Ischemia-induced Ventricular Arrhythmia Research Articles

The differential benefit of using Handgrip in patients with ischemiainduced ventricular arrhythmia

The differential benefit of using Handgrip in patients with ischemiainduced ventricular arrhythmia

Chronic Expression of Interleukin-10 Transgene Modulates Cardiac Sympathetic Ganglion Resulting in Reduced Ventricular Arrhythmia.

The cardiac autonomic nervous system (CANS) is intimately connected to the regulation of electrophysiology and arrhythmogenesis in cardiac systems. This work aimed at investigating whether interleukin-10 (IL-10) could effectively modulate CANS and suppress ischemia-induced ventricular arrhythmia (VA) through chronically acting on the cardiac sympathetic ganglion (CSG). Using an adeno-associated virus (AAV), we achieved local chronic overproduction of IL-10 in the CSG, left stellate ganglion (LSG). As a result, in the IL-10 group, we observed a decreased number of tyrosine hydroxylase-positive (TH+) cells in the LSG. IL-10 markedly downregulated the nerve growth factor, synaptophysin, as well as growth-associated protein 43 expression. In vivo, results from ambulatory electrocardiography showed that IL-10 overexpression significantly inhibited the cardiac sympathetic nervous system activity and improved heart rate variability. Meanwhile, we observed decreased LSG function as well as prolonged ventricular effective refractory period and suppressed VA after myocardial infarction (MI) in the IL-10 group. In addition, IL-10 overexpression attenuated inflammation and decreased norepinephrine levels in the myocardium after acute MI. In conclusion, our data suggest that chronic IL-10 overexpression modulates cardiac sympathetic nerve remodeling and suppresses VA induced by MI. Neuromodulation through AAV-mediated IL-10 overexpression may have the characteristics of and advantages as a potential neuroimmunotherapy for preventing MI-induced VAs.

Metabolism regulator adiponectin prevents cardiac remodeling and ventricular arrhythmias via sympathetic modulation in a myocardial infarction model.

The stellate ganglia play an important role in cardiac remodeling after myocardial infarction (MI). This study aimed to investigate whether adiponectin (APN), an adipokine mainly secreted by adipose tissue, could modulate the left stellate ganglion (LSG) and exert cardioprotective effects through the sympathetic nervous system (SNS) in a canine model of MI. APN microinjection and APN overexpression with recombinant adeno-associated virus vector in the LSG were performed in acute and chronic MI models, respectively. The results showed that acute APN microinjection decreased LSG function and neural activity, and suppressed ischemia-induced ventricular arrhythmia. Chronic MI led to a decrease in the effective refractory period and action potential duration at 90% and deterioration in echocardiography performance, all of which was blunted by APN overexpression. Moreover, APN gene transfer resulted in favorable heart rate variability alteration, and decreased cardiac SNS activity, serum noradrenaline and neuropeptide Y, which were augmented after MI. APN overexpression also decreased the expression of nerve growth factor and growth associated protein 43 in the LSG and peri-infarct myocardium, respectively. Furthermore, RNA sequencing of LSG indicated that 4-week MI up-regulated the mRNA levels of macrophage/microglia activation marker Iba1, chemokine ligands (CXCL10, CCL20), chemokine receptor CCR5andpro-inflammatory cytokine IL6, and downregulated IL1RN and IL10 mRNA, which were reversed by APN overexpression. Our results reveal that APN inhibits cardiac sympathetic remodeling and mitigates cardiac remodeling after MI. APN-mediated gene therapy may provide a potential therapeutic strategy for the treatment of MI.

