Abstract 24055: Naturally Occurring Hypertension is Related to Cardiac Diastolic Dysfunction in Rhesus Monkeys

Abstract

Introduction: The lack of effective treatment for Diastolic Dysfunction (DD) is partially due to the differences between widely used preclinical rodent models and humans in the physiology and function of the heart. In previous studies, we have demonstrated that rhesus monkeys with naturally occurring adult onset Type 2 Diabetes (T2DM) frequently have DD that is similar in characteristics to DD in diabetic patients. To further characterize DD in rhesus monkeys, we studied the relationship between hypertension and DD, and evaluated the response of rhesus monkeys with DD to Entresto (sacubitril/valsartan). Methods: Blood pressure, fasting plasma glucose and cardiac function were measured in 322 adult rhesus monkeys ( Macaca mulatta , 7-22 yrs) under light anesthesia with ketamine. Monkeys with LV hypertrophy, e'<8 cm/s and E/e'>10 were defined as DD. Ten monkeys with DD were enrolled in the validation study and divided into the Entresto group (n=5) and the vehicle group (n=5). Cardiac function and blood pressure were measured before and at the end of 13 weeks of treatment. Results: Among the 322 adult rhesus monkeys studied, 53 monkeys (16.46%) had SBP>140 mm Hg or DBP>90 mm Hg. Among the 174 monkeys with fasting glucose >80 mg/dL, 67 monkeys had isolated DD, and 8 had DD+ SD (systolic dysfunction). The incidence of isolated DD was 31% in monkeys with SBP<140 mm Hg and 74% in monkeys with SBP>140 mm Hg. Following Entresto administration (1.66 to 13.33 mg/kg) for 13 weeks, DD and BP evaluation showed an increase of e’ (5.27±0.51 to 6.43±1.27 cm/s), a decrease of E/e’ (12.74±2.23 to 10.53±2.09) and a decrease of SBP (128±5 to 113±16 mm Hg). These parameters remained stable and unchanged in the vehicle group. Conclusions: The incidence of naturally occurring hypertension in adult rhesus monkeys was similar to that in adult humans. Entresto reduced blood pressure, but led to no significant improvement of DD in monkeys. The extent of change in rhesus monkeys was similar to that observed in clinical trials. In rhesus monkeys, as in patients, hypertension is significantly related to cardiac diastolic dysfunction. These monkeys, therefore, provide important new opportunities to understand the pathogenesis of DD, as well as to predict the human response to new therapeutic agents.