Search Results (29)

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

Inherited cardiac channelopathies are major causes of sudden cardiac death (SCD) in young people. Genetic testing is focused on the identification of single-nucleotide variants (SNVs) by Next-Generation Sequencing (NGS). However, genetically elusive cases can carry copy number variants (CNVs), which need specific detection tools. We underlie the utility of identifying CNVs by investigating the literature data and internally analyzing cohorts with CNVs in KCNQ1, KCNH2, SCN5A, and RYR2. CNVs were reported in 119 patients from the literature and 21 from our cohort. Young patients with CNVs in KCNQ1 show a Long QT (LQT) phenotype > 480 ms and a higher frequency of syncope. None of them had SCD. All patients with CNV in KCNH2 had a positive phenotype for QT > 480 ms. CNVs in SCN5A were represented by the Brugada pattern, with major cardiac events mainly in males. Conversely, adult females show more supraventricular arrhythmias. RYR2-exon3 deletion showed a broader phenotype, including left ventricular non-compaction (LVNC) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Pediatric patients showed atrial arrhythmias and paroxysmal atrial fibrillation. Relatively higher syncope and SCA were observed in young females. The detection of CNVs can be of greater yield in two groups: familial channelopathies and patients with suspected Jervell and Lange-Nielsen syndrome or CPVT. The limited number of reported individuals makes it mandatory for multicentric studies to give future conclusive results. 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

Background: Exercise training in patients with HCM has evidenced benefits on functional capacity, cardiac function, and a reversion of adverse cardiac remodeling. The objective of this study was to assess the effect of a concurrent resistance and cardiorespiratory training program on functional capacity, biochemical parameters, and echocardiographic variables in a pilot group. Methods: Two HCM patients were evaluated before and after 12 weeks of individualized concurrent training with two sessions/week. Pre- and post-training data were compared for each patient. Evaluations included a cardiopulmonary exercise test (CPET), body composition, echocardiography, electrocardiography, and blood analysis. Results: Training promoted an increase in functional capacity (+4 mL·kg⁻¹·min⁻¹), ventilatory thresholds, and other CPET-derived variables associated with a better prognosis and long-term survival. Muscular mass was augmented (0.8 and 1.2 kg), along with a mean increase of 62% in upper and lower body strength. Echocardiographic features demonstrated the maintenance of cardiac function with signs of positive left ventricular remodeling and an improvement in diastolic function. Blood analyses, including cardiac troponins and NT-proBNP, displayed uneven changes in each patient, but the values fell into normal ranges in both cases. Conclusions: The available data suggest a positive effect of concurrent resistance and cardiorespiratory training on patients’ functional capacity and cardiac function that may improve their functional class, quality of life, and long-term prognosis. The replication of this protocol in a larger cohort of patients is warranted to confirm these preliminary results. Full article

Marfan syndrome (MIM: # 154700; MFS) is an autosomal dominant disease representing the most common form of heritable connective tissue disorder. The condition presents variable multiorgan expression, typically involving a triad of cardiovascular, eye, and skeletal manifestations. Other multisystemic features are often underdiagnosed. Moreover, the disease is characterized by age related penetrance. Diagnosis and management of MFS in the adult population are well-described in literature. Few studies are focused on MFS in the pediatric population, making the clinical approach (cardiac and multiorgan) to these cases challenging both in terms of diagnosis and serial follow-up. In this review, we provide an overview of MFS manifestations in children, with extensive revision of major organ involvement (cardiovascular ocular and skeletal). We attempt to shed light on minor aspects of MFS that can have a significant progressive impact on the health of affected children. MFS is an example of a syndrome where an early personalized approach to address a dynamic, genetically determined condition can make a difference in outcome. Applying an early multidisciplinary clinical approach to MFS cases can prevent acute and chronic complications, offer tailored management, and improve the quality of life of patients. Full article

Sotos syndrome is an autosomal dominant condition characterized by overgrowth with advanced bone age, macrodolicocephaly, motor developmental delays and learning difficulties, and characteristic facial features caused by heterozygous pathogenetic variants in the NSD1 gene located on chromosome 5q35. The prevalence of heart defects (HDs) in individuals with Sotos syndrome is estimated to be around 15–40%. Septal defects and patent ductus arteriosus are the most commonly diagnosed malformations, but complex defects have also been reported. The aim of our study was to analyze the prevalence of HD, the anatomic types, and the genetic characteristics of 45 patients with Sotos syndrome carrying pathogenetic variants of NSD1 or a 5q35 deletion encompassing NSD1, who were followed at Bambino Gesù Children’s Hospital in Rome. Thirty-nine of the forty-five patients (86.7%) had a mutation in NSD1, while six of the forty-five (13.3%) had a deletion. Most of the patients (62.2%, 28/45) were male, with a mean age of 14 ± 7 years (range 0.2–37 years). A total of 27/45 (60.0%) of the patients had heart defects, isolated or combined with other defects, including septal defects (12 patients), aortic anomalies (9 patients), mitral valve and/or tricuspid valve dysplasia/insufficiency (1 patient), patent ductus arteriosus (3 patients), left ventricular non-compaction/hypertrabeculated left ventricle (LV) (4 patients), aortic coarctation (1 patient), aortopulmonary window (1 patient), and pulmonary valve anomalies (3 patients). The prevalences of HD in the two subgroups (deletion versus intragenic mutation) were similar (66.7% (4/6) in the deletion group versus 58.91% (23/39) in the intragenic variant group). Our results showed a higher prevalence of HD in patients with Sotos syndrome in comparison to that described in the literature, with similar distributions of patients with mutated and deleted genes. An accurate and detailed echocardiogram should be performed in patients with Sotos syndrome at diagnosis, and a specific cardiological follow-up program is needed. 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

