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(Circulation Research. 2003;92:1145.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Sympathetic Nerve Sprouting, Electrical Remodeling, and Increased Vulnerability to Ventricular Fibrillation in Hypercholesterolemic Rabbits

Yen-Bin Liu, Chau-Chung Wu, Long-Sheng Lu, Ming-Jai Su, Chii-Wann Lin, Shien-Fong Lin, Lan S. Chen, Michael C. Fishbein, Peng-Sheng Chen, Yuan-Teh Lee

From the Division of Cardiology, Department of Internal Medicine (Y.-B.L., C.-C.W., Y.-T.L.), National Taiwan University Hospital and National Taiwan University School of Medicine; Departments of Pharmacology (L.-S.L., M.J.S.) and Biomedical Engineering (C.-W.L.), National Taiwan University School of Medicine, Taipei, Taiwan; Division of Cardiology, Department of Medicine (Y.-B.L., S.-F.L., P.-S.C.), Cedars-Sinai Medical Center; Department of Neurology (L.S.C.), Children’s Hospital and USC Keck School of Medicine; and Department of Pathology and Laboratory Medicine (M.C.F.), David Geffen School of Medicine, UCLA, Los Angeles, Calif.

Correspondence to Yuan-Teh Lee, MD, PhD, Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, 10016, Taiwan, Republic of China. E-mail ytlee{at}ha.mc.ntu.edu.tw; and Peng-Sheng Chen, MD, Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, Room 5342, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail chenp@cshs.org

Whether hypercholesterolemia (HC) can induce proarrhythmic neural and electrophysiological remodeling is unclear. We fed rabbits with either high cholesterol (HC, n=10) or standard (S, n=10) chows for 12 weeks (protocol 1), and with HC (n=12) or S (n=10) chows for 8 weeks (protocol 2). In protocol 3, 10 rabbits were fed with various protocols to observe the effects of different serum cholesterol levels. Results showed that the serum cholesterol levels were 2097±288 mg/dL in HC group and 59±9 mg/dL in S group for protocol 1 and were 1889±577 mg/dL in HC group and 50±21 mg/dL in S group for protocol 2. Density of growth-associated protein 43– (GAP43) and tyrosine hydroxylase– (TH) positive nerves in the heart was significantly higher in HC than S in protocol 1. Compared with S, HC rabbits had longer QTc intervals, more QTc dispersion, longer action potential duration, increased heterogeneity of repolarization and higher peak calcium current (I_Ca) density (14.0±3.1 versus 9.1±3.4 pA/pF; P<0.01) in protocol 1 and 2. Ventricular fibrillation was either induced or occurred spontaneously in 9/12 of hearts of HC group and 2/10 of hearts in S group in protocol 2. Protocol 3 showed a strong correlation between serum cholesterol level and nerve density for GAP43 (R²=0.94; P<0.001) and TH (R²=0.91; P<0.001). We conclude that HC resulted in nerve sprouting, sympathetic hyperinnervation, and increased I_Ca. The neural and electrophysiological remodeling was associated with prolonged action potential duration, longer QTc intervals, increased repolarization dispersion, and increased ventricular vulnerability to fibrillation.

Key Words: arrhythmia • lipids • ion channels • nervous system • pathology

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