Developing a Large Animal Model of Heart Failure with Preserved Ejection Fraction

Abstract

Objective Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome representing more than 50% of heart failure cases. Currently, available treatment options do not improve patient outcomes and the mechanics of HFpEF remain largely misunderstood. This makes animal models of HFpEF a valuable resource and currently there are few animal models that replicate the clinical characteristics of this disease. Previous studies have replicated associated cardiac hypertrophy and diastolic dysfunction, however exercise intolerance is a cardinal sign of HFpEF but is rarely investigated in animal models. The aim of this study was to develop a clinically relevant large animal model of HFpEF using the two-kidney-one-clip renovascular hypertension method and investigate exercise intolerance. We hypothesized that chronic hypertension would lead to a reduced cardiac output (CO) and stunted heart rate (HR) response during exercise. Methods Hypertension (HTN) was induced by clipping of the renal artery in adult female sheep (N=4), while the contralateral kidney remained intact. Sheep were left to develop HTN for 6 weeks, after which sheep were instrumented to record cardiac output (CO), heart rate (HR) and mean arterial pressure (MAP). A normal cohort (N=3) of sheep also underwent this same instrumentation surgery. After recovery from surgery, the animals were acclimatized to walk on a treadmill and following acclimatization, they entered a treadmill protocol where the incline and speed was increased every 3 min. Results Renal artery clipping caused a significant rise in MAP (123±6 mmHg from 77±9 mmHg) while CO was not different. In normotensive sheep exercise led to large changes in CO (17±2 L/min from 9+/-0.7 L/min) and HR (153±15 bpm from 107±14 bpm). Exercise in the hypertensive sheep led to attenuated increases in CO (11+/-1 L/min from 6±0.4 L/min) and HR (137±7 bpm from 115±8 bpm). Interestingly, the hypertensive sheep reached their maximum heart rates earlier than the normotensive sheep. Discussion/Conclusion Our data suggest that chronic hypertension leads to a decrease in the maximum cardiac output reached during exercise suggesting a loss of cardiac reserve. Overall this indicates that the 2-kidney-1-clip renovascular HTN model may be a good method to induce HFpEF.