Exercise: The ultimate treatment to all ailments?

Abstract Extensive clinical research has provided robust evidence that exercise is a cost‐effective measure to substantially alleviate the burden of a large number of diseases, many of which belong to the cardiovascular (CV) spectrum. In terms of cardiac benefit, the positive effects of exercise are attributed to improvements in standard risk factors for atherosclerosis, as well as to its positive impact on several pathophysiological mechanisms for CV diseases. For secondary prevention, exercise, optimally in the context of a cardiac rehabilitation program, has been shown to improve functional capacity and survival. Clinicians should encourage physical activity and provide exercise recommendations for all patients, taking into consideration any underlying pathology. In the present review, the benefits of exercise for the prevention and treatment of major CV risk factors and heart conditions are analyzed.


| INTRODUCTION
The notion that exercise is important for well-being, health, and longevity has been documented throughout history and all over the world. 1 Susruta, an Indian physician who lived during 600 Before Common Era (BCE) was the first healer who prescribed exercise and advised that the regimen should be performed daily and be of half the extent of the patient's capacity. Hippocrates  identified the joined importance of food and exercise and was the first physician to prescribe exercise in written form for a patient "suffering from consumption." Bernardino Ramazzini, the father of occupational medicine, noted that professional messengers were generally healthier compared to those with sedentary jobs such as tailors. Since the seminal studies from the 1950s, a burgeoning amount of evidence has accumulated, supporting exercise as a highly cost-effective measure for the prevention and treatment of disease. Currently, exercise has been shown to be capable of preventing over 35 chronic conditions, many of which are within the cardiovascular (CV) spectrum, as well as of reducing CV and allcause mortality. 2 Despite the world-wide strategies to promote sufficient physical activity (PA) at a population level, adoption rates of a physically active lifestyle have been far from ideal. It is estimated that one in five adults lack acceptable PA and that only half the population in developed countries follow the widely applied recommendation of a minimum of 150 minutes of moderate-intensity exercise weekly. 3 Physical inactivity is a principal contributor to the global burden of disease. Calculations of population-attributable fractions have shown that PA not meeting current recommendations is the cause of 6% of the burden of coronary artery disease (CAD), 7% of type 2 diabetes mellitus (T2DM), and 9% of premature death. 4 Exercise may protect against certain cancers such as breast, colon, prostate, and pancreatic cancer. It also reduces rates of osteoporosis and hip fractures, dementia, anxiety and depression. The importance of exercise for CV protection is supported by mostly epidemiological data in the setting of primary prevention and randomized clinical study data in the setting of secondary prevention. 5 In the present article, the current evidence of the associations of exercise with CV outcome will be reviewed. The benefits of exercise for the prevention and treatment of major CV risk factors and conditions will be analyzed.

| TERMINOLOGY AND CLASSIFICATION BASICS
A number of different terms related to PA have been examined in clinical research relating to CV and non-CV outcomes (Table 1). 2 Sedentarism refers to prolonged periods of minimal energy expenditure associated with common practices such as television viewing and time on the computer. PA is any leisure or occupational activity that is accompanied by an increase in energy expenditure compared to the resting state. Exercise is PA that is planned and structured with the goal of promoting fitness and health. PA and exercise lead to improvements in physical and cardiorespiratory fitness (CRF), an effect that is also modulated by genetic factors. 7 Classification of exercise is largely based on the principal form of energy production, the extent of body movement, the participating muscles, and the main benefitting component of physical fitness. 6 Dynamic or isotonic exercise refers to the purposeful activity with repetitive movement of large muscles groups and joints that leads to substantial elevations in heart rate and expenditure of energy (eg, jogging, skiing, bicycling, and swimming). Static or isometric exercise is the contraction of muscles without movements of the joints. Resistance (strength) exercise is performed against an opposing force in order to improve muscular strength and/or endurance. It may be dynamic with changes in the length and tension of muscles (eg, weight-lifting, circuit training, and elastic resistance bands) or static (eg, handgrip and plank position). Exercise sessions and their load are defined by their duration, frequency, intensity, and weekly volume.
Intensity of exercise is traditionally defined by percentage of peak heart rate or peak oxygen consumption. For ease of patient communication, mild activity would allow singing, moderate activity would allow speaking, and vigorous activity would allow only a few words to be exhaled (the so-called talk test). An exercise session is defined as aerobic or anaerobic based on the availability of oxygen for production of energy required for muscle contraction. Energy expenditure is generally expressed as Metabolic Equivalent of Task (MET) where 1 MET is energy expenditure at rest and equates to a peak oxygen consumption of 3.5 mL/min/kg. Energy expenditure of 3-5.9 MET defines moderate-intensity exercise and of >6 METs defines vigorous exercise. A proposed method to quantify aerobic exercise volume is to calculate the MET score by multiplying the frequency and duration per week of exercise by the intensity of exercise in MET. Current guidelines recommend approximately 7.5 MET-hours/week of exercise. 8 The most studied training modality is continuous exercise training, characterized by predominantly dynamic, moderate-intensity exercise at a constant workload for a prolonged period of time. This modality has been shown to effectively improve maximum work capacity and reduce mortality in health and CV disease. High-intensity interval training (HIIT) has been derived from standard athletic training programs and has emerged as one of the fastest growing exercise programs in recent years. A typical session consists of four to six repeated, short (1-4 minutes) bouts of vigorous effort interspersed Terminology related to physical activity 2,6 Term Definition Examples/components

