Cardiogenetics

13 pages, 263 KB

Open AccessEditor’s ChoiceArticle

Evaluation of Classical and New Clinical Criteria for Diagnosing Familial Hypercholesterolemia in Childhood

by Raffaele Buganza, Giulia Massini, Cecilia Nobili, Martina Ferrandino, Maria Donata Di Taranto, Luisa de Sanctis and Ornella Guardamagna

Cardiogenetics 2026, 16(2), 12; https://doi.org/10.3390/cardiogenetics16020012 - 3 Jun 2026

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Abstract

Background: Heterozygous familial hypercholesterolemia (HeFH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased cardiovascular risk, making early diagnosis essential; however, the diagnostic performance of pediatric criteria is heterogeneous. This study evaluated the effectiveness of different diagnostic criteria and scoring systems to [...] Read more.

Background: Heterozygous familial hypercholesterolemia (HeFH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased cardiovascular risk, making early diagnosis essential; however, the diagnostic performance of pediatric criteria is heterogeneous. This study evaluated the effectiveness of different diagnostic criteria and scoring systems to select children for genetic testing. Materials and methods: A total of 214 pediatric subjects with suspected HeFH were included, recruited from patients followed at a tertiary care center, based on LDL-C levels ≥ 95th age- and sex-specific percentile in both the proband and one biological parent. All subjects underwent genetic analysis of the main FH-associated genes (LDLR, APOB, PCSK9). The following diagnostic criteria and scoring systems were retrospectively evaluated and compared with genetic findings: Simon Broome Register (SBR), Dutch Lipid Clinic Network (DLCN), European Atherosclerosis Society (EAS), American Heart Association (AHA), Familial Hypercholesterolemia Canada Network (FH-CAN), Japanese Atherosclerosis Society (JAS), Lipid TransPort Disorders Italian Genetic Network for Italian pediatric patients (LIPIGEN-FH-PED), and the Familial Hypercholesterolemia Pediatric Diagnostic Score (FH-PeDS). Results: Pathogenic variants were identified in 91.8% of subjects. Approaches using lower LDL-C thresholds minimized the loss of variant-positive individuals (particularly JAS and FH-PeDS, with a missed diagnoses rate of 1.6%), whereas more restrictive definitions excluded a substantial proportion of affected patients (10.5% SBR, 56.3% DLCN, 6.3% EAS, 6.3% AHA, 7.4% FH-CAN, and 6.3% LIPIGEN-FH-PED). The mutation detection rate (MDR) was >91% for all examined criteria. Conclusions: Several current diagnostic criteria may underestimate the true number of children carrying FH-associated variants. Less selective criteria enable the identification of a greater number of FH-positive individuals while maintaining a high MDR, thus supporting the prioritization of identifying as many affected children as possible in the pediatric setting. This cohort reflects a tertiary referral population rather than the general population; therefore, further studies are needed to evaluate the applicability of our findings to broader public health contexts and screening settings. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

16 pages, 1011 KB

Open AccessEditor’s ChoiceArticle

Beyond Wall Thickness: Clinical Predictors of Genotype Positivity in Hypertrophic Cardiomyopathy

by Filippo Angelini, Veronica Dusi, Amedeo Maria Feneziani, Rossella Manai, Matteo Bianco, Enrica Lonni, Giulia Margherita Brach Del Prever, Pier Paolo Bocchino, Giuseppe Giannino, Daniele Melis, Giulia Gobello, Francesco Ravera, Lucia Elena Laiso, Federico Juvenal, Guglielmo Gallone, Stefano Pidello, Barbara Mabritto, Daniela Giachino, Giuseppe Musumeci, Alessandra Chinaglia, Walter Grosso Marra, Silvia Deaglio, Gaetano Maria De Ferrari and Claudia Raineri Show full author list Hide full author list

Cardiogenetics 2026, 16(2), 10; https://doi.org/10.3390/cardiogenetics16020010 - 11 May 2026

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Abstract

Background: Genetic testing in hypertrophic cardiomyopathy (HCM) yields variable positivity rates. Identifying clinical predictors of positive genetic tests could improve pre-test counseling and refine expectations about diagnostic yield. Methods: We analyzed consecutive genotyped HCM probands from a contemporary multicenter cohort across four Italian [...] Read more.

Background: Genetic testing in hypertrophic cardiomyopathy (HCM) yields variable positivity rates. Identifying clinical predictors of positive genetic tests could improve pre-test counseling and refine expectations about diagnostic yield. Methods: We analyzed consecutive genotyped HCM probands from a contemporary multicenter cohort across four Italian tertiary centers. Genotype positivity was defined as the presence of ≥1 pathogenic or likely pathogenic variant (ACMG classes 4–5). Multivariable logistic regression identified predictors of genotype positivity. Sensitivity analyses assessed the incremental value of left atrial volume index (LAVI) ≥ 34 mL/m² and the mode of first clinical presentation. Results: Among 274 genotyped probands (median age at diagnosis 54 years; 62% male), 86 (31%) were genotype-positive (38% MYBPC3, 29% MYH7). Age at diagnosis <40 years (OR 2.38, 95%CI 1.26–4.51, p = 0.008), family history of sudden cardiac death/major ventricular arrhythmias (OR 2.34, 95%CI 1.16–4.84, p = 0.019) and family history of non-ischemic cardiomyopathy (OR 1.92, 95%CI 1.04–3.54, p = 0.038), were independently associated with genotype positivity whereas arterial hypertension was inversely associated (OR 0.42, 95%CI 0.23–0.77). Maximal left ventricular wall thickness > 20 mm and gender were not predictive of genotype positivity. Inclusion of LAVI modestly improved the model performance (AUC 0.769, p = 0.016, ΔAUC +0.024; DeLong p = 0.016) but without leading to meaningful patient reclassification. Conclusions: Genotype positivity in HCM links to earlier onset and family history; traditional severity markers and initial presentation may not independently suggest genetic causality. These findings may help shape a personalized approach to genetic counseling in HCM. Full article

(This article belongs to the Special Issue Contemporary and Future Approaches to Inherited Cardiomyopathies)

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22 pages, 1275 KB

Open AccessEditor’s ChoiceReview

The Genetic Architecture of Sudden Cardiac Death: A State-of-the-Art Review

by Sabrina Montuoro, Emanuele Monda, Gaetano Diana, Emanuele Bobbio, Vera Fico, Marta Rubino, Martina Caiazza, Adelaide Fusco, Annapaola Cirillo, Federica Verrillo, Francesca Dongiglio, Giuseppe Palmiero, Federica Barra, Giulia Frisso, Maria Giovanna Russo, Paolo Calabrò and Giuseppe Limongelli

Cardiogenetics 2026, 16(1), 6; https://doi.org/10.3390/cardiogenetics16010006 - 19 Mar 2026

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Abstract

Sudden cardiac death (SCD) is a major global health issue, defined as sudden natural death presumed to be of cardiac cause. While in the elderly SCD is commonly associated with coronary artery disease, in the younger population it is linked to inherited cardiomyopathies [...] Read more.

Sudden cardiac death (SCD) is a major global health issue, defined as sudden natural death presumed to be of cardiac cause. While in the elderly SCD is commonly associated with coronary artery disease, in the younger population it is linked to inherited cardiomyopathies or channelopathies, even though SCD can remain unexplained even after a comprehensive autopsy in a substantial proportion of cases. In this context, genetic testing has gained importance, supported by the widespread availability of techniques such as next-generation and whole-exome/genome sequencing and their reduced costs. This state-of-the-art review summarizes the genetic bases of sudden cardiac death among cardiomyopathies, channelopathies and in sudden unexplained death presumed to be of arrhythmic cause. Among the structural causes, inherited cardiomyopathies such as hypertrophic, dilated, non-dilated left ventricular, arrhythmogenic right ventricular and restrictive ones represent major substrates for malignant ventricular arrhythmias mostly arising from variants in sarcomeric or desmosomal genes. Channelopathies (long or short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia) are caused by variants in genes encoding cardiac ion channels and/or regulatory proteins, which equally predispose to high risk of life-threatening ventricular arrhythmias. In sudden arrhythmic death syndrome, with a structurally normal heart, post-mortem genetic testing (molecular autopsy) can uncover an underlying inherited condition. However, variants of uncertain significance are detected in more than half of the cases, underscoring the need for a multidisciplinary approach. Genetic testing also plays a key role in cascade screening of first-degree relatives. While monogenic variants drive risk in inherited cardiac disorders, emerging evidence suggests that polygenic contributions may modulate SCD susceptibility, highlighting future roles for polygenic risk scores in risk stratification. Full article

(This article belongs to the Special Issue Genetic Insights into Sudden Cardiac Death: From Risk Stratification to Precision Prevention)

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14 pages, 2724 KB

Open AccessEditor’s ChoiceSystematic Review

Genetic Variants as a Potentially Arrhythmogenic Substrate in Mitral Annular Disjunction: Case Report and a Systematic Review of the Literature

by Lorenzo Bianchi, Marialaura Buscemi, Domenico Coviello, Massimiliano Cecconi, Andrea Minghini, Stefano Cornara, Matteo Astuti, Francesco Pentimalli, Pietro Bellone, Emmanuel Androulakis and Alberto Somaschini

Cardiogenetics 2026, 16(1), 3; https://doi.org/10.3390/cardiogenetics16010003 - 26 Feb 2026

Viewed by 899

Abstract

Mitral annular disjunction (MAD) is associated with an increased risk of ventricular arrhythmias and sudden cardiac death, yet its genetic background remains poorly defined. We report the case of a 50-year-old man with MAD who survived cardiac arrest and carries three variants of [...] Read more.