FAT10 protects against ischemia-induced ventricular arrhythmia by decreasing Nedd4-2/Nav1.5 complex formation

The human leukocyte antigen F-associated transcript 10 (FAT10) is a member of the small ubiquitin-like protein family that binds to its target proteins and subjects them to degradation by the ubiquitin–proteasome system (UPS). In the heart, FAT10 plays a cardioprotective role and affects predisposition to cardiac arrhythmias after myocardial ischemia (MI). However, whether and how FAT10 influences cardiac arrhythmias is unknown. We investigated the role of FAT10 in regulating the sodium channel Nav1.5, a major regulator of cardiac arrhythmias. Fat10 was conditionally deleted in cardiac myocytes using Myh6-Cre and Fat10F/F mice (cFat10−/−). Compared with their wild-type littermates, cFat10−/− mice showed prolonged RR, PR, and corrected QT (QTc) intervals, were more likely to develop ventricular arrhythmia, and had increased mortality after MI. Patch-clamp studies showed that the peak Na+ current was reduced, and the late Na+ current was significantly augmented, resulting in a decreased action potential amplitude and delayed depolarization. Immunoblot and immunofluorescence analyses showed that the expression of the membrane protein Nav1.5 was decreased. Coimmunoprecipitation experiments demonstrated that FAT10 stabilized Nav1.5 expression by antagonizing Nav1.5 ubiquitination and degradation. Specifically, FAT10 bound to the lysine residues in the C-terminal fragments of Nav1.5 and decreased the binding of Nav1.5 to the Nedd4-2 protein, a ubiquitin E3 ligase, preventing degradation of the Nav1.5 protein. Collectively, our findings showed that deletion of the Fat10 in cardiac myocytes led to increased cardiac arrhythmias and increased mortality after MI. Thus, FAT10 protects against ischemia-induced ventricular arrhythmia by binding to Nav1.5 and preventing its Neddylation and degradation by the UPS after MI.

Gut microbe-derived metabolite trimethylamine N-oxide activates the cardiac autonomic nervous system and facilitates ischemia-induced ventricular arrhythmia via two different pathways

BackgroundWe previously demonstrated the gut microbes-derived metabolite trimethylamine N-oxide (TMAO) could activate the atrial autonomic ganglion plexus and promote atrial arrhythmia. The cardiac sympathetic nervous system (CSNS) play important roles in modulating ventricular arrhythmia (VA). MethodsPart 1: To test whether TMAO can directly activate the CSNS, we performed local injection of TMAO into the left stellate ganglion (LSG). Part 2: To test whether TMAO can indirectly activate the CSNS through the central nervous system, we performed intravenous injection of TMAO. Ventricular electrophysiology and LSG function and neural activity were measured before and after TMAO administration. Then, the left anterior descending coronary artery was ligated, and electrocardiograms were recorded for 1 h. At the end of the experiment, LSG and paraventricular nucleus (PVN) tissues were excised for molecular analyses. FindingsCompared with the control, both intravenous and local TMAO administration significantly increased LSG function and activity, shortened effective refractory period, and aggravated ischemia-induced VA. Proinflammatory markers and c-fos in the LSG were also significantly upregulated in both TMAO-treated groups. Particularly, c-fos expression in PVN was significantly increased in the systemic TMAO administration group but not the local TMAO administration group. InterpretationThe gut microbe-derived metabolite TMAO can activate the CSNS and aggravate ischemia-induced VA via the direct pathway through the LSG and the indirect pathway through central autonomic activation. FundThis work was supported by the National Key R&D Program of China [2017YFC1307800], and the National Natural Science Foundation of China [81530011, 81770364, 81570463, 81871486, 81600395, 81600367 and 81700444].

