Recent Trials Regarding Exercise and Cardiovascular Outcomes

Lifestyle-related risk factors can prevent or promote atherosclerotic cardiovascular disease (ASCVD). Thus, management of lifestyle factors is crucial in addressing the burden of ASCVD. Nonetheless, addressing these factors has often been overshadowed by the administration of medications. Over the past few years, there has been increasing interest in a key lifestyle component — exercise — and its influence on cardiovascular disease (CVD) risk. Several recent studies illustrate the cardioprotective impact of exercise.

The association of leisure-time running with all-cause and CVD mortality in adults was recently examined.1 Participants were grouped into six groups: non-runners and five quintiles of varying amounts of running. When compared with non- runners, runners at every quintile had lower all-cause and CVD mortality (30 and 45 percent lower risk). The mortality benefits were similar between lower and higher doses of running. There were no significant differences in the hazard ratios of all-cause and CVD mortality across quintiles of weekly running time. Even running at slower speeds and at lower “doses” (defined as < 51 minutes, < 6 miles, 1-2 times/week, < 6 miles/hour) was associated with significant and similar benefit.

The Copenhagen City Heart Study examined the relationship between all-cause mortality and dose of jogging as calibrated by pace, quantity, and frequency.2 Physical activity was graded, with joggers divided into light, moderate, and strenuous categories. Jogging from one to 2.4 hours/week was associated with the lowest mortality. Each group of joggers were compared to the sedentary non-joggers group. Light joggers had the most favorable hazard ratio (HR) for all-cause mortality (0.22: 95 percent CI: 0.10 to 0.47); the HR for moderate joggers was 0.66 (95 percent CI: 0.32 to 1.38) and for strenuous joggers was 1.97 (95 percent CI: 0.48 to 8.14). The group of strenuous joggers had almost the same mortality risk as the sedentary non-joggers. This U-shaped association suggests the existence of an optimal upper limit for exercise dosing. The dose of running that is most favorable for reducing mortality was jogging from 1 to 2.4 hours/week with no more than three running days/week, at a pace suggested to be from 6 to 7 miles/hour. It is notable that two deaths occurred in the 40-person “strenuous” group, which was not statistically significant.

An overall healthy lifestyle has been shown in recent studies to be beneficial.  A healthy lifestyle was associated with decreased risk for coronary heart disease (CHD) in the Nurse’s Health Study.3 In a study of men in Sweden, low-risk behavior (included five factors: a healthy diet, moderate alcohol consumption, no smoking, being physically active, and having no abdominal obesity) was found to be protective against myocardial infarction(MI).4  In post- menopausal women from the Women’s Health Initiative, increasingly healthy lifestyles were associated with decreasing heart failure risk.5

The concept of improved overall healthy lifestyle habits contributing to improved cardiovascular outcomes is not a new one. In the Study of Risk Factors for First Myocardial Infarction in 52 countries and more than 27,000 subjects (INTERHEART), lifestyle-related risk factors accounted for most of the risk of MI internationally.6 Furthermore, Gulati et al. showed that exercise capacity was a strong, independent predictor of all-cause mortality in asymptomatic women.7 Numerous additional prior studies have shown the association with exercise or fitness, healthy lifestyle, and improved cardiovascular outcomes.8-12 (Table 1)

What do the guidelines recommend in terms of exercise?
The American Heart Association, American College of Cardiology, and the Centers for Disease Control recommend at least 150 minutes/week of moderate-intensity physical activity, or 75 minutes/week of vigorous-intensity aerobic physical activity or a combination of both, performed in episodes of at least 10 minutes, preferably spread throughout the week.13 The American College of Sports Medicine recommends 30 to 60 minutes of moderate-intensity exercise five days/week or 20 to 60 minutes of vigorous-intensity exercise three days/week).14,15 Walking, in forms such as parking farther away, taking stairs, and using a pedometer (approximately 2,000 steps equal one mile), is the most common type of moderate- intensity exercise and has significant health benefits.

