or vigorous-intensity aerobic physical activity for a minimum of 20 minutes on 3 days each week. Combinations of moderate- and vigorous-intensity activity can be performed to achieve this recommendation. Moderate-intensity aerobic activity, which for many middle-aged and older adults corresponds to a brisk walk, can be accumulated toward the 30-minute minimum by performing bouts each lasting 10 or more minutes.

The threshold or minimal effective intensity for improving cardiorespiratory fitness in unfit and fit individuals with and without CAD is lower than previously thought, approximating 30% to 45% of the oxygen uptake reserve or approximately 60% to 69% of the highest heart rate achieved during peak or symptom-limited exercise testing. Over time, the exercise intensity should be increased to 50% to 80% of the oxygen uptake reserve (or maximal heart rate reserve) to further increase cardiorespiratory fitness. Nevertheless, because symptomatic or silent myocardial ischemia may be highly arrhythmogenic, the target heart rate for endurance exercise should be set safely below (≥ 10 beats per minute) the ischemic ECG or anginal threshold.

There are several adjunctive methodologies to regulate the exercise intensity, including the Borg rating of perceived exertion scale. The Borg category scale consists of 15 grades, from 6 to 20; 6, seated or standing rest; 7, very, very light; 9, very light; 11, fairly light; 13, somewhat hard; 15, hard; 17, very hard; and, 19, very, very hard. Exercise rated as 11-14, which generally approximates a moderate-to-vigorous intensity, should serve to maintain and enhance health and cardiorespiratory fitness.

The Rule of 2 and 3 Miles per Hour (mph). Because most patients prefer to walk at moderate intensities, it is helpful to recognize that walking on level ground at 2 and 3 mph speeds approximates 2 and 3 METs, respectively. At a 2-mph walking speed, each 3.5% increase in treadmill grade adds approximately 1 MET to the gross energy cost. For patients who can negotiate a 3-mph walking speed, recognize that each 2.5% increase in treadmill grade adds 1 additional MET to the gross energy expenditure. For example: 2 mph, 7% grade = 4 METs; 3.0 mph, 7.5% grade = 6 METs.

Structured exercise should be complemented by upper body and resistance training, calisthenics to enhance flexibility, and increased lifestyle physical activity (e.g., parking the car farther away from stores when shopping, avoiding elevators/escalators, walk breaks at work). Using a pedometer can be helpful in tracking daily step totals. According to one systematic review, pedometer users in varied exercise interventions significantly increased their physical activity by an average of approximately 2,500 steps per day more than their control counterparts.

Too much sitting, independent of structured, leisure-time physical activity, is associated with higher rates of all-cause and cardiovascular mortality, obesity, type 2 diabetes, and metabolic syndrome, as well as other physiologic derangements. In addition to the promotion of moderate-to-vigorous structured physical activity and increased lifestyle activity, physicians should discourage sitting for extended periods (or too few breaks from sitting). Breaks may include standing, light activities, stair climbing, walking, or combinations thereof.

A. Immediate management.

  • Prolonged bed rest as advocated before the 1950s is no longer recommended in the care of uncomplicated and clinically stable patients with acute myocardial infarction (AMI).

  • Extended bed rest has been shown to result in physiologic deconditioning, resting tachycardia, reduced cardiorespiratory fitness, and other consequences (e.g., muscle atrophy, orthostatic intolerance, depression).

  • Early mobilization after AMI (e.g., chair rest, encouragement of self-care activities) has been shown to be associated with numerous physiologic, psychological, and economic benefits, as well as a reduced mortality rate.

  • Exposure to simple orthostatic or gravitational stress, such as intermittent sitting or standing, during hospitalization and early convalescence, may prevent much of the deterioration in cardiorespiratory fitness that normally follows AMI.

  • Structured, formalized in-hospital exercise programs after AMI appear to offer little additional physiologic or behavioral benefits over routine medical care.

B. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Favorable physiologic adaptations to chronic endurance exercise include a decreased heart rate and systolic blood pressure at rest and at any given submaximal workload, and increased cardiorespiratory fitness. Simple serial measures of the resting heart rate can be used to provide evidence of a conditioning bradycardia.