Sedentary behavior
Waking behavior with energy expenditure ≤1.5 metabolic equivalents of task while in seated, reclined, or lying posture.
Television viewing, computer use, video games, lying in bed, sleeping, etc.
Physical activity Any bodily movement produced by the contraction of skeletal muscles, which increases energy expenditure above the basal level of the resting state.
Household and occupational activities; commuting; gardening; dancing; exercise and sports, etc.
Physical inactivity Physical activity levels less than those recommended for optimization of health and prevention of premature disease and death.
-Exercise A subset of physical activity that is repetitive, planned, structured, and often goal-oriented, intending to promote physical fitness and health.
Aerobic and endurance exercise; and resistance exercise.
Exercise training A subsidiary of exercise that denotes physical activity performed during leisure time, targeting the improvement or maintaining of physical fitness and performance.
-Physical fitness An individual's attribute resulting from physical activity and exercise and denoting the ability to carry out standard physical tasks without undue fatigue, and sufficient energy to enjoy leisure-time activities and respond to emergencies.
Muscular strength; power, and endurance; cardiorespiratory endurance and fitness; flexibility; balance; speed of movement; and reaction time.

Sports
An activity involving physical exertion, coordination, and skill that is mastered through planned and vigorous training and is performed for improvement in physical fitness, entertainment or competition.

Athlete
An individual performing regular exercise training (for an arbitrarily defined volume of at least 4 to 5 h a week) in one or more sports disciplines in order to participate in competitive events at an amateur or professional level.
Power, endurance, skill, and mixed. cise, with an optimal benefit in terms of longevity and protection from CV events expected in three to five times as much for either. 5,8,9 Little exercise is better than none and even simple standing exhibits a dose-response relationship with lower rates of mortality. 18 Similarly, moderate or vigorous exercise that is below the recommended volume by current guidelines is still associated with lower rates of CV and all-cause mortality. There is a curvilinear relationship between aerobic exercise volume and CV risk, where at the lower end of PA levels even small increases lead to large reductions in risk, while at the higher end there is a progressive decrease in the amount of benefit achieved. 9 Exercise inevitably improves CRF, which is optimally evaluated by measurement of peak VO2 during cardiopulmonary exercise testing but may also be assessed by exercise time, maximum power output and other exams such as the 6-minute walk test. CRF is actually a stronger predictor of outcome compared to PA or exercise training, as evident in studies in healthy populations and populations with or at risk of CV disease. 19 A decrease in CV and all-cause mortality risk ranging from 10% to 25% per 1 MET increase in exercise capacity has been observed in healthy individuals, and those with multiple risk factors or established CV disease and independently of gender, age or race. 12,13,20 The association between CRF and mortality may be curvilinear, as is the case with exercise.

