Peter Kokkinos

Exercise Capacity and Mortality in Older Men A 20-Year Follow-Up Study

BACKGROUND Epidemiological findings, based largely on middle-aged populations, support an inverse and independent association between exercise capacity and mortality risk. The information available in older individuals is limited. METHODS AND RESULTS Between 1986 and 2008, we assessed the association between exercise capacity and all-cause mortality in 5314 male veterans aged 65 to 92 years (mean+/-SD, 71.4+/-5.0 years) who completed an exercise test at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, Calif. We established fitness categories based on peak metabolic equivalents (METs) achieved. During a median 8.1 years of follow-up (range, 0.1 to 25.3), there were 2137 deaths. Baseline exercise capacity was 6.3+/-2.4 METs among survivors and 5.3+/-2.0 METs in those who died (P<0.001) and emerged as a strong predictor of mortality. For each 1-MET increase in exercise capacity, the adjusted hazard for death was 12% lower (hazard ratio=0.88; confidence interval, 0.86 to 0.90). Compared with the least fit individuals (< or =4 METs), the mortality risk was 38% lower for those who achieved 5.1 to 6.0 METs (hazard ratio=0.62; confidence interval, 0.54 to 0.71) and progressively declined to 61% (hazard ratio=0.39; confidence interval, 0.32 to 0.49) for those who achieved >9 METs, regardless of age. Unfit individuals who improved their fitness status with serial testing had a 35% lower mortality risk (hazard ratio=0.65; confidence interval, 0.46 to 0.93) compared with those who remained unfit. CONCLUSIONS Exercise capacity is an independent predictor of all-cause mortality in older men. The relationship is inverse and graded, with most survival benefits achieved in those with an exercise capacity >5 METs. Survival improved significantly when unfit individuals became fit.

Effects of regular exercise on blood pressure and left ventricular hypertrophy in African-American men with severe hypertension

BACKGROUND The prevalence of hypertension and its cardiovascular complications is higher in African Americans than in whites. Interventions to control blood pressure in this population are particularly important. Regular exercise lowers blood pressure in patients with mild-to-moderate hypertension, but its effects in patients with severe hypertension have not been studied. We examined the effects of moderately intense exercise on blood pressure and left ventricular hypertrophy in African-American men with severe hypertension. METHODS We randomly assigned 46 men 35 to 76 years of age to exercise plus antihypertensive medication (23 men) or antihypertensive medication alone (23 men). A total of 18 men in the exercise group completed 16 weeks of exercise, and 14 completed 32 weeks of exercise, which was performed three times per week at 60 to 80 percent of the maximal heart rate. RESULTS After 16 weeks, mean (+/- SD) diastolic blood pressure had decreased from 88 +/- 7 to 83 +/- 8 mm Hg in the patients who exercised, whereas it had increased slightly, from 88 +/- 6 to 90 +/- 7 mm Hg, in those who did not exercise (P = 0.002). Diastolic blood pressure remained significantly lower after 32 weeks of exercise, even with substantial reductions in the dose of antihypertensive medication. In addition, the thickness of the interventricular septum (P = 0.03), the left ventricular mass (P = 0.02), and the mass index (P = 0.04) had decreased significantly after 16 weeks in the patients who exercised, whereas there was no significant change in the nonexercisers. CONCLUSIONS Regular exercise reduced blood pressure and left ventricular hypertrophy in African-American men with severe hypertension.

Exercise Capacity and Mortality in Black and White Men

Background— Exercise capacity is inversely related to mortality risk in healthy individuals and those with cardiovascular diseases. This evidence is based largely on white populations, with little information available for blacks. Methods and Results— We assessed the association between exercise capacity and mortality in black (n=6749; age, 58±11 years) and white (n=8911; age, 60±11 years) male veterans with and without cardiovascular disease who successfully completed a treadmill exercise test at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, Calif. Fitness categories were based on peak metabolic equivalents (METs) achieved. Subjects were followed up for all-cause mortality for 7.5±5.3 years. Among clinical and exercise test variables, exercise capacity was the strongest predictor of risk for mortality. The adjusted risk was reduced by 13% for every 1-MET increase in exercise capacity (hazard ratio, 0.87; 95% confidence interval, 0.86 to 0.88; P<0.001). Compared with those who achieved <5 METs, the mortality risk was ≈50% lower for those with an exercise capacity of 7.1 to 10 METs (hazard ratio, 0.51; 95% confidence interval, 0.47 to 0.56; P<0.001) and 70% lower for those achieving >10 METs (hazard ratio, 0.31; 95% confidence interval, 0.26 to 0.36; P<0.001). The findings were similar for those with and without cardiovascular disease and for both races. Conclusions— Exercise capacity is a strong predictor of all-cause mortality in blacks and whites. The relationship was inverse and graded, with a similar impact on mortality outcomes for both blacks and whites.