Mitral annular disjunction (MAD) is associated with an increased risk of ventricular arrhythmias and sudden cardiac death, yet its genetic background remains poorly defined. We report the case of a 50-year-old man with MAD who survived cardiac arrest and carries three variants of unknown significance (VUS) in genes involved in cardiomyopathy pathogenesis. To explore the genetic basis of non-syndromic MAD, we performed a systematic review of the literature, identifying five case reports and one retrospective cohort study. The case reports described patients with MAD harboring four pathogenic variants and ten VUS. Two pathogenic variants were linked to cardiomyopathies, involving proteins of the nuclear envelope and cytoskeleton, while two were associated with channelopathies. The retrospective cohort study identified a recurrent variant in a gene involved in intercellular adhesion segregating within a family affected by MAD. Overall, available evidence suggests that genetic factors may hypothetically modulate susceptibility to MAD, not only in connective tissue disorders but also in isolated mitral valve disease. Variants associated with arrhythmogenic cardiomyopathies and channelopathies appear to cluster in families with non-syndromic MAD and arrhythmic phenotypes, suggesting a role in the arrhythmic substrate. However, in absence of definitive functional, segregation, or longitudinal data, the contribution of genetic variants to MAD should be interpreted with caution. Further genomic studies are needed to clarify their genetic contribution and prognostic implications. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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15 pages, 2866 KB

Open AccessEditor’s ChoiceArticle

Sinus Bradycardia and Long QT Syndrome: Double Heterozygosity for Variants in KCNH2 and HCN4

by Jaël S. Copier, Fenna Tuijnenburg, Karolina Andrzejczyk, Alex V. Postma, Saskia N. van der Crabben, Oussama Najih, Caroline Pham, Leander Beekman, Arie O. Verkerk, Ahmad S. Amin and Elisabeth M. Lodder

Cardiogenetics 2025, 15(4), 31; https://doi.org/10.3390/cardiogenetics15040031 - 13 Nov 2025

Viewed by 1683

Abstract

Introduction: Clinical variability within families harbouring disease-causing genetic variants hampers clinical care and risk stratification. We studied a multigenerational family presenting with sinus bradycardia and long QT syndrome type 2 (LQTS2). The family harboured a pathogenic variant in KCNH2, which co-segregated [...] Read more.

Introduction: Clinical variability within families harbouring disease-causing genetic variants hampers clinical care and risk stratification. We studied a multigenerational family presenting with sinus bradycardia and long QT syndrome type 2 (LQTS2). The family harboured a pathogenic variant in KCNH2, which co-segregated with the observed LQTS2. We studied the genetic cause of the high occurrence of sinus bradycardia in this family. Methods: Clinical data was collected, including heart rate, QT-interval, symptoms, and echocardiographic parameters. QTc was calculated using the Bazett and the Fridericia formula. Sanger sequencing of HCN4 was performed, followed by segregation analysis of the identified variant with sinus bradycardia. The biophysiological consequences of two variants, KCNH2-p.L69P (c.206T>C) and HCN4-p.R666W (c.1996C>T), were assessed by patch-clamp experiments. Therefore, a heterologous model was generated by transfection of HEK293A or CHO-k1 cells, respectively. Results: Sanger sequencing of HCN4 identified HCN4-p.R666W (c.1996C>T), which has a stronger segregation with the observed sinus bradycardia than KCNH2-p.L69P. Patch-clamp experiments revealed that KCNH2-p.L69P and HCN4-p.R666W lead to a decrease in the corresponding current densities, which explains the LQTS and sinus bradycardia observed in the patients. Carriers of both genetic variants have a more severe LQTS2 phenotype, reflected in longer QT and higher incidence of syncope. Conclusions: We identified two (likely) pathogenic variants, KCNH2-p.L69P and HCN4-p.R666W, co-segregating with LQTS2 and sinus bradycardia, respectively. Patients carrying both variants showed a more severe phenotype. These findings highlight the importance of additional genetic testing when discordant features are present, thereby enabling more accurate diagnosis, risk prediction, and management. Full article

(This article belongs to the Section Molecular & Translational Genetics)

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6 pages, 1074 KB

Open AccessEditor’s ChoiceCase Report

Integrating Genetic, Clinical, and Histopathological Data for Definitive Diagnosis of PRKAG2-Related Disease

by Martina Caiazza, Emanuele Monda, Francesco Loffredo, Rossana Bussani, Vera Fico, Emanuele Bobbio, Chiara Cirillo, Anna Murredda, Immacolata Viscovo, Alessandra Scatteia, Santo Dellegrottaglie, Diego Colonna, Berardo Sarubbi, Maria Giovanna Russo, Paolo Golino, Gianfranco Sinagra and Giuseppe Limongelli

Cardiogenetics 2025, 15(4), 30; https://doi.org/10.3390/cardiogenetics15040030 - 4 Nov 2025

Cited by 2 | Viewed by 2303

Abstract

Background: PRKAG2-related disease is an autosomal dominant disorder caused by pathogenic variants in the PRKAG2 gene, leading to glycogen accumulation in cardiomyocytes. It is characterized by left ventricular hypertrophy (LVH), ventricular pre-excitation, and conduction disease. Due to the rarity of the condition and [...] Read more.

Background: PRKAG2-related disease is an autosomal dominant disorder caused by pathogenic variants in the PRKAG2 gene, leading to glycogen accumulation in cardiomyocytes. It is characterized by left ventricular hypertrophy (LVH), ventricular pre-excitation, and conduction disease. Due to the rarity of the condition and the frequent occurrence of private variants, functional or pathological testing is required for definitive pathogenicity classification. Case Presentation: We describe a 22-year-old male referred for evaluation after experiencing exertional dyspnea and a syncopal episode. Family history revealed sudden cardiac deaths and conduction disease requiring pacemaker implantation. The patient exhibited mild LVH on imaging, conduction abnormalities on electrophysiological study, and a heterozygous PRKAG2 variant (c.1643C>T; p.Ser548Leu), classified as likely pathogenic according to ACMG guidelines. Cascade screening identified the variant in three family members, one of whom exhibited a positive phenotype. Endomyocardial biopsy revealed glycogen accumulation, providing histopathological confirmation of PRKAG2-related disease. Conclusions: This case underscores the importance of integrating genetic, clinical, and histopathological data in variant interpretation. Endomyocardial biopsy can provide definitive evidence to reclassify a PRKAG2 variant as pathogenic, thereby guiding management and family screening. Full article

(This article belongs to the Section Rare Cardiovascular Disorders)

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18 pages, 762 KB

Open AccessEditor’s ChoiceSystematic Review

MicroRNA and DNA Methylation Adaptation Mechanism to Endurance Training in Cardiovascular Disease: A Systematic Review

by Jil Delhez, Jeanne Ougier, Francisco Xavier de Araujo, Raphael Martins de Abreu and Camilo Corbellini

Cardiogenetics 2025, 15(4), 28; https://doi.org/10.3390/cardiogenetics15040028 - 11 Oct 2025

Cited by 1 | Viewed by 2402

Abstract

Background: Regular endurance training induces physiological changes in cardiac structure and function. The precise epigenetic mechanisms by which cardiovascular adaptations are mediated are still unclear. This review seeks to clarify the role of epigenetic regulation in exercise-induced cardiovascular adaptation. Methods: This systematic review [...] Read more.

Background: Regular endurance training induces physiological changes in cardiac structure and function. The precise epigenetic mechanisms by which cardiovascular adaptations are mediated are still unclear. This review seeks to clarify the role of epigenetic regulation in exercise-induced cardiovascular adaptation. Methods: This systematic review was conducted in accordance with the PRISMA guidelines up to 30 April 2025, using the databases PubMed, VHL, and LILACS Plus. Studies were included if they focused on microRNA expression and DNA methylation in individuals with cardiovascular disease who underwent endurance training. Results: Six articles, including 384 participants with heart failure, coronary artery disease, and hypertension, were included in the final analysis. Changes in DNA methylation and microRNA expression of specific genes involved in cardiovascular structural and functional adaptation were observed. Significant improvements were found in body composition, VO_2peak, systolic and diastolic blood pressure, and left ventricular function and structure. Conclusions: Endurance training has a positive impact on epigenetic mechanisms related to cardiovascular structural and functional adaptation. A clear causal link between epigenetic modifications and clinical outcomes remains to be established. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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10 pages, 383 KB

Open AccessEditor’s ChoiceReview

Polygenic Risk Scores and Coronary Artery Disease

by Salman Ansari, Suvasini Lakshmanan and Matthew J. Budoff

Cardiogenetics 2025, 15(4), 27; https://doi.org/10.3390/cardiogenetics15040027 - 26 Sep 2025

Cited by 3 | Viewed by 6853

Abstract

Background: Polygenic risk scores (PRSs) aggregate the effects of many common genetic variants and are being investigated as tools to refine coronary artery disease (CAD) risk prediction beyond traditional clinical models. Methods and Results: We review the development of PRS from early unweighted [...] Read more.

