The term idiopathic ventricular fibrillation (IVF) describes survivors of unexplained cardiac arrest (UCA) without a specific diagnosis after clinical and genetic testing. Previous reports have described a subset of IVF individuals with ventricular arrhythmia initiated by short-coupled trigger premature ventricular contractions (PVCs) for which the term short-coupled ventricular fibrillation (SCVF) has been proposed. The aim of this article is to establish the phenotype and frequency of SCVF in a large cohort of UCA survivors. We performed a multicentre study including consecutive UCA survivors from the CASPER registry. Short-coupled ventricular fibrillation was defined as otherwise unexplained ventricular fibrillation initiated by a trigger PVC with a coupling interval of <350 ms. Among 364 UCA survivors, 24/364 (6.6%) met diagnostic criteria for SCVF. The diagnosis of SCVF was obtained in 19/24 (79%) individuals by documented ventricular fibrillation during follow-up. Ventricular arrhythmia was initiated by a mean PVC coupling interval of 274 ± 32 ms. Electrical storm occurred in 21% of SCVF probands but not in any UCA proband (P < 0.001). The median time to recurrent ventricular arrhythmia in SCVF was 31 months. Recurrent ventricular fibrillation resulted in quinidine administration in 12/24 SCVF (50%) with excellent arrhythmia control. Short-coupled ventricular fibrillation is a distinct primary arrhythmia syndrome accounting for at least 6.6% of UCA. As documentation of ventricular fibrillation onset is necessary for the diagnosis, most cases are diagnosed at the time of recurrent arrhythmia, thus the true prevalence of SCVF remains still unknown. Quinidine is effective in SCVF and should be considered as first-line treatment for patients with recurrent episodes. Short-coupled ventricular fibrillation (SCVF) is a distinct primary electrical disorder accounting for at least 6.6% of otherwise idiopathic VF. Quinidine is highly effective for SCVF.

Since current experimental models of Atrial Fibrillation (AF) have significant limitations, we used human embryonic stem cells (hESCs) to generate an atrial-specific tissue model of AF for pharmacologic testing. We generated atrial-like cardiomyocytes (CMs) from hESCs which preferentially expressed atrial-specific genes, and had shorter action potential (AP) durations compared to ventricular-like CMs. We then generated confluent atrial-like CM sheets and interrogated them using optical mapping techniques. Atrial-like CM sheets (~1 cm in diameter) showed uniform AP propagation, and rapid re-entrant rotor patterns, as seen in AF could be induced. Anti-arrhythmic drugs were tested on single atrial-like CMs and cell sheets. Flecainide profoundly slowed upstroke velocity without affecting AP duration, leading to reduced conduction velocities (CVs), curvatures and cycle lengths of rotors, consistent with increased rotor organization and expansion. By contrast, consistent with block of rapid delayed rectifier K+ currents (Ikr) and AP prolongation in isolated atrial-like CMs, dofetilide prolonged APs and reduced cycle lengths of rotors in cell sheets without affecting CV. In conclusion, using our hESC-derived atrial CM preparations, we demonstrate that flecainide and dofetilide modulate reentrant arrhythmogenic rotor activation patterns in a manner that helps explain their efficacy in treating and preventing AF.

Genetic testing is recommended in specific inherited heart diseases but its role remains unclear and it is not currently recommended in unexplained cardiac arrest (UCA). We sought to assess the yield and clinical utility of genetic testing in UCA using whole-exome sequencing (WES). Survivors of UCA requiring external defibrillation were included from the Cardiac Arrest Survivor with Preserved Ejection fraction Registry. Whole-exome sequencing was performed, followed by assessment of rare variants in previously reported cardiovascular disease genes. A total of 228 UCA survivors (mean age at arrest 39 ± 13 years) were included. The majority were males (66%) and of European ancestry (81%). Following advanced clinical testing at baseline, the likely aetiology of cardiac arrest was determined in 21/228 (9%) cases. Whole-exome sequencing identified a pathogenic or likely pathogenic (P/LP) variant in 23/228 (10%) of UCA survivors overall, increasing the proportion of ‘explained’ cases from 9% only following phenotyping to 18% when combining phenotyping with WES. Notably, 13 (57%) of the 23 P/LP variants identified were located in genes associated with cardiomyopathy, in the absence of a diagnosis of cardiomyopathy at the time of arrest. Genetic testing identifies a disease-causing variant in 10% of apparent UCA survivors. The majority of disease-causing variants was located in cardiomyopathy-associated genes, highlighting the arrhythmogenic potential of such variants in the absence of an overt cardiomyopathy diagnosis. The present study supports the use of genetic testing including assessment of arrhythmia and cardiomyopathy genes in survivors of UCA. Study flowchart and summary results. ARVC, arrhythmogenic right ventricular cardiomyopathy; BrS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; CRDS, RYR2 Ca²⁺ release deficiency syndrome; DCM, dilated cardiomyopathy; ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome; LV, left ventricular; MRI, magnetic resonance imaging; MVP, mitral valve prolapse; SQTS, short QT syndrome; UCM, unclassified cardiomyopathy; WES, whole-exome sequencing.

