Physical activity, fitness and mortality

Hypertension, dyslipidemia, smoking and diabetes are firmly established risk factors for cardiovascular morbidity and mortality. By contrast, physical inactivity has encountered more difficulties to be accepted as a risk factor for which several reasons can be invoked. Unlike the so-called major risk factors, physical activity is more difficult to quantify. It furthermore may involve leisure-time, occupational and/or commuting activities with variable dynamic and static components, which may have different effects on health. Studies have used various questionnaires and sometimes interviews relating to the patient's physical activity over different periods of time. Most authors accept that the estimation of physical activity by questionnaire or interview is a poor, but nevertheless useful, and possibly the best available tool. The optimal methodology to establish a causal relationship between a risk factor and disease incidence is a randomized controlled intervention trial. Needless to say that it is nearly impossible to organize such an outcome trial with regard to the role of exercise in the population or among hypertensive patients, as well for practical as for financial reasons. The next best method is the prospective follow-up of cohorts with assessment of physical activity at baseline, although a causal relationship cannot be proven and selection bias cannot be excluded. In 1987, Powell et al.[1] published a milestone critical review on the role of habitual physical activity in the primary prevention of coronary heart disease. They performed a systematic review of the literature, only included articles that met predetermined minimal requirements, critically examined the methods used in the studies and provided an assessment of the quality of each study. Forty-three studies met the selection criteria. The authors concluded that the inverse association between physical activity and incidence of coronary heart disease met a number of so-called causality criteria: the association was consistently observed, especially in the better designed studies, it was appropriately sequenced, biologically graded, plausible and coherent with existing knowledge. Therefore, the observations reported in the literature appeared to support the inference that physical activity is inversely and causally related to the incidence of coronary heart disease. Moreover, the relative risk of coronary heart disease associated with inactivity ranged from 1.5 to 2.4, with a median of about 1.9 (2.4 in the better studies), which is similar in magnitude to that of traditional risk factors. The strength of the crude association was generally diminished only slightly by adjustment for these risk factors. After this study by Powell et al.[1], numerous additional studies have been published. In a subsequent review, Lee and Skerrett [2] assessed the association between physical activity and all-cause mortality and found an inverse association between volume of physical activity and mortality rates in women and in men, and in younger and older persons. More recently, Nocon et al.[3] performed a proper meta-analysis of selected studies with a minimum population size of 5000 and a minimum follow-up of 3 years. The authors reported risk reductions on the basis of comparisons between the least active and the most active population subgroups, with the least active subgroup as the reference group. Concerning cardiovascular mortality, self-reported physical activity was associated with a risk reduction of 30% [95% confidence interval (CI): 26–34%], and all-cause mortality was reduced by 29% (95% CI: 24–34%). The authors concluded that physical activity is associated with a marked reduction in cardiovascular and all-cause mortality in both men and women, even after adjustment for other relevant risk factors. The overall results of studies performed in the general population are compatible with an impressive protective effect of physical activity, but the question arises whether physical activity is also protective in patients with hypertension. In this issue of the journal, Rossi et al.[4] examine the impact of physical activity on mortality in patients with high blood pressure (BP), followed up for a minimum of 1 year after the baseline examination. Six articles, evaluating a combined total of 48 448 men and 47 625 women, satisfied their inclusion criteria. Because of the heterogeneity among studies with regard to BP measurement, definition of hypertension and the assessment of physical activity, the authors could not perform a proper meta-analysis but scrutinized each of the studies in detail. They concluded that cardiovascular and/or all-cause mortality were shown to be inversely related to physical activity in all of the six studies. For example, patients with high BP who participated in any level of physical activity had a reduced risk of cardiovascular mortality by 16–67% and of all-cause mortality by 17–57%, whereas a greater than two-fold increase in risk of cardiovascular death was noted in nonactive individuals. The results of studies performed in hypertensive patients are, therefore, comparable to those observed in population-based studies, but more research is needed to clarify the contribution of the various components of physical activity, that is intensity, duration, frequency and type of exercise. It is of note that Rossi et al.[4] only considered studies in which physical activity was estimated by interview of questionnaire. A number of other studies in hypertensive patients have measured physical fitness more objectively through exercise testing, but it is of note that the relationship between physical activity and physical fitness is of a low order [5]. Research in twins revealed that about half of the variance in fitness results from genetic composition [6]. Furthermore, even adequate dynamic physical training will only lead to an on average 15% increase in exercise performance, and there is evidence that also this effect is partly genetically determined. Nevertheless, studies with objective assessment of physical fitness confirm the results on physical activity in patients with hypertension. Pardaens et al.