Aims:ST-segment elevation myocardial infarction (STEMI) networks often face false-positive activations, leading to unnecessary catheterization laboratory use. To optimize resource allocation, STEMI alerts are sometimes cancelled after telematics evaluation; however, this strategy may result in missed cases of acute coronary occlusion (ACO) requiring urgent revascularization. Methods and results:This prospective, single-centre study included patients with initially activated but subsequently cancelled STEMI alerts via the ODISEA digital platform between January 2022 and December 2024. Based on coronary angiography, patients were classified as having ACO (TIMI 0-1 flow with thrombotic appearance) or no occlusion. Baseline characteristics, electrocardiogram (ECG) findings, angiographic data, and in-hospital mortality were compared. Of 2259 STEMI activations, 665 alerts (29.4%) were cancelled following a telematic assessment. Among these, 28 patients (4.2%) had ACO. Compared to the remaining cohort, they had higher rates of hypertension (78.6% vs. 60.3%; P = 0.03), diabetes (46.4% vs. 28.4%; P = 0.03), and prior coronary artery bypass grafting (10.7% vs. 2.5%; P = 0.01). Predominant ECG findings included <1 mm ST-segment elevation (67.8%) and ST-segment depression (25%). The left anterior descending artery was most frequently involved. In-hospital mortality was 10.7% in the ACO group and 7.7% in the non-ACO group (P = 0.50). Conclusion:Among cancelled STEMI alerts, missed ACO cases were infrequent, often presenting with subtle or non-classical ECG findings. These patients showed a higher burden of cardiovascular risk and increased in-hospital mortality.

BACKGROUND:Left ventricular (LV) hypertrabeculation, formerly termed LV noncompaction, is a heterogeneous myocardial entity linked to adverse cardiovascular outcomes. This study evaluated embolic risk in patients with dilated cardiomyopathy (DCM) according to the presence of hypertrabeculation and examined its prevalence and prognostic relevance across DCM genotypes. METHODS:Clinical data from 1160 patients with DCM evaluated by cardiac magnetic resonance imaging and genetic testing (n=997 [86%]) were collected from 22 international centers. End points included embolic events, advanced heart failure events, and major ventricular arrhythmias. RESULTS:LV hypertrabeculation was identified in 354 patients (30.5%) by fractal analysis and in 343 (29.7%) according to Petersen criteria, with good concordance. After a median follow-up of 5.1 years (interquartile range, 2.8-7.4), embolic events occurred in 37 patients (3.2%), advanced heart failure in 62 (5.3%), and major ventricular arrhythmias in 136 (11.7%). Hypertrabeculation was not associated with increased embolic risk (hazard ratio, 1.5 [95% CI, 0.75-3.00]), even among patients in sinus rhythm with LV ejection fraction ≤40% (hazard ratio, 1.89 [95% CI, 0.7-5.5]). In contrast, atrial fibrillation and reduced LV ejection fraction were associated with embolic events (both P<0.01). LV hypertrabeculation was not associated with an increased risk of major ventricular arrhythmias or advanced heart failure; genotype, LV ejection fraction, and late gadolinium enhancement emerged as the main predictors of adverse outcomes. The prevalence of LV hypertrabeculation varied across genotypes, with the highest prevalence observed in patients with sequence variants in motor sarcomeric genes (58%), TTN (38%), and genotype-negative status (33%), and the lowest prevalence observed among those with variants in cytoskeletal/Z-disk (7%) and nuclear envelope (5%) genes. Hypertrabeculation was not associated with adverse outcomes within any genotype. CONCLUSIONS:Although LV hypertrabeculation is common in DCM, it is not associated with worse outcomes and should not prompt differential clinical management. The embolic risk in patients with DCM and hypertrabeculation is low, including in those with reduced LV ejection fraction without atrial fibrillation, and does not support prophylactic anticoagulation in these patients.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by adrenergically induced ventricular arrhythmias that cause sudden cardiac death. Using non-integrative episomal plasmids we reprogrammed skin fibroblasts of three heterozygous and two homozygous carriers of a mutation in the gene that encodes the ryanodine receptor type 2 (RYR2), RYR2_c.G1069A/p.G357S, previously associated to CPVT in a large family of the Gran Canaria Island. The resulting hiPSC cell lines have normal karyotype, differentiate into cells of the 3 germ layers, and express pluripotency markers and genes.