MAST CELLS MODULATE THE PATHOGENESIS OF LEPTIN-INDUCED VENTRICULAR ARRHYTHMIAS IN CANINE

Mast cells are important immune cells that drive the obesity-related inflammation. Adipocytokine leptin was shown to promote the activation of the left stellate ganglion (LSG) leading to enhanced ischemia-induced ventricular arrhythmia (VA). This study aims to investigate the role of mast cell in

GW28-e1210 Leptin promotes acute ischemia-induced ventricular arrhythmia by increasing nerve activity of left stellate ganglion

GW28-e1210 Leptin promotes acute ischemia-induced ventricular arrhythmia by increasing nerve activity of left stellate ganglion

Blocking the Nav1.8 channel in the left stellate ganglion suppresses ventricular arrhythmia induced by acute ischemia in a canine model

Left stellate ganglion (LSG) hyperactivity promotes ischemia induced ventricular arrhythmia (VA). Blocking the Nav1.8 channel decreases neuron activity. Therefore, the present study aimed to investigate whether blocking the Nav1.8 channel with its specific blocker A-803467 in the LSG reduces sympathetic activity and exerts anti-arrhythmic effects. Forty canines were divided into dimethylsulfoxide (DMSO) group and 10 mM, 15 mM, and 20 mM A-803467 groups. A volume of 0.1 ml of A-803467 or DMSO was injected into the LSG. The ventricular electrophysiological parameters, LSG function were measured before and 30 min after the injection. VA was assessed for 60 min after ischemia and then LSG tissues were collected for molecular biological experiments. Compared with DMSO, concentration-dependent prolonged action potential duration and effective refractory period, decreased LSG function were identified after A-803467 treatment. Moreover, the severity of ischemia induced VA was decreased in A-803467 groups. Furthermore, decreased nerve growth factor, decreased c-fos and increased sympathetic neuron apoptosis were found in the LSG after A-803467 injection. In conclusion, blocking the Nav1.8 channel could significantly attenuate ischemia-induced VA, primarily by suppressing LSG activity.

Effects of antiarrhythmic peptide 10 on acute ventricular arrhythmia.

To observe the effects antiarrhythmic peptide 10 (AAP10) aon acute ventricular arrhythmia and the phosphorylation state of ischemic myocardium connexin. Acute total ischemia and partial ischemia models were established by ceasing perfusion and ligating the left anterior descending coronary artery in SD rats. The effects of AAP10 (1 mg/L) on the incidence rate of ischemia-induced ventricular arrhythmia were observed. The ischemic myocardium was sampled to detect total-Cx43 and NP-Cx43 by immunofluorescent staining and western blotting. the total-Cx43 expression was detected through image analysis system by semi-quantitative analysis. AAP10 could significantly decrease the incidence of ischemia-induced ventricular tachycardia and ventricular fibrillation. During ischemic stage, total ischemia (TI) and AAP10 total ischemia (ATI) groups were compared with partial ischemia (PI) and AAP10 partial ischemia (API) groups. The rates of incidence for arrhythmia in the ATI and API groups (10% and 0%) were lower than those in the TI and PI groups (60% and 45%). The difference between the two groups was statistically significant (P=0.019, P=0.020). The semi-quantitative analysis results of the ischemic myocardium showed that the total-Cx43 protein expression distribution areas for TI, ATI, PI and API groups were significantly decreased compared with the control group. On the other hand, the NP-Cx43 distribution areas of TI, ATI, PI and API groups were significantly increased compared with the control group (P>0.05). AAP10 could increase the total-Cx43 expression in the ischemic area and decrease the NP-Cx43 expression. Western blot results were consistent with the results of immunofluorescence staining. AAP10 can significantly decrease the rate of incidence of acute ischemia-induced ventricular tachycardia and ventricular fibrillation. Acute ischemic ventricular arrhythmias may have a relationship with the decreased phosphorylation of Cx43 induced by ischemia. AAP10 may stimulate the phosphorylation of Cx43 by increasing the total-Cx43 expression and decreasing the NP-Cx43 expression in the ischemic area, so as to decrease ventricular arrhythmia.