Background: Polygenic risk scores (PRSs) aggregate the effects of many common genetic variants and are being investigated as tools to refine coronary artery disease (CAD) risk prediction beyond traditional clinical models. Methods and Results: We review the development of PRS from early unweighted scores to contemporary genome-wide models and summarize evidence from major studies. We identified key studies through PubMed searches using the terms “polygenic risk score,” “genetic risk prediction,” and “coronary artery disease,” supplemented by citation chaining of highly cited articles and recent reviews. Large cohorts, such as the UK Biobank, show that individuals in the highest PRS percentiles have a 3–5-fold higher risk of CAD, and may gain the greatest benefit from statin therapy. PRS can also reclassify younger adults at borderline or intermediate risk and may complement coronary artery calcium (CAC) scoring. Conclusions: PRSs hold promise for lifetime risk stratification and targeted prevention in CAD but are limited by ancestry bias in GWAS, underrepresentation of diverse populations, inconsistency in individual estimates, and lack of standardized reporting. Future research should focus on expanding multi-ancestry databases, standardizing methods, prospective validation, and effective communication strategies to support equitable and evidence-based clinical use. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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7 pages, 1560 KB

Open AccessEditor’s ChoiceCase Report

TNNC1 Gene Mutation in Ebstein’s Anomaly and Left Ventricular Hypertrabeculation: A Case Report of a New Causative Mutation?

by Irene Raso, Claudia Chillemi, Giorgia Prontera, Arianna Laoreti, Elisa Cattaneo, Valeria Calcaterra, Gian Vincenzo Zuccotti and Savina Mannarino

Cardiogenetics 2025, 15(3), 24; https://doi.org/10.3390/cardiogenetics15030024 - 26 Aug 2025

Cited by 1 | Viewed by 3368

Abstract

Background: Ebstein’s anomaly (EA) is a rare congenital heart defect characterized by failure of tricuspid valve delamination during embryogenesis. Left ventricular (LV) hypertrabeculation results from incomplete myocardial compaction during fetal development. EA is associated with LV hypertrabeculation in 0.14% of cases, and EA [...] Read more.

Background: Ebstein’s anomaly (EA) is a rare congenital heart defect characterized by failure of tricuspid valve delamination during embryogenesis. Left ventricular (LV) hypertrabeculation results from incomplete myocardial compaction during fetal development. EA is associated with LV hypertrabeculation in 0.14% of cases, and EA is the most common congenital heart disease in LV hypertrabeculation (up to 29%), suggesting a shared embryogenetic pathway. Case Report: We describe a female patient prenatally diagnosed with EA and a large ventricular septal defect. Postnatal echocardiography confirmed EA with moderate regurgitation and revealed previously unnoticed left ventricular excessive trabeculations. Whole exome sequencing revealed a heterozygous never-described variant of unknown significance in the TNNC1 gene. Discussion: The genetic link between EA and LV hypertrabeculation remains unclear, though variants in sarcomeric or cytoskeletal genes like MYH7, TPM1, and NKX2.5—essential for cardiac development—have been implicated. A developmental hypothesis suggests that aberrant contraction during endocardial-to-mesenchymal and epicardial-to-mesenchymal transformation (5th–8th gestational weeks) may affect valve delamination and ventricular compaction via parallel signaling pathways. TNNC1 encodes troponin C1, a subunit of the troponin complex involved in muscle contraction. Its mutations are known to alter calcium sensitivity and impair cardiac contractility. Conclusions: EA and LV hypertrabeculation patients diagnosed in infancy have a greater risk of negative outcomes. Early, especially prenatal, diagnosis is crucial. Genetic analysis can provide fundamental insight into cardiac development. This new and rare variant of TNNC1 gene supports the hypothesis that early cardiomyocytes dysfunction disrupts both valve delamination and left ventricular compaction and that the two diseases share a common genetic pathway related to cardiomyocyte contraction. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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24 pages, 649 KB

Open AccessEditor’s ChoiceReview

Desmosomal Versus Non-Desmosomal Arrhythmogenic Cardiomyopathies: A State-of-the-Art Review

by Kristian Galanti, Lorena Iezzi, Maria Luana Rizzuto, Daniele Falco, Giada Negri, Hoang Nhat Pham, Davide Mansour, Roberta Giansante, Liborio Stuppia, Lorenzo Mazzocchetti, Sabina Gallina, Cesare Mantini, Mohammed Y. Khanji, C. Anwar A. Chahal and Fabrizio Ricci

Cardiogenetics 2025, 15(3), 22; https://doi.org/10.3390/cardiogenetics15030022 - 1 Aug 2025

Cited by 3 | Viewed by 4790

Abstract

Arrhythmogenic cardiomyopathies (ACMs) are a phenotypically and etiologically heterogeneous group of myocardial disorders characterized by fibrotic or fibro-fatty replacement of ventricular myocardium, electrical instability, and an elevated risk of sudden cardiac death. Initially identified as a right ventricular disease, ACMs are now recognized [...] Read more.

Arrhythmogenic cardiomyopathies (ACMs) are a phenotypically and etiologically heterogeneous group of myocardial disorders characterized by fibrotic or fibro-fatty replacement of ventricular myocardium, electrical instability, and an elevated risk of sudden cardiac death. Initially identified as a right ventricular disease, ACMs are now recognized to include biventricular and left-dominant forms. Genetic causes account for a substantial proportion of cases and include desmosomal variants, non-desmosomal variants, and familial gene-elusive forms with no identifiable pathogenic mutation. Nongenetic etiologies, including post-inflammatory, autoimmune, and infiltrative mechanisms, may mimic the phenotype. In many patients, the disease remains idiopathic despite comprehensive evaluation. Cardiac magnetic resonance imaging has emerged as a key tool for identifying non-ischemic scar patterns and for distinguishing arrhythmogenic phenotypes from other cardiomyopathies. Emerging classifications propose the unifying concept of scarring cardiomyopathies based on shared structural substrates, although global consensus is evolving. Risk stratification remains challenging, particularly in patients without overt systolic dysfunction or identifiable genetic markers. Advances in tissue phenotyping, multi-omics, and artificial intelligence hold promise for improved prognostic assessment and individualized therapy. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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33 pages, 4016 KB

Open AccessEditor’s ChoiceArticle

Integrated Deep Learning Framework for Cardiac Risk Stratification and Complication Analysis in Leigh’s Disease

by Md Aminul Islam, Jayasree Varadarajan, Md Abu Sufian, Bhupesh Kumar Mishra and Md Ruhul Amin Rasel

Cardiogenetics 2025, 15(3), 19; https://doi.org/10.3390/cardiogenetics15030019 - 15 Jul 2025

Cited by 1 | Viewed by 1916

Abstract

Background: Leigh’s Disease is a rare mitochondrial disorder primarily affecting the central nervous system, with frequent secondary cardiac manifestations such as hypertrophic and dilated cardiomyopathies. Early detection of cardiac complications is crucial for patient management, but manual interpretation of cardiac MRI is labour-intensive [...] Read more.

Background: Leigh’s Disease is a rare mitochondrial disorder primarily affecting the central nervous system, with frequent secondary cardiac manifestations such as hypertrophic and dilated cardiomyopathies. Early detection of cardiac complications is crucial for patient management, but manual interpretation of cardiac MRI is labour-intensive and subject to inter-observer variability. Methodology: We propose an integrated deep learning framework using cardiac MRI to automate the detection of cardiac abnormalities associated with Leigh’s Disease. Four CNN architectures—Inceptionv3, a custom 3-layer CNN, DenseNet169, and EfficientNetB2—were trained on preprocessed MRI data (224 × 224 pixels), including left ventricular segmentation, contrast enhancement, and gamma correction. Morphological features (area, aspect ratio, and extent) were also extracted to aid interpretability. Results: EfficientNetB2 achieved the highest test accuracy (99.2%) and generalization performance, followed by DenseNet169 (98.4%), 3-layer CNN (95.6%), and InceptionV3 (94.2%). Statistical morphological analysis revealed significant differences in cardiac structure between Leigh’s and non-Leigh’s cases, particularly in area (212,097 vs. 2247 pixels) and extent (0.995 vs. 0.183). The framework was validated using ROC (AUC = 1.00), Brier Score (0.000), and cross-validation (mean sensitivity = 1.000, std = 0.000). Feature embedding visualisation using PCA, t-SNE, and UMAP confirmed class separability. Grad-CAM heatmaps localised relevant myocardial regions, supporting model interpretability. Conclusions: Our deep learning-based framework demonstrated high diagnostic accuracy and interpretability in detecting Leigh’s disease-related cardiac complications. Integrating morphological analysis and explainable AI provides a robust and scalable tool for early-stage detection and clinical decision support in rare diseases. Full article

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42 pages, 643 KB

Open AccessEditor’s ChoiceReview

Systematic Review of Pharmacogenetics of Immunosuppressants in Heart Transplantation

by Juan Eduardo Megías-Vericat, Tomás Palanques-Pastor, Mireya Fernández-Sánchez, Eduardo Guerrero-Hurtado, Mayte Gil-Candel, Antonio Solana-Altabella, Octavio Ballesta-López, María Centelles-Oria, Javier García-Pellicer and José Luis Poveda-Andrés

Cardiogenetics 2025, 15(2), 18; https://doi.org/10.3390/cardiogenetics15020018 - 17 Jun 2025

Cited by 1 | Viewed by 2895

Abstract

The standard immunosuppressive treatments in heart transplantation are calcineurin inhibitors, corticosteroids, and antimetabolite agents or inhibitors of the mammalian target of rapamycin. Pharmacogenetic studies show the impact on clinical course of genetic variability in genes that encode transporters, metabolizers, or molecular targets of [...] Read more.

