Measures of repolarization variability predict ventricular arrhythmogenesis in heptanol-treated Langendorff-perfused mouse hearts

Objective: Ventricular arrhythmia episodes are not infrequent in patients with atrial septal defect (ASD). Disturbance in cardiac volume and pressures may lead to enlargement and fibrosis in heart. An interatrial volume displacement through septal defect, briefly interatrial shunt, is the major reason for this complication. Prolongation of the interval between the peak and end of the T wave (Tpeak to Tend, Tp-e) on the 12-lead electrocardiogram (ECG), is utilized as a marker of ventricular arrhythmogenesis during last years. The aim of this study was to assess if there is an impact of shunt ratio on ventricular repolarization in patients with ASD by using Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio. Methods: Patient records of Samsun Training and Research Hospital were retrospectively analyzed. Electrocardiograms of 133 patients, who were diagnosed as ASD between January 2016 and December 2019 were obtained and scanned. ECG intervals were measured. Shunt ratios, right ventricle diameters and volumes were also acquired. Patients were grouped into two by their calculated shunt ratio, ratio of ≥2.0 is accepted as a high shunt group and <2.0 as a low shunt group. Results: Both groups’ baseline characteristics were similar. Right ventricular dimensions and systolic pulmonary artery pressure were higher in high shunt group. Furthermore, ASD patients with higher shunt ratio had significantly higher ECG measurements than controls, Tp-e: 103.0 (22.1) vs 76.2 (10.2); Tp-e/QT: 0.25 (0.03) vs 0.21 (0.02); Tp-e/QTc: 0.22 (0.03) vs, 0.17 (0.02); for all p<0.001). Of all ECG parameters; Tp-e (r=0.631, p<0.001), Tp-e/QT (r=0.531, p<0.001) and Tp-e/QTc (r=0.614, p<0.001) had moderate correlation with shunt ratio. Conclusion: T wave peak-to-end interval is a measure of transmural dispersion of repolarization and accepted as a surrogate for increased ventricular arrhythmogenesis risk. Our findings show that ASD patients whose shunt ratio are ≥2.0 show increased risk for arrhythmias. Key words: atrial septal defect, electrocardiogram, ventricular arrhythmia, risk, ventricular repolarization

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Macrophage depletion in stellate ganglia attenuates cardiac sympathetic overactivation and ventricular arrhythmogenesis by inhibiting neuroinflammation in heart failure

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.02071 ◽

2021 ◽

Vol 35 (S1) ◽

Author(s):

Dongze Zhang ◽

Huiyin Tu ◽

Wenfeng Hu ◽

Michael Wadman ◽

Yulong Li

Keyword(s):

Heart Failure ◽

Macrophage Depletion ◽

Stellate Ganglia ◽

Ventricular Arrhythmogenesis

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Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure

Cardiovascular Research ◽

10.1093/cvr/cvaa018 ◽

2020 ◽

Author(s):

Dongze Zhang ◽

Huiyin Tu ◽

Chaojun Wang ◽

Liang Cao ◽

Wenfeng Hu ◽

...

Keyword(s):

Heart Failure ◽

Coronary Artery ◽

Ventricular Arrhythmias ◽

Sympathetic Neurons ◽

Coronary Artery Ligation ◽

Channel Blockers ◽

Artery Ligation ◽

Cell Excitability ◽

Ventricular Arrhythmogenesis

Abstract Aims Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Methods and results Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats. Conclusions Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.

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