Development of Isolated Diastolic Dysfunction Associated with Early Impairment in Coronary Blood Flow in Hypertensive Diabetes
Authors: Varagic Jasmina , Ahmad Sarfaraz , Ola Mohammad , VonCannon Jessica L. , Wright Kendra , Ramirez Santiago Reyes , Wang Hao , Groban Leanne , Cheng Che Ping , Ferrario Carlos M. 
Published: June 2021

While diabetes mellitus and hypertension are independent risk factors for development of cardiomyopathy and coronary artery disease, little data are available regarding coronary blood flow dysfunction in the early hypertensive diabetic heart. The present study investigated changes in coronary flow in hypertensive diabetic animals and its relation to cardiac function in the early stage of diabetes. Since angiotensin II (Ang II) contributes to both diabetes and hypertension we also assessed the activities of two major enzymes involved in Ang II formation (angiotensin converting enzyme; ACE) and degradation (ACE2). Diabetes was induced in male spontaneously hypertensive rats (SHR) by a single injection of streptozotocin (STZ: 65 g/kg, i.p.; n=7). Age matched male SHR served as controls (CTL: n=6). Cardiac structure, systolic and diastolic function, and left coronary artery peak diastolic coronary flow velocity were evaluated by transthoracic echocardiography in anesthetized rats using the VevoLAZR imaging system two weeks after STZ injection. ACE and ACE2 activities were assessed by HPLC in plasma membranes isolated from the left ventricle. When compared to control animals, blood glucose was higher (470 ± 26 vs 126 ± 3 mg/dL; p<0.01) whereas thickness of the left ventricular posterior (1.57 ± 0.09 vs 2.04 ± 0.10 mm; p<0.01) and anterior (1.34 ±0.05 vs 1.93 ± 0.08 mm; p<0.01) walls and relative wall thickness (0.46 ± 0.3 vs 0.60 ± 0.03; p<0.01) were reduced in diabetic hypertensive animals. Two weeks of hyperglycemia did not affect arterial pressure in diabetic hypertensive rats (179 ± 5 vs 170 ± 4 mmHg; p=NS) while it markedly reduced left coronary artery peak diastolic flow velocity (235 ± 47 vs 460 ± 38 mm/s). Despite high blood pressure and reduced wall thickness, cardiac systolic function assessed by fractional shortening (46 ± 1 vs 49 ± 2 %; p=NS) and ejection fraction (76 ± 1 vs 79 ± 2 %; p=NS) remained unchanged. In contrast, significant diastolic impairment reflected in decreased tissue velocity of mitral annulus (28 ± 1 vs 57 ± 2 mm/s; p<0.01) and increased filling pressure (30 ± 1 vs 22 ± 1; p<0.01) was observed in the early stages of STZ‐induced diabetes. While ACE2 activity was decreased in left ventricles of diabetic SHR (17.62 ± 0.53 vs 20.01 ± 0.32 fmol/mg/min; p<0.01), there was no change in cardiac ACE activity between the two groups (4.21 ± 0.36 vs 4.50 ± 0.62 fmol/mg/min; p=NS). Our results suggest that impaired early coronary flow dynamics associated with decreased cardiac ACE2 activity might contribute to the development of isolated diastolic dysfunction in diabetic hypertensive rats independent of blood pressure.Support or Funding InformationP01‐HL051592This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.