Exercise and Physical Activity: Clinical Outcomes and Applications

The association between physical activity and health was recognized as early as the fifth century BC by the Greek physician Hippocrates, who wrote the following: “All parts of the body, if used in moderation and exercised in labors to which each is accustomed, become thereby healthy and well developed and age slowly; but if they are unused and left idle, they become liable to disease, defective in growth and age quickly.” With the decline of the Hellenic civilization, this concept faded. For centuries, physical activity and fitness were considered largely for military purposes and associated with youth sports and athletics even through the post–World War II era. The landmark work by Morris and coworkers1 changed modern views of the relationship between physical activity, fitness, and health and inspired a new era in which the association between physical activity and human health, disease, and mortality was scrutinized scientifically. For more than half a century, a plethora of evidence has accumulated from large, long-term epidemiological studies that support a strong, inverse, and independent association between physical activity, health, and cardiovascular and overall mortality in apparently healthy individuals2,–,23 and in patients with documented cardiovascular disease.8 The exercise-related health benefits are related in part to favorable modulations in both the traditional and novel cardiovascular risk factors that have been observed with increased physical activity patterns or structured exercise programs.10 In this review, we present a synopsis of some of the most influential studies examining the association between physical activity, fitness, and health. The studies cited represent only a small number of the many studies available, and more in-depth reviews are available on each of the topics discussed in the present review. In addition, the favorable effects of physical activity on the traditional and novel cardiovascular risk …

Physical Activity and Cardiorespiratory Fitness as Major Markers of Cardiovascular Risk: Their Independent and Interwoven Importance to Health Status

The evolution from hunting and gathering to agriculture, followed by industrialization, has had a profound effect on human physical activity (PA) patterns. Current PA patterns are undoubtedly the lowest they have been in human history, with particularly marked declines in recent generations, and future projections indicate further declines around the globe. Non-communicable health problems that afflict current societies are fundamentally attributable to the fact that PA patterns are markedly different than those for which humans were genetically adapted. The advent of modern statistics and epidemiological methods has made it possible to quantify the independent effects of cardiorespiratory fitness (CRF) and PA on health outcomes. Based on more than five decades of epidemiological studies, it is now widely accepted that higher PA patterns and levels of CRF are associated with better health outcomes. This review will discuss the evidence supporting the premise that PA and CRF are independent risk factors for cardiovascular disease (CVD) as well as the interplay between both PA and CRF and other CVD risk factors. A particular focus will be given to the interplay between CRF, metabolic risk and obesity.

Obesity Paradox and Cardiorespiratory Fitness in 12,417 Male Veterans Aged 40 to 70 Years

OBJECTIVE To evaluate the influence of cardiorespiratory fitness (fitness) on the obesity paradox in middle-aged men with known or suspected coronary artery disease. PATIENTS AND METHODS This study consists of 12,417 men aged 40 to 70 years (44% African American) who were referred for exercise testing at the Veterans Affairs Medical Centers in Washington, DC, or Palo Alto, CA (between January 1, 1983, and June 30, 2007). Fitness was quantified as metabolic equivalents achieved during a maximal exercise test and was categorized for analysis as low, moderate, and high (defined as <5, 5-10, and >10 metabolic equivalents, respectively). Adiposity was defined by body mass index (BMI) according to standard clinical guidelines. Separate and combined associations of fitness and adiposity with all-cause mortality were assessed by Cox proportional hazards analyses. RESULTS We recorded 2801 deaths during a mean+/-SD follow-up of 7.7+/-5.3 years. Multivariate hazard ratios (95% confidence interval) for all-cause mortality, with normal weight (BMI, 18.5-24.9 kg/m2) used as the reference group, were 1.9 (1.5-2.3), 0.7 (0.7-0.8), 0.7 (0.6-0.7), and 1.0 (0.8-1.1) for BMIs of less than 18.5, 25.0 to 29.9, 30.0 to 34.9, and 35.0 or more kg/m2, respectively. Compared with highly fit normal-weight men, underweight men with low fitness had the highest (4.5 [3.1-6.6]) and highly fit overweight men the lowest (0.4 [0.3-0.6]) mortality risk of any subgroup. Overweight and obese men with moderate fitness had mortality rates similar to those of the highly fit normal-weight reference group. CONCLUSION Fitness altered the obesity paradox. Overweight and obese men had increased longevity only if they registered high fitness.

