Impact of Ghrelin on Ventricular Arrhythmia and Related Mechanism After Myocardial Infarction

<b><i>Introduction:</i></b> Ghrelin is an endogenous peptide with potential protective effects on ischemic heart. <b><i>Methods:</i></b> Synthetic ghrelin was administered (100 μg·kg^-1 subcutaneous injection, twice daily) for 4 weeks in a rat model of myocardial infarction (MI) with coronary artery occlusion. At the 5th week, electrocardiogram, monophasic action potentials and autonomic nerve function were evaluated. Cardiac tyrosine hydroxylase (TH) was determined by immunofluorescence staining. <b><i>Results:</i></b> MI significantly increased sympathetic nerve activity (SNA) and ventricular arrhythmias, and prolonged APD dispersion and APD alternans (<i>p</i> &#x3c; 0.01). Ghrelin treatment significantly increased ventricular fibrillation threshold (VFT), shortened APD dispersion and APD alternans, inhibited SNA and promoted vagus nerve activities (<i>p</i> &#x3c; 0.01). Ghrelin also markedly reversed abnormal expression of TH in the peri-infarcted area of the heart (<i>p</i> &#x3c; 0.01). <b><i>Discussion/Conclusion:</i></b> Ghrelin provides a sustained electrophysiological protection by the increase of VFT and improvement of APD dispersion and APD alternans. The mechanism may be related to the regulation of autonomic nerve and sympathetic nerve remodeling. Thus, ghrelin represents a novel drug to prevent ventricular arrhythmia in ischemic heart disease.

Blockade of NaV1.8 Increases the Susceptibility to Ventricular Arrhythmias During Acute Myocardial Infarction

SCN10A/NaV1.8 may be associated with a lower risk of ventricular fibrillation in the setting of acute myocardial infarction (AMI), but if and by which mechanism NaV1.8 impacts on ventricular electrophysiology is still a matter of debate. The purpose of this study was to elucidate the contribution of NaV1.8 in ganglionated plexi (GP) to ventricular arrhythmias in the AMI model. Twenty beagles were randomized to either the A-803467 group (n = 10) or the control group (n = 10). NaV1.8 blocker (A-803467, 1 μmol/0.5 mL per GP) or DMSO (0.5 mL per GP) was injected into four major GPs. Ventricular effective refractory period, APD90, ventricular fibrillation threshold, and the incidence of ventricular arrhythmias were measured 1 h after left anterior descending coronary artery occlusion. A-803467 significantly shortened ventricular effective refractory period, APD90, and ventricular fibrillation threshold compared to control. In the A-803467 group, the incidence of ventricular arrhythmias was significantly higher compared to control. A-803467 suppressed the slowing of heart rate response to high-frequency electrical stimulation of the anterior right GP, suggesting that A-803467 could inhibit GP activity. SCN10A/NaV1.8 was readily detected in GPs, but was not validated in ventricles by quantitative RT-PCR, western blot and immunohistochemistry. While SCN10A/NaV1.8 is detectible in canine GPs but not in ventricles, blockade of NaV1.8 in GP increases the incidence of ventricular arrhythmias in AMI hearts. Our study shows for the first time an influence of SCN10A/NaV1.8 on the regulation of ventricular arrhythmogenesis via modulating GP activity in the AMI model.

Moderate but not severe hypothermia causes pro-arrhythmic changes in cardiac electrophysiology