Abstract 12610: Renal Sympathetic Denervation Modulates Ventricular Electrophysiology and Arrhythmogenesis

Introduction: Previous studies suggest that renal sympathetic nerves can modulate central sympathetic tone. Recently, a beneficial effect of renal sympathetic denervation (RSD) has been seen in patients with different settings of ventricular electrical storm. However, the effect of RSD on ventricular electrophysiology remains unclear. Methods: Twenty-eight adult mongrel dogs were included in the present study. Eighteen dogs were subjected to RSD which was performed by ablating the adventitial surface of the renal artery. In Group 1 (n=8), programmed stimulation was performed before and after RSD to determinate ventricular effective refractory period (ERP) and action potential duration (APD) restitution properties. In Group 2 (n=10), acute myocardial ischemia (AMI) was induced by ligating the proximal left anterior descending coronary artery after the performance of RSD and the incidence of ventricular arrhythmia (VA) was calculated during 1-hour recording. In another 10 dogs (Group 3), AMI was induced and VA was measured with sham RSD. Results: In Group 1, RSD significantly prolonged ventricular ERP and APD, reduced the maximum slope (Smax) of the restitution curve and suppressed APD alternans at each site (Fig. 1A, C, E). RSD also significantly decreased the spatial dispersions of ERP, APD and Smax (Fig. 1B, D, F). The occurrence of spontaneous VA during 1-h AMI in Group 2 was significantly lower than that in Group 3 (Tab. 1). Conclusions: RSD significantly prolongs ventricular ERP and APD, attenuates APD restitution properties and reduces the incidence of ischemia-induced VA, suggesting that RSD may exert an anti-arrhythmic role for VA.

Left renal nerves stimulation facilitates ischemia-induced ventricular arrhythmia by increasing nerve activity of left stellate ganglion.

Renal sympathetic nerve (RSN) activity plays a key role in systemic sympathetic hyperactivity. Previous studies have shown that cardiac sympathetic hyperactivity, especially the left stellate ganglion (LSG), contributes to the pathogenesis of ventricular arrhythmias (VAs) after acute myocardial infarction (AMI). Twenty-eight dogs received 3 hours of continuous left-sided electrical stimulation of RSN (LRS; Group-1, n = 9), sham RSN stimulation (Group-2, n = 9), or LSG ablation plus 3 hours of LRS (Group-3, n = 10) were included. AMI was induced by ligating the proximal left anterior descending coronary artery. LRS was performed using electrical stimulation on the adventitia of left renal artery at the voltage increasing the systolic blood pressure (BP) by 10%. BP, heart rate variability (HRV), serum norepinephrine (NE) level, and LSG function were measured at baseline and the end of each hour of LRS. C-fos and nerve growth factor (NGF) protein expressed in the LSG were examined in Group-1 and Group-2. Compared with baseline, 3 hours of LRS induced a significant increase in BP, sympathetic indices of HRV, serum NE level, and LSG function. The incidence of VAs in Group-1 was significantly higher than other groups. The expression of c-fos and NGF protein in the LSG was significantly higher in Group-1 than Group-2. Three hours of LRS induces both systemic and cardiac sympathetic hyperactivity and increases the incidence of ischemia-induced VAs.

Genetic study of ischemia-induced ventricular arrhythmia associated with potassium channels

ObjectiveRecent reports and our preliminary research showed that sodium channel gene is one of the disease-causing gene in ischemia-induced ventricular arrhythmia. In this study, candidate potassium genes were screened using...

Genetic Study of Ischemia-Induced Ventricular Arrhythmia Associated with Potassium Channels

