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

Chiu, Yung-Tsung; Cheng, Ching-Chang; Lin, Nai-Nu; Hung, Yi-Wen; Chen, Ying-Tsung; Hsu, Shih-Lan; Chi, Ching-Shiang; Fu, Yun-Ching

doi:10.1016/S1726-4901(09)70271-0

Next »Journal of the Chinese Medical Association
Volume 69, Issue 8 , Pages 343-350, August 2006

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

Yung-Tsung Chiu
- Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
Ching-Chang Cheng
- Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
Nai-Nu Lin
- Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
Yi-Wen Hung
- Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
Ying-Tsung Chen
- Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
Shih-Lan Hsu
- Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
Ching-Shiang Chi
- Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
Yun-Ching Fu
- Department of Pediatrics, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.
- Department of Pediatrics, National Yang-Ming University School of Medicine, Taipei, Taiwan, R.O.C.
- Correspondence to: Dr Yun-Ching Fu, Department of Pediatrics, Taichung Veterans General Hospital, 160, Section 3, Chung-Kang Road, Taichung 407, Taiwan, R.O.C.

Received 29 September 2005; accepted 19 June 2006.

Background

Intravenous norepinephrine (NE) at a dose of 1-6 μg/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.

Methods

After intraperitoneal urethane-chloralose anesthesia, 7 cats (3.03 ± 0.58 kg) received intravenous infusion of NE 30 (ig/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 echocardio-graphy 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.

Results

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.