Hypertrophic cardiomyopathy (HCM) is a monogenic disease with autosomal dominant inheritance. Genotype–phenotype relationships are complex, with variable penetrance even within the same family. The involvement of other modulating genetic and environmental factors is unknown. We aimed to analyze the HCM in monozygotic twins, carriers of the same founder pathogenic variant MYBPC3 p.G263*. The relationship was verified using the PowerPlex 16 HS System kit. Phenotypic differences and environmental differences (overloading conditions, coexistence and location, lifestyle, sport, and intensity) were analyzed. Three pairs of twins genetically identical for all markers and carriers of MYBPC3 G263* were identified. No environmental differences were identified. One of the 89-year-old twins had symptomatic severe obstructive HCM that required septal ablation, while her twin has remained asymptomatic with mild phenotype >80 years. A 49-year-old twin had a severe phenotype of obstructive HCM and pending myectomy, while his twin had a mild asymptomatic phenotype. In the last pair of twins, one presented a much larger left ventricular hypertrophy than his identical twin. In summary, we present three pairs of HCM twin patients sharing not only the genetic cause of the inherited disease but the entire genetic background. Despite identical genetic information and the absence of other known clinical, environmental, or lifestyle differences, the severity of the HCM phenotype is strikingly different. These unexplained differences should prompt the study of other unknown modulating factors, either epigenetic or environmental.

Long QT syndrome (LQTS) is an inherited (autosomal dominant) channelopathy associated with susceptibility to ventricular arrhythmias due to malfunction of ion channels in cardiomyocytes, that could lead to sudden death (SD). Most pathogenic variants are in the main 3 genes: KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3). Efforts to improve the understanding of the genotype-phenotype relationship are essential to improve the medical clinical practice. In this study, we identified all index patients referred for NGS genetic sequencing due to LQTS, in a Spanish cohort, who were carriers of a new pathogenic variant (KCNH2 p.Gly262AlafsTer98). Genetic and clinical family screening was performed in order to describe its phenotypic characteristics. We identified 22 relatives of Romani ethnicity, who were carriers of the variant. Penetrance reached a 100% and adherence to medical treatment was low. There was a high rate of clinical events, particularly arrhythmic events and SD (1 in every 4 patients presented syncope, 1 presented an aborted SD, 2 obligated carriers suffered SD before the age of 40 and 4 out of 6 carriers of an implantable cardioverter-defibrillator (ICD) had appropriate ICD therapies. Correct adherence to medical treatment in all carriers should be specially encouraged in this population. ICD implantation decision in non-compliant patients, and refusing left cardiac sympathetic denervation, should be carefully outweighed.

Mitochondrial DNA (mtDNA) differs from the nuclear genome in many aspects: a maternal inheritance pattern; being more prone to acquire somatic de novo mutations, accumulative with age; and the possible coexistence of different mtDNA alleles (heteroplasmy). Mitochondria are key cellular organelles responsible for energy production and involved in complex mechanisms, including atherosclerosis. In this scenario, we aimed to evaluate mtDNA variants that could be associated with premature cardiovascular disease. We evaluated 188 consecutive patients presenting with premature myocardial infarction with ST elevation (STEMI) confirmed by coronary angiogram. mtDNA polymorphisms and clinical data were evaluated and compared with 271 individuals from the same population (control group). Tobacco consumption (80.85% vs. 21.21%, p < 0.01) and dyslipidemia (38.83% vs. 28.41%, p = 0.02) were significantly more frequent among STEMI patients. Moreover, C16223T mtDNA mutation and poly-C heteroplasmy were significantly more frequent among premature STEMI male patients than in controls. The OR associated C16223T mtDNA with the increased presence of cardiovascular risk factors. Our data suggest that mtDNA 16223T and heteroplasmy may be associated with unstable premature atherosclerosis disease in men. Moreover, the presence of cardiovascular risk factors (CVRFs) was associated with C16223T mtDNA, with a cumulative effect. Protective mitochondrial pathways are potential therapeutic targets. Preventing exposure to the damaging mechanisms associated with CVRFs is of utmost importance.