The standard immunosuppressive treatments in heart transplantation are calcineurin inhibitors, corticosteroids, and antimetabolite agents or inhibitors of the mammalian target of rapamycin. Pharmacogenetic studies show the impact on clinical course of genetic variability in genes that encode transporters, metabolizers, or molecular targets of immunosuppressants. The aim of this systematic review is to elucidate the role that pharmacogenetics of immunosuppressant drugs plays in clinical outcomes upon heart transplantation. PubMed, EMBASE, the Cochrane Central Register, and the Database of Abstracts of Reviews of Effects were searched without restrictions. The 64 studies analyzed followed these criteria: (1) were based on clinical data on heart transplantation patients; (2) analyzed the associations between polymorphisms and clinical response; (3) analyzed the impact of polymorphisms on immunosuppressant safety. CYP3A4/5 variants were associated with higher doses of tacrolimus, whereas POR*28 variants with lower doses—ABCB1, ABCC2, SLCO1B1, and SLC13A1—contribute to interindividual variability in drug absorption, distribution, and toxicity. An ABCC2 polymorphism (rs717620) was related to higher risk of graft rejection in pediatrics. Variations in HLA-G, TNF-α and TGF-β genes influence transplant rejection risk and immune response. Implementing pharmacogenetic screening of polymorphisms could enhance therapeutic outcomes by improving drug efficacy, reducing toxicity, and ultimately increasing heart graft survival rates. Strong evidence supports genotyping for CYP3A5 and TPMT, but further research is required for transporter genes and cytokine polymorphisms. Full article

(This article belongs to the Section Molecular & Translational Genetics)

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8 pages, 186 KB

Open AccessEditor’s ChoiceArticle

Cardiac Involvement in Patients with MELAS-Related mtDNA 3243A>G Variant

by Aino-Maija Vuorinen, Lauri Lehmonen, Mari Auranen, Sini Weckström, Sari Kivistö, Miia Holmström and Tiina Heliö

Cardiogenetics 2025, 15(2), 16; https://doi.org/10.3390/cardiogenetics15020016 - 6 Jun 2025

Cited by 2 | Viewed by 2937

Abstract

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare disease with variable clinical manifestations. MELAS is most often caused by the human mitochondrial DNA (mtDNA) m.3243A>G variant. We describe cardiac magnetic resonance (CMR) imaging findings and clinical features of [...] Read more.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare disease with variable clinical manifestations. MELAS is most often caused by the human mitochondrial DNA (mtDNA) m.3243A>G variant. We describe cardiac magnetic resonance (CMR) imaging findings and clinical features of 22 subjects with the m.3243A>G mutation and endeavored to discover the role of CMR in MELAS cardiomyopathy diagnostics. The clinical symptoms, ECG findings, and laboratory tests were retrospectively collected from the electronic medical record. Ten subjects (46%) had cardiac symptoms, and eighteen subjects (82%) had some clinical symptoms or signs of MELAS. Seventeen subjects (77%) showed cardiac findings compatible with MELAS. An ECG showed a short PR interval in six subjects (27%). Two patients had a first-degree atrioventricular block. Repolarization changes in the ECG were observed in thirteen subjects (59%), whereas left ventricular hypertrophy voltage criteria were only observed in one subject. Patients with ECG abnormalities had a strong link between proBNP value and cardiac tissue composition (T1 relaxation, p < 0.02) and showed decreased CMR-based strain (p < 0.025). The CMR findings are heterogeneous in subjects with m.3243A>G. Cardiac MELAS may include left ventricular hypertrophy, which mimics sarcomericcardiomyopathy but maypredispose individuals to severe heart failure episodes triggered by acute critical situations. CMR may be used to clarify ECG findings. This study indicates that the genetic testing of MELAS should be considered in new cases of HCM or sudden heart failure phenotypes of unknown etiology. Full article

15 pages, 2701 KB

Open AccessEditor’s ChoiceSystematic Review

Genotype–Phenotype Correlation of EVC Variants in Ellis-Van Creveld Syndrome: A Systematic Review and Case Report

by Sandra Rodriguez-Cambranis, Addy-Manuela Castillo-Espinola, Claudia-Daniela Fuentelzas-Rosado, Paulina Salazar-Sansores, Claudia-Gabriela Nuñez-Solis, Hugo-Antonio Laviada-Molina, Aurea-Karina Zetina-Solorzano and Felix-Julian Campos-Garcia

Cardiogenetics 2025, 15(2), 11; https://doi.org/10.3390/cardiogenetics15020011 - 23 Apr 2025

Cited by 1 | Viewed by 4063

Abstract

Ellis-van Creveld syndrome (EvC) is a rare genetic disorder (7:10,000,000) caused by biallelic pathogenic variants in EVC and EVC2, which are located in close proximity on chromosome 4p16.2 in a divergent orientation. These genes encode ciliary complex proteins essential for Hedgehog signaling. [...] Read more.

Ellis-van Creveld syndrome (EvC) is a rare genetic disorder (7:10,000,000) caused by biallelic pathogenic variants in EVC and EVC2, which are located in close proximity on chromosome 4p16.2 in a divergent orientation. These genes encode ciliary complex proteins essential for Hedgehog signaling. EvC is characterized by congenital heart disease (CHD), postaxial polydactyly, and rhizomelic shortening. We present a case of a female newborn from southeast Mexico carrying a novel missense variant in EVC, which is aligned with a systematic review aimed at exploring genotype–phenotype correlations in EVC-related EvC. A PRISMA-based systematic review was conducted in PubMed, Web of Science, and OVID/Medline (until December 2024). Studies reporting EVC variants in EvC were included. Data extraction and quality assessment were performed independently by four reviewers, and genotype–phenotype correlation analysis was conducted. Fifteen studies (n = 66 patients) met the inclusion criteria. The most prevalent features were postaxial polydactyly (95.5%), nail hypoplasia (68.2%), and CHD (66.7%) with atrioventricular canal as the most frequent subtype. Fifty-five distinct EVC variants across 132 alleles were identified, predominantly affecting the N-terminal region (first 699 amino acids). They were syndactyly correlated with pathogenic variants in exons 6, 12, and 13, which were proximal to the second and third coiled-coil domains. This review confirms the key clinical features of EVC-related EvC and highlights genetic heterogeneity. The correlation between syndactyly and specific exonic variants suggests potential genotype–phenotype associations, warranting further functional studies. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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27 pages, 22222 KB

Open AccessEditor’s ChoiceReview

Cardiomyopathies and Arrythmias in Neuromuscular Diseases

by Giuseppe Sgarito, Calogero Volpe, Stefano Bardari, Raimondo Calvanese, Paolo China, Giosuè Mascioli, Martina Nesti, Carlo Pignalberi, Manlio Cipriani and Massimo Zecchin

Cardiogenetics 2025, 15(1), 7; https://doi.org/10.3390/cardiogenetics15010007 - 3 Mar 2025

Cited by 2 | Viewed by 5103

Abstract

Neuromuscular diseases (NMDs) encompass various hereditary conditions affecting motor neurons, the neuromuscular junction, and skeletal muscles. These disorders are characterized by progressive muscle weakness and can manifest at different stages of life, from birth to adulthood. NMDs, such as Duchenne and Becker muscular [...] Read more.

Neuromuscular diseases (NMDs) encompass various hereditary conditions affecting motor neurons, the neuromuscular junction, and skeletal muscles. These disorders are characterized by progressive muscle weakness and can manifest at different stages of life, from birth to adulthood. NMDs, such as Duchenne and Becker muscular dystrophies, myotonic dystrophy, and limb–girdle muscular dystrophies, often involve cardiac complications, including cardiomyopathies and arrhythmias. Underlying genetic mutations contribute to skeletal and cardiac muscle dysfunction, particularly in the DMD, EMD, and LMNA genes. The progressive nature of muscle deterioration significantly reduces life expectancy, mainly due to respiratory and cardiac failure. The early detection of cardiac involvement through electrocardiography (ECG) and cardiac imaging is crucial for timely intervention. Pharmacological treatment focuses on managing cardiomyopathies and arrhythmias, with an emerging interest in gene therapies aimed at correcting underlying genetic defects. Heart transplantation, though historically controversial in patients with muscular dystrophies, is increasingly recognized as a viable option for individuals with advanced heart failure and moderate muscle impairment, leading to improved survival rates. Careful patient selection and management are critical to optimizing outcomes in these complex cases. Full article

(This article belongs to the Section Rare Cardiovascular Disorders)

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12 pages, 1474 KB

Open AccessEditor’s ChoiceArticle

Familial Hypercholesterolemia Screening in a Cardiac Rehabilitation Program After Myocardial Infarction

by Carlos Bertolín-Boronat, Víctor Marcos-Garcés, Héctor Merenciano-González, María Luz Martínez Mas, Josefa Inés Climent Alberola, Nerea Perez, Laura López Bueno, María Concepción Esteban Argente, María Valls Reig, Ana Arizón Benito, Alfonso Payá Rubio, César Ríos-Navarro, Elena de Dios, Jose Gavara, Manuel F. Jiménez-Navarro, Francisco Javier Chorro, Juan Sanchis and Vicente Bodi

Cardiogenetics 2025, 15(1), 6; https://doi.org/10.3390/cardiogenetics15010006 - 24 Feb 2025

Cited by 2 | Viewed by 3214

Abstract

Familial hypercholesterolemia (FH) is relatively prevalent in myocardial infarction (MI) sufferers, and its diagnosis could improve preventive treatment in family members. We aim to analyze the diagnosis of FH and the rate of genetic testing in a prospective cohort of 245 patients submitted [...] Read more.