[7] investigated the prognostic value of aerobic power recorded during a bicycle exercise test up to volitional fatigue in 216 hypertensive men and women and followed them up for a median of 16.5 years. In multivariable analysis, the hazard ratio associated with 1 l/min higher peak oxygen uptake amounted to 0.45 (95% CI: 0.23–0.88) for an aggregate of cardiovascular events, and to 0.28 (95% CI: 0.10–0.79) for all-cause mortality. Investigators from the Cooper Clinic in Dallas repeatedly reported on the results in hypertensive men from the Aerobic Center Longitudinal Study [8–10]. The most recent study included 13 155 participants, who completed a health examination and a symptom-limited maximal treadmill exercise test at baseline. The multivariable hazard ratios for all-cause mortality, using low fitness as the reference group, were 0.58 (95% CI: 0.48–0.69) and 0.43 (95% CI: 0.35–0.54) for moderate-fit and high-fit groups, respectively, and a similar pattern was observed for cardiovascular mortality. Similar analyses were performed in the Lipids Research Clinics Prevalence Study [11]. Comparing the lowest with the highest quintile of fitness by treadmill exercise testing, the adjusted all-cause mortality was 2.0 (95% CI: 1.2–3.4) among 1009 hypertensive men, and 1.7 (95% CI: 0.9–3.2) among 708 hypertensive women. Elevated risks were also observed for cardiovascular mortality. In their meta-analysis of population-based studies, Nocon et al.[3] also considered 10 studies in which physical fitness was actually measured. Again, the results proved to be similar in the population and in hypertensive patients, as the overall hazard ratio amounted to 0.43 (95% CI: 0.33–0.57) for cardiovascular mortality and 0.59 (95% CI: 0.35–0.60) for all-cause mortality when the most fit were compared with the least fit. In conclusion, the results from prospective observational studies indicate that the results on the effects of physical activity and physical fitness on outcome are concordant in the population and in hypertensive patients. Nevertheless, the observational nature of these studies is a limitation so that causality, although suggested by a number of causality criteria, cannot be definitely inferred. It is of note, however, that randomized controlled trials are available in patients with coronary heart disease, which usually include a substantial number of patients with history of hypertension. First of all, aerobic power is a significant predictor of all-cause and cardiovascular mortality in these patients [12]. After controlling for age, hypertension, diabetes, ST-segment depression and drug use, a 1 l/min higher peak oxygen uptake was associated with decreases in all-cause and cardiovascular mortality of 57% (P < 0.05) and 71% (P < 0.01), respectively. The effectiveness of exercise-based cardiac rehabilitation on outcome was reviewed in two recent meta-analyses of randomized controlled clinical trials in patients with coronary heart disease [13] or post myocardial infarction (MI) [14]. Both meta-analyses concluded that patients randomized to cardiac rehabilitation had lower risks of cardiac and all-cause mortality in comparison with the control groups. In the patients with coronary heart disease, the odds ratios (ORs) amounted to 0.74 (95% CI: 0.61–0.96) for cardiac mortality and to 0.80 (95% CI: 0.68–0.93) for all-cause mortality [13], and in the patients who recently survived a MI, the OR was 0.64 (95% CI: 0.46–0.88) for cardiac mortality, 0.74 (95% CI: 0.58–0.95) for all-cause mortality and 0.53 (95% CI: 0.38–0.76) for reinfarction [14]. One further study may shed some light on the role of exercise and particularly the response to exercise in the rehabilitation program [15]. Three months of physical training increased peak oxygen uptake by 33% in 417 patients with coronary heart disease, but the variability of the individual response appeared to be large. Subsequent cardiovascular mortality was lowest in the patients with the largest increase in peak oxygen uptake. A 1% greater increase in peak oxygen uptake after training was associated with a decrease of cardiovascular mortality of 2%, independent from age and other covariates. Therefore, the change in peak oxygen uptake in response to training appears to be an independent predictor for cardiovascular mortality in patients with coronary artery disease. Whether the beneficial effect of physical activity derives from the influence of physical activity or fitness itself or through other risk factors or mechanisms is an important scientific issue but of lesser concern for public health. There is evidence from meta-analyses of randomized controlled trials that both dynamic aerobic training [16] and resistance training [17] significantly reduce BP by, respectively, 3.0 (95% CI: 2.0–4.0)/2.4 mmHg (95% CI: 1.7–3.1) and 3.9 (95% CI: 1.5–6.2)/3.6 mmHg (95% CI: 2.1–5.0). Only a few studies on resistance training have been performed in hypertensive patients, but the larger amount of data on endurance training allowed us to conclude that this type of training reduces BP by 6.9 (95% CI: 4.6–9.1)/4.9 mmHg (95% CI: 3.3–6.5) in hypertensives [16]. Furthermore, there is evidence that endurance training reduces body weight, body fatness, abdominal circumference and plasma triglycerides, increases high-density lipoprotein cholesterol and improves insulin sensitivity [16], arterial stiffness [18], endothelial function [19] and oxidized low-density lipoprotein cholesterol [20]. Also exercise-based cardiac rehabilitation had favorable effects on cardiovascular risk factors, including smoking, BP, body weight and lipid profile [13,14]. A final important question is the dose relationship between exercise and outcome. There is little doubt that moderate activity is better than none at all. There is, however, less unanimity whether vigorous or intense physical activity is better than just moderate activity. Whereas a plateau and sometimes a reversal of benefit have been observed by some authors, others found that vigorous activity was most protective. In view of feasibility and safety, the general advice to the public and to hypertensive patients should be to exercise with moderation, with the exception of patients who want to take up vigorous exercise, which requires more specific advice and testing, depending on the patient's age and medical history [21]. On the basis of the current evidence, the following exercise prescription is recommended: frequency, at least 5 and preferably all days of the week; intensity, moderate intensity; time, at least 30 min of physical activity per day; and type, primarily endurance exercise, supplemented by resistance exercise [21–23]. Efforts to increase physical activity deserve as much consideration as those aimed at influencing more traditional risk factors, because the estimates of population-attributable risks derived from published studies amounted to 22–39% for low levels of leisure-time physical activity [24]. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.