Phenotype of Pacing-Induced Heart Failure in Lean and Obese Ossabaw Swine

Caleb Reagor*, Jonathan Sweeney*, Matthew Biggerstaff*, and Johnathan D. Tune *Authors contributed equally Purpose: There are numerous preclinical models of heart failure in large animals; however, almost all reflect heart failure with reduced ejection fraction (HFrEF). There are currently no suitable large animal models of heart failure with preserved ejection fraction (HFpEF). The lack of HFpEF models represents a significant gap in translational studies to understand pathophysiological mechanisms and elucidate potential treatments for approximately 50% of all heart failure cases. Obesity and its related comorbidities are more strongly associated with risk of future HFpEF versus HFrEF. We hypothesized that obese animals would develop HFpEF in response to 4 weeks of tachypacing, whereas lean animals would develop HFrEF in response to the same stimulus. Methods: Three groups of Ossabaw swine were studied, including lean swine without pacing (n = 9; control), lean swine with pacing (n = 5), and obese swine with pacing (n = 5). Ossabaw swine are an ideal model for these studies, as they demonstrate a human-like response to a high calorie, high fat diet (e.g., obesity, insulin resistance, and dyslipidemia). Swine were anesthetized and pacemakers were implanted to drive the right ventricle at 180 beats/min. After recovery and 4 weeks of pacing, animals were anesthetized, and a pressure-volume catheter was inserted into the left ventricle to assess the type and degree of heart failure. Results: Paced animals had grossly enlarged heart chambers and significant abdominal ascites. Tachypacing increased heart weight (176 ± 11, 229 ± 13, and 234 ± 14 g in control, lean, and obese swine, respectively; p < 0.01). Ejection fraction was not different between groups (58 ± 6, 53 ± 6, and 59 ± 6% in control, lean, and obese swine, respectively; p = 0.86). Tachypacing increased left ventricular end diastolic pressure (LVEDP), a hallmark of heart failure (12 ± 1, 28 ± 4, and 26 ± 1 mmHg in control, lean, and obese swine, respectively; p < 0.001). Conclusions: The data indicate that we have created a tachypacing-induced model of HFpEF in Ossabaw swine. However, in direct contrast to our prediction, tachypacing produced HFpEF in both lean and obese Ossabaw swine. Tachypacing significantly elevated filling pressure (LVEDP) to pathophysiological levels, but ventricular performance (ejection fraction) was maintained. Our findings support the idea that Ossabaw swine subjected to tachypacing represent a clinically relevant large animal model of HFpEF.