Characterization of cardiac remodeling in a large animal "one-kidney, one-clip" hypertensive model

Abstract

Objective. The aim of this study is to characterize cardiac remodeling in a large animal model of hypertension. Methods. 23 sheep were subjected to unilateral nephrectomy followed by clamping of the remaining renal artery to 60% (“one kidney-one clip”, 1K1C) 3 weeks later. Blood pressure (BP) was monitored invasively over 73±28 days. Cardiac function was assessed with magnetic resonance imaging and compared with 12 size-matched controls. Detailed atrial histopathological analysis was performed. Results. In the 1K1C animals, BP rose from baseline to reach a plateau by 4 weeks (systolic BP: 107±12 to 169±27, diastolic BP: 71±10 to 118±29 mmHg, both p< 0.0001); cardiac hypertrophy was significant when compared with controls with increased left ventricular weight [left ventricular (LV)/body wt: 2.7±0.5 vs 2.1±0.2 g/kg, p=0.01] as well as bi-atrial enlargement (right atrial, RA: 22.9±4.9 vs 15.7±2.8g, p=0.003; left atrial, LA: 35.5±6.7 vs 20.9±4.1g, p=0.0003); cardiac magnetic imaging demonstrated significantly increased LA volumes (end-diastolic volume: 42.9±6.8 vs 28.7±6.3 ml, p< 0.0001) and reduced LA ejection fraction (24.1±3.6 vs 31.6±3.0%, p=0.001) while LV function was relatively preserved (42.3±4.7 vs 46.4±4.1%, p=0.1); degeneration and necrosis of atrial myocytes were evident with increased atrial lymphocytic infiltration and interstitial fibrosis. Conclusions. The ovine 1K1C model produces reliable and reproducible hypertension with demonstrable cardiac end-organ damage.