Diastolic dysfunction and impaired cardiac output reserve in dysmetabolic nonhuman primate with proteinuria

Cardiorenal complications are common in patients with dysmetabolism and diabetes. The present study aimed to examine if a nonhuman primate (NHP) model with spontaneously developed metabolic disorder and diabetes develops similar complications to humans, such as proteinuria and cardiac dysfunction at resting condition or diminished cardiac functional reserve following dobutamine stress echocardiography (DSE).

A total of 66 dysmetabolic and diabetic cynomolgus (Macaca fascicularis) NHPs were enrolled to select 19 NHPs (MetS) with marked metabolic disorders and diabetes (fasting blood glucose: 178 ± 18 vs. 61 ± 3 mg/dL) accompanied by proteinuria (ACR: 134 ± 34 vs. 1.5 ± 0.4 mg/mmol) compared to 8 normal NHPs (CTRL). Under resting condition, MetS NHPs showed mild left ventricular (LV) diastolic dysfunction (E/A: 1 ± 0.06 vs. 1.5 ± 0.13), but with preserved ejection fraction (EF: 65 ± 2 vs. 71 ± 3%) compared to CTRL. DSE with an intravenous infusion of dobutamine at ascending doses (5, 10, 20, 30 and 40 μg/kg/min, 7 min for each dose) resulted in a dose-dependent increase in cardiac function, however, with a significantly diminished magnitude at the highest dose of dobutamine infusion (40 μg/kg/min) in both diastole (E/A: -12 ± 3 vs. -38 ± 5%) and systole (EF: 25 ± 3 vs. 33 ± 5%) as well as ~42% reduced cardiac output reserve (COR: 63 ± 8 vs. 105 ± 18%, p < 0.02) in the MetS compared to CTRL NHPs.

These data demonstrate that MetS NHPs with cardiorenal complications: proteinuria, LV diastolic dysfunction and preserved LV systolic function under resting conditions displayed compromised cardiac functional reserve under dobutamine stress. Based on these phenotypes, this NHP model of diabetes with cardiorenal complications can be used as a highly translational model mimic human disease for pharmaceutical research.