Objective: Recent research shows that sodium channel gene mutation is one of the disease-causing gene in ischemia-induced ventricular arrhythmia. In this study, in order to reveal the relationship between ischemia-induced ventricular arrhythmia and potassium channel mutation. Methods: 23 patients with ischemia-induced ventricular arrhythmia were selected. 5ML peripheral blood was taken and DNA extracted. 11 candidate genes including HERG, KCNQ1, KCNE1, KCNE2, KCNJ2, KCNJ3, KCNJ8, KCNJ11, KCNJ12, KCND3 and KCNA5 were screened with direct sequencing methods. Results: 10 Potassium channel SNP have been found. The G216G is a novel SNP, which shows a change from T base to C base at the position of 1353 on the third exon of KCNJ12 gene. The SNP distribution from KCNJ12-Q192H, KCNJ12-P156L, HERG-I489I, KV1.5-P513P, Kir2.1-L382L, Kir6.2-V337I, KCNQ1-P448R and KCNQ1-S546S are similar with reported. The SNP of F513F is at the position of 1545 C base substitution T base on the seventh exon of the HERG gene. 5 patients have been found the SNP of F513F while 44 in the control group. Chi-square test shows that there is a difference in the incidence of the F513F SNP between the two groups. Conclusion: No potassium channel gene mutation has been found. A novel SNP of KCNJ12-G216G was discovered in Chinese people. The SNP of HERG-F513F might be a predisposing factor in ischemia-induced ventricular arrhythmia.

Noradrenaline Reduces Ischemia‐Induced Arrhythmia in Anesthetized Rats: Involvement of α1‐Adrenoceptors and Mitochondrial KATPChannels

We have evaluated the part played by the mitochondrial ATP-sensitive potassium (mK(ATP)) channels on effect of alpha(1)-adrenoceptor activation by noradrenaline in ischemia-induced ventricular arrhythmia. Anesthetized rats were subjected to 25 minutes of regional ischemia, and infarct size (IS) and ischemia-induced ventricular arrhythmia were measured. Group I served as saline control with ischemia (n = 9). In group II (n = 9), the ischemic period was preceded by three short episodes of ischemia, followed by reperfusion. In group III, noradrenaline (2 microg/kg, IV, n = 9) was injected prior to ischemia. In group IV, an alpha(1)-adrenoceptor blocker (prazosin, 0.5 mg/kg, IV, n = 6) was administrated prior to noradrenaline injection. In Groups V and VI, rats received a specific mitochondrial K(ATP) channel inhibitor [5-hydroxydecanoic acid (5-HD), 10 mg/kg, IV, n = 6] prior to or after noradrenaline injection. Ischemic preconditioning (IPC) and noradrenaline markedly reduced incidences of ventricular fibrillation (VF) (0%, 0% vs. 55.5% in control, P < 0.05) and ventricular tachycardia (VT) (11%, 44.5% vs. 100% in control, P < 0.001 and P < 0.05), duration of VF + VT (3 +/- 1 seconds, 4.7 +/- 2.1 seconds vs. 52.9 +/- 6 seconds in control, P < 0.001), number of VF + VT episodes (1.7 +/- 1.7, 5.75 +/- 2.4 vs. 60.5 +/- 8 in control, P < 0.001), severity of arrhythmias (0.3 +/- 0.3, 1.7 +/- 0.5 vs. 3.9 +/- 0.3 in control rats, P < 0.001 and P < 0.01), and IS (13.6 +/- 1.8%, 18.2 +/- 1.5% vs. 49.6 +/- 2.4% in control, P < 0.001). Administration of prazosin or 5-HD prior to or after noradrenaline injection intensified incidences of VF (66.6%, 66.6% and 50%, P < 0.05) and VT (100%, 100%, and 100%, P < 0.05), duration of VF + VT episodes (70.2 +/- 10.5 seconds, 69.8 +/- 6.75 seconds, and 60.8 +/- 14.9 seconds, P < 0.001), number of VF + VT episodes (56 +/- 16.4, 67 +/- 11, and 45 +/- 3.5, P < 0.01, P < 0.001, and P < 0.05), severity of arrhythmias(3.8 +/- 0.3, 4 +/- 0.5, and 3.7 +/- 0.2, P < 0.01, P < 0.05, and P < 0.01), and IS (45.5 +/- 3%, 46.8 +/- 3.4%, and 43 +/- 2.5%, respectively, P < 0.001) compared with the noradrenaline-treated group. Prazosin or 5-HD treatment eliminated the beneficial effects of noradrenaline on arrhythmogenesis and infarct size.