Familial hypercholesterolemia (FH) is relatively prevalent in myocardial infarction (MI) sufferers, and its diagnosis could improve preventive treatment in family members. We aim to analyze the diagnosis of FH and the rate of genetic testing in a prospective cohort of 245 patients submitted to our Cardiac Rehabilitation Program (CRP) after MI. Baseline characteristics were registered, and basal low-density lipoprotein cholesterol (LDL-C) was calculated after correction for lipid-lowering therapies (LLT) before or during admission. Simplified Dutch Lipid Clinic Network Scores (sDLCNS) were retrospectively calculated based on personal and familial history of premature cardiovascular disease and basal LDL-C levels. Mean age was 62.19 ± 13.93 years, and most patients were male (81.6%). Mean LDL-C before admission and basal LDL-C corrected for LLT were 131.79 ± 45.34 mg/dL and 162.87 ± 44.17 mg/dL, respectively. Patients in the cohort were retrospectively categorized in the “unlikely” (<3 points; n = 162, 66.1%), “possible” (3–5 points; n = 72, 29.4%) and “probable” (6–8 points; n = 11, 4.5%) sDLCNS categories. Genetic testing for FH was requested in four (1.6%) patients, and no clinically significant genetic variants were detected. Patients who underwent genetic testing depicted significantly higher basal LDL-C (233 ± 49.09 vs. 161.71 ± 43.25 mg/dL, p = 0.001). However, the rate of individuals undergoing genetic testing was negligible even in the “possible” (n = 2, 2.8%) and “probable” (n = 1, 9.1%) sDLCNS categories. In conclusion, genetic testing for FH in our CRP after MI is largely underutilized, even in patients with a “possible” or “probable” diagnosis based on sDLCNS criteria, which represent about a third of the cohort. Strategies to improve screening for FH should be prospectively implemented. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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12 pages, 627 KB

Open AccessEditor’s ChoiceArticle

Revisiting the Link Between Keratoconus and Mitral Valve Prolapse

by Christian K. Five, Nina E. Hasselberg, Hilde Bjerkreim, Linda T. Aaserud, Anna Isotta Castrini, Cecilie Bugge, Eivind W. Aabel, Thomas Helle-Valle, Håvard Dalen, Olav Kristianslund and Kristina H. Haugaa

Cardiogenetics 2025, 15(1), 4; https://doi.org/10.3390/cardiogenetics15010004 - 5 Feb 2025

Cited by 1 | Viewed by 2660

Abstract

Keratoconus is a progressive eye disease that results in thinning of the cornea, leading to visual impairment. Mitral valve prolapse (MVP) is a common disorder affecting around 2–4% of the general population. Previous studies have found an overrepresentation of MVP in individuals with [...] Read more.

Keratoconus is a progressive eye disease that results in thinning of the cornea, leading to visual impairment. Mitral valve prolapse (MVP) is a common disorder affecting around 2–4% of the general population. Previous studies have found an overrepresentation of MVP in individuals with keratoconus, with a prevalence of 38–65%, suggesting a shared underlying mechanism. In this case-control study, patients with keratoconus were enrolled from a quality and research registry. They were examined by a 2D echocardiography to identify if they had MVP, billowing or normal mitral leaflets. Controls were matched from the population-based Trøndelag Health Study. Patients and controls underwent a detailed echocardiographic examination to detect abnormal mitral valves. We included 101 patients (age 33 [IQR 29–40], 75% male) with keratoconus and 101 matched individuals. MVP was found in 2 (2%), while billowing was found in 5 (5%) of keratoconus patients. No significant association was found between keratoconus and the prevalence of MVP or billowing compared to the control group. Moreover, no associations were found between severity of keratoconus with presence of MVP nor with billowing of the mitral valves. We could not confirm the previously reported association between keratoconus and MVP, suggesting that routine screening for MVP in keratoconus patients may not be warranted. However, we cannot rule out the possibility of an association in other gender, age and ethnic groups different than ours. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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18 pages, 1710 KB

Open AccessEditor’s ChoiceReview

Cardiovascular Involvement in SYNE Variants: A Case Series and Narrative Review

by Francesco Ravera, Veronica Dusi, Pier Paolo Bocchino, Giulia Gobello, Giuseppe Giannino, Daniele Melis, Giulia Margherita Brach Del Prever, Filippo Angelini, Andrea Saglietto, Carla Giustetto, Guglielmo Gallone, Stefano Pidello, Margherita Cannillo, Marco Matteo Cingolani, Silvia Deaglio, Walter Grosso Marra, Gaetano Maria De Ferrari and Claudia Raineri

Cardiogenetics 2025, 15(1), 2; https://doi.org/10.3390/cardiogenetics15010002 - 20 Jan 2025

Cited by 2 | Viewed by 4676

Abstract

Cardiac laminopathies encompass a wide range of diseases caused by defects in nuclear envelope proteins, including cardiomyopathy, atrial and ventricular arrhythmias and conduction system abnormalities. Two genes, namely LMNA and EMD, are typically associated with these disorders and are part of the [...] Read more.

Cardiac laminopathies encompass a wide range of diseases caused by defects in nuclear envelope proteins, including cardiomyopathy, atrial and ventricular arrhythmias and conduction system abnormalities. Two genes, namely LMNA and EMD, are typically associated with these disorders and are part of the routine genetic panel performed in affected patients. Yet, there are other markedly fewer known proteins, the nesprins, encoded by SYNE genes, that play a pivotal role in connecting the nuclear envelope to cytoskeletal elements. So far, SYNE gene variants have been described in association with neurodegenerative diseases; their potential association with cardiac disorders, albeit anecdotally reported, is still largely unexplored. This review focuses on the role of nesprins in cardiomyocytes and explores the potential clinical implications of SYNE variants by presenting five unrelated patients with distinct cardiac manifestations and reviewing the literature. Emerging research suggests that SYNE-related cardiomyopathies involve disrupted nuclear–cytoskeletal coupling, leading to impaired cardiac function. Understanding these mechanisms is critical for furthering insights into the broader implications of nuclear envelope proteins in cardiac health and for potentially developing targeted therapeutic strategies. Additionally, our data support the inclusion of SYNE genes in the cardiac genetic panel for cardiomyopathies and cardiac conduction disorders. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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17 pages, 317 KB

Open AccessEditor’s ChoiceReview

Dietary Approach in Familial Hypercholesterolemia

by Joanna Popiolek-Kalisz, Klaudia Salamon, Michal Mazur, Klaudia Mikolajczyk and Grzegorz Kalisz

Cardiogenetics 2025, 15(1), 1; https://doi.org/10.3390/cardiogenetics15010001 - 1 Jan 2025

Cited by 2 | Viewed by 13532

Abstract

Introduction: Familial hypercholesterolemia (FH) is a genetic disorder that remains underdiagnosed and undertreated. It is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), which leads to an increased cardiovascular disease risk. Pharmacotherapy of FH is based on high-dose statin therapy, often combined [...] Read more.

Introduction: Familial hypercholesterolemia (FH) is a genetic disorder that remains underdiagnosed and undertreated. It is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), which leads to an increased cardiovascular disease risk. Pharmacotherapy of FH is based on high-dose statin therapy, often combined with ezetimibe and proprotein convertase subtilisin/kexin 9 inhibitors. The dietary approach is an important and supportive part of FH management. Methods: This review aimed to present the available evidence on dietary strategies in FH patients. The analyzed aspects included macronutrients such as fat and carbohydrate intake, as well as the role of dietary fiber, nutraceuticals (omega-3, beta-glucan, phytosterols, and red yeast fermented rice extract), and overall dietary models. Results and Conclusions: Based on the available data, the Mediterranean diet is a dietary model advised in cardiovascular prevention, including patients with FH. Regarding detailed recommendations, the current state of knowledge indicates dietary fat and saturated fatty acids intake limitation as an advised strategy. Supplementation of phytosterols and fiber can be also helpful in FH. Full article

(This article belongs to the Section Rare Cardiovascular Disorders)

26 pages, 2427 KB

Open AccessEditor’s ChoiceReview

Exosome-Derived microRNAs in Hypertrophic Cardiomyopathy

by Brian Xiangzhi Wang

Cardiogenetics 2024, 14(4), 228-253; https://doi.org/10.3390/cardiogenetics14040019 - 9 Dec 2024

Cited by 3 | Viewed by 5161

Abstract

Hypertrophic cardiomyopathy (HCM), characterized by myocardial hypertrophy and an increased risk of sudden cardiac death, poses a significant health burden worldwide. Recent studies have revealed the involvement of exosome-derived microRNAs (miRNAs) in the pathogenesis of HCM, shedding light on novel regulatory mechanisms in [...] Read more.