| RISK FACTORS
The beneficial effect of exercise on CV outcome is primarily through modulation of standard CV risk factors for atherosclerosis including hypertension (HTN), diabetes, dyslipidemia, and obesity. 21 More than two-thirds of the expected risk reduction related to exercise seems to arise from improvements in these classic risk factors (Figure 1). In addition, individuals who exercise regularly would be expected to be leading a healthy lifestyle that includes abstaining from smoking. An acute bout of exercise has been shown to effectively reduce the urge of smoking in both men and women. 22 The benefits of exercise on traditional CV risk factors are described below.

| Hypertension
The effectiveness of exercise in reducing BP is evident from the phe- with HTN or high normal BP. 24 Twenty-four-hour BP evaluations in hypertensive individuals reveal that aerobic training has a greater impact on daytime rather than night time systolic BP. 25 In patients with resistant HTN, an aerobic exercise program has been shown to decrease ambulatory BP by 6/3 mmHg. 26 Isometric and resistance exercise were previously approached with skepticism in hypertensive patients due to fear of an exaggerated BP response, increases in arterial stiffness and further deterioration of HTN. In recent years, it has been shown that these are safe exercise modalities for hypertensive patients that also lower BP but perhaps to a lower extent compared to aerobic training. However, a metaanalysis of 64 controlled studies of moderate-intensity dynamic resistance training in patients with pre-HTN showed a BP-lowering effect comparable to aerobic exercise, and also identified a dose-response effect that was greater in individuals with a higher resting BP and in populations who were not taking antihypertensive drugs. 27 In another large meta-analysis of 93 randomized controlled trials attempting a head-to-head comparison of the effects of different types of exercise, it was shown that endurance, dynamic resistance, and isometric resistance training lower both systolic and diastolic BP, with the effect being more evident for isometric exercise; however, the conclusions were based on a relatively small number of studies including isometric exercise. 28 Resistance exercise is recommended two to three times per week in the current HTN guidelines, but these recommendations may be refined in the future with more accumulating evidence. 24 Regular exercise is also effective in preventing HTN, with some data supporting that higher exercise loads are associated with lower rates of developing HTN. In a meta-analysis of 29 studies on over 3000 normotensives, it was shown that the risk of HTN decreased by 6% for every 10 METs of task hours/week increase in leisure-time PA. 29 In the same study a similar risk reduction was observed in individuals meeting the standard exercise recommendations compared to inactive participants. Along these lines, a hypertensive BP response to exercise has been associated with a higher risk of HTN, target organ damage, and a worse CV outcome. Regular aerobic exercise and increased fitness have been shown to ameliorate this phenomenon in various populations including treated hypertensive patients. 30 It is self-explanatory that the estimated BP-lowering effect of exercise in patients with HTN is also associated with significant improvements in CV outcomes. A decrease in BP of 6 to 7 mmHg would translate to a CV risk reduction of up to 20% to 30%. Accordingly, exercise capacity has been associated with lower mortality in both prehypertensive and hypertensive individuals. Even among older F I G U R E 1 Cardiovascular effects of exercise. Regular exercise is accompanied by diverse beneficial effects in virtually all pathways associated with atherosclerosis and cardiovascular diseases. Reduction in primary and secondary cardiovascular risk is achieved primarily by improvements in classic risk factors, but also through alternate mechanisms such as autonomic modulation and anti-inflammatory protection hypertensive individuals, every 1-MET increase in exercise capacity is associated with an 11% lower risk of death. 31

| Lipid metabolism
Aerobic exercise has been associated with a beneficial effect on lipoprotein levels in both normolipidemic and hyperlipidemic individuals, even though the overall effect is small and concurrent weight loss may have contributed in the positive findings of some of the relevant studies. Beneficial effects have been noted mostly for high-density lipoprotein-cholesterol (HDL-C) levels but also for low-density lipoprotein-cholesterol (LDL-C) particle size and apolipoprotein B and triglyceride levels. 32 The combination of exercise with dietary changes provides greater reductions in LDL-C compared to either measure alone. Exercise volume rather than intensity seem to be better associated with lipid changes. It has been estimated that the minimal exercise volume in order to increase HDL-C level is 900 kcal of energy expenditure or 120 minutes of exercise per week. 33

| Insulin sensitivity and diabetes mellitus
Regular leisure-time activity of different intensities has been associated with a 25% to 40% reduction in the risk of T2DM. 17 Similarly, each 1 MET higher CRF has been associated with an 8% lower risk of T2DM. 36

