Search

Parasympathetic stimulation of the heart, which provides protection from arrhythmias and sudden death, involves activation of the G protein--coupled inward rectifying [K.sup.+] channel GIRK1/4 and results in an acetylcholine-sensitive [K.sup.+] current, [I.sub.KACh]. We describe a unique relationship between lipid homeostasis, the lipid-sensitive transcription factor SREBP-1, regulation of the cardiac parasympathetic response, and the development of ventricular arrhythmia. In embryonic chick atrial myocytes, lipid lowering by culture in lipoprotein-depleted serum increased SREBP-1 levels, GIRK1 expression, and [I.sub.KACh] activation. Regulation of the GIRK1 promoter by SREBP-1 and lipid lowering was dependent on interaction with 2 tandem sterol response elements and an upstream E-box motif. Expression of dominant negative SREBP-1 (DN--SREBP-1) reversed the effect of lipid lowering on [I.sub.KACh] and GIRK1. In SREBP-1 knockout mice, both the response of the heart to parasympathetic stimulation and the expression of GIRK1 were reduced compared with WT. [I.sub.KACh], attenuated in atrial myocytes from SREBP-1 knockout mice, was stimulated by SREBP-1 expression. Following myocardial infarction, SREBP-1 knockout mice were twice as likely as WT mice to develop ventricular tachycardia in response to programmed ventricular stimulation. These results demonstrate a relationship between lipid metabolism and parasympathetic response that may play a role in arrhythmogenesis., Introduction The balance between the response of the heart to sympathetic and parasympathetic stimuli not only determines the rate and force of contraction but also plays a role in regulating [...]

Retrospective studies suggest that statins might exert an antiarrhythmic effect on the heart. The mechanism of this effect is unclear. Parasympathetic stimulation of the heart has been shown to protect against ventricular arrhythmias. The goal of this study was to determine the effect of statins on ventricular arrhythmias and its correlation with changes in parasympathetic responsiveness and Gαi2 expression. Patients were randomized to pravastatin and simvastatin in a double-blind crossover design. Ventricular arrhythmias were determined by analysis of 24-hour Holter recordings. Spectral RR interval analysis of Holter studies determined peak high-frequency power fraction, which reflects parasympathetic modulation of heart rate. Expression of Gαi2, a molecular component of the parasympathetic response pathway, was determined by Western blots of patients'' lymphocytes. Pravastatin treatment decreased the incidence of ventricular premature complexes by 22.5 ± 3.4% (n = 20, p <0.05), couplets, and runs of 3 to 6 beats of nonsustained ventricular tachycardia from 9.8 ± 2.67 to 3.9 ± 1.25 events/patient/24 hours (n = 12, p <0.05). Pravastatin increased peak high-frequency fraction by 29.8 ± 4.3% (n = 33, p <0.001), while Gαi2 expression increased by 51.3 ± 22.5% (n = 21, p <0.05). Effects of simvastatin on ventricular premature complexes and nonsustained ventricular tachycardia were not significant. Relative changes in couplets and nonsustained ventricular tachycardia in pravastatin-treated patients correlated negatively with changes in Gαi2 and high-frequency fraction (ρ = −0.588 and ρ = −0.763, respectively, n = 12, p <0.05). In conclusion, these data suggest that pravastatin might decrease cardiac irritability via an increase in parasympathetic responsiveness and that changes in Gαi2 expression might serve as a molecular marker for this effect, which might play a role in the molecular mechanism of the antiarrhythmic effect of statins. [Copyright &y& Elsevier]

The article presents a study that analyzes the mechanism of sterol regulatory element binding protein-1 (SREBP-1) for insulin regulation of cardiac parasympathetic response in Ins2Akita diabetic mice. It cites the results of Western blot analysis of Akita mice extracts which show that insulin treatment increased GIRK1 expression, SREBP-1, and IKAch activity in atrial myocytes. Moreover, insulin treatment of atrial myocytes induced expression of GIRK1.

Parasympathetic stimulation of the heart, which provides protection from arrhythmias and sudden death, involves activation of the G protein-coupled inward rectifying K+ channel GIRK1/4 and results in an acetylcholine-sensitive K+ current, IKACh. We describe a unique relationship between lipid homeostasis, the lipid-sensitive transcription factor SREBP-1, regulation of the cardiac parasympathetic response, and the development of ventricular arrhythmia. In embryonic chick atrial myocytes, lipid lowering by culture in lipoprotein-depleted serum increased SREBP-1 levels, GIRK1 expression, and IKACh activation. Regulation of the GIRK1 promoter by SREBP-1 and lipid lowering was dependent on interaction with 2 tandem sterol response elements and an upstream E-box motif. Expression of dominant negative SREBP-1 (DN-SREBP-1) reversed the effect of lipid lowering on IKACh and GIRK1. In SREBP-1 knockout mice, both the response of the heart to parasympathetic stimulation and the expression of GIRK1 were reduced compared with WT. IKACh, attenuated in atrial myocytes from SREBP-1 knockout mice, was stimulated by SREBP-1 expression. Following myocardial infarction, SREBP-1 knockout mice were twice as likely as WT mice to develop ventricular tachycardia in response to programmed ventricular stimulation. These results demonstrate a relationship between lipid metabolism and parasympathetic response that may play a role in arrhythmogenesis. [ABSTRACT FROM AUTHOR]