Ibrutinib (IB) is an oral Bruton's tyrosine kinase (BTK) inhibitor that has demonstrated benefit in B cell cancers, but is associated with a dramatic increase in atrial fibrillation (AF). We employed cell-specific differentiation protocols and optical mapping to investigate the effects of IB and other tyrosine kinase inhibitors (TKIs) on the voltage and calcium transients of atrial and ventricular human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). IB demonstrated direct cell-specific effects on atrial hPSC-CMs that would be predicted to predispose to AF. Second-generation BTK inhibitors did not have the same effect. Furthermore, IB exposure was associated with differential chamber-specific regulation of a number of regulatory pathways including the receptor tyrosine kinase pathway, which may be implicated in the pathogenesis of AF. Our study is the first to demonstrate cell-type-specific toxicity in hPSC-derived atrial and ventricular cardiomyocytes, which reliably reproduces the clinical cardiotoxicity observed.

A polygenic risk score (PRS) is derived from a genome-wide association study and represents an aggregate of thousands of single-nucleotide polymorphisms that provide a baseline estimate of an individual’s genetic risk for a specific disease or trait at birth. However, it remains unclear how PRSs can be used in clinical practice. We provide an overview of the PRSs related to cardiometabolic disease and discuss the evidence supporting their clinical applications and limitations. The Preferred Reporting Items For Systematic Reviews and Meta-Analysis Extension for Scoping Reviews protocol was used to conduct a scoping review of the MEDLINE, EMBASE, and CENTRAL databases. Across the 4863 studies screened, 82 articles met the inclusion criteria. The most common PRS related to coronary artery disease, followed by hypertension and cerebrovascular disease. Limited ancestral diversity was observed in the study sample populations. Most studies included only individuals of European ancestry. The predictive performance of most PRSs was similar to or superior to traditional risk factors. More than half of the included studies reported an integrated risk model combining a derived PRS and clinical risk tools such as the Framingham Risk Score and Pooled Cohort Equations. The inclusion of a PRS into a clinical risk model tended to improve predictive accuracy consistently. This scoping review is the first of its kind and reports strong evidence for the clinical utility of PRSs in coronary artery disease, hypertension, cerebrovascular disease, and atrial fibrillation. However, most PRSs are generated in cohorts of European ancestry, which likely contributes to a lack of PRS transferability across different ancestral groups. Future prospective studies should focus on further establishing the clinical utility of PRSs and ensuring diversity is incorporated into genome-wide association study cohorts.

Same-day discharge is increasingly common after catheter ablation for atrial fibrillation (AF). However, the impact of same-day discharge on healthcare utilization after ablation and whether this differs by ablation modality remains uncertain. We examined the safety, efficacy, and subsequent healthcare utilization of a same-day discharge protocol for AF ablation, including radiofrequency (RF) and cryoballoon ablation, in a contemporary cohort. All consecutive patients for whom full healthcare utilization data were available at two centres and who underwent AF ablation from 2018 to 2019 were included. Same-day discharge was the default strategy for all patients. The efficacy and safety outcomes were proportions of same-day discharge and readmission/emergency room (ER) visits, and post-discharge complications, respectively. Of the 421 patients who underwent AF ablation (mean 63.3 ± 10.2 years, 33% female), 90.5% (381/421) achieved same-day discharge with no difference between RF and cryoballoon ablation (89.8 vs. 95.1%, adjusted P = 0.327). Readmission ≤30 days occurred in 4.8%, with ER visits ≤30 days seen in 26.1% with no difference between ablation modalities (P = 0.634). Patients admitted overnight were more likely to present to the ER (40.0 vs. 24.7% with same-day discharge, P = 0.036). The overall post-discharge complication rate was low at 4/421 (1.0%), with no difference between ablation modality (P = 0.324) and admission/same-day discharge (P = 0.485). Same-day discharge can be achieved in a majority of patients undergoing RF or cryoballoon ablation for AF. Healthcare utilization, particularly ER visits, remains high after AF ablation, regardless of ablation modality or same-day discharge.