Abstract 4342582: Modifying the progression of heart failure with preserved ejection fraction (HFpEF) in pigs by a regular exercise regimen; Effects on LV function and structure

Background: HFpEF commonly arises from a persistent left ventricular (LV) pressure overload (LVPO) ultimately causing hypertrophy, and resistance to LV filling resulting in increased pulmonary capillary wedge pressure (PCWP) and left atrial area (LAA). Increased LV collagen content (fibrosis) is a structural underpinning of this process. While exercise programs have shown favorable results with HFpEF patients, whether and to what degree an exercise program overlaid with progressive LVPO may alter HFpEF progression remains unclear. Methods/Results: Pigs (25 kg) underwent progressive LVPO for 5 weeks without (n=8) or with daily exercise (n=8, 10 degrees elevation, 2.5 mph, 10 min, 5 days/week). Age matched pigs with no LVPO served as controls (n=8). LV function and geometry was determined by transthoracic echocardiography (Table). With LVPO only, LV mass increased by over 50%, and PCWP and LAA area increased, but LVEF remained within normal limits- consistent with the HFpEF phenotype. In the LVPO group, LV mass increased to a similar degree, but PCWP and LAA were both reduced. Histomorphometry revealed myocyte cross-sectional area increased in both LVPO groups, and while LV collagen percent area increased by 2-fold with LVPO, indicative of myocardial fibrosis, this was prevented in the LVPO exercise group. (Table) LV fibrillar collagen mRNA levels (collagen type 1a, by PCR) increased by 2-fold with LVPO but returned to within referent normal values with LVPO and exercise. A similar pattern was observed for mRNA levels of the profibrotic factor transforming growth factor beta (TGF-B). (Table) Conclusions: The unique and significant findings from this study were 2-fold. First, a concomitant exercise protocol overlayed with a progressive LVPO stimulus prevented the HFpEF phenotype, but did not alter the LV hypertrophic response. Second, the structural/molecular basis for this was likely reduced collagen content and expression. Thus, while clinical studies are required, these results suggest that a regular exercise protocol for patients at risk for HFpEF represents a potential preventive strategy.