Search Results (59)

Hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, represents a paradigmatic condition for precision cardiovascular medicine. Once regarded as a monogenic autosomal dominant disorder driven by rare sarcomeric variants, HCM is now recognized as a genetically complex disease characterized by incomplete penetrance, variable expressivity, and heterogeneous clinical trajectories. This review summarizes current evidence on the evolving genetic architecture of HCM, emphasizing the predominant role of definitively validated sarcomeric genes, particularly MYBPC3 and MYH7, and the clinical value of gene panel expansion. Phenotypic variability reflects interactions among variant classes, gene-specific mechanisms, and modifying factors. Differences between missense and truncating variants, haploinsufficiency and poison-peptide effects, allelic imbalance, and age-dependent penetrance contribute to diverse disease expression. Emerging data further support oligogenic inheritance and polygenic modulation, with genome-wide association studies and polygenic risk scores elucidating their contribution to disease susceptibility and variability, especially in genotype-negative patients and carriers of rare variants. We also address genes with emerging evidence and underrecognized pathogenic mechanisms, including deep intronic and splice-altering variants that may explain part of the missing heritability. The importance of distinguishing phenocopies is highlighted, advocating for phenotype-anchored diagnostic pathways integrating clinical assessment, multimodality imaging, and targeted genetic testing. Overall, contemporary data support a targeted, gene-validity-driven approach to genetic testing, where molecular findings primarily inform diagnosis and cascade screening, while risk stratification remains phenotype-led and longitudinal. Future progress will depend on integrative models combining rare variants, polygenic background, imaging, and biomarkers to translate genetic complexity into actionable precision care. Full article

Diagnosis of cardiomyopathies often depends on overt phenotypic manifestations, delaying patient management. This underscores the need for population-level opportunistic screening tools using clinically indicated CT scans to detect subclinical myocardial disease. This study developed an Ensemble Machine Learning (ML) model to automatically segment the left ventricular myocardium from CT data and estimate the probability of underlying myocardial disease using radiomic feature analysis. A total of 60 CT scans (~12,000 images) were used to train ML models for left ventricular myocardium segmentation, including scans from both healthy individuals and patients with myocardial disease. A novel Ensemble model was developed and externally validated on 10 independent CT scans. Subsequently, 100 unseen CT scans were segmented manually and automatically for radiomic feature analysis. After removing highly correlated features through intra-class variation and correlation filtering, the refined dataset was used for model training and testing. Key predictive features were identified, and model performance was evaluated. The four best-performing models (Unet++, ED w/ASC, FPN, and TresUNET) were combined to form an Ensemble model, achieving a final DICE score of 0.882 after hyperparameter optimization. External validation yielded a DICE score of 0.907. Radiomic feature analysis identified 15 key predictors of myocardial disease in both manual and automatic segmentation datasets. The model demonstrated strong performance in detecting underlying myocardial disease, with AUCs of 0.85 and 0.8, respectively. This study presents a fully automated CT-based framework for LV myocardial segmentation and radiomic phenotyping that accurately estimates the probability of underlying myocardial disease. The model demonstrates strong generalizability across different CT protocols and highlights the potential role of AI-driven CT analysis for early, non-invasive cardiomyopathy screening at a population level. Full article

Background: Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy in the absence of secondary causes. This study aimed to investigate the genetic, clinical, and epidemiological profile of individuals with clinical HCM or a family history of sudden cardiac death (SCD). Methods: A total of 200 participants (58% male, median age 52 years) underwent genetic testing using a 19-gene panel associated with HCM and phenocopies. Variants were classified as pathogenic/likely pathogenic (P/LP), variants of uncertain significance (VUS), or negative. Clinical and imaging data were correlated with genetic findings. Results: P/LP variants were identified in 31% of individuals, while 40.5% carried VUS, and 28.5% tested negative. A positive genotype was more frequent among patients with clinical HCM (37.7%) than among those with only a family history (18.6%, p = 0.006). Sarcomeric mutations represented 77.4% of positive results, while 22.6% involved phenocopy genes, notably TTR (amyloidosis). Positive genotypes were significantly associated with a family history of SCD (68% vs. 46%, p = 0.004) and with greater interventricular septal thickness (17 mm vs. 15 mm, p < 0.001). Conclusions: Septal thickness >17 mm and family history of SCD were strong predictors of positive genetic results. These findings emphasize the importance of genetic screening and counseling in high-risk individuals and highlight the value of integrating genetic testing into clinical practice for diagnosis, risk stratification, and family management. Full article

