Journal
CIRCULATION RESEARCH
Volume 92, Issue 10, Pages 1145-1152Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000072999.51484.92
Keywords
arrhythmia; lipids; ion channels; nervous system; pathology
Funding
- NHLBI NIH HHS [R01-HL66389, R01-HL71140, R01-HL58533, P50-HL52319] Funding Source: Medline
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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 (R-2 = 0.94; P < 0.001) and TH (R-2 = 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.
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