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Calcium dysregulation increases right ventricular outflow tract arrhythmogenesis in rabbit model of chronic kidney disease.

ABSTRACT: Chronic kidney disease (CKD) increases the risk of arrhythmia. The right ventricular outflow tract (RVOT) is a crucial site of ventricular tachycardia (VT) origination. We hypothesize that CKD increases RVOT arrhythmogenesis through its effects on calcium dysregulation. We analysed measurements obtained using conventional microelectrodes, patch clamp, confocal microscopy, western blotting, immunohistochemical examination and lipid peroxidation for both control and CKD (induced by 150 mg/kg neomycin and 500 mg/kg cefazolin daily) rabbit RVOT tissues or cardiomyocytes. The RVOT of CKD rabbits exhibited a short action potential duration, high incidence of tachypacing (20 Hz)-induced sustained VT, and long duration of isoproterenol and tachypacing-induced sustained and non-sustained VT. Tachypacing-induced sustained and non-sustained VT in isoproterenol-treated CKD RVOT tissues were attenuated by KB-R7943 and partially inhibited by KN93 and H89. The CKD RVOT myocytes had high levels of phosphorylated CaMKII and PKA, and an increased expression of tyrosine hydroxylase-positive neural density. The CKD RVOT myocytes exhibited large levels of I_to , I_Kr , NCX and L-type calcium currents, calcium leak and malondialdehyde but low sodium current, SERCA2a activity and SR calcium content. The RVOT in CKD with oxidative stress and autonomic neuron hyperactivity exhibited calcium handling abnormalities, which contributed to the induction of VT.

SUBMITTER: Huang SY

PROVIDER: S-EPMC8650029 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background The ventricular premature complexes (PVCs) originating from the superior right ventricular outflow tract (RVOT) have high success rates by catheter ablation. It may not be the same when the origin is in the inferior RVOT. Objective To identify electrocardiographic (ECG) characteristics that predict the site for successful ablation of PVCs originating in the inferior RVOT. Methods Of 309 consecutive patients with symptomatic PVCs despite medical therapy, 124 had PVCs originating from the RVOT, and 107 RVOT cases without structural heart disease and no bundle branch block in sinus rhythm were enrolled in the study. Among them, 74 have a superior RVOT origin, and 33 have an inferior RVOT origin. Results The proportion with multiple morphologies of PVC was significantly higher in the inferior RVOT group than in the superior RVOT group (24.24 vs. 6.76%, P = 0.011). The QRS duration of PVCs with an inferior RVOT origin was more expansive than PVCs with a superior RVOT origin (162.42 ± 19.69 ms vs. 140.90 ± 11.30 ms; P < 0.001). Furthermore, the QRS wave in V1 in patients in the inferior RVOT group was more likely to have a negative delta wave at the onset of the QRS (27.27 vs. 1.39%, P < 0.001). We found that the areas under the receiver-operating characteristic curve (AUCs) for PVC diagnosis with an inferior RVOT origin ranged from 0.812 to 0.841 depending on ECG features, with the highest AUC for the QRS duration of PVCs and the amplitude of R waves in lead II. These ECG indices had good predictability for judging the origin of PVCs in the RVOT; the best threshold for the QRS duration of PVCs was 145 ms, and the best thresholds for the amplitude of R waves in leads II, III, and aVF were 1.35, 1.35, and 1.15 mV, respectively. Conclusion When evaluating a patient with PVCs, the source is likely to be the inferior RVOT if the ECG presentation conforms to the morphological characteristics of the RVOT, meanwhile, the QRS wave is relatively broad and polymorphic, and the main waves in limb leads (II, III, and aVF) are upward with low amplitude.

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Calcium dysregulation increases right ventricular outflow tract arrhythmogenesis in rabbit model of chronic kidney disease.

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