Modifying the structural substrate and progression of heart failure with preserved ejection fraction using a regular exercise regimen in pigs

<i>Background:</i> Heart failure (HF) with a preserved ejection fraction (HFpEF) arises from a persistent left ventricular (LV) pressure overload (LVPO) ultimately causing increased LV myocardial stiffness (Km) 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 benefit in HF patients, whether and to what degree an exercise program overlaid with progressive LVPO may alter HFpEF progression remains unclear. <i>Methods/Results:</i> 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). In both LVPO groups, LV mass increased by approximately 55% but in the LVPO exercise group Km was reduced (19.30 ± 2.62 vs 47.97 ± 8.63 kPa, p<0.05) as was PCWP (10.52 ± 0.35 vs 11.88 ± 0.34 mmHg, p<0.05) and LAA (8.55 ± 0.43 ± vs. 9.83± 0.43 cm2, p<0.05. LV collagen percent area was reduced in the LVPO exercise group compared to LVPO (5.96 ± 0.50 vs 10.82 ± 0.39 %, p<0.05). LV fibrillar collagen mRNA levels (collagen type 1a) increased by 2-fold with LVPO (p<0.05) but returned to within referent normal values with LVPO and exercise. <i>Conclusions.</i> 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.