“May I suggest that more attention be paid to the simple rules of health … . These, if adequately carried out, especially by candidates for certain diseases such as hypertension and coronary atherosclerosis, might … prevent or delay the onset of these diseases.”—Dr. Paul Dudley White (1)

Although important gains have been made in the treatment of heart failure with pharmacological and device therapies, there is a need for new approaches that are safe and effective, particularly in the elderly. Targeting patients with stage A heart failure, those at high risk of developing clinical heart failure but without detectable structural heart disease, is a worthwhile strategy (2). Lifestyle interventions, such as exercise, are especially appealing because they can be personalized, are cost-effective, and carry an intuitive appeal.

In this issue of the Journal, deFilippi et al. (3) report an analysis of 2,933 participants in the CHS (Cardiovascular Health Study) composed of older adults (65 years of age and older) who were free of heart failure at study onset. N-terminal pro–B-type natriuretic peptide (NT-proBNP) and cardiac troponin T levels were measured at baseline and 2 to 3 years later. Available data on self-reported physical activity and walking pace were developed into a previously validated composite activity score. The investigators found that the probability of significant increases in both biomarker concentrations between baseline and follow-up visits was inversely related to physical activity scores. Compared with participants with the lowest score (worst), those with the highest activity scores (best) had half the risk of an increase in NT-proBNP (odds ratio: 0.50; 95% confidence interval: 0.33 to 0.77) and a third of the risk of an increase in cardiac troponin T (odds ratio: 0.30; 95% confidence interval: 0.16 to 0.55). Within 3 clinically relevant categories of activity (low, moderate, or high), increases in either biomarker identified those at increased risk of new-onset heart failure.

This study simultaneously addresses key questions about the role of exercise in heart failure among the elderly, both at the population and molecular levels. The incidence and prevalence of heart failure are growing dramatically in this age group, but current therapeutic agents have failed to yield substantial improvements in clinically relevant outcomes (4). Data from nonrandomized and 14 small phase II randomized, controlled trials, as well as the landmark HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study of >2,300 heart failure patients, have supported the conclusion that exercise training improves quality of life and exercise capacity, and reduces the risk of heart failure hospitalization ((5),(6),7). Professional societies advocate regular physical activity and exercise training in patients with heart failure, and recently published European guidelines have afforded these recommendations 1A status ((8),(9),10). Nonetheless, this treatment modality remains significantly underused in real-world settings, and its effectiveness in elderly patients with early stage heart failure has not been well studied (11). The current study adds credence to the notion that this population, too, may benefit from exercise.

Previous studies of the mechanisms by which exercise promotes cardiovascular health have focused largely on physiological parameters (12). As our understanding of heart failure pathophysiology has shifted from adverse hemodynamics to maladaptive molecular mechanisms, there is greater interest in examining the effects of therapeutics on biological processes via assessment of biomarkers (13). Natriuretic peptides provide key information about disease stability that can potentially be used to guide therapeutic decisions (14). The ability of commonly used biomarkers to change with exercise intensity and their relationship to heart failure events is an important finding. This observation, if confirmed in future studies, may put forth surrogate endpoints that explore the relationship between exercise training and cardiovascular health in understudied patient populations. These findings also provide an impetus for future investigations into how physical activity modifies a variety of biological processes, such as inflammation and ventricular remodeling, via serial measurements of representative biomarkers. Finally, the possibility that biomarker measurement might provide an objective assessment of exercise efficacy, for which clinicians currently have no reliable measure, is an exciting proposition and deserves further evaluation with a controlled trial.

The authors are to be commended for their investigation of a clinically important question that has rarely been addressed; however, the limitations of their approach must be acknowledged. This study was not a randomized comparison of exercise training versus usual care, and the results cannot be used to establish causality. The propensity to exercise at high levels is often associated with less sick patients who may be able to demonstrate greater changes in biomarkers as well as fewer heart failure events. Additionally, measurements of exercise activity were qualitative and self-reported. These observations, therefore, require validation in an independent dataset that has appropriate controls and uses quantitative measures of exercise performance and cardiovascular fitness, such as peak Vo₂ and 6-min walk distance. Despite these limitations, such studies catalyze further investigations that will help advance the field and positively contribute to our knowledge of exercise as a preventive and therapeutic intervention.

At present, the totality of evidence from observational studies and randomized, controlled trials suggests that exercise is good for the heart, even in the elderly. Biomarker analyses are uncovering new mechanisms by which exercise can slow the progression of cardiovascular disease and possibly prevent progression to heart failure. However, key questions remain: How do the benefits of exercise vary according to the stage of heart failure? How do frequency, intensity, and duration of exercise training influence outcomes? What is the minimum adherence rate necessary to achieve benefit? What is the mechanism of benefit? Can biomarkers be used as reliable surrogate markers of exercise efficacy or as measures of adherence? Despite many gains and the multitude of questions that remain, we echo Dr. White's firm belief in the vital importance of regular exercise for a healthy life.

⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.