BACKGROUND AND AIMS:Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. METHODS:The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter-defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. RESULTS:A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62-0.72] and 0.59 (95% CI 0.48-0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68-0.80) and 0.60 (95% CI 0.47-0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59-1.41) for AE and 1.00 (95% CI 0.69-1.32) for nf/fAE. CONCLUSIONS:These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

BACKGROUND:Atrial fibrillation (AF) is the most common cardiac arrhythmia. Although familial AF frequently follows an autosomal dominant inheritance pattern, the genetic mechanisms remain incompletely defined. We sought to identify the causal variant within a previously established linkage region on chromosome 10q22-q24. METHODS:Additional recombination events and fine mapping reduced the original linkage interval to 0.8 Mb. Targeted sequencing of the locus was performed in affected and unaffected family members. Patient-specific human induced pluripotent stem cells (hiPSCs) were differentiated into atrial cardiomyocytes to assess gene expression and ion channel function. RESULTS:Refinement of the locus identified 3 genes (KCNMA1; DLG5; and POLR3A). A novel 15-kb tandem duplication within intron 1 of KCNMA1 segregated with disease in 6 families and was absent in controls and population databases. Patient-derived hiPSC atrial cardiomyocytes demonstrated reduced KCNMA1 and POLR3A mRNA and protein expression, accompanied by decreased paxilline-sensitive outward current. CONCLUSION:We identified a rare intronic structural variant in KCNMA1 associated with familial AF. The variant segregates with disease and is associated with reduced KCNMA1 expression and large-conductance calcium- and voltage-activated K+ channel (BK) channel activity in patient-specific cardiomyocytes. These findings implicate the 10q22-q24 locus and highlight the potential contribution of noncoding structural variation to inherited atrial arrhythmia.

INTRODUCTION:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially life-threatening arrhythmic disorder typically treated with beta-blockers and, occasionally, with flecainide. METHODS:All patients underwent genetic testing, electrocardiogram, echocardiogram, and exercise testing. Ventricular arrhythmias were assessed using qualitative and quantitative scoring systems. Flecainide dosing was progressively titrated, and follow-up extended from 2007 to 2024. RESULTS:Among 235 genetically confirmed carriers of the RyR2 (ryanodine receptor 2) p.Gly357Ser mutation, 32 required combination therapy with beta-blockers and flecainide (age at diagnosis 18 [1-55] years; age at flecainide initiation 32 [15-66] years; 50% male). Forty-seven percent had an implantable cardioverter defibrillator (ICD). Flecainide was indicated for exercise-induced ventricular arrhythmias despite beta-blocker therapy, and the median treatment duration was 7.3 years. All patients received propranolol (median dose 65 mg/day). Flecainide (median dose 100 mg/day) was well tolerated, with no syncope or stress-induced symptoms. Before flecainide, five patients (16%) experienced ventricular arrhythmic events recorded by the ICD, including two requiring appropriate shocks; no events occurred after treatment initiation. Both qualitative (2.07 ± 0.77 vs. 1.22 ± 1.08, p < 0.001) and quantitative (69.78 ± 83.17 vs. 15.29 ± 5.53, p < 0.001) arrhythmic scores improved significantly. Additionally, maximum heart rate and the percentage of age-predicted maximum heart rate were significantly reduced, while metabolic equivalents increased significantly (12.3 ± 3.8 vs. 14.7 ± 7.5; p = 0.010). CONCLUSION:In CPVT patients, the addition of flecainide to beta-blocker therapy was associated with a significant reduction in arrhythmic burden and improvement in exercise-related parameters during long-term follow-up.

Patient-derived induced pluripotent stem cells (hiPSC) are a valuable approach to model cardiovascular diseases. We nucleofected non-integrating episomal vectors in skin fibroblasts of four family members. Two of them carried the single nucleotide variant (SNV) SCN5A_c.287 T > C, leading to NaV1.5_p.L96P, and two were non-carrier family members. The resulting hiPSC cell lines differentiate into cells of the 3 germ layers, display normal karyotypes and express markers of the undifferentiated hPSC state. Thus, they are a reliable source to study the effect of the identified mutation in a physiologically relevant environment.