How does exercise affect cholesterol levels?
Aerobic physical activity in adults has been shown to reduce low-density lipoprotein cholesterol (LDL-C) by 3-6 mg/dL,16-21 non-high-density lipoprotein cholesterol (non-HDL-C) by 6 mg/dL,19,22,23 and low density lipoprotein particle number (LDL- P) by 75 nmol/liter.22,24,25 Although the results have not been consistent, aerobic exercise has been shown to increase HDL-C 

in some studies.16-19,23,26-29 Similarly, aerobic exercise has not been consistently shown to decrease triglycerides, although some studies suggest a benefit of as much as a 24-percent reduction in triglycerides.16-20,28,30-32 Triglyceride levels have been shown to be affected by body weight and body fat distribution. Individuals who are overweight are likely to have elevated triglycerides,33 and visceral adipose tissue is strongly associated with elevated triglycerides.34 Physical activity can improve body weight and body fat; therefore physical activity’s effect to reduce body weight and fat may explain why triglycerides lower with exercise. Furthermore, those with increased body fat are more likely to show a reduction in body fat and the concomitant lipid panel changes with exercise. In addition, the triglyceride reduction tends to be larger when an individual has higher baseline triglycerides, higher body fat, or both.

Residual Risk
Residual cardiovascular risk is a term coined for the persistence of CVD risk after aggressive LDL-C reduction, typically with high-intensity statins. In statin trials, although statins reduced CVD events compared to placebo, there remained a significant CVD event rate in the statin-treated arms. 

In the Scandinavian Simvastatin Survival Study (4S), a significant reduction in CVD events occurred with statin treatment compared to placebo, but a 20 percent CVD event rate was noted in statin patients.35 Similar findings were seen in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI)36   and Treating to New Targets (TNT) studies.37 In the recent past, there has been increased attention placed on the relationship of cardiovascular risk and other lipid parameters, particularly triglyceride- rich particles, which are contained within non-HDL-C. High triglycerides have been associated with CVD.38,39 In a large meta-analysis, triglycerides were shown to be a strong and independent predictor of cardiovascular disease risk.40 However, our knowledge of the impact of triglyceride- lowering therapies on cardiovascular events is limited by the fact that no major outcome trials have focused on patients with moderate to severe hypertriglyceridemia.

Non-HDL-C has been shown to be strongly related to CVD risk41-43 and it has been shown to be a stronger predictor of CVD risk than LDL-C. This finding was independent of whether the triglyceride level was < 200 mg/dL or > 200 mg/dl.44 A cluster of factors tends to be present in patients with high triglycerides, including low HDL-C; high non-HDL-C; the presence of small, dense LDL particles; the presence of increased very low-density lipoprotein cholesterol (VLDL-C); insulin resistance; and increases in coagulability and viscosity.45-48 Importantly, regular physical activity can improve this cluster of metabolic abnormalities, including the reduction of non-HDL-C.13

New Directions
Can lack of exercise and healthy lifestyle habits explain the residual risk of CVD in patients on optimal medical therapy for ASCVD? Exercise and fitness can improve cardiovascular outcomes and may result in beneficial effects on the lipid profile and other risk factors.

It may be that a lifetime of inactivity and poor diet leads to a cluster of metabolic factors. These are the hallmarks of the metabolic syndrome and include high triglycerides, low HDL-C, high non-HDL-C, hypertension, and hyperglycemia. This can explain much of the residual risk that remains present, despite optimal medical therapy.49 All too often the patient who continues to have CVD events despite optimal LDL-C levels and appropriate statin intensity fits this metabolic picture to a T. The cluster of factors may be explained by a lifetime of poor diet and exercise habits. Perhaps a trial that specifically targets this group with a focus on exercise and nutrition could answer this question.

Conclusion
In recent months, important studies have been published that explored the impact of exercise and diet in CVD prevention. Patients should be counseled on the appropriate dose of exercise to reduce CVD events. The interplay of exercise, diet and lipid levels often explains a substantial portion of residual risk. Reducing that risk may require a greater emphasis on lifestyle change than is currently the rule.

Disclosure statement: Dr. Sharma has no disclosures to report. Dr. Gulati’s spouse has received salary for employment at Bayer.

References are listed on page 37 of the PDF.