Impaired cardiovascular function in obese Ossabaw swine model of heart failure with preserved ejection fraction

Presenter: Ted Weber Authors: Ted Weber, OMS-II; Deitrich Gerlt, Alex Bale, Cooper Warne, Gregory Dick PhD, Johnathan Tune, PhD Title: Impaired cardiovascular function in obese Ossabaw swine model of heart failure with preserved ejection fraction Background: The lack of pre-clinical large animal models of heart failure with preserved ejection fraction (HFpEF) remains a growing, yet unmet obstacle to improving understanding of this complex condition. Objective: The goal of this study was to examine cardiovascular responses to acute reductions in blood pressure in lean-control vs. obese Ossabaw swine with HFpEF (obese HF). Heart failure was induced by chronic tachycardia at 180 beats/min for ~4 weeks. We tested the hypothesis that rapid ventricular pacing would augment left ventricular end diastolic pressure, impair cardiac contractile function, and diminish regional myocardial perfusion. Methods: Following completion of pacing protocol, swine were anesthetized and instrumented for continuous measurements of hemodynamic parameters, left ventricular pressure, volume, and coronary blood flow. After measurements were obtained under baseline conditions, blood was serially removed to lower blood pressure in ~10 mmHg increments down to a mean arterial pressure of ~40 mmHg. Arterial and coronary venous blood samples were obtained at rest and during each reduction in blood pressure. Results: Chronic tachycardia significantly increased left ventricular end diastolic pressure (P < 0.001) but did not affect ejection fraction (P = 0.79) in obese HF (n = 5) vs. lean-control (n = 7) swine. Hemorrhage reduced blood pressure from 106 ± 5 mmHg to 40 ± 1 mmHg vs. 102 ± 4 mmHg to 41 ± 1 mmHg in lean-control and obese HF swine, respectively. Reductions in arterial pressure robustly increased heart rate from 73 ± 8 to 136 ± 19 beats/min in lean swine. In contrast, the reflexive heart rate response was significantly attenuated in obese HF, as evidenced by a 4-fold reduction in the slope of the relationship between heart rate and blood pressure in obese HF vs. lean-control swine (P < 0.01). These changes were associated with significant reductions in the relationship between cardiac index (cardiac output/body weight) and end diastolic volume (P < 0.01), while the ratio of subendocardial to subepicardial blood flow to the left ventricle remained consistent as blood pressure was diminished in lean-control and obese HF (P = 0.53). Conclusions: These findings support that chronic high-rate ventricular pacing of obese Ossabaw swine induces key phenotypic features of HFpEF, including elevated left ventricular end diastolic pressure with normal ejection fraction, chronotropic incompetence, and impaired ventricular contractility.