Carlo Napolitano

Aims: Various clinical risk factors impact the natural history of Brugada syndrome (BrS) and establish the basis of current clinical practice guidelines (CPG) indications for implantable cardioverter-defibrillator (ICD). Due to the time-dependent expressivity of BrS, their performance in predicting the actual occurrence of arrhythmic events after ICD implantation remains unknown. Objectives: To assess the occurrence of arrhythmic events based on the CPG indications and whether the genetic substrate can add to the prediction of arrhythmic events at follow-up. Methods and results: We enrolled consecutive patients who underwent ICD implant either for primary or secondary prevention. Prospective clinical data included arrhythmic history, electrocardiographic findings, therapies, SCN5A gene mutations, and genotyping of three BrS-associated single nucleotide variants. Eleven per cent of 551 patients experienced life-threatening arrhythmic events (LAE) over a median follow-up of 8.1 years. Patients with ESC class IIA indication had a similar risk profile as those implanted for secondary prevention. The recently developed BrS 5-year risk score, including clinical and genetic variables, was a determinant of outcome in the whole cohort and in patients implanted for primary prevention: 26.93 ± 3.33 vs. 4.41 ± 0.61 and 11.67 ± 1.52 vs. 5.36 ± 0.99 in patients with LAEs compared with those without events (P < 0.0001). Conclusion: CPG class IIa and I had a similar rate of ICD shock at follow-up. We also provide robust evidence indicating that the quantification of the BrS arrhythmic risk score at the moment of ICD implant may improve the identification of patients who will benefit from ICD at follow-up.

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 − 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 P =0.021), and double DGVs (HR, 3.4 [95% CI, 1.7–6.9]; P 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.

Aims: Exercise stress test (EST) represents the gold standard for diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). We aimed to determine the relevance of exercise induced VT for the occurrence of LAE at follow-up. Methods and results: In RYR2-related CPVT patients who underwent a baseline EST, we assessed the incidence and severity of ventricular arrhythmias (VA). Data were analysed using logistic regression models and Cox proportional hazards models. The primary outcome was the occurrence of life-threatening arrhythmic event (LAE; composite of sudden cardiac death, aborted cardiac arrest, or hemodynamically non-tolerated VT) at follow-up. In 102 RYR2-related CPVT patients (65 females; median age 16 years, IQR: 11–36 years), exercise-induced VT (bidirectional in 64% of cases) was elicited in 56% patients. VT could not be induced in pre-school children. Lower basal heart rate, early onset VA (within the first step of EST) and heart rate at the first minute of recovery were associated with exercise-induced VT. Cox analyses showed that early onset VA (HR 6.0, 95% CI: 1.3–27.9, P = 0.022) and exercise-induced VT (HR 6.6, 95% CI: 1.5–29.1, P = 0.012) at baseline EST were significantly associated with the occurrence of LAE at follow-up, and remained associated even after correction for symptoms. Conclusion: Early onset VA and exercise-induced VT at baseline EST was associated with LAE at follow-up, allowing to identify a sub-set of patients at higher risk already at diagnosis.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na_V1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na_V1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings.

Background: Acquired long QT syndrome (aLQTS) is a serious unpredictable adverse drug reaction. Pharmacogenomic markers may predict risk. Methods: Among 153 aLQTS patients (mean age 58 years [range, 14–88], 98.7% White, 85.6% symptomatic), computational methods identified proteins interacting most significantly with 216 QT-prolonging drugs. All cases underwent sequencing of 31 candidate genes arising from this analysis or associating with congenital LQTS. Variants were filtered using a minor allele frequency <1% and classified for susceptibility for aLQTS. Gene-burden analyses were then performed comparing the primary cohort to control exomes (n=452) and an independent replication aLQTS exome sequencing cohort. Results: In 25.5% of cases, at least one rare variant was identified: 22.2% of cases carried a rare variant in a gene associated with congenital LQTS, and in 4% of cases that variant was known to be pathogenic or likely pathogenic for congenital LQTS; 7.8% cases carried a cytochrome-P450 (CYP) gene variant. Of 12 identified CYP variants, 11 (92%) were in an enzyme known to metabolize at least one culprit drug to which the subject had been exposed. Drug-drug interactions that affected culprit drug metabolism were found in 19% of cases. More than one congenital LQTS variant, CYP gene variant, or drug interaction was present in 7.8% of cases. Gene-burden analyses of the primary cohort compared to control exomes (n=452), and an independent replication aLQTS exome sequencing cohort (n=67) and drug-tolerant controls (n=148) demonstrated an increased burden of rare (minor allele frequency<0.01) variants in CYP genes but not LQTS genes. Conclusions: Rare susceptibility variants in CYP genes are emerging as potentially important pharmacogenomic risk markers for aLQTS and could form part of personalized medicine approaches in the future.