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.

Cardiovascular disease (CVD) is the leading cause of death worldwide, with coronary artery disease (CAD) being one of its main manifestations. Both environmental and genetic factors are widely known to be related to CAD, such as smoking, diabetes mellitus, dyslipidemia, and a family history of CAD. However, there is still a lack of information about other risk factors, especially those related to genetic mutations. Sex represents a classic CAD risk factor, as men are more likely to suffer CAD, but there is lack of evidence with regard to sex-specific genetic factors. We evaluated the Y chromosome haplogroups in a cohort of young Spanish male patients who suffered from STEMI. In this cohort, haplogroup R was significantly more frequent in STEMI patients.

Background: Dilated cardiomyopathy (DCM) can be an inherited condition related to premature sudden cardiac death (SCD). Pathogenic variants in some genes, like LMNA, SCN5A, FLNC or RBM20, have been linked to an increased risk of SCD. Although genetic study can help to stratify the arrhythmic risk, there are no specific guidelines for RBM20 carriers’ management. We aimed to evaluate the genetic profile and clinical features of all DCM patients with pathogenic variants in RBM20.Methods: We identified all carriers of pathogenic variants in RBM20 in a single national center that specializes in inherited cardiac conditions. Forensic and molecular autopsies provided crucial information. Results: We identified a large family with inherited DCM due to RBM20 p.Arg636Cy and several SCDs. The proband was a 37-year-old male who suffered an unexpected SCD despite presenting a mild DCM phenotype with normal left ventricular ejection fraction. Family screening identified four other carriers, who were asymptomatic, but presented concealed mild DCM phenotypes. Family history revealed that six other relatives (two of them obligate carriers) had also suffered sudden deaths at young ages. Conclusions: We present an informative family with DCM, due to RBM20 p.Arg636Cys, and high rates of SCD, even in members with mild DCM phenotypes. ICD implantation to prevent SCD should be carefully evaluated in all RBM20 p.Arg636Cys carriers. Moreover, the frequent development of AF and HF progression requires specific awareness.

Heart transplantation remains the gold standard for the treatment of advanced heart failure (HF). Identification of the etiology of HF is mandatory, as the specific pathology can determine subsequent treatment. Early identification of familial hypercholesterolemia (FH), the most common genetic disorder associated with premature cardiovascular disease, has a potential important impact on clinical management and public health. We evaluated the genetic information in the genes associated with FH in a cohort of 140 heart-transplanted patients. All patients underwent NGS genetic testing including LDLR, APOB, and PCSK9. We identified four carriers of rare pathogenic variants in LDLR and APOB. Although all four identified carriers had dyslipidemia, only the one carrying the pathogenic variant LDLR c.676T>C was transplanted due to CAD. Another patient with heart valvular disease was carrier of the controversial LDLR c.2096C>T. Two additional patients with non-ischemic dilated cardiomyopathy were carriers of variants in APOB (c.4672A>G and c.5600G>A). In our cohort, we identified the genetic cause of FH in patients that otherwise would not have been diagnosed. Opportunistic genetic testing for FH provides important information to perform personalized medicine and risk stratification not only for patients but also for relatives at concealed high cardiovascular risk. Including the LDLR gene in standard NGS cardiovascular diagnostics panels should be considered.

Background/Objectives: Catheter ablation for atrial fibrillation (AF) is a well-established therapeutic approach for maintaining sinus rhythm, though its efficacy remains suboptimal in certain patients. The left atrium (LA) volume, commonly assessed through transthoracic echocardiography (TTE), is a recognized predictor of AF recurrence after pulmonary vein isolation (PVI). However, the complex three-dimensional structure of the LA makes precise measurement challenging with traditional TTE techniques. Electroanatomic mapping (EAM) offers a more accurate evaluation of LA geometry and volume, which may enhance the prediction of ablation outcomes. Methods: This prospective study included 197 patients with AF who were referred for PVI to our center (Hospital Universitario Central de Asturias, Spain) between 2016 and 2020. All participants underwent pre-ablation TTE and EAM to assess the electric active volume (EAV) of the LA. Clinical follow-up included regular Holter monitoring and electrocardiograms to detect AF recurrences. Results: The mean age was 56.3 ± 9.67 years, and 34% had persistent AF. The mean LA volumes measured by TTE and the EAV by EAM were 62.86 ± 15.58 mL and 126.75 ± 43.35 mL, respectively, with a moderate positive correlation (r = 0.49, p < 0.001). AF recurrences were observed in 51.27% of patients over a 36 ± 15-month follow-up period. Cox regression analyses (univariate and multivariate), Kaplan–Meier curves and log-rank tests were used to illustrate freedom from atrial arrhythmia during follow-up. Both EAV by EAM and TTE volumes were significant predictors of AF recurrence in the univariate analysis (HR 1.002 [1.001–1.003], p = 0.033 and HR 1.001 [1.006–1.012], p < 0.01, respectively). Among clinical variables, persistent AF was significantly associated with a higher risk of recurrence (HR 1.17 [1.096–1.268], p = 0.02). Conclusions: EAV of the LA assessment by EAM demonstrates a significant correlation with TTE measurements and is a predictor of AF post-ablation recurrence. In patients selected for catheter ablation, EAV by EAM provides additional insights that could contribute to therapeutic decision-making and risk stratification of AF recurrences.

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.