We have employed both submaximal and peak or symptom-limited exercise testing to assess serial changes in cardiorespiratory fitness. Submaximal testing is particularly easy to administer and requires no medical supervision. The baseline exercise test protocol is followed, facilitating a comparison of the heart rate, blood pressure, and rating of perceived exertion at standard submaximal workloads (e.g., 1.7 mph, 0%; 1.7 mph, 5%; 1.7 mph, 10% grade). The endpoint of the test is that work load at which the upper limit of the prescribed target or training heart rate has been achieved. Aerobic capacity can be estimated by plotting the submaximal or minitest heart rate versus work load (i.e., MET) relationship, extrapolated to the peak heart rate attained on initial exercise testing. Each 10 bpm reduction in heart rate at a given submaximal workload approximates a 1 MET increase in aerobic capacity.

Field tests are commonly used to predict aerobic capacity, expressed as mL O2/kg/min or as METs. These tests involve endurance walks or runs over level terrain designed to either (1) cover a fixed distance (such as 1 or 1.5 miles) with time as the criterion measure, or (2) measure the distance covered in a fixed period of time (such as 6 or 12 minutes). One widely used, validated walking test (1 mile) incorporates several predictor variables, including age, gender, walk time, and heart rate response, where aerobic capacity (VO2max, mL O2/kg/min) = 132.853 – 0.1692 (body mass in kg) – 0.3877 (age in years) + 6.315 (gender) – 3.2649 (time in minutes) – 0.1565 (HR); gender = 0 for female, 1 for male; heart rate (HR) is taken at end of walk.

Simple questionnaires, such as the Duke Activity Status Index and the Veterans Specific Activity Questionnaire can also be used to estimate an individual's functional capacity.

C. Long-term management.

  • Serial exercise testing permits evaluation of the following variables: the body's aerobic capacity (peak METs); hemodynamics (assessed by the heart rate and systolic/diastolic blood pressure responses during and after exercise); limiting clinical signs or symptoms; and associated changes in electrical functions of the heart, especially supraventricular and ventricular arrhythmias and ST-segment displacement.

  • Limitation. A major limitation of exercise testing is that ischemic ST-segment depression, anginal symptoms, or both, require the presence of a flow-limiting coronary lesion, whereas most acute cardiac events in previously asymptomatic subjects are due to vulnerable plaque disruption at mild-to-moderate coronary stenoses (<70% obstruction). Consequently, an exercise stress test with or without concomitant myocardial perfusion imaging can be "normal" despite the presence of coronary plaque that may rupture.

D. Common Pitfalls and Side-Effects of Management

Strenuous physical exertion, especially when it is sudden, unaccustomed, or involving high levels of anaerobic metabolism, appears to transiently increase the risk of AMI and sudden cardiac death in susceptible individuals. Nevertheless, the absolute risk of exertion-related cardiovascular events is small.

Acute exercise-induced cardiovascular events, while representing potentially catastrophic complications, are far less common than musculoskeletal injuries such as strains, sprains, and fractures. According to the National Health Interview Survey, sports, recreational, and exercise-related injuries account for approximately 2.0 to 2.5 million hospital visits each year, with men experiencing a twofold to threefold greater number of injuries each year.

Metabolic and pulmonary complications appear to increase transiently during strenuous physical activity compared with the risk at other times. Because exercise has an insulin-like effect, hypoglycemia is the most common problem experienced by exercising diabetics who take exogenous insulin or, to a lesser extent, oral hypoglycemic agents. Moreover, diabetic neuropathies can alter cardiovascular, skin blood flow, and sweating responses to exercise in hot/humid environments, increasing the risk of heat injury.

Many patients with moderate-to-severe asthma or chronic obstructive pulmonary disease may experience an exacerbation of pulmonary symptoms during exercise due to ventilatory limitations and/or oxygen desaturation. In patients in whom reactive airway disease is suspected or asthma has been documented, exercise-induced bronchoconstriction frequently occurs.