Molecular autopsy can identify candidate variants in unexplained sudden cardiac death (SUD), but functional evidence is often required to support pathogenic interpretation and family risk assessment. Here, we investigated the functional consequences of the SCN5A c.287 T > C (NaV1.5_p.Leu96Pro) variant, identified in a 29-year-old man who died of SUD. Cascade screening identified additional relatives carrying the variant, with variable clinical expression. Sodium current (INa) was analyzed in heterologously transfected human embryonic kidney (HEK) tsA201 cells and in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from two variant carriers and two non-carrier relatives. SCN5A transcript levels, NaV1.5 membrane expression, and additional arrhythmia-associated genetic variation were also assessed. In HEK tsA201 cells, NaV1.5_p.Leu96Pro produced no measurable INa when expressed alone, whereas co-expression with wild-type SCN5A caused an approximately 50% reduction in peak INa density. Cell-surface biotinylation showed preserved total and membrane NaV1.5 expression, indicating that loss of current was not explained by impaired trafficking. hiPSC-CMs from both carriers showed reduced INa density compared with non-carrier relatives, despite no reduction in SCN5A transcript levels. Targeted sequencing did not identify variants explaining the differences between the two hiPSC-CM carriers, but revealed an additional SCN5A splice-site deletion in family members with more severe clinical manifestations. These findings show that NaV1.5_p.Leu96Pro causes severe loss of sodium channel function and support the value of combining molecular autopsy, family evaluation, and functional studies for variant interpretation in SUD.

Sudden cardiac death is the leading cause of death among athletes during exercise. These events are devastating for both the family and society, especially when they occur in children and young adults. Some of these unexpected deceases occur in athletes who carry genetic alterations that predispose them to malignant arrhythmias, and exercise is the main trigger for these lethal episodes. These genetic alterations are the origin of inherited arrhythmogenic syndromes, often latent, and the first clinical manifestation can be sudden death itself. It is also important to take into account the toxicology data, since high doses of certain substances, as well as mixtures of them, can also be significant triggers of malignant arrhythmias, especially in genetically predisposed hearts. Genetic studies that can provide a diagnosis can be performed on deceased individuals (molecular autopsy) or on their relatives, who may be carriers of the genetic defect and at risk of malignant arrhythmogenic events. Early identification of individuals at risk allows adoption of preventive measures helping to reduce risk of life-threatening arrhythmogenic episodes. Our study examines the main arrhythmogenic causes of sudden cardiac death in athletes during exercise, highlighting a multidisciplinary interpretation of forensic, clinical, genetic and molecular data to obtain a definite cause for the lethal episode.

BACKGROUND:Arrhythmia-induced cardiomyopathy develops unpredictably in a subset of patients with atrial fibrillation, with marked interindividual variability in severity and recurrence risk. Whether genetic susceptibility contributes to this heterogeneity remains uncertain. OBJECTIVES:To determine the prevalence and clinical impact of deleterious variants in cardiomyopathy-associated genes among patients with arrhythmia-induced cardiomyopathy. METHODS:In this retrospective, multicenter study, patients with arrhythmia-induced cardiomyopathy underwent genetic testing targeting cardiomyopathy-associated genes. Individuals carrying pathogenic or likely pathogenic variants were classified as genotype-positive. Baseline characteristics, clinical severity and follow-up outcomes were compared between genotype-positive and genotype-negative patients. RESULTS:In 100 patients (mean age 59.9±11.1 years, 18% women, baseline left ventricular ejection fraction 28.2±7.3%), 16 (16%) were genotype-positive, with TTN truncating variants accounting for 75% of variants. Compared with genotype-negative individuals, genotype-positive patients more frequently had a family history of cardiomyopathy (31.2% vs 4.8%, p=0.005) and sudden death (25% vs 6%, p=0.034), presented with more severe disease -including lower ejection fraction (24.6% vs 28.8%, p=0.034) and higher incidence of cardiogenic shock (25% vs 3.6%, p=0.012)- and exhibited a higher risk of recurrence (18.8% vs 2.4%, p=0.028). CONCLUSIONS:Arrhythmia-induced cardiomyopathy patients exhibit a substantial prevalence of deleterious variants in cardiomyopathy-associated genes, particularly TTN truncating variants. Genotype-positive individuals represent a high-risk subgroup with greater familial burden, more severe clinical presentation and increased recurrence risk. Genetic testing may identify at-risk patients, refine prognostic stratification and guide therapy and follow-up.