Background/Objectives: Long QT Syndrome type 2 (LQT2) is a cardiac channelopathy linked to pathogenic variants in the KCNH2 gene, which encodes the Kv11.1 potassium channel, essential for cardiac repolarization. Variants affecting splice sites disrupt potassium ion flow, prolong QT interval, and increase the risk of arrhythmias and sudden cardiac death (SCD). Understanding genotype–phenotype correlations is key, given the variability of clinical manifestations even within families sharing the same variant. We aimed to evaluate new pathogenic variants by analyzing genotype–phenotype correlations in informative families. Methods: Genetic and clinical assessments were performed on index cases and family members carrying KCNH2 pathogenic variants, referred for genetic testing between 2010 and June 2023. The next-generation sequencing (NGS) of 210 cardiovascular-related genes was conducted. Clinical data, including demographic details, family history, arrhythmic events, electrocardiographic parameters, and treatments, were collected. Results: Among 390 patients (152 probands) tested for LQTS, only 2 KCNH2 variants had over 5 carriers. The detailed clinical information of 22 carriers of this KCNH2 p.Ser261fs. has already been reported by our research group. Moreover, we identified 12 carriers of the KCNH2 c.77-2del variant, predicted to disrupt a splice site and not previously reported. Segregation analysis showed its high penetrance, supporting its classification as pathogenic. Conclusions: The newly identified KCNH2 c.77-2del variant is a pathogenic, as strongly supported by the segregation analysis. Our findings underscore the importance of further research into splice site variants to enhance clinical management and genetic counseling for affected families.

Background: Sex-related differences in outcomes after implantable cardioverter-defibrillator (ICD) implantation remain incompletely understood. Although women receive ICDs less frequently, whether their long-term survival differs from that of men in real-world clinical practice is not well established. We aimed to evaluate sex-specific mortality and relative survival in a large consecutive cohort of ICD recipients from a tertiary hospital. Methods: We conducted a retrospective cohort study including all consecutive patients who underwent ICD implantation at a tertiary hospital between 2015 and 2025. Demographic features, device indication, and mortality were obtained through clinical records. Relative survival (observed vs. expected) was estimated using the Ederer II method with national life tables. A Cox proportional hazards model assessed the effect of sex on mortality. Results: A total of 1091 patients (82.1% men; mean age 63.1 ± 13.1 years) were included. During a mean follow-up of 4.33 ± 3.22 years, 230 patients died (21.1%). Women showed lower unadjusted all-cause mortality than men: 24 deaths (18.0%) vs. 206 (20.6%). Women had significantly higher left ventricular ejection fraction (41.5 ± 23.6% vs. 37.2 ± 18.1%, p = 0.0046), less ischemic cardiomyopathy, and lower prevalence of cardiovascular risk factors. Although univariable analysis suggested lower mortality in women (HR 0.58, 95% CI 0.38–0.90; p = 0.014), multivariable analysis indicated that sex was not an independent predictor of mortality (HR 0.81, 95% CI 0.53–1.26). Relative survival revealed a substantial long-term mortality burden in ICD carriers, especially in men: men: 4-year survival 82.3% (expected 93.2%); 8-year 66.7% (85.6%); 12-year 56.0% (76.8%); women: 4-year survival 89.1% (expected 96.7%); 8-year 77.1% (92.8%); 12-year 77.1% (89.2%). Conclusions: In this large real-world cohort of ICD recipients, women showed lower unadjusted mortality and a smaller excess mortality compared with the general population. However, sex was not an independent predictor of survival after multivariable adjustment. These findings may indicate that observed survival differences are largely explained by differences in clinical profile and comorbidity burden rather than by sex itself.

Background: Short QT syndrome (SQTS) is a rare inherited cardiac channelopathy associated with high risk of atrial and ventricular arrhythmias and sudden cardiac death (SCD). Data on its natural history, genotype–phenotype correlations, and risk stratification remain limited. We aimed to evaluate all families with a confirmed diagnosis of SQTS identified at our National Referral Center through a descriptive case series, thereby contributing additional real-world data on this rare condition. Methods: A retrospective review was conducted of all families evaluated for suspected SQTS between 2011 and 2025 at the Inherited Cardiac Diseases Unit. Diagnosis was based on 2022 ESC guidelines (QTc ≤320 ms or ≤360 ms plus supportive features), clinical evaluation, and genetic testing. Families meeting diagnostic criteria were included for detailed phenotypic and genotypic characterization and longitudinal follow-up. Results: Among all patients assessed, two families met the criteria for SQTS. One family with three phenotype-positive individuals was gene-elusive. This family had a history of SCD and the proband presented atrial fibrillation. The second family carried a pathogenic KCNJ2 variant (p.Asp172Asn). However, only the proband fulfilled ECG criteria for SQTS (phenotype-positive) and there was no family history of SCD. No patients were treated with pharmacological therapy for QT prolongation. All affected individuals showed stable QT intervals (none <320 ms) and there were no malignant arrhythmic events during follow-up. Conclusions: These two families illustrate the wide phenotypic spectrum of SQTS and underscore the difficulty of risk stratification in asymptomatic individuals. The rarity of the disease, variable penetrance, and absence of robust prospective data hinder evidence-based management. Systematic registry participation and longitudinal studies are essential to refine risk prediction and therapeutic strategies.