| Obesity
Regular PA protects against weight gain throughout life, maintains long-term weight loss and preserves lean body mass during caloric restriction. 42 Long-term exercise also seems to result in larger reductions in predominantly abdominal fat. 43 Nevertheless, meta-analyses that have examined the effects of exercise on weight loss have shown that both high or low intensity exercise were associated with only modest reductions in weight (by about 1.5 Kgr). 44 Even when added to caloric restriction the additional effect of exercise on weight loss remains limited. Of note, it has been shown that CRF modulates the association of weight with mortality, and obese but fit individuals exhibit similar survival to individuals with normal weight. 45

| CV CONDITIONS AND SECONDARY PREVENTION
In the setting of secondary prevention, multiple studies have shown that PA and exercise as well as CRF reduce the risk of new CV events.
Exercise may be performed at home, in community facilities or, ideally, in the context of a cardiac rehabilitation program. 5 The latter provides the foundations for structured exercise prescription combined with lifestyle advice and psychosocial support. Resistance exercise should be included in the training routine in order to maintain muscle mass and strength, further reduce body fat, increase CRF and improve quality of life. 46

| Coronary artery disease
Lack of PA is an independent predictor for CAD development. In a case control study evaluating multiple CV risk factors for acute myocardial infarction (MI) across 52 countries, regular exercise was associated with a 14% lower risk of MI among men and women of all age groups and ethnicities. 47

| Heart failure
Historically, exercise was prohibited in patients with HF due to fear of haemodynamic compromise. Since the 1980's, a large set of evidence has been accumulated that supports exercise as a strong preventive, prognostic, and therapeutic modality in HF both in the setting of primary and secondary prevention. PA is associated with a lower risk of HF across a wide range of body weights and independently of comorbidities. 55 68 The protective effect of exercise for AF may disappear and actually reverse with long-term, high-volume endurance training. Atrial dilatation, pulmonary vein stretch and induction of profibrotic pathways have been suggested as potential mechanisms for this observation. Of note, atrial enlargement with normal or supranormal atrial mechanics is considered to be a feature of the athlete's heart that results from increased cardiac output and volume overload and is not associated with a higher prevalence of supraventricular arrhythmias. 69 In patients with AF, exercise is safe, as long as sufficient rate control has been achieved, and it has been shown to improve AF-related symptoms, exercise tolerance, and quality of life. Exercise may also have a favorable effect on AF burden and AF recurrence, while more study data are needed regarding the optimal training regimen as well as the effects on hard endpoints in these patients. 70 More recently, in a randomized controlled trial in patients with either paroxysmal or persistent AF, 12 weeks of aerobic HIIT was associated with significant improvements in time in AF, exercise capacity and left atrial and ventricular function. 71 6 | CAN TOO MUCH EXERCISE HARM THE HEART?
There are emerging studies reporting a J-shaped relationship between exercise dose and CV morbidity and mortality. Some studies have also shown there are diminishing returns beyond an exercise capacity of 12 METs. 72,73 Small studies in lifelong endurance athletes have revealed evidence of coronary artery calcification (CAC) in almost 1 in 5 master male athletes and myocardial fibrosis in approximately 1 in 10 master male athletes. 74 Coupled with an increased prevalence of AF, there is a possibility that the stresses of lifelong intensive exercise may have a potentially deleterious effect in some individuals with a previously normal heart in male athletes, as the same has not been reported in master female athletes. Short-and medium-term studies have failed to show any association with increased CAC and CV mortality but larger prospective studies are required to understand why one man's high may represent another man's poison. 75

| CONCLUSIONS
The strong assets of regular moderate exercise are its free availability at low cost and its simultaneous benefits for preventing and improving several cardiac diseases. Integration of exercise in the daily routine of all individuals is essential to improve global health. It is important to emphasize that current evidence suggest that exercising for three to five times the current recommendations is the ideal dose for maximum benefit to prevent several CV diseases, although even 1 hour per week of exercise is associated with a health benefit. Some individuals engaging in lifelong endurance exercise show a high prevalence of CAC, myocardial fibrosis and AF, the long-term significance of which is uncertain. Overall regular exercise is associated with a significant reduction in CV morbidity and mortality and longevity of an additional 2 to 7 years of life.