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.

BACKGROUND: Current guidelines recommend a stepwise strategy to achieve low-density lipoprotein cholesterol (LDL-C) goals after acute coronary syndrome (ACS). Earlier intensive strategies based on a combination of lipid-lowering therapies (LLTs) could be useful from the onset of ACS. However, the role of bempedoic acid in ACS, particularly when combined with high-intensity statins and ezetimibe, remains uncertain. The aim of ES-BempedACS (Efficacy and Security of Bempedoic Acid in Acute Coronary Syndrome) was to compare the efficacy and safety of triple LLT (high-dose, high-intensity statin+ezetimibe+bempedoic acid) versus standard of care (high-dose, high-intensity statin+ezetimibe) after ACS. METHODS: ES-BempedACS is a multicenter, independent, pragmatic, prospective, randomized, open, blinded end point controlled trial conducted in 12 Spanish hospitals between November 2023 and October 2024. The primary end point was the proportion of patients achieving LDL-C <55 mg/dL (<1.4 mmol/L) at 8 weeks after ACS, comparing triple LLT with standard of care. RESULTS: A total of 206 patients (59.5±10.9 years of age [mean±SD]; 21.4% women) were randomized within the first 72 hours of ACS to triple LLT or standard therapy of high-intensity statin+ezetimibe (ie, dual LLT). The baseline LDL-C level was 133.6±28.8 mg/dL. After 8 weeks, the LDL-C level was reduced to 50%) of adequate LDL-C control (<55 mg/dL) at 8 weeks. Adding bempedoic acid to statin–ezetimibe therapy in the setting of ACS is safe but failed to improve the percentage of patients achieving the LDL-C goal (<55 mg/dL) at 8 weeks. Larger, randomized studies are needed to confirm our findings. REGISTRATION: URL: https://www.clinicaltrialsregister.eu ; Unique identifier: 2021-006550-31.

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: 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.

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.