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: Cardiac amyloidosis (CA) manifests in a hypertrophic phenotype with a poor prognosis, making differentiation from hypertrophic cardiomyopathy (HCM) challenging and delaying early treatment. The extent to which magnetic resonance imaging (MRI) quantifies the right atrial strain (RAS) and strain rate (RASR), providing valuable diagnostic information, is not yet clinically established. Aims: This study assesses diagnostic differences in the longitudinal RAS and RASR between CA and HCM patients, control subjects (CTRL) and CA subtypes in addition to the impact of atrial fibrillation (AF) on the right atrial function in CA patients. The RAS and RASR of tricuspid regurgitation (TR) patients are used to assess the potential for diagnostic overlap. Methods: RAS and RASR quantification was conducted via MRI feature-tracking for biopsy-confirmed CA patients with subtypes identified. Strain parameters were compared for CTRL, HCM and TR patients. Post hoc testing identified intergroup differences. Results: In total, 41 CA patients were compared to 47 CTRL, 20 HCM and 31 TR patients. Reservoir (R), conduit and booster RAS and RASRs allow for significant differentiation (p < 0.001) between CA and HCM patients (R: 10.6 ± 14.3% vs. R: 33.5 ± 16.3%) and CTRL (R: 44.6 ± 15.7%). Booster and reservoir RAS and RASRs qualified as reliable diagnostic tests (AUC > 0.8). CA patients with AF, in contrast to sinus rhythm, demonstrated a significantly impaired reservoir RAS and RASR and booster RASR. The discriminative power of RAS for CA vs. TR was insufficient (R: 10.6% ± 14.3% vs. 7.0% ± 6.0%, p = 0.069). Differentiation between 21 transthyretin and 20 light-chain amyloidosis subtypes was not achievable (R: 0.7% ± 1.0% vs. 0.7% ± 1.0%, p = 0.827). Conclusion: The MRI-derived RAS and RASR are impaired in CA patients and may support noninvasive differentiation between CA, HCM and CTRL. Full article

Cardiomyopathies comprise a heterogeneous group of cardiac diseases identified by myocardium disorders and diminished cardiac function. They often lead to heart failure or heart transplantation and constitute one of the principal causes of morbidity and mortality worldwide. Circular RNAs (circRNAs) are a novel type of noncoding RNAs. They are covalently closed and single-stranded and derived from the exons and introns of genes by alternative splicing. This specific structure renders them resistant to exonuclease digestion. Many recent studies have demonstrated that circRNAs are highly abundant and conserved and can play central roles in biological functions such as microRNA (miRNA) sponging, splicing, and transcription regulation. Emerging evidence indicates that circRNAs can play significant roles in cardiovascular diseases, including cardiomyopathies. In this review, we briefly describe the current understanding regarding the classification, nomenclature, characteristics, and function of circRNAs and report recent significant findings concerning the roles of circRNAs in cardiomyopathies. Furthermore, we discuss the clinical application potential of circRNAs as the therapeutic targets and diagnostic biomarkers of cardiomyopathies. Full article

The regulatory mechanism of PCSK7 gene is still unknown, although its encoded protein PC7 is the most ancient and highly conserved of all proprotein convertases and exhibits enzymatic and non-enzymatic functions in liver triglyceride regulation. Bioinformatics algorithms were used to predict regulatory microRNAs (miRNAs) of PCSK7 expression. This led to the identification of four miRNAs, namely miR-125a-5p, miR-143-3p, miR-409-3p, and miR-320a-3p, with potential binding sites on the 3′-untranslated region (3′-UTR) of human PCSK7 mRNA. The expression patterns of these miRNAs and PCSK7 mRNA were assessed in three different cell lines with quantitative polymerase chain reaction (qPCR), which revealed reciprocal expression patterns between the expression levels of the four selected miRNAs and PCSK7. Next, the interactions and effects of these miRNAs on PCSK7 expression levels were investigated via cell-based expression analysis, dual-luciferase assay, and Western blot analysis. The data revealed that PCSK7 mRNA levels decreased in cells transfected with vectors overexpressing miR-125a-5p, miR-143-3p, and miR-409-3p, but not miR-320a-3p. The dual-luciferase assay demonstrated that the above three miRNAs could directly interact with putative target sites in PCSK7 3′-UTR and regulate its expression, whereas miR-320-3p exhibited no interaction. Western blot analysis further revealed that the overexpression of miR-125a-5p in Huh7 cells inhibits the expression and ability of PC7 to cleave human transferrin receptor 1. Our results support a regulatory role of these miRNAs on PCSK7 expression and function and open the way to assess their roles in the regulation of PC7 activity in vivo in the development of hepatic steatosis. Full article