IV. Management with Co-Morbidities

Hypertension

Frequency: 3-7 days/week; Duration: 30-60 minutes/session; Intensity: 40%-70% peak METs; Caloric expenditure: 700-2000 kcal/week; Resistance training should involve lower resistance with higher repetitions (e.g., 15 reps/set).

Diabetes

Frequency: 4-6 days/week, or daily at low to moderate intensity; Duration: 20-60 minutes/session; Intensity: 50%-85% peak METs; Type 2 diabetes: maximize caloric expenditure, if obese; May need to use perceived exertion as an adjunct to heart rate for monitoring exercise intensity.

Obesity

Frequency: 5 days/week or daily; Duration: 40-60 minutes/session (or 2 sessions/day of 20-30 minutes); Intensity: 40%/50%-70% peak METs, initially emphasize increasing duration rather than intensity with goal of optimizing caloric expenditure; Use low-impact modes of activity; Resistance training may serve as a valuable adjunct to aerobic training.

V. Patient Safety and Quality Measures

A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patient safety and quality measures

Recommendations to potentially reduce the risk of exercise-related complications include:

  • Encourage sedentary individuals to initially engage in regular walking so as to move them out of the least fit, least active, "high-risk" cohort

  • Counsel inactive individuals to avoid unaccustomed, vigorous to near-maximal physical activity (e.g., racquet sports, snow shoveling)

  • Advocate appropriate warm-up and cool-down

  • Promote education of warning signs/symptoms (e.g., chest pain or pressure, lightheadedness, heart palpitations/arrhythmias)

  • Emphasize strict adherence to prescribed training pulse rates

  • Use continuous or instantaneous ECG monitoring in selected coronary patients;

  • Minimize competition and modify recreational games to decrease the energy cost and heart rate response to play

  • Adapt exercise to the environment (e.g., because heart rate increases disproportionately in hyperthermic conditions, a reduced exercise intensity should be employed)

  • Gas exchange may be impaired during exercise in some patients with respiratory disease (e.g., a decrease in the percent saturation of arterial oxygen of ≥ 4% is considered abnormal)

  • Avoid exercise if the glucose level is below 100 mg/dL or above 300 mg/dL (or greater than 240 mg/dL with urinary ketone bodies). Physical activity may be undertaken in insulin-dependent diabetics with low blood sugar, provided that 20 to 30 grams of additional carbohydrate is ingested before exercise.

Appropriate prophylaxis and other measures to prevent readmission

Contemporary studies now suggest that multifactorial risk-factor modification—especially smoking cessation and more intensive measures to control hyperlipidemia—may slow, halt, and even reverse (albeit modestly) atherosclerotic coronary artery disease. Although regular exercise and/or improved cardiorespiratory fitness are highly effective in reducing initial and recurrent cardiovascular events, these should be complemented by comprehensive risk reduction strategies for patients with known or suspected CAD. These can be summarized as the "ABCDESs" of primary and secondary prevention. Each letter represents one or more specific interventions: Antiplatelet agents/anticoagulants; ACE inhibitors post-MI; Beta-blockers; Blood pressure control; Cholesterol management; Diabetes management; Diet; Exercise; Social support; Stop smoking; Stress series.

B. What's the Evidence for specific management and treatment recommendations?

Patel, MR, Dehmer, GJ, Hirshfeld, JW, Smith, PK, Spertus, JA. " ACCF/SCAI/STS/AATS/AHA/ASNC/HFSA/SCCT 2012 appropriate use criteria for coronary revascularization focused update". J Am Coll Cardiol. vol. 59. 2012. pp. 857-881.

Hendel, RC, Berman, DS, Di Carli, MF, Heidenreich, PA, Henkin, RE, Pellikka, PA, Pohost, GM, Williams, KA. " ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging". J Am Coll Cardiol. vol. 53. 2009. pp. 2201-29.

Taylor, AJ, Cerqueira, M, Hodgson, JM, Mark, D, Min, J, O'Gara, P, Rubin, GD. " ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for cardiac computed tomography". J Am Coll Cardiol. vol. 56. 2010. pp. 1864-94.

