Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus. Methods and results: In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05–7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65–0.75)] and calibration slope of 1.01 (95% CI 0.99–1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%. Conclusion: Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC.

Risk stratification of patients with long QT syndrome (LQTS) represents a difficult task. In 2018, we proposed a granular estimate of the baseline 5-year risk of life-threatening arrhythmias (LAE) for patients with LQTS, based on the genotype (long QT syndrome Type 1, long QT syndrome Type 2, and long QT syndrome Type 3) and the duration of the QTc interval. We sought to externally validate a novel risk score model (1-2-3-LQTS-Risk model) in a geographically diverse cohort from the USA and to evaluate its performance and assess potential clinical implication of this novel model. The prognostic model (1-2-3-LQTS-Risk model) was derived using data from a prospective, single-centre longitudinal cohort study published in 2018 (discovery cohort) and was validated using an independent cohort of 1689 patients enrolled in the International LQTS Registry (Rochester NY, USA). The validation study revealed a C-index of 0.69 [95% confidence interval (CI): 0.61–0.77] in the validation cohort, when compared with C-index of 0.79 (95% CI: 0.70–0.88) in the discovery cohort. Adopting a 5-year risk ≥5%, as suggested by the ROC curve analysis as the most balanced threshold for implantable cardioverter-defibrillator (ICD) implantation, would result in a number needed to treat (NNT) of nine (NNT = 9; 95% CI: 6.3–13.6). The 1-2-3-LQTS-Risk model, the first validated 5-year risk score model for patients with LQTS, can be used to aid clinicians to identify patients at the highest risk of LAE who could benefit most from an ICD implant and avoid unnecessary implants.

Mitral valve prolapse is a common cardiac condition, with an estimated prevalence between 1% and 3%. Most patients have a benign course, but ever since its initial description mitral valve prolapse has been associated to sudden cardiac death. Although the causal relationship between mitral valve prolapse and sudden cardiac death has never been clearly demonstrated, different factors have been implicated in arrhythmogenesis in patients with mitral valve prolapse. In this work, we offer a comprehensive overview of the etiology and the genetic background, epidemiology, pathophysiology, and we focus on the state-of-the-art imaging-based diagnosis of mitral valve prolapse. Going beyond the classical, well-described clinical factors, such as young age, female gender and auscultatory findings, we investigate multimodality imaging features, such as alterations of anatomy and function of the mitral valve and its leaflets, the structural and contractile anomalies of the myocardium, all of which have been associated to sudden cardiac death.

Background and Aims: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. Methods: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. Results: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. Conclusions: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

BACKGROUND: Desmosomal gene variants (DGVs) have been associated with a diverse spectrum of phenotypic manifestations within arrhythmogenic cardiomyopathy, but data on genotype-specific outcomes are lacking. We investigated genotype-specific arrhythmic and heart failure (HF) outcomes in DGV carriers. METHODS: This cohort study included consecutive patients referred for screening for desmosomal genes. Carriers of pathogenic and rare (allele frequency <10 ^{− 4} ) variants of uncertain significance were included. The arrhythmic end point was the occurrence of a life-threatening arrhythmic event, defined as sudden cardiac death, aborted cardiac arrest, or hemodynamically unstable ventricular tachycardia. The end-stage HF outcome was the composite of a fatal HF episode or cardiac transplantation. RESULTS: We included 533 DGV carriers (59% male; median [interquartile range] age, 39 [22–54] years) from 214 families: 503 of 533 had a single DGV (212 [40%] PKP2 , 160 [30%] DSP , 97 [18%] DSG2 , 34 [6%] DSC2 ) and 30 of 533 (6%) double DGVs. Overall, 83 of 533 (16%) experienced a life-threatening arrhythmic event (at age 40 [33–51] years), and 14 of 533 (3%) experienced end-stage HF (at age 57 [50–60] years). Multivariable analysis demonstrated that, compared with nonmissense PKP2 variants, nonmissense DSP variants (hazard ratio [HR], 2.3 [95% CI, 1.3–4.1]; P =0.008), missense variants in hotspot domains in DSP (HR, 2.7 [95% CI, 1.2–6.2]; P =0.010) and PKP2 (HR, 3.6 [95% CI, 2.0–6.5]; P <0.001), male sex (HR, 1.7 [95% CI, 1.1–2.8]; P =0.021), and double DGVs (HR, 3.4 [95% CI, 1.7–6.9]; P <0.001) were associated with a higher risk of a life-threatening arrhythmic event. Nonmissense DSP variants (HR, 5.0 [95% CI, 1.5–18.2]; P =0.009) and double DGVs (HR, 4.7 [95% CI, 1.0–19.3]; P =0.044) were also associated with increased risk of end-stage HF. CONCLUSIONS: Among carriers of DGVs, genotype was associated with arrhythmic and HF outcomes, with type and location of the variant further modulating the natural history.

Advances in understanding the genetic architecture and novel imaging techniques have profoundly impacted research on arrhythmogenic right ventricular cardiomyopathy (ARVC). As knowledge of ARVC has evolved, so has its classification: originally termed “arrhythmogenic right ventricular dysplasia”, it was later broadened to “arrhythmogenic cardiomyopathy” (ACM) to include left ventricular forms. However, the 2023 European Society of Cardiology guidelines advocate reintroducing ARVC for fibro-fatty right ventricular disease and adopting “non-dilated left ventricular cardiomyopathy” for left-sided phenotypes previously labelled as ACM variants. Genetic testing has become critical in ARVC diagnosis, particularly for identifying mutations in desmosomal genes (e.g., PKP2, DSP, DSG2, DSC2, JUP), which are the primary genetic contributors to ARVC and inform family screening and diagnostic decisions. Recent expert consensus confirmed that only TMEM43, PLN, and DES gene mutations among non-desmosomal genes had sufficient evidence to suggest a causative relationship. While genotype-specific risk assessment models are being developed, at present, genetic background does not represent an independent risk factor for patients with ARVC. Novel gene therapies, particularly AAV-mediated PKP2 gene replacement, have recently been demonstrated to be useful in reversing ARVC phenotypes in preclinical models. FDA-approved trials are currently evaluating PKP2-targeted therapies, and CRISPR/Cas9 methods are being explored for PLN-R14del mutations. Overall, current evidence supports distinct gene-specific manifestations within ARVC, aligning clinical phenotypes with specific genetic variants. This progress points to a future in which risk stratification and management are personalized through gene- and mutation-specific approaches, advancing the potential for precision medicine in ARVC care.