Modifying the structural substrate and progression of heart failure with preserved ejection fraction using a regular...

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. Although exercise programs have shown benefit in patients with HF, whether and to what degree an exercise program overlaid with progressive LVPO may alter HFpEF progression remains unclear. Pigs (25 kg) underwent progressive LVPO for 5 wk without (n = 8) or with daily exercise (n = 8, 10 degrees elevation, 2.5 mph, 10 min, 5 days/wk). 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 with LVPO (5.96 ± 0.50 vs. 10.82 ± 0.39%, P < 0.05). LV fibrillar collagen mRNA levels (collagen type 1a) increased by twofold with LVPO (P < 0.05) but returned to within referent normal values with LVPO and exercise. The unique and significant findings from this study were twofold. 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, although clinical studies are required, these results suggest that a regular exercise protocol for patients at risk for HFpEF represents a potential preventive strategy.NEW & NOTEWORTHY This is a translational research study that demonstrated that with left ventricular pressure overload, such as that which occurs with hypertension, that an exercise program can prevent changes in heart muscle function and structure, which in turn lead to heart failure.