This study investigates the genetic background of pediatric-onset cardiac channelopathies, a rare group of genetic disorders causing arrhythmias and sometimes sudden death, whose genetic background remains partially unknown. The research analyzed 59 pediatric patients (<18 years of age) diagnosed with different channelopathies (LQTS, BrS, CPVT, SQTS, and conduction disorders), along with 40 of their family members, using Next-Generation Sequencing (NGS) after genetic counseling. A causative genetic variant was found in 47% of cases, mainly in the KCNQ1 (42%), RYR2 (16%), CACNA1C (10%), and SCN5A (10%) genes. Notably, a de novo large deletion in KCNH2 was detected in an LQTS patient, and a pathogenic CALM1 variant was identified in a child. A compound heterozygous KCNQ1 was consistent with Jervell and Lange-Nielsen syndrome. In light of these data, genetic testing is crucial for diagnosis, prognosis, and treatment planning; cascade screening allowed early risk identification and preventive interventions for family members. Expanding NGS technologies and research on new candidate genes may enhance personalized therapies in the future. Full article

Background and Objectives: Ventricular extrasystoles, which are the most common arrhythmias in healthy children and adolescents, could be a reliable factor for the prognosis of structural heart diseases. However, extrasystoles arising in hearts with primary myocardial diseases or channelopathies might cause life-threatening events or be associated with arrhythmia-induced cardiomyopathy. The relationship between ventricular extrasystoles and ventricular abnormalities in children remains controversial. The aim of this study was to evaluate prevalence of ventricular abnormalities in children with ventricular extrasystoles. Materials and Methods: This was a retrospective cohort study of pediatric outpatients in Vilnius University Hospital Santaros Clinics because of ventricular extrasystoles. The inclusion criteria were 3–18-year-old children with more than 5% extrasystoles per 24 h. The exclusion criteria were previous diagnoses of congenital heart defects, cardiomyopathies, and channelopathies. We reviewed the results of electrocardiography, cardiac imaging, and cardiogenetic tests. Results: In total, 131 patients (55.7% males) were included from a database of 915 patients, of whom 79.4% ventricular extrasystoles were found incidentally. Ventricular extrasystoles were monomorphic—95.4%, multiform—4.6%, and consecutive—29.8%. Cardiac magnetic resonance imaging was performed on 22.9% of patients with one-third of the pathological findings (ventricular dysfunction and myocardial fibrosis). Ventricular dysfunction was associated with a higher frequency of ventricular extrasystoles, with a median highest frequency of 26.5% per 24 h. Cardiogenetic testing was performed on only five (3.8%) patients, and RyR2 mutation was detected in one. Conclusions: According to our results, ventricular dysfunction was strongly associated with a higher burden of ventricular extrasystoles. Full article

Congenital titinopathies reported to date show autosomal recessive inheritance and are caused by a variety of genomic variants, most of them located in metatranscript (MTT)-only exons. The aim of this study was to describe additional patients and establish robust genotype–phenotype associations in titinopathies. This study involved analyzing molecular, clinical, pathological, and muscle imaging features in 20 patients who had at least one pathogenic or likely pathogenic TTN variant in MTT-only exons, with onset occurring antenatally or in the early postnatal stages. The 20 patients with recessive inheritance exhibited a heterogeneous range of phenotypes. These included fetal lethality, progressive weakness, cardiac or respiratory complications, hyper-CKemia, or dystrophic muscle biopsies. MRI revealed variable abnormalities in different muscles. All patients presented severe congenital myopathy at birth, characterized by arthrogryposis (either multiplex or axial–distal) or neonatal hypotonia in most cases. This study provides detailed genotype–phenotype correlations in congenital titinopathies caused by mutations in MTT-only exons. The findings highlight the variability in clinical presentation and the severity of phenotypes associated with these specific genetic alterations. RNA-seq analyses provided valuable insights into the molecular consequences of TTN variants, particularly in relation to splicing defects and nonsense-mediated RNA decay. In conclusion, this study reinforces the genotype–phenotype correlations between congenital myopathies and variants in TTN MTT-only exons, improves their molecular diagnosis, and provides a better understanding of their pathophysiology. Full article

Background and Objectives: Although left ventricular excessive trabeculation (LVET) can cause heart failure, arrhythmia and thromboembolism, limited literature is available on the ECG characteristics of primary LVET with preserved left ventricular function (EF). We aimed to compare the ECG characteristics and cardiac MR (CMR) parameters of LVET individuals with preserved left ventricular EF to a control (C) group, to identify sex-specific differences, and to compare the genetic subgroups of LVET with each other and with a C population. Methods: In our study, we selected 69 LVET individuals (EF > 50%) without any comorbidities and compared them to 69 sex- and age-matched control subjects (42% females in both groups, p = 1.000; mean age LVET-vs-C: 38 ± 14 vs. 38 ± 14 years p = 0.814). We analyzed the pattern and notable parameters of the 12-lead ECG recordings. We determined the volumetric and functional parameters, as well as the muscle mass values of the left and right ventricles (LV, RV) based on the CMR recordings. Based on the genotype, three subgroups were established: pathogenic, variant of uncertain significance and benign. Results: In the LVET group, we found normal but elevated volumetric and muscle mass values and a decreased LV_EF, wider QRS, prolonged QTc, higher RV Sokolow index values and lower T wave amplitude compared to the C. When comparing MR and ECG parameters between genetic subgroups, only the QTc showed a significant difference. Over one-third of the LVET population had arrhythmic episodes and a positive family history. Conclusions: The subclinical morphological and ECG changes and the clinical background of the LVET group indicate the need for follow-up of this population, even with preserved EF. Full article

