(851.9) Chronic High-Rate Pacing Induces Heart Failure with Preserved Ejection Fraction-Like Phenotype in Obese Ossabaw Swine

Poster Board Number: E62

Johnathan Tune (University of North Texas Health Sciences Center), Adam Goodwill (Northeast Ohio Medical University), Hana Baker (Eli Lilly and Company), Gregory Dick (University of North Texas Health Sciences Center), Cooper Warne (University of North Texas Health Sciences Center), Chastidy Bailey (University of Missouri), Jessica Klasing (University of Missouri), Jacob Russell (University of Missouri), Patricia McCallinhart (The Abigail Wexner Research Institute at Nationwide Children’s Hospital), Aaron Trask (The Abigail Wexner Research Institute at Nationwide Children’s Hospital), Shawn Bender (University of Missouri)

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. This study tested the hypothesis that chronic, high-rate pacing induces a HFpEF-like phenotype in obese Ossabaw swine. Swine were fed standard chow or an excess calorie, high-fat, high-fructose diet for ~18 weeks. Obese swine were implanted with a pacemaker to increase heart rate to 180 beats/min for 4 weeks (obese HF). Compared to lean swine, chronic pacing did not affect baseline (un-paced) blood pressure or heart rate, but increased heart weight (P = 0.03), fibrosis (P lt; 0.001), and tended to reduce capillary density (P = 0.06). Cardiac output was increased in obese HF (P = 0.02) and associated with ~45% increase in ventricular stroke volume (P = 0.01), elevated end-diastolic pressure (25 ± 2 mmHg; P lt; 0.001), and a normal ejection fraction of 56 ± 7% (P = 0.57). Baseline coronary blood flow was increased in obese HF (P = 0.03); however, MVO2 (P = 0.48) and coronary venous PO2 (P = 0.14) remained unchanged. Hemorrhage studies revealed impairment of the chronotropic response (59 ± 10 to 158 ± 19 bpm in lean control vs. 70 ± 5 vs. 84 ± 5 bpm in obese HF; P lt; 0.001) and augmented reductions in coronary blood flow (0.39 ± 0.03 to 0.19 ± 0.04 ml/min/g in lean control vs. 0.60 ± 0.05 to 0.21 ± 0.04 ml/min/g in obese HF) as blood pressure decreased from 109 ± 3 to 42 ± 1 mmHg in lean control vs. 102 ± 4 to 42 ± 1 mmHg in obese HF swine. These findings support that chronic high-rate pacing of obese Ossabaw swine induces key phenotypic features of the human HFpEF condition and provides a distinct preclinical tool for future mechanistic and therapeutic study.

National Institutes of Health grants R01 HL136386 (SBB), R00 HL116769 and R21 EB026518 (AJT)