AimsThe aim of this study was to investigate the topological distribution of single nucleotide variants (SNVs) in the KCNH2 gene from patients with type 2 long QT syndrome (LQT2) and to explore the genotype-phenotype relationships.MethodsInformation on KCNH2 variants in LQT2 patients was retrospectively obtained from the HGMD, ClinVar, and PubMed databases through October 2022. Pathogenicity of SNV was classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Unpaired t-tests and Fisher's exacts were used to analyze the SNV distributions across structural and functional domains, and their correlation with clinical phenotypes.ResultsA total of 2826 variants were obtained; 2152 were SNVs, 1328 of which were nonsynonymous SNVs (nsSNVs) associated with LQT2. Enrichment analysis revealed that 602 pathogenic (P) and likely pathogenic (LP) nsSNVs were significantly enriched at S5, H5, S6, Extra3, and Extra4. In addition, 759 nsSNVs and 289 P/LP nsSNVs within function domain were enriched at the per-arnt-sim (PAS) and selectivity filter (SF) functional domain. Clinical data revealed that patients with nsSNVs enriched at the N-terminal, S5-H5-S6 region and PAS domain were associated with an increased risk of syncope. Moreover, nsSNVs located at the N-terminal, S5-H5-S6 region, and PAS, SF domains were associated with an increased risk of life-threatening cardiac events, including Torsade de Pointes (TdP) and sudden cardiac death (SCD), and were predominantly female.ConclusionKCNH2 nsSNVs located at the N-terminal, S5-H5-S6 region, and the PAS and SF functional domains are associated with an increased risk of life-threatening cardiac events in LQT2 patients.

A conclusive and early diagnosis of cardiomyopathy is essential for implementing preventive therapeutic measures and, therefore, reducing the risk of malignant arrhythmias and even sudden cardiac death. Occasionally, this lethal event can be the first manifestation of cardiomyopathy, with or without a clear structural defect. In cases of sudden death, especially in young patients, the autopsy may be ambiguous and therefore lack a definitive diagnosis of cardiomyopathy, although it can sometimes identify signs that lead us to suspect it. This is one of the current challenges of forensic science, where occult cardiomyopathies often remain unidentified without additional testing that is not routinely included in current forensic protocols. In this protocol, it is crucial to perform a molecular autopsy but also to include additional data, especially family history, that will help conclude or at least suspect this entity. Obtaining this diagnosis or suspicion of concealed cardiomyopathy not only provides an answer to the unexpected death but also helps the relatives determine the cause of death. In addition, physicians should initiate a family assessment to identify other family members who may be at risk early and adopt personalized preventive measures.

An episode of sudden death in a young individual is a dramatic event for family members but also a challenge for cardiologists, pediatricians, forensic pathologists and researchers. In the young population, most of sudden deaths are of cardiac origin, in particular due to hereditary cardiac disorders. The autopsy protocol includes a proper macroscopic heart examination and a comprehensive histological analysis. The identification of pathognomonic histopathologic findings may help to unravel the cause of death, but microscopic features are often non-specific and highly ambiguous. Negative autopsy leads to classify the decease as a sudden arrhythmic death syndrome despite concealed cardiomyopathies may be also suspected. The molecular autopsy helps to identify the pathogenic genetic alteration associated with the arrhythmogenic episode leading to the sudden cardiac death. Due to genetic diseases, clinical assessment and genotype-phenotype correlation of relatives is mandatory to early identification of family members at risk and thus adoption of preventive measures, especially in asymptomatic genetic carriers. Specialized teams must carry out a personalized interpretation, integrating all the autopsy findings along with the family history to obtain a conclusive cause of the sudden death. In this review we pretend to update these critical issues.