Obesity and Prevalence of Cardiovascular Diseases and Prognosis—The Obesity Paradox Updated

The prevalence and severity of obesity have increased in the United States and most of the Westernized World over recent decades, reaching worldwide epidemics. Since obesity worsens most of the cardiovascular disease (CVD) risk factors, not surprisingly, most CVDs, including hypertension, coronary heart disease, heart failure, and atrial fibrillation, are all increased in the setting of obesity. However, many studies and meta-analyses have demonstrated an obesity paradox with regards to prognosis in CVD patients, with often the overweight and mildly obese having a better prognosis than do their leaner counterparts with the same CVD. The implication for fitness to markedly alter the relationship between adiposity and prognosis and the potential impact of weight loss, in light of the obesity paradox, are all reviewed.

EXERCISE AS HYPERTENSION THERAPY

In conclusion, the findings of most recent studies show that moderate-intensity aerobic exercise training can lower BP in patients with stage 1 and 2 essential hypertension. The average reduction in BP is 10.5 mm Hg for systolic and 7.6 mm Hg for diastolic BP. The reductions do not appear to be gender- or age-specific. Significant reductions in BP and LVH regression in patients with stage 3 hypertension have also been reported following aerobic exercise training. Resistance training exercise has not consistently shown to significantly lower BP and is not recommended as the only form of exercise for hypertensive patients. The exercise training program for optimal benefits should consist of 3 to 5 times per week, 30 to 60 minutes per session, at 50% to 80% of PMHR. However, exercise programs should be individualized to meet the patients needs and abilities. Exercise intensity and duration should be manipulated to promote a safe and effective antihypertensive program. Initially, the exercise intensity should be low and the duration short. Both intensity and duration should progressive increase over a period of weeks until the desired goal, is achieved. The rate of progression must be tailored to meet individual patient needs and abilities. The exercise program for overweight or obese hypertensive patients should aim to promote a caloric expenditure of 300 to 500 Kcal per day and 1000 to 2000 Kcal per week. Such an approach, combined with a prudent diet, is likely to reduce body weight. The mechanisms mediating exercise-induced BP reduction are poorly understood. BP reductions appear to be independent of changes in body weight or body composition. There are also no indications of age- or gender-related differences in BP response to exercise. The use of ambulatory blood pressure measuring devices in exercise studies is not extensive. The few studies available indicate a more moderate reduction in BP than that reported by casual observations.

Physical activity and high density lipoprotein cholesterol levels. What is the relationship

AbstractHigh density lipoprotein cholesterol (HDL-C) levels are strongly, inversely and independently associated with coronary heart disease (CHD). Increased physical activity is associated with reduced CHD mortality. This protection against CHD may partially be explained by the increase in HDL-C levels observed following aerobic exercise training. Many also agree that an exercise threshold needs to be met before such favourable changes in HDL-C metabolism can occur. Most likely, the exercise-induced changes in HDL-C are the result of the interaction amongst exercise intensity, frequency, duration of each exercise session and length of the exercise training period. Although a relative contribution of each exercise component (intensity, duration and frequency) is also likely, it has not been established. There is also substantial support for a dose-response relationship. Favourable changes in HDL-C appear to occur incrementally and reach statistical significance at approximately 7–10 miles per week or 1200 to 1600kcal.Exercise-induced changes in HDL-C may also be gender dependent. The volume of exercise required to increase HDL-C levels appears to be substantially more for women than men. This perhaps is due to higher HDL-C levels in women at baseline compared with men. However, the many other health benefits derived from increased physical activity should encourage women to participate in regular exercise regardless of the exercise effects on HDL-C levels.A practical approach in prescribing exercise for patients is to use moderate intensity exercises (70 to 80% of predicted maximal heart rate), 3 to 5 times per week, for a total of 7 to 14 miles per week. This is equivalent to approximately 1200 to 1600kcal per week. Moderate to low intensity exercise should be preferred because such exercise carries a lower risk for cardiac complications. In addition, patients are more likely to participate and sustain a lower than higher intensity exercise programme. It is also important to recognise that other modes of physical activity can also be encouraged for patients. Such activities should be associated with similar increases in HDL-C levels as long as they meet or exceed the caloric expenditure of 1200 to 1600kcal (7 to 14 miles per week of jogging).

