Abstract
The lack of animal models that accurately represent heart failure with preserved ejection fraction (HFpEF) has been a major barrier to the mechanistic understanding and development of effective therapies for this prevalent and debilitating syndrome characterized by multisystem impairments. Herein, we describe the development and characterization of a novel large animal model of HFpEF in older, female sheep with chronic 2-kidney, 1-clip hypertension. At 6-wk post unilateral renal artery clipping, hypertensive HFpEF sheep had higher mean arterial pressure compared with similarly aged ewes without unilateral renal artery clipping (mean arterial pressure = 112.7 ± 15.9 vs. 76.0 ± 10.1 mmHg, P < 0.0001). The hypertensive HFpEF sheep were characterized by 1) echocardiographic evidence of diastolic dysfunction (lateral e' = 0.11 ± 0.02 vs. 0.14 ± 0.04 m/s, P = 0.011; lateral E/e' = 4.25 ± 0.77 vs. 3.63 ± 0.54, P = 0.028) and concentric left ventricular hypertrophy without overt systolic impairment, 2) elevated directly measured left ventricular end-diastolic pressure (13 ± 5 vs. 0.5 ± 1 mmHg, P = 2.1 × 10-6), and 3) normal directly measured cardiac output. Crucially, these hypertensive HFpEF sheep had impaired exercise capacity as demonstrated by their 1) attenuated cardiac output (P = 0.001), 2) augmented pulmonary capillary wedge pressure (P = 0.026), and 3) attenuated hindlimb blood flow (P = 3.4 × 10-4) responses, during graded treadmill exercise testing. In addition, exercise renal blood flow responses were also altered. Collectively, our data indicates that this novel ovine model of HFpEF may be a useful translational research tool because it exhibits similar and clinically relevant impairments as that of patients with HFpEF.NEW & NOTEWORTHY We show that older, female sheep with chronic 2-kidney, 1-clip hypertension have similar cardiac and noncardiac exercise hemodynamic abnormalities as patients with HFpEF. This clinically relevant, translatable, and novel large animal model of HFpEF may be useful for elucidating mechanisms and developing treatments for this increasingly common syndrome with few clinically impactful therapies.