Hypertrophic cardiomyopathy (HCM), characterized by myocardial hypertrophy and an increased risk of sudden cardiac death, poses a significant health burden worldwide. Recent studies have revealed the involvement of exosome-derived microRNAs (miRNAs) in the pathogenesis of HCM, shedding light on novel regulatory mechanisms in cardiac remodeling and dysfunction. This literature review synthesizes current evidence on the role of exosome-derived miRNAs in HCM. It discusses key miRNAs identified from diverse cellular origins, including cardiomyocytes, stem cells, and conduction cells, elucidating their contributions to hypertrophic signaling pathways, fibrosis, and changes in cellular metabolism. Notable miRNAs highly expressed in exosomes such as miR-1, miR-133, and miR-208 are highlighted for their implications in HCM pathophysiology. Moreover, this review explores the diagnostic and therapeutic potential of exosome-derived miRNAs as biomarkers and therapeutic targets in HCM management. The studies summarized in this review demonstrate that exosome-derived miRNAs play a crucial role in orchestrating the molecular events underlying HCM, offering new insights into disease mechanisms and potential therapeutic avenues. Understanding the intricate interplay between exosome-mediated miRNA communication and HCM pathophysiology holds promise for the development of personalized diagnostic tools and targeted therapies to improve patient outcomes in HCM. Full article

(This article belongs to the Section Molecular & Translational Genetics)

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7 pages, 547 KB

Open AccessEditor’s ChoiceArticle

Comprehensive Diagnostic Work-Up for Uncovering the Causes of Sudden Cardiac Death: The Role of Family Members

by Emanuele Monda, Gaetano Diana, Daniele Bruno, Marta Rubino, Giuseppe Palmiero, Federica Verrillo, Chiara Cirillo, Annapaola Cirillo, Adelaide Fusco, Martina Caiazza, Santo Dellegrottaglie, Diego Colonna, Berardo Sarubbi, Pietro Buono, Maria Giovanna Russo and Giuseppe Limongelli

Cardiogenetics 2024, 14(4), 221-227; https://doi.org/10.3390/cardiogenetics14040018 - 9 Dec 2024

Cited by 2 | Viewed by 3265

Abstract

Background: The aim of this study was to evaluate the performance of the diagnostic pathway proposed by the European Society of Cardiology (ESC) guidelines for identifying the underlying aetiology of sudden cardiac death (SCD) through the screening of first-degree family members of patients [...] Read more.

Background: The aim of this study was to evaluate the performance of the diagnostic pathway proposed by the European Society of Cardiology (ESC) guidelines for identifying the underlying aetiology of sudden cardiac death (SCD) through the screening of first-degree family members of patients with SCD who either had a negative autopsy or no autopsy performed. Methods: To be eligible for enrolment, patients had to meet the following inclusion criteria: a family history of SCD in a first-degree relative under the age of 50 years; the SCD decedents must not have undergone an autopsy, or if an autopsy was performed, non-cardiac and structural cardiac causes must have been excluded. Patients underwent a comprehensive assessment, including the evaluation of family and medical history, electrocardiography (ECG) and ECG with high precordial leads, Holter ECG monitoring, echocardiography, cardiac magnetic resonance imaging, and exercise stress testing. A sodium channel blocker test (i.e., flecainide test) was performed when other clinical investigations were negative and the suspicion of Brugada syndrome was high. Results: Forty-one patients from 25 different families fulfilled the inclusion criteria and represented the final study cohort. After the comprehensive diagnostic work-up, a total of seven patients from five different families (5/25, 20%) were diagnosed with an inherited cardiac condition: two families with arrhythmogenic right ventricular cardiomyopathy, one with dilated cardiomyopathy, one with non-dilated left ventricular cardiomyopathy, and one with long QT syndrome. Conclusions: The comprehensive cardiologic work-up of relatives of mainly young SCD victims results in the diagnosis of inherited cardiac conditions in one-fifth of cases. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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10 pages, 1326 KB

Open AccessFeature PaperEditor’s ChoiceReview

Calcium Release Deficiency Syndrome (CRDS): Rethinking “Atypical” Catecholaminergic Polymorphic Ventricular Tachycardia

by Alessandra P. Porretta, Etienne Pruvot and Zahurul A. Bhuiyan

Cardiogenetics 2024, 14(4), 211-220; https://doi.org/10.3390/cardiogenetics14040017 - 11 Nov 2024

Cited by 3 | Viewed by 4680

Abstract

Since the first description of catecholaminergic polymorphic ventricular tachycardia (CPVT) in the 1970s, new insights have progressively unraveled the understanding of this inherited arrhythmia syndrome. The identification of new distinct clinical entities related to RYR2, the gene encoding the cardiac ryanodine receptor, [...] Read more.

Since the first description of catecholaminergic polymorphic ventricular tachycardia (CPVT) in the 1970s, new insights have progressively unraveled the understanding of this inherited arrhythmia syndrome. The identification of new distinct clinical entities related to RYR2, the gene encoding the cardiac ryanodine receptor, has allowed significant refinement in the diagnosis of previously labeled “atypical” CPVT cases. Among RYR2-ryanodinopathies, the characterization of calcium release deficiency syndrome (CRDS) is still in its infancy and represents a diagnostic challenge due to the need for functional studies which may confirm the loss-of-function nature of the RYR2 variant. The present review summarizes current evidence on CRDS. First, by providing an overview on RYR2 structure and function, we will elucidate the different pathophysiological underpinnings of CRDS and CPVT. Second, by retrieving in detail reported CRDS variants and their clinical phenotypes, we will provide, if any, genetic and clinical red flags that should raise suspicion for CRDS in daily clinical practice. Finally, we will discuss available therapies to provide clinicians with practical therapeutic options for CRDS management. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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15 pages, 1448 KB

Open AccessEditor’s ChoiceArticle

Circulating Cell-Free Nuclear DNA Predicted an Improvement of Systolic Left Ventricular Function in Individuals with Chronic Heart Failure with Reduced Ejection Fraction

by Tetiana Berezina, Oleksandr O. Berezin, Michael Lichtenauer and Alexander E. Berezin

Cardiogenetics 2024, 14(4), 183-197; https://doi.org/10.3390/cardiogenetics14040014 - 1 Oct 2024

Cited by 3 | Viewed by 3032

Abstract

Background: Patients with heart failure (HF) with improved ejection fraction (HFimpEF) demonstrate better clinical outcomes when compared with individuals without restoration of cardiac function. The identification of predictors for HFimpEF may play a crucial role in the individual management of HF with reduced [...] Read more.

Background: Patients with heart failure (HF) with improved ejection fraction (HFimpEF) demonstrate better clinical outcomes when compared with individuals without restoration of cardiac function. The identification of predictors for HFimpEF may play a crucial role in the individual management of HF with reduced ejection fraction (HFrEF). Cell-free nuclear (cf-nDNA) DNA is released from damaged cells and contributes to impaired cardiac structure and function and inflammation. The purpose of the study was to elucidate whether cf-nDNA is associated with HFimpEF. Methods: The study prescreened 1416 patients with HF using a local database. Between October 2021 and August 2022, we included 452 patients with chronic HFrEF after prescription of optimal guideline-based therapy and identified 177 HFimpEF individuals. Circulating biomarkers were measured at baseline and after 6 months. Detection of cf-nDNA was executed with real-time quantitative PCR (qPCR) using NADH dehydrogenase, ND2, and beta-2-microglobulin. Results: We found that HFimpEF was associated with a significant decrease in the levels of cf-nDNA when compared with the patients from persistent HFrEF cohort. The presence of ischemia-induced cardiomyopathy (odds ration [OR] = 0.75; p = 0.044), type 2 diabetes mellitus (OR = 0.77; p = 0.042), and digoxin administration (OR = 0.85; p = 0.042) were negative factors for HFimpEF, whereas NT-proBNP ≤ 1940 pmol/mL (OR = 1.42, p = 0.001), relative decrease in NT-proBNP levels (>35% vs. ≤35%) from baseline (OR = 1.52; p = 0.001), and cf-nDNA ≤ 7.5 μmol/L (OR = 1.56; p = 0.001) were positive predictors for HFimpEF. Conclusions: We established that the levels of cf-nDNA ≤ 7.5 μmol/L independently predicted HFimpEF and improved the discriminative ability of ischemia-induced cardiomyopathy, IV NYHA class, and single-measured NT-proBNP and led to a relative decrease in NT-proBNP levels ≤35% from baseline in individuals with HFrEF. Full article

(This article belongs to the Section Molecular & Translational Genetics)

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21 pages, 1600 KB

Open AccessEditor’s ChoiceReview

Beyond the Beat: Understanding Inherited Risk and Therapeutic Opportunities in Cardiovascular Diseases with Emphasis on Inherited Cardiomyopathies and Inherited Arrhythmic Syndromes

by Antea Krsek, Lara Baticic and Vlatka Sotosek

Cardiogenetics 2024, 14(3), 149-169; https://doi.org/10.3390/cardiogenetics14030012 - 2 Sep 2024

Cited by 3 | Viewed by 4931

Abstract

Over the past three decades, significant progress has been made in elucidating the intricate connection between genetic predispositions and cardiovascular diseases (CVDs). Through extensive investigation, numerous genetic variants linked to various cardiovascular conditions have been discovered, shedding crucial light on the underlying biological [...] Read more.

