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 (ICa) 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 ICa. The neural and electrophysiological remodeling was associated with prolonged action potential duration, longer QTc intervals, increased repolarization dispersion, and increased ventricular vulnerability to fibrillation.
Background and Purpose-Stroke is a known cerebrovascular complication in lung cancer patients; however, whether lung cancer patients are at elevated risk of developing stroke relative to the noncancer population remains unclear. Methods-The present study used population-based claims data from the Taiwan National Health Insurance, which identified 52 089 patients with an initial diagnosis of lung cancer between 1999 and 2007, and 104 178 matched noncancer subjects from all insured subjects age 20 years and older. Subsequent occurrence of stroke was measured until 2008, and the association between lung cancer and the hazard of developing stroke was estimated using Cox proportional hazard models. Results-The incidence of stroke was 1.5 times higher (25.9 versus 17.4 per 1000 person-years) in the lung cancer group compared with the comparison group. The multivariate-adjusted hazard ratio (HR) comparing lung cancer patients with the noncancer group was 1.47 (95% CI, 1.39 -1.56) for stroke, 1.78 (95% CI, 1.54 -2.05) for hemorrhagic stroke, and 1.43 (95% CI, 1.34 -1.51) for ischemic stroke. The risk of stroke fell over time, decreasing after 1 year of follow-up for men and after 2 years of follow-up for women. Within the first year of follow-up, the risk of stroke peaked during the first 3 months for men and within 4 to 6 months for women. Conclusions-Lung cancer is associated with increased risk of subsequent stroke within 1 year after diagnosis for men and 2 years after diagnosis for women. (Stroke. 2011;42:3034-3039.)
Abstract-Homocysteine (Hcy) contributes to atherogenesis and angiostasis by altering the phenotype of arterial endothelial cells (ECs). The present study was aimed at elucidating potential mechanisms by which Hcy can slow EC proliferation and induce EC apoptosis, thereby disrupting endothelial integrity. Given the strong mitogenic and antiapoptotic properties of fibroblast growth factor (FGF)2, we examined whether Hcy can modulate its expression. In cultured human coronary and bovine aortic ECs, Hcy exerted time-and concentration-dependent (0 to 500 mol/L) reduction of the mRNA and protein levels of FGF2, whereas vascular endothelial growth factor expression was not affected until Hcy reached a proapoptotic 500 mol/L. By testing a panel of signal transduction inhibitors, we found that the Hcy-induced downregulation of FGF2 was specifically attenuated by pertussis toxin, an inhibitor of Gi protein signaling. Hcy induced cell cycle arrest at the G 1 /S transition and increased TUNEL-positive apoptotic cells in a graded manner. These effects were effectively counteracted by exogenous FGF2. Reporter gene assays showed that Hcy downregulated FGF2 by transcriptional repression of the gene promoter encompassed in a CpG dinucleotide-rich island. This region was heavily methylated at the cytosine residues by Hcy despite decreased methylation potential (S-adenosylmethionine to S-adenosylhomocysteine ratio). Normal levels of FGF2 transcription were restored to ECs simultaneously exposed to Hcy and 5-aza-deoxycytidine. We conclude that homocysteine disrupts the growth and survival of ECs through a G protein-mediated pathway associated with altered promoter DNA methylation and the transcriptional repression of FGF2.
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