Mineralocorticoid Stress Precipitates Elevations in Resting Left Ventricular Filling Pressure in Swine with Increased LV Chamber Stiffness

Background: Many patients with heart failure and a preserved ejection fraction (HFpEF) are compensated at rest, with normal left ventricular (LV) filling pressures and minimal symptoms of congestion despite increased LV chamber stiffness. Nevertheless, increases in LV diastolic stiffness lead to sensitivity to sodium excess and volume overload that can precipitate pulmonary venous hypertension at rest. We tested the hypothesis that fludrocortisone, an aldosterone analog, could chronically elevate filling pressure in swine with normal resting filling pressure and increased LV stiffness from repetitive pressure overload (RPO). Methods: We subjected swine (n=5) to RPO using daily 2-hour infusions of phenylephrine to intermittently elevate LV preload and afterload for 2-weeks. They subsequently received fludrocortisone with their usual diet for 3-weeks (0.5 mg /day po). Serial invasive hemodynamic assessment of resting LV filling pressures and echocardiographic LV volume were performed at baseline, after 2-weeks of RPO, and following 3-weeks of fludrocortisone. LV chamber stiffness was calculated as ∆LVEDP / ∆LVEDV using simultaneous LV pressure and volume measurements at rest (LVEDP ~12 mmHg) and during elevated preload (LVEDP ~30 mmHg). Results: Two-weeks of RPO resulted in a non-significant rise in resting LVEDP (from 10.8±1.2 mmHg to 14.7±1.2 mmHg, p=0.16) but a markedly increased LV diastolic chamber stiffness (0.34±0.01 mmHg/mL/m2 to 1.68±0.22 mmHg/mL/m2, p < 0.01). After fludrocortisone LVEDP increased to 19.2±1.9 mmHg (p=0.01 vs. baseline). There was a commensurate increase in pulmonary capillary wedge pressure that exceeded the clinical cutoff typically used to diagnose post-capillary pulmonary hypertension (from 6.0 ±0.2 mmHg at baseline to 16.7±1.9 mmHg, p< 0.01). Conclusions: While resting LV filling pressures remain normal in swine subjected to RPO, mineralocorticoid challenge in the absence of excess dietary salt unmasks susceptibility to HFpEF with resting LV filling pressures above clinically recognized thresholds associated with symptomatic pulmonary congestion. These results highlight the importance of LV chamber stiffness and sodium retention as factors precipitating pulmonary venous hypertension that underlies decompensation and the progression from stage B to stage C HFpEF. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.