Association of Leisure-Time Physical Activity on Inflammation Markers (C-Reactive Protein, White Cell Blood Count, Serum Amyloid A, and Fibrinogen) in Healthy Subjects (from the ATTICA Study)

T the 20th century, many researchers focused their interest on prevention and therapy of cardiovascular diseases. Among the factors that may influence the occurrence of disease is the beneficial effect of physical activity, which has been discussed in several studies.1–3 In addition, recent studies have provided evidence that inflammation plays a role in the pathogenesis of cardiovascular disease.4,5 Several investigators have addressed the association between fitness and the inflammation process,6–9 but the strength of this relation has not been fully investigated. The aim of this study is to evaluate the effect of various levels of leisure-time physical activity on inflammation markers, such as high-sensitivity C-reactive protein (CRP), fibrinogen, amyloid A, and white blood cell (WBC) counts, in a population-based sample of healthy adults. • • • The ATTICA study is a health and nutrition crosssectional survey that was carried out in the province of Attica from 2001 to 2002. A sample of 891 men and 965 women, aged 18 years old, was drawn from the general population, which excluded persons living in institutions, or subjects with mobility problems or who had chronic disease that could restrict their physical activity status (e.g., arthritis). Also, all subjects entered into this study were without any clinical evidence of coronary heart disease, stroke, or any atherosclerotic disease according to a detailed medical history, a physical examination, and electrocardiography as performed by a cardiologist. The stratification was random and based on the age/gender/city distribution of the Attica area (census of 2001). The study’s design anticipated enrolling only 1 participant per household (78% of the selected subjects participated). The number of the participants was determined by power analysis. All participants were interviewed by trained personnel who used a standard questionnaire. Physical activity was defined as any type of nonoccupational physical exercise 1 time per week, during the past year. A self-reported questionnaire was applied that was based on a special questionnaire for the assessment of leisure-time physical activity.10 Physical activity was graded in qualitative terms as follows: light (expended calories 4 kcal/min, i.e., walking slowly, stationary cycling, light stretching, and so forth), moderate (expended calories 4 to 7 kcal/min, i.e., walking briskly, cycling outdoors, swimming with moderate effort, and so forth), and high (expended calories 7 kcal/min, i.e., walking briskly uphill, long distance running, cycling fast or racing, swimming fast crawl, and so forth). The remaining subjects were defined as physically inactive. The duration of physical activity, in years of exercise, was also taken into account. Venous blood samples were collected between 8 and 10 A.M., with patients seated after 12 hours of fasting and avoidance of alcohol. High-sensitivity CRP levels, as well as fibrinogen levels, were measured by BNII Dade Behring Inc. (Leiderbach, Germany) automatic nephelometry. For the determination of plasma fibrinogen, blood was anticoagulated with 3.8% trisodium citrate (9:1 volume/volume) and cooled on ice until centrifugation. The intraand interassay coefficients of variation of fibrinogen did not exceed 9%, total cholesterol 8%). All other biochemical examinations (uric acid, urea, creatinine, total cholesterol, low-density lipoprotein cholesterol, highdensity lipoprotein cholesterol, triglycerides) were measured using a chromatographic enzymatic method with a Technicon RA-1000 automatic analyzer (TexLab Inc., Houston, Texas). Blood pressure at rest was measured with subject sitting comfortably for 5 to 10 minutes and the cuff arm supported at the heart level. Hypertension was defined as systolic blood pressure 140 mm Hg, diastolic blood pressure 90 mm Hg, or the use of any antihypertensive medication. Hypercholesterolemia was defined as total cholesterol levels 220 mg/dl or the use of antilipidemic medication. Diabetes mellitus was defined as a fasting blood sugar 125 mg/dl or the use of antidiabetic medication. The questionnaire given to subjects included the following demographic characteristics: age, gender, financial status (classified as low, moderate, high, and very high), and educational level (as an index of social status) that was measured in years of schooling. DiFrom the Cardiology Clinic, School of Medicine, University of Athens; Hellenic Heart Foundation, Athens, Greece; and Cardiology Division, Georgetown University, Washington, DC. The ATTICA study is funded by research grants from the Hellenic Cardiological Society and the Hellenic Heart Foundation, Athens, Greece. Dr. Panagiotakos’ address is: 48-50 Chiou Str., Glyfada, 165 61, Attica, Greece. E-mail: D.b.Panagiotakos@usa.net. Manuscript received July 29, 2002; revised manuscript received and accepted September 24, 2002.