The emergence of gene therapy offers opportunities for treating a myriad of genetic disorders and complex diseases that previously had limited or no treatment options. The key basic strategies for gene therapy involve either the addition, inhibition, or introduction of a new gene, with a crucial component being the use of a delivery vector to effectively target cells. Particularly promising is the application of gene therapy for the treatment of inherited arrhythmia syndromes, conditions associated with significant mortality and morbidity that have limited treatment options, and a paucity of disease modifying therapy. This review aims to summarize the utility of gene therapy for the treatment of inherited arrhythmia syndromes by exploring the current state of knowledge, limitations, and future directions. Full article

Cardiomyopathies have evolved from being considered rare and idiopathic to being increasingly linked to genetic factors. This shift was enabled by advancements in understanding genetic variants and the widespread use of next generation sequencing (NGS). Current guidelines emphasize the importance of evidence-based gene panels that can offer “clinically actionable results”, which provide diagnostic and prognostic insights. They also advise against indiscriminate family screening after finding variants of uncertain significance (VUS) and recommend collaboration among multidisciplinary teams for an accurate variant pathogenicity assessment. This article presents an innovative “cardiogenetic clinic” approach involving cardiologists and medical geneticists to provide genetic testing and family screening. This study attempts to improve the diagnostic process for suspected genetic cardiomyopathies; this includes direct patient recruitment during cardiology appointments, NGS analysis, and combined consultations with cardiologists and geneticists to assess the results and screen the families. The study cohort of 170 patients underwent genetic testing, which identified 78 gene variants. Positive results (C4 or C5 variants) occurred in 20 (19.8%) cases, with rates varying by cardiomyopathy phenotype, while 57 (73.1%) of the variants found were classified as C3-VUS, causing a significant management issue. This model shortened the time to results, increased patient adherence, and improved patients’ diagnoses. Family screening was pondered depending on the relevance of the detected variants, showing this method’s potential to impact patient management. Full article

Cardiomyopathies (CMPs) are a group of myocardial disorders that are characterized by structural and functional abnormalities of the heart muscle. These abnormalities occur in the absence of coronary artery disease (CAD), hypertension, valvular disease, and congenital heart disease. CMPs are an increasingly important topic in the field of cardiovascular diseases due to the complexity of their diagnosis and management. In 2023, the ESC guidelines on cardiomyopathies were first published, marking significant progress in the field. The growth of techniques such as cardiac magnetic resonance imaging (CMR) and genetics has been fueled by the development of multimodal imaging approaches. For the diagnosis of CMPs, a multimodal imaging approach, including CMR, is recommended. CMR has become the standard for non-invasive analysis of cardiac morphology and myocardial function. This document provides an overview of the role of CMR in CMPs, with a focus on tissue mapping. CMR enables the characterization of myocardial tissues and the assessment of cardiac functions. CMR sequences and techniques, such as late gadolinium enhancement (LGE) and parametric mapping, provide detailed information on tissue composition, fibrosis, edema, and myocardial perfusion. These techniques offer valuable insights for early diagnosis, prognostic evaluation, and therapeutic guidance of CMPs. The use of quantitative CMR markers enables personalized treatment plans, improving overall patient outcomes. This review aims to serve as a guide for the use of these new tools in clinical practice. Full article

Inherited cardiomyopathies represent a highly heterogeneous group of cardiac diseases. DNA variants in genes expressed in cardiomyocytes cause a diverse spectrum of cardiomyopathies, ultimately leading to heart failure, arrythmias, and sudden cardiac death. We applied massive parallel DNA sequencing using a 72-gene panel for studying inherited cardiomyopathies. We report on variants in 25 families, where pathogenicity was predicted by different computational approaches, databases, and an in-house filtering analysis. All variants were validated using Sanger sequencing. Familial segregation was tested when possible. We identified 41 different variants in 26 genes. Analytically, we identified fifteen variants previously reported in the Human Gene Mutation Database: twelve mentioned as disease-causing mutations (DM) and three as probable disease-causing mutations (DM?). Additionally, we identified 26 novel variants. We classified the forty-one variants as follows: twenty-eight (68.3%) as variants of uncertain significance, eight (19.5%) as likely pathogenic, and five (12.2%) as pathogenic. We genetically characterized families with a cardiac phenotype. The genetic heterogeneity and the multiplicity of candidate variants are making a definite molecular diagnosis challenging, especially when there is a suspicion of incomplete penetrance or digenic-oligogenic inheritance. This is the first systematic study of inherited cardiac conditions in Cyprus, enabling us to develop a genetic baseline and precision cardiology. Full article