Aims Treatment of arrhythmias evoked by hypothermia/rewarming remains challenging, and the underlying mechanisms are unclear. This in vitro experimental study assessed cardiac electrophysiology in isolated rabbit hearts at temperatures occurring in therapeutic and accidental hypothermia. Methods and results Detailed ECG, surface electrogram, and panoramic optical mapping were performed in isolated rabbit hearts cooled to moderate (31°C) and severe (17°C) hypothermia. Ventricular activation was unchanged at 31°C while action potential duration (APD) was significantly prolonged (176.9 ± 4.2 ms vs. 241.0 ± 2.9 ms, P &lt; 0.05), as was ventricular repolarization. At 17°C, there were proportionally similar delays in both activation and repolarization. These changes were reflected in the QRS and QT intervals of ECG recordings. Ventricular fibrillation threshold was significantly reduced at 31°C (16.3 ± 3.1 vs. 35 ± 3.5 mA, P &lt; 0.05) but increased at 17°C (64.2 ± 9.9, P &lt; 0.05). At 31°C, transverse conduction was relatively unchanged by cooling compared to longitudinal conduction, but at 17°C both transverse and longitudinal conduction were proportionately reduced to a similar extent. The gap junction uncoupler heptanol had a larger relative effect on transverse than longitudinal conduction and was able to restore the transverse/longitudinal conduction ratio, returning ventricular fibrillation threshold to baseline values (16.3 ± 3.1 vs. 36.3 ± 4.3 mA, P &lt; 0.05) at 31°C. Rewarming to 37°C restored the majority of the electrophysiological parameters. Conclusions Moderate hypothermia does not significantly change ventricular conduction time but prolongs repolarization and is pro-arrhythmic. Further cooling to severe hypothermia causes parallel changes in ventricular activation and repolarization, changes which are anti-arrhythmic. Therefore, relative changes in QRS and QT intervals (QR/QTc) emerge as an ECG-biomarker of pro-arrhythmic activity. Risk for ventricular fibrillation appears to be linked to the relatively low temperature sensitivity of ventricular transmural conduction, a conclusion supported by the anti-arrhythmic effect of heptanol at 31°C.

Effect of Wenxin Granules on Gap Junction and MiR-1 in Rats with Myocardial Infarction

Myocardial infarction (MI) patients are at high risk of potential lethal arrhythmia. Gap junction and microRNA-1 (miR-1) are both arrhythmia generating conditions. The present study investigated whether Wenxin Granules (Wenxin-Keli, WXKL) could prevent potential lethal arrhythmia by improving gap junctions and miR-1 following MI. Male Sprague-Dawley rats were divided randomly into control, model, metoprolol, low dose WXKL, and high dose WXKL groups. The MI rat model was created by coronary artery ligation. Treatments were administrated intragastrically to the rats for 4 weeks. Conventional transmission electron microscopy was performed to observe the ultrastructure of gap junctions. Quantitative real-time PCR and western blotting were used to detect the expression of miR-1, protein kinase C (PKC), and related proteins. Additionally, a programmatic electrophysiological stimulation test was performed to detect the ventricular fibrillation threshold (VFT). WXKL protected the ultrastructure of the gap junctions and their constituent Cx43 by regulating miR-1 and PKC mediated signal transduction and increased the VFT significantly in the rat MI model. The results suggested that WXKL is an effective alternative medicine to prevent potentially lethal arrhythmia following MI.

STUDY CARDIOTOXIC PROPERTIES OF NATIVE PEAT HUMIC ACIDS

The earlier pathomorphological studies of toxic properties of peat humic acids (PHAs) at intraperitoneal injection revealed that one of the causes of lethality is the direct cardiotoxic action of PHAs. For the further study of the mechanism of cardiotoxic action, electrocardiogram was recorded and ventricular fibrillation threshold was determined in male rats after intraperitoneal injection of humic acids in knowingly lethal dose – 480 mg/kg bwt. A single intraperitoneal injection of PHA to rats in knowingly lethal dose caused a significant decrease of the ventricular fibrillation threshold in comparison with intact animals. It was found that the PHA injection exerted no significant effect on the heart rate in rats and change of the PQ, QT, and QTc intervals. At the same time, the significant shortening of the QRS complex in comparison with intact animals was observed. Judging from the results obtained, the single injection of humic acids in the lethal dose induced a decrease in the electrical stability of heart, as evidenced by the drop of the ventricular fibrillation threshold. This decrease of the electrical stability of heart can be a cause of sudden cardiac death of trial rats. Disorder of the heart electrical stability is likely connected with the ionophoric action of humic acids and change of electrophysiological properties of cell membranes.