High prevalence and distinctive clinical features of LMNA-associated atrioventricular block in young patients.

BACKGROUND AND AIMS: Atrioventricular block (AVB) is a degenerative disease and more commonly encountered in elderly patients, but unusual and often of unknown etiology in young patients. This study aimed to investigate the potential contributions of genetic variations to AVB of unknown reasons in young patients. METHODS: We enrolled 41 patients aged <55 years with high-degree AVB of unknown etiology whose clinical and genetic data were collected. RESULTS: Genetic variants were identified in 20 (20/41, 48.8%) patients, 11 (11/20, 55%) of whom had LMNA variants including 3 pathogenic (c.961C > T, c.936+1G > T and c.646C > T), 4 likely pathogenic (c.1489-1G > C, c.265C > A, c.1609-2A > G and c.1129C > T) and 3 of uncertain significance (c.1158-3C > G, c.776A > G and c.674G > T). Compared to those without LMNA variants, patients with LMNA variants demonstrated a later age at onset of AVB (41.45 ± 9.89 years vs 32.93 ± 12.07 years, P = .043), had more prevalent family history of cardiac events (81.8% vs 16.7%, P < .000), suffered more frequently atrial (81.8% vs 10.0%, P < .000) and ventricular (72.7% vs 10.0%, P < .000) arrhythmias, and were more significantly associated with enlargement of left atrium (39.91 ± 7.83 mm vs 34.30 ± 7.54 mm, P = .043) and left ventricle (53.27 ± 8.53 mm vs 47.77 ± 6.66 mm, P = .036). CONCLUSIONS: Our findings provide insights into the genetic etiology of AVB in young patients. LMNA variants are predominant in genotype positive patients and relevant to distinctive phenotypic properties.

Diagnostic Challenges in Atrioventricular Block Preceding Cardiomyopathy.

This case report describes a patient in their 30s with ventricular tachycardia and coexisting atrioventricular block and atrial fibrillation with normal cardiac structure and function.

Nomogram for predicting cardiac death and heart transplantation in arrhythmogenic right ventricular cardiomyopathy.

AIMS: In this study, we aimed to develop and validate a competing risk nomogram for predicting cardiac death and heart transplantation (HT) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS: We retrospectively enrolled 149 consecutive patients with ARVC diagnosed at our institution between 2008 and 2022. Cox proportional hazards model was primarily used to identify variables associated with cardiac death and HT. On the basis of these indicators, a competing risk nomogram was developed to predict the 1, 3, and 5 year probabilities of cardiac death and HT. The area under the receiver operating characteristic curve (AUC), Harrell's C-index, and calibration curves were used to evaluate and internally validate the performance of the model. Decision curve analysis was performed to assess the clinical utility of the nomogram. RESULT: Of the 149 patients with ARVC, the mean age was 38.77 ± 15.94 years, and most of the patients were men (67.11%, 100/149). Fourteen patients experienced cardiac death and nine underwent HT, during a median follow-up period of 5.8 years (interquartile range, 0.62-5.56 years). Multivariable COX analysis revealed that extent of TWI in the anterior and inferior leads (P = 0.0057), right atrial diameter on transthoracic echocardiography (P = 0.0498), RVEF (P = 0.1036), and LVEF (P < 0.001) all showed statistical significance. The 1-, 3-, and 5-year cumulative incidence of cardiac death and HT were 3.35%, 8.05%, and 11.4%, respectively. The area under the receiver operating characteristic curve of the nomogram for predicting cardiac death and HT at 1, 3, and 5 years after diagnosis of ARVC were 0.860, 0.935, and 0.956. The value of Harrell's C-index is 0.9273 (95% confidence interval 0.8954-0.9590; P < 0.001), indicating that the model had good discriminative ability in internal validation. Decision curve analysis revealed that our model was clinically useful within the entire range of potential treatment thresholds in most cases. The cumulative incidence of the primary outcomes was significantly different between the three risk groups according to nomogram-derived scores (P < 0.001). CONCLUSIONS: On the basis of a retrospective review of patients with ARVC at a single centre, we developed a novel nomogram for predicting the risk of cardiac death and HT after ARVC diagnosis. This competing risk nomogram based on four readily available clinical parameters (right atrial diameter, right and left ventricular ejection fraction, and T-wave inversion) is a potentially useful tool for individualized prognostic assessment in patients with ARVC.

Piezo1 Participated in Decreased L-Type Calcium Current Induced by High Hydrostatic Pressure via. CaM/Src/Pitx2 Activation in Atrial Myocytes.

Hypertension is a major cardiovascular risk factor for atrial fibrillation (AF) worldwide. However, the role of mechanical stress caused by hypertension on downregulating the L-type calcium current (ICa,L), which is vital for AF occurrence, remains unclear. Therefore, the aim of the present study was to investigate the role of Piezo1, a mechanically activated ion channel, in the decrease of ICa,L in response to high hydrostatic pressure (HHP, one of the principal mechanical stresses) at 40 mmHg, and to elucidate the underlying pathways. Experiments were conducted using left atrial appendages from patients with AF, spontaneously hypertensive rats (SHRs) treated with valsartan (Val) at 30 mg/kg/day and atrium-derived HL-1 cells exposed to HHP. The protein expression levels of Piezo1, Calmodulin (CaM), and Src increased, while that of the L-type calcium channel a1c subunit protein (Cav1.2) decreased in the left atrial tissue of AF patients and SHRs. SHRs were more vulnerable to AF, with decreased ICa,L and shortened action potential duration, which were ameliorated by Val treatment. Validation of these results in HL-1 cells in the context of HHP also demonstrated that Piezo1 is required for the decrease of ICa,L by regulating Ca2+ transient and activating CaM/Src pathway to increase the expression of paired like homeodomain-2 (Pitx2) in atrial myocytes. Together, these data demonstrate that HHP stimulation increases AF susceptibility through Piezo1 activation, which is required for the decrease of ICa,L via. the CaM/Src/Pitx2 pathway in atrial myocytes.