Pancreatic ductal adenocarcinoma (PDAC) is mostly diagnosed at advanced or even metastasized stages, limiting the prognoses of patients. Metastasis requires high tumor cell plasticity, implying phenotypic switching in response to changing environments. Here, epithelial–mesenchymal transition (EMT), being associated with an increase in cancer stem cell (CSC) properties, and its reversion are important. Since it is poorly understood whether different CSC phenotypes exist along the EMT axis and how these impact malignancy-associated properties, we aimed to characterize CSC populations of epithelial and mesenchymal-like PDAC cells. Single-cell cloning revealed CSC (Holoclone) and non-CSC (Paraclone) clones from the PDAC cell lines Panc1 and Panc89. The Panc1 Holoclone cells showed a mesenchymal-like phenotype, dominated by a high expression of the stemness marker Nestin, while the Panc89 Holoclone cells exhibited a SOX2-dominated epithelial phenotype. The Panc89 Holoclone cells showed enhanced cell growth and a self-renewal capacity but slow cluster-like invasion. Contrarily, the Panc1 Holoclone cells showed slower cell growth and self-renewal ability but were highly invasive. Moreover, cell variants differentially responded to chemotherapy. In vivo, the Panc1 and Panc89 cell variants significantly differed regarding the number and size of metastases, as well as organ manifestation, leading to different survival outcomes. Overall, these data support the existence of different CSC phenotypes along the EMT axis in PDAC, manifesting different metastatic propensities. Full article

Novel genetic risk markers have helped us to advance the field of cardiovascular epidemiology and refine our current understanding and risk stratification paradigms. The discovery and analysis of variants can help us to tailor prognostication and management. However, populations underrepresented in cardiovascular epidemiology and cardiogenetics research may experience inequities in care if prediction tools are not applicable to them clinically. Therefore, the purpose of this article is to outline the barriers that underrepresented populations can face in participating in genetics research, to describe the current efforts to diversify cardiogenetics research, and to outline strategies that researchers in cardiovascular epidemiology can implement to include underrepresented populations. Mistrust, a lack of diverse research teams, the improper use of sensitive biodata, and the constraints of genetic analyses are all barriers for including diverse populations in genetics studies. The current work is beginning to address the paucity of ethnically diverse genetics research and has already begun to shed light on the potential benefits of including underrepresented and diverse populations. Reducing barriers for individuals, utilizing community-driven research processes, adopting novel recruitment strategies, and pushing for organizational support for diverse genetics research are key steps that clinicians and researchers can take to develop equitable risk stratification tools and improve patient care. Full article

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare, inherited heart rhythm disorder that is caused by variants in genes responsible for cardiac calcium homeostasis. The aim of this study was to analyze different genotype-specific clinical manifestations of this disease. Methods and Results: We analyzed five CPVT cases from our institution in the context of specific patient characteristics and genotype–phenotype correlations. In this cohort, three of the index patients were male. The median age at diagnosis was 11 (11–30) years, and median age at disease onset was 12 (12–33) years. Four index patients suffered from syncope, while one female index patient suffered from out-of-hospital cardiac arrest. Two index patients experienced concomitant atrial flutter and atrial fibrillation. Three patients received an implantable cardioverter defibrillator and one patient received an event recorder. All index patients had causative genetic variants in the RYR2-gene. Conclusions: This study presents various phenotypic presentations of patients with CPVT harboring different pathogenic variants in the RYR2 gene, some of which have not previously been described in published studies. Syncope was the most prevalent symptom on admission. Adjustment of beta-blocker therapy may be necessary due to side effects. Moreover, our work further highlights the common occurrence of atrial tachyarrhythmias in these patients. Full article

Coronary artery calcification (CAC) is mainly associated with coronary atherosclerosis, which is an indicator of coronary artery disease (CAD). CAC refers to the accumulation of calcium phosphate deposits, classified as micro- or macrocalcifications, that lead to the hardening and narrowing of the coronary arteries. CAC is a strong predictor of future cardiovascular events, such as myocardial infarction and sudden death. Our narrative review focuses on the pathophysiology of CAC, exploring its link to plaque vulnerability, genetic factors, and how race and sex can affect the condition. We also examined the connection between the gut microbiome and CAC, and the impact of genetic variants on the cellular processes involved in vascular calcification and atherogenesis. We aimed to thoroughly analyze the existing literature to improve our understanding of CAC and its potential clinical and therapeutic implications. Full article