Progressive Hemodynamic and Cardiac Autonomic Impairment as a Function of Metabolic State: Local Adipose vs. Systemic Inflammation

Abstract

Cardiac autonomic neuropathy (CAN) commonly occurs early in the course of diabetes with significant cardiovascular mortality and morbidity. CAN development is linked to hyperglycemia; however, current understanding extends cardiovascular risk to pre‐diabetic patients without glycemic changes. Recent evidence suggests that anti‐diabetic drugs reduce the risk of cardiovascular complications in pre‐diabetes. The mechanism leading to early CAN development, its temporal evolution from pre‐diabetes to diabetes, and the response to therapeutic interventions were not previously described. To address these questions, we developed a rat model of mildly increased caloric intake (HC‐rat) with delayed development of hyperglycemia. Twelve weeks of feeding were not associated with an increase in neither body weight, blood pressure, nor blood glucose levels. These rats only showed an elevated serum insulin level indicative of insulin resistance. Type 2 diabetes was induced by the injection of low‐dose streptozotocin (STZ, 40 mg/kg). Echocadiography and invasive hemodynamic recording were used to assess cardiac autonomic function. Western blotting, PCR, and immunohistochemistry were employed to investigate different changes on the structural and molecular levels. Pre‐diabetic rats showed localized perivascular adipose inflammation together with parasympathetic dysfunction (suppression of baroreflex sensitivity in response to vasopressors), with no signs of cardiac structural or functional impairment. These abnormalities were reversed by non‐hypoglycemic doses of Metformin (Met, 100 mg/Kg) and Pioglitazone (Pio, 2.5 mg/Kg). On the other hand, rats with overt hyperglycemia developed systemic inflammation, with increased IL‐1b levels in serum, brainstem, and heart apex. Augmentation of inflammation in diabetic rats was associated with worsening cardiac autonomic function extending to sympathetic function (suppression of baroreflex sensitivity in response to vasodilators). While control of hyperglycemia through insulin treatment reversed the sympathetic deficit, parasympathetic function was only restored by combined treatment with Insulin+Met or Insulin+Pio producing the highest decrease in systemic inflammation in diabetic rats. As well, diabetic rats showed signs of focal ischemia in ventricular tissues together with an impaired systolic function apparent as >50% decrease in maximal rate of rise of left ventricular pressure. Our present results outline a framework for sequential involvement of disparate detrimental mechanisms in the course of metabolic disease leading to a differential impact on cardiac autonomic control. Furthermore, our findings emphasize the value of early intervention with antidiabetic drugs with potential pleotropic effects.Support or Funding InformationSupported by AUB‐FM MPP grant # 320148This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.