Wilson, PWF, D'Agostino, RB, Levy, D, Belanger, AM, Silbershatz, H, Kannel, WB. " Prediction of coronary heart disease using risk factor categories". Circulation. vol. 97. 1998. pp. 1837-47.

(The articles listed above are outstanding recent reviews of criteria for coronary revascularization, radionuclide imaging, cardiac computed tomography, and risk stratification methodologies for patients with suspected coronary artery disease.)

Iestra, JA, Kromhout, D, van der Schouw, YT, Grobbee, DE, Boshuizen, HC, van Staveren, WA. " Effect size estimates of lifestyle and dietary changes on all-cause mortality in coronary artery disease patients: a systematic review". Circulation. vol. 112. 2005. pp. 924-34.

(This review highlights the fact that lifestyle and dietary modification in coronary patients compare favorably with the mortality reductions reported for low-dose aspirin, statins, beta-blockers, and ACE inhibitors after AMI.)

Convertino, VA. " Effect of orthostatic stress on exercise performance after bed rest: relation to inhospital rehabilitation". J Cardiac Rehabil. vol. 3. 1983. pp. 660-3.

(This article highlights the beneficial role of regular orthostatic stress in attenuating the pronounced decrease in aerobic capacity (VO2 peak) that normally accompanies prolonged bed rest.)

Barnard, RJ, MacAlpin, R, Kattus, AA, Buckberg, GD. " Ischemic response to sudden strenuous exercise in healthy men". Circulation. vol. 48. 1973. pp. 936-42.

(In this classic report, healthy men subjected to sudden strenuous exertion often [2/3 of the time] demonstrated ischemic exercise ECGs, frequent ventricular ectopy, or both, despite normal responses to peak or symptom-limited progressive exercise testing.)

Swain, DP, Franklin, BA. "VO2 reserve and the minimal intensity for improving cardiorespiratory fitness". Med Sci Sports Exerc. vol. 34. 2002. pp. 152-7.

Swain, DP, Franklin, BA. "Is there a threshold intensity for aerobic training in cardiac patients?". Med Sci Sports Exerc. vol. 34. 2002. pp. 1071-5.

(The above two analyses demonstrated the minimal or threshold intensity for improving aerobic capacity in fit and unfit individuals, as well as patients with coronary artery disease.)

Nocon, M, Hiemann, T, Müller-Riemenschneider, F, Thalau, F, Roll, S, Willich, SN. "Association of physical activity with all-cause and cardiovascular mortality: a systematic review and meta-analysis". Eur J Cardiovasc Prev Rehabil. vol. 15. 2008. pp. 239-46.

(A recent systematic review and meta-analysis of 33 physical activity studies (n = 883,372 participants) reported risk reductions of 30% to 50% for cardiovascular mortality and 20% to 50% for all-cause mortality.)

American College of Sports Medicine: American College of Sports Medicine's Guidelines for Exercise Testing and Prescription. Lippincott Williams & Wilkins. 2000.

(One of the most widely cited references in the field, updated every 5 to 7 years, on the rationale for and methodology associated with exercise testing and prescription.)

Franklin, BA. "Walking: the undervalued prescription". Prev Cardiol. vol. 9. 2006. pp. 56-9.

(This article highlights the role of brisk walking in improving health and cardiorespiratory fitness, with specific reference to the associated physiologic adaptations, the advantages of walking over more vigorous forms of exercise, and the prescription rule of 2 and 3 mph.)

Borg, GA. " Psychophysical bases of perceived exertion". Med Sci Sports Exerc. vol. 14. 1982. pp. 377-81.

(This is a seminal article highlighting the physiologic basis for the methodology underlying the Borg scales for perceived exertion [i.e., category and category-ratio scales]).

Pratt, CM, Welton, DE, Squires, WG, Kirby, TE, Hartung, GM, Miller, RR. " Demonstration of training effect during chronic beta-adrenergic blockade in patients with coronary artery disease". Circulation. vol. 64. 1981. pp. 1125-9.

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