Over the past three decades, significant progress has been made in elucidating the intricate connection between genetic predispositions and cardiovascular diseases (CVDs). Through extensive investigation, numerous genetic variants linked to various cardiovascular conditions have been discovered, shedding crucial light on the underlying biological mechanisms and pathways. These discoveries have not only revolutionized risk assessment for patients but have also paved the way for personalized treatment strategies, allowing healthcare providers to tailor interventions according to individual genetic profiles. Furthermore, genetic testing has facilitated cascade screening, enabling the early identification and intervention of potential cardiovascular issues among at-risk biological family members. This review aims to comprehensively summarize the current state of knowledge regarding inherited risk and novel insights from human genome and epigenome research, as well as therapeutic opportunities in CVDs with special emphasis on inherited cardiomyopathies and inherited arrhythmic syndromes. The newest translational trials for CVDs and pharmaceutical approaches are discussed, including gene therapy options for heart failure and cardiomyopathies. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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17 pages, 1594 KB

Open AccessEditor’s ChoiceReview

Gene Therapy for Inherited Arrhythmia Syndromes

by Cameron J. Leong, Sohat Sharma, Jayant Seth, Archan Dave, Abdul Aziz Abdul Ghafoor and Zachary Laksman

Cardiogenetics 2024, 14(3), 132-148; https://doi.org/10.3390/cardiogenetics14030011 - 2 Aug 2024

Cited by 3 | Viewed by 8505

Abstract

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, [...] Read more.

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

(This article belongs to the Special Issue Genetics of Inherited Arrhythmogenic Syndromes Associated with Sudden Death)

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10 pages, 1532 KB

Open AccessEditor’s ChoiceArticle

Genetic Testing for Patients with Cardiomyopathies: The INDACO Study—Towards a Cardiogenetic Clinic

by Matteo Bianco, Noemi Giordano, Valentina Gazzola, Carloalberto Biolè, Giulia Nangeroni, Maurizio Lazzero, Giulia Margherita Brach del Prever, Fiorenza Mioli, Giulia Gobello, Amir Hassan Mousavi, Monica Guidante, Silvia Deaglio, Daniela Francesca Giachino and Alessandra Chinaglia

Cardiogenetics 2024, 14(3), 122-131; https://doi.org/10.3390/cardiogenetics14030010 - 22 Jul 2024

Cited by 1 | Viewed by 3360

Abstract

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 [...] Read more.

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

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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16 pages, 4679 KB

Open AccessEditor’s ChoiceReview

Exploring the Role of Genetics in Sarcoidosis and Its Impact on the Development of Cardiac Sarcoidosis

by Sanjay Sivalokanathan

Cardiogenetics 2024, 14(2), 106-121; https://doi.org/10.3390/cardiogenetics14020009 - 3 Jun 2024

Cited by 5 | Viewed by 10072

Abstract

Sarcoidosis is a multifaceted and multisystemic inflammatory disorder, the etiology of which remains unknown. However, it has been suggested that an intricate interplay between genetic, environmental, and inflammatory factors may contribute to the development and progression of sarcoidosis. Although 30–50% of patients demonstrate [...] Read more.

Sarcoidosis is a multifaceted and multisystemic inflammatory disorder, the etiology of which remains unknown. However, it has been suggested that an intricate interplay between genetic, environmental, and inflammatory factors may contribute to the development and progression of sarcoidosis. Although 30–50% of patients demonstrate extra-pulmonary manifestations, cardiac involvement is rare, affecting only 2–5% of cases. Diagnosis is often challenging, relying on the careful application of clinical judgment, histopathological evidence, and imaging biomarkers. In this literature review, we aim to provide a comprehensive overview of the current understanding of the genetic basis of sarcoidosis, the contribution to the pathogenesis of the disorder, and discuss the potential link between certain genetic variants and the development of cardiac sarcoidosis. Full article

(This article belongs to the Special Issue Cardiogenetics: Feature Papers 2024)

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13 pages, 1234 KB

Open AccessEditor’s ChoiceArticle

Gene Polymorphisms LEP, LEPR, 5HT2A, GHRL, NPY, and FTO-Obesity Biomarkers in Metabolic Risk Assessment: A Retrospective Pilot Study in Overweight and Obese Population in Romania

by Ovidiu Nicolae Penes, Bernard Weber, Anca Lucia Pop, Mihaela Bodnarescu-Cobanoglu, Valentin Nicolae Varlas, Aleksandru Serkan Kucukberksun, Dragos Cretoiu, Roxana Georgiana Varlas and Cornelia Zetu

Cardiogenetics 2024, 14(2), 93-105; https://doi.org/10.3390/cardiogenetics14020008 - 20 May 2024

Cited by 6 | Viewed by 6524

Abstract

Genome-wide association studies (GWAS) have successfully revealed numerous susceptibility loci for obesity. The PREDATORR study (2014) shows that in Romania, 346% of adults aged 20–79 y/o are overweight, and 31.4% are obese with a high risk of cardiometabolic complications, a number that puts [...] Read more.

Genome-wide association studies (GWAS) have successfully revealed numerous susceptibility loci for obesity. The PREDATORR study (2014) shows that in Romania, 346% of adults aged 20–79 y/o are overweight, and 31.4% are obese with a high risk of cardiometabolic complications, a number that puts almost 67% of Romania’s population in the abnormal weight group. Our study aims to investigate the current status of the genetic foundation in metabolic disease associated with obesity, applied to a pilot group of patients specifically examining the impact of known polymorphisms and their haplotype of six food intake-regulating genes, namely leptin (LEP), leptin receptor (LEP-R), serotonin receptor (5HTR2A), ghrelin (GHRL), neuropeptide Y (NPY), and fat-mass and obesity-associated protein (FTO) with the following polymorphisms: LEP A-2548G, LEPR A-223G, 5HTR2A G-1439A, GHRL G-72T, NPY T-29063C, FTO A-T, and body mass index (BMI). A notable link between the LEP-2548 rs7799039 gene’s AG genotype and the risk of obesity was observed, particularly pronounced in males aged 40–49, with an approximately seven-fold increased likelihood of obesity. The 5HTR2A rs6311 AA genotype was associated with a higher BMI, which was not statistically significant. The FTO rs9939609 gene’s AA genotype emerged as a significant predictor of obesity risk. Besides these significant findings, no substantial associations were observed with the LEPR, 5HTR2A, GHRL, and NPY genes. Haplotype association analysis showed a suggestive indication of GRGMLA (rs7799039, rs1137101, rs6311, rs696217, rs16139, rs9939609 sequence) haplotype with a susceptibility effect towards obesity predisposition. Linkage disequilibrium (LD) analysis showed statistically significant associations between LEP and LEPR gene (p = 0.04), LEP and GHRL gene (p = 0.0047), and GHRL and FTO gene (p = 0.03). Our study, to the best of our knowledge, is one of the very few on the Romanian population, and aims to be a starting point for further research on the targeted interventional strategies to reduce cardiometabolic risks. Full article

(This article belongs to the Special Issue Metabolic and Genetic Bases of Cardiovascular Diseases)

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10 pages, 3384 KB

Open AccessEditor’s ChoiceCase Report

Anderson–Fabry Disease Homozygosity: Rare Case of Late-Onset Variant

by Gabriela Dostalova, Jaroslav Januska, Michaela Veselá, Petra Reková, Anna Taborska, Martin Pleva, David Zemanek and Aleš Linhart

Cardiogenetics 2024, 14(2), 74-83; https://doi.org/10.3390/cardiogenetics14020006 - 7 Apr 2024

Cited by 1 | Viewed by 5526

Abstract

Anderson–Fabry Disease (AFD) is a rare, X-linked lysosomal storage disorder caused by a mutation in the α-Galactosidase A gene resulting in α-Galactosidase A enzyme (α-Gal A) deficiency. The metabolic defect leads to the progressive accumulation of glycosphingolipids and the structural and functional impairment [...] Read more.

