High-dose Norepinephrine Induces Disruption of Myocardial Extracellular Matrix and Left Ventricular Dilatation and Dysfunction in a Novel Feline Model

Abstract

Intravenous norepinephrine (NE) at a dose of 1-6 microg/kg/minute can induce increased extracellular matrix (ECM) and hypertrophic cardiomyopathy. This study aimed to investigate the effects of a higher dose of NE on cardiac remodeling. After intraperitoneal urethane-chloralose anesthesia, 7 cats (3.03 +/- 0.58 kg) received intravenous infusion of NE 30 microg/kg/minute for 3 hours. Aortic blood pressure and heart rate (HR) were measured by polygraphy at 0, 5, 15, 30, 60, 90, 120, and 180 minutes. Left ventricular size and ejection fraction (EF) were measured by M-mode echocardiography before and after NE administration. Histopathology was performed by hematoxylin-eosin, silver impregnation, and Sirius red staining. Activity of matrix metalloproteinases (MMP) in the left ventricle was measured by zymography. Mean blood pressure (mmHg) increased from 139 +/- 20 to 198 +/- 19, 187 +/- 23, and 166 +/- 16 at 15, 30, and 60 minutes, respectively, during NE infusion. HR (beats/minute) decreased from 214 +/- 10 to 158 +/- 28 at 15 minutes and then recovered gradually. The left ventricles showed significant dilatation (end-diastolic diameter: from 1.20 +/- 0.18 to 1.58 +/- 0.23cm, p=0.003; end-systolic diameter: from 0.62 +/- 0.23 to 1.35 +/- 0.29cm, p=0.002) and hypokinesia (EF: from 86.2 +/- 5.2 to 33.1 +/- 16.5%, p < 0.001). Histopathology revealed that left ventricular myocytes were elongated, wavy, and fragmented, while collagen fibers were overstretched, straightened, and disrupted. MMP-9 activity was significantly elevated (p = 0.003 vs. control), while MMP-2 activity was unchanged. High-dose NE increases MMP-9 activity and causes ECM disruption, left ventricular dilatation and dysfunction.