Genetic testing, as part of the medicolegal autopsy in cases of suspected sudden cardiac death, has been recommended for several years; however, it is rarely performed. The aim was to assess the value of postmortem genetic testing in unexplained sudden death in the young. This is a prospective study including all cases with unexplained natural sudden death cases in individuals aged ≤50 years undergoing a legal autopsy. Postmortem genetic testing was routinely performed in cases aged ≤35 years and aged >35 years only when no cause of death was identified or there was suspicion of a possible inherited cardiac phenotype after a complete autopsy. In cases aged ≤35 years, genetic testing showed a positivity rate of 7.6%. The most striking finding has been the positivity rate of thoracic aorta aneurysms and myocarditis cases at 33%. In cases between the ages of 36 and 50 years, the positivity rate was 4.9%. If this group was approached with direct genetic analysis, as was done with the younger cohort, the yield of positive genetic testing would decrease to 2.5%. This is the largest study of postmortem genetic testing in the young to date, and the first to address its value in consecutive cases, free of selection bias.

Brugada syndrome (BrS) is a cardiac channelopathy associated with an elevated risk of arrhythmias and sudden cardiac death compared with the general population. Since its initial description in 1992 by Pedro and Josep Brugada, there has been tremendous progress in our understanding and management of BrS. The condition is characterized by ‘coved’ ST segment elevations in the anterior precordial electrocardiogram leads, which occasionally requires additional pharmacological provocation for diagnosis. Substantial geographical variation in the prevalence, genetic characteristics and clinical behaviour of BrS exists. Improvements in the understanding of the genetic and molecular mechanisms of the condition have been made over the past 30 years, opening avenues for the discovery of diagnostic and management opportunities. In this Primer, we discuss the evolving epidemiology of BrS, the emerging genetic understanding of the condition, as well as its diagnosis and management. We summarize the major societal guideline recommendations pertaining to BrS and highlight the potential for technological advancements, such as digital health and machine learning, to improve patient care. Brugada syndrome is a rare heart condition that results in abnormal cardiac electrophysiology. In this Primer, Narasimhan and colleagues discuss the epidemiology, mechanisms, diagnosis and management of Brugada syndrome, and outline how the syndrome affects patient quality of life.

Brugada syndrome (BrS) is a cardiac channelopathy associated with an elevated risk of arrhythmias and sudden cardiac death compared with the general population. Since its initial description in 1992 by Pedro and Josep Brugada, there has been tremendous progress in our understanding and management of BrS. The condition is characterized by ‘coved’ ST segment elevations in the anterior precordial electrocardiogram leads, which occasionally requires additional pharmacological provocation for diagnosis. Substantial geographical variation in the prevalence, genetic characteristics and clinical behaviour of BrS exists. Improvements in the understanding of the genetic and molecular mechanisms of the condition have been made over the past 30 years, opening avenues for the discovery of diagnostic and management opportunities. In this Primer, we discuss the evolving epidemiology of BrS, the emerging genetic understanding of the condition, as well as its diagnosis and management. We summarize the major societal guideline recommendations pertaining to BrS and highlight the potential for technological advancements, such as digital health and machine learning, to improve patient care. Brugada syndrome is a rare heart condition that results in abnormal cardiac electrophysiology. In this Primer, Narasimhan and colleagues discuss the epidemiology, mechanisms, diagnosis and management of Brugada syndrome, and outline how the syndrome affects patient quality of life.

Sudden cardiac death represents a significant public health concern and is one of the leading causes of early mortality worldwide. The escalating use of illicit drugs, approximately 269 million people in 2018, represents a growing public health. Some of these drugs are stimulants that may have multiple effects on the cardiovascular system including the cardiac rhythm, then substance abuse increases the risk of sudden death. For instance, drugs like cocaine and methamphetamine, may be responsible for myocardial infarction as well as occlusive coronary thrombosis with acute infarction. The consequences of such occurrences are far-reaching, with considerable effects not only on the victims but also on their families. Sudden cardiac death presents considerable forensic diagnostic challenges, particularly in the presence of high but non-lethal drug levels increasing the possibility of a genetic predisposition to malignant arrhythmogenic events. Our review aims to discuss the complex relationship between illicit drugs and congenital cardiac disorders, stressing the forensic issues deriving from their interaction and from the differential diagnosis. Indeed, especially when a non-lethal dose of illicit drug in presence of ambiguous microscopic findings is reported, being able to discriminate between a toxic sudden death (entailing criminal implications for the drug dealer) and a natural sudden death is a forensic issue of upmost importance.