Anderson–Fabry Disease (AFD) is a rare, X-linked lysosomal storage disorder caused by a mutation in the α-Galactosidase A gene resulting in α-Galactosidase A enzyme (α-Gal A) deficiency. The metabolic defect leads to the progressive accumulation of glycosphingolipids and the structural and functional impairment of affected organs. Due to the inheritance pattern, male patients are hemizygous with more severe manifestations of the disease as compared to females who, in most cases, are heterozygous with delayed and variable clinical presentation caused by uneven X-chromosome inactivation. Fabry disease cases are often identified by targeted screening programs in high-risk groups, such as in patients with end-stage renal disease, premature stroke, or unexplained cardiomyopathy. Here, we describe a unique case of a homozygous female patient identified by a nationwide screening program in hypertrophic cardiomyopathy patients. Before the systematic screening, the patient had a diagnosis of hypertrophic obstructive cardiomyopathy and was treated accordingly, including with alcohol septal ablation to reduce the obstructive gradient. The confirmation of Fabry disease led to the discovery of the same variant in several members of her family. The identified variant was c.644A>G, p.Asn215Ser (p.N215S), which is known to cause predominant cardiac involvement with late onset of the disease. This variant is amenable to oral therapy with the small-molecule chaperone migalastat, which was started and then interrupted due to the recurrence of the patient’s migraine and then re-initiated again after two years. During this period, the patient received enzyme replacement therapy with agalsidase beta but developed progressively worsening venous access. Our case illustrates the importance of the systematic screening of patients with clinical evidence of hypertrophic cardiomyopathy in whom the routine diagnostic process fails to discover Fabry disease, in particular variants with late-onset cardiac manifestations. Many of the late-onset variants are amenable to orally active therapy with migalastat, which significantly improves the comfort of the treatment. Its long-term results are being analyzed by a large international “Follow-me” registry, which was designed to verify the validity of pivotal trials with migalastat in Fabry disease. Full article

(This article belongs to the Special Issue Metabolic and Genetic Bases of Cardiovascular Diseases)

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15 pages, 6096 KB

Open AccessEditor’s ChoiceReview

Consideration of the Medical Economics of Cardiac Genetics, Focusing on the Cost-Effectiveness of P2Y12 Inhibitor Selection Based on the CYP2C19 Loss-of-Function Allele: A Semi-Systematic Review

by Tomoyuki Takura

Cardiogenetics 2024, 14(2), 59-73; https://doi.org/10.3390/cardiogenetics14020005 - 3 Apr 2024

Cited by 1 | Viewed by 4196

Abstract

Medical economics is essential in cardiac genetics for the clinical application and development of research results. However, related economic evaluations are unclear, and limited systematic reviews are available on the cost-effectiveness of drug selection based on the CYP2C19 LOF allele. This review analyzed [...] Read more.

Medical economics is essential in cardiac genetics for the clinical application and development of research results. However, related economic evaluations are unclear, and limited systematic reviews are available on the cost-effectiveness of drug selection based on the CYP2C19 LOF allele. This review analyzed research in the MEDLINE database from January 2012 to June 2023 using more evidence than a well-designed cohort study, owing to the lack of relevant research in the database. For example, cost-effectiveness analyses are often reported as simulation assays, and were included in this analysis. No conditions related to patient background or antiplatelet drug therapy were selected. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (2020). Twenty-one cardiac genetic studies were selected, of which nineteen involved antiplatelet therapy after PCI. A universal group consisting of clopidogrel and other drugs was used as the baseline and compared with the drug selection groups based on the CYP2C19 LOF allele. The incremental cost–effectiveness ratio was generally below 50,000 (US$/Qaly), and drug selection based on the CYP2C19 LOF allele was the most cost-effective, followed by universal clopidogrel. Although cardiac genetic and economic data are rudimentary, this review indicates that antiplatelet therapy (drug selection based on the CYP2C19 LOF allele) after PCI is generally cost-effective. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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12 pages, 664 KB

Open AccessEditor’s ChoiceReview

Hypertrophic Cardiomyopathy and Chronic Kidney Disease: An Updated Review

by Sheefah Dhuny, Henry H. L. Wu, Manova David and Rajkumar Chinnadurai

Cardiogenetics 2024, 14(1), 26-37; https://doi.org/10.3390/cardiogenetics14010002 - 12 Jan 2024

Cited by 2 | Viewed by 8843

Abstract

The links between chronic kidney disease (CKD) and cardiac conditions such as coronary heart disease or valvular disease are well established in the literature. However, the relationship between hypertrophic cardiomyopathy (HCM) and CKD is not as frequently described or researched. HCM is the [...] Read more.

The links between chronic kidney disease (CKD) and cardiac conditions such as coronary heart disease or valvular disease are well established in the literature. However, the relationship between hypertrophic cardiomyopathy (HCM) and CKD is not as frequently described or researched. HCM is the most common form of inherited cardiac disease. It is mainly transmitted in an autosomal dominant fashion and caused by mutations in genes encoding sarcomere proteins. HCM is estimated to affect 0.2% of the general population and has an annual mortality rate of between approximately 0.5 and 1%. Our review article aims to summarize the genetics of HCM; discuss the potential clinical mimics that occur concurrently with HCM and CKD, potential interlinks that associate between these two conditions, the role of renal dysfunction as a poor prognostic indicator in HCM; and based on currently available evidence, recommend a management approach that may be suitable when clinicians are faced with this clinical scenario. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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14 pages, 1610 KB

Open AccessEditor’s ChoiceReview

Sarcomeric versus Non-Sarcomeric HCM

by Felice Borrelli, Maria Angela Losi, Grazia Canciello, Gaetano Todde, Errico Federico Perillo, Leopoldo Ordine, Giulia Frisso, Giovanni Esposito and Raffaella Lombardi

Cardiogenetics 2023, 13(2), 92-105; https://doi.org/10.3390/cardiogenetics13020009 - 2 Jun 2023

Cited by 14 | Viewed by 15350

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disorder and is characterized by left ventricular hypertrophy (LVH), which is unexplained by abnormal loading conditions. HCM is inherited as an autosomal dominant trait and, in about 40% of patients, the causal mutation is [...] Read more.

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disorder and is characterized by left ventricular hypertrophy (LVH), which is unexplained by abnormal loading conditions. HCM is inherited as an autosomal dominant trait and, in about 40% of patients, the causal mutation is identified in genes encoding sarcomere proteins. According to the results of genetic screening, HCM patients are currently categorized in two main sub-populations: sarcomeric-positive (Sarc+) patients, in whom the causal mutation is identified in a sarcomeric gene; and sarcomeric-negative (Sarc−) patients, in whom a causal mutation has not been identified. In rare cases, Sarc− HCM cases may be caused by pathogenic variants in non-sarcomeric genes. The aim of this review is to describe the differences in the phenotypic expression and clinical outcomes of Sarc+ and Sarc− HCM and to briefly discuss the current knowledge about HCM caused by rare non-sarcomeric mutations. Full article

(This article belongs to the Section Cardiovascular Genetics in Clinical Practice)

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14 pages, 295 KB

Open AccessEditor’s ChoiceReview

Brugada Syndrome within Asian Populations: State-of-the-Art Review

by Muzamil Khawaja, Yusuf Kamran Qadeer, Rehma Siddiqui, Mihail G. Chelu, Noppawit Aiumtrakul, June K. Pickett, Ramon Brugada, Josep Brugada, Pedro Brugada and Chayakrit Krittanawong

Cardiogenetics 2023, 13(2), 61-74; https://doi.org/10.3390/cardiogenetics13020007 - 26 Apr 2023

Cited by 7 | Viewed by 12200

Abstract

Brugada syndrome (BrS) is an inherited cardiac channelopathy with variable expressivity that can lead to sudden cardiac arrest (SCA). Studies worldwide suggest that BrS and Brugada pattern (BrP) have low prevalences in general. However, studies also note that BrS is most prevalent among [...] Read more.

Brugada syndrome (BrS) is an inherited cardiac channelopathy with variable expressivity that can lead to sudden cardiac arrest (SCA). Studies worldwide suggest that BrS and Brugada pattern (BrP) have low prevalences in general. However, studies also note that BrS is most prevalent among certain Asian populations. Among the different global regions, the highest prevalence is believed to be in Southeast Asia, followed by the Middle East, South Asia, East Asia, Europe, and North America. It is not only important to recognize such varying degrees of BrS prevalence within Asia but also to understand that there may be significant differences in terms of presenting symptoms, occult risk factors, and the impact on clinical outcomes. The importance of identifying such differences lies in the necessity to develop improved risk assessment strategies to guide secondary prevention and treatment for these patients. Specifically, the decision to pursue placement of an implantable cardiac defibrillator (ICD) can be lifesaving for high-risk BrS patients. However, there remains a significant lack of consensus on how to best risk stratify BrS patients. While the current guidelines recommend ICD implantation in patients with spontaneous Type 1 ECG pattern BrS who present with syncope, there may still exist additional clinical factors that may serve as better predictors or facilitate more refined risk stratification before malignant arrhythmias occur. This carries huge relevance given that BrS patients often do not have any preceding symptoms prior to SCA. This review seeks to delineate the differences in BrS presentation and prevalence within the Asian continent in the hope of identifying potential risk factors to guide better prognostication and management of BrS patients in the future. Full article

(This article belongs to the Special Issue Genetics of Inherited Arrhythmogenic Syndromes Associated with Sudden Death)

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16 pages, 830 KB

Open AccessEditor’s ChoiceArticle

Lower Circulating Cell-Free Mitochondrial DNA Is Associated with Heart Failure in Type 2 Diabetes Mellitus Patients

by Tetiana A. Berezina, Mykola P. Kