Reducing Heart Failure Risk in Late-Life With Physical Activity: Impact on Cardiac Structure and Function and Proteomic Signatures

Lifestyle modification with physical activity (PA) appears to be protective of several age-related cardiovascular (CV) outcomes, including heart failure (HF), in a dose-dependent manner. While many studies with exercise training have demonstrated improvement in quality of life and cardiorespiratory fitness, findings have not been consistent with regards to the potential for exercise to preserve or even improve cardiac function in adults with HF. There remains incomplete understanding of the molecular pathways by which PA mitigates HF risk. Furthermore, exercise studies often exclude older adults, who are disproportionately affected by HF, though our preliminary data suggest the protective effects of PA extend to late-life. Older adults are at particularly heightened risk for HF with preserved ejection fraction (HFpEF), which is characterized by impaired left ventricular (LV) diastolic function and impaired systolic deformation despite preserved LV ejection fraction (LVEF). Unlike with HF with reduced ejection fraction (HFrEF), effective pharmacologic therapies or interventions to improve cardiac function among individuals with preserved LVEF are limited. Thus, there is a critical need to define the cardiovascular mechanisms by which PA impacts HF risk in older adults that may enable the identification of novel therapeutic targets to prevent HF and HFpEF in particular.

As proteins orchestrate and carry out cellular functions in health and in diseases, one method of characterizing changes in CV function is to investigate cell signaling by studying the circulating proteome. Proteomic approaches have previously been used to identify pathways relevant to myocardial infarction and have also been used to investigate molecular pathways characterizing PA and CV disease. A recent study demonstrated upregulation of inflammation-related proteins in HFpEF patients (n=228) compared to controls, and their association with worse indices of cardiac function. Specific proteomic patterns have also been associated with aerobic exercise, with 2 proteomic modules that were specifically preserved with aging in habitual exercisers. Data from Swedish cohorts has also shown an association of leisure-time PA with 28 CV-specific proteins involved in atherosclerotic processes. Serial multi-omic measures (including proteomics) have been used to demonstrate marked intra-individual changes in circulating proteins with acute exercise. More recently, high-throughput proteomic profiling has been successfully employed in younger adults to identify baseline protein levels associated with change in cardiorespiratory fitness following an exercise intervention. However, to-date, limited data exist regarding intervention-related changes in the proteome in older adults at risk for HF and the extent to which these changes correlate with changes in cardiorespiratory fitness.

Supervised exercise-training with cardiac rehabilitation (CR) has been well established as an effective method to improve maximal oxygen consumption (VO2 max), a measure of cardiorespiratory fitness. Improvement in VO2 max has also been demonstrated with exercise training in sedentary older adults over 65 years of age.

The objective of this proposal is to identify protein signatures characterizing the known benefits of a structured CR program on VO2 max. Our working hypotheses is that proteomic approaches will identify novel biomarkers that uniquely characterize molecular pathways associated with exercise training and CR-related changes in proteins will correlate with changes in VO2 max. Successful completion of this aim will identify possible novel protein signatures underlying the protective biological pathways mediated by a structured CR program that may be used as preliminary data for future grant proposals.

Aim: Identify molecular pathways underlying the beneficial effect of a structured PA intervention on functional capacity with the use of plasma proteomics in older sedentary adults at high risk of HF. (BWH-based cohort). Hypotheses: (1) Randomization to participation in a cardiac rehabilitation (CR) program will result in improvement in circulating levels of 4 plasma proteins associated with change in VO2max, a measure of cardiorespiratory fitness, and with genetic evidence supporting a causal effect on HF and cardiac structure (ATF6, STC1, JAG1, PTK7). The investigators will randomize 42 sedentary adults at high risk of HF (stage B HF) to participation in a CR program and perform proteomic analysis, cardiopulmonary exercise testing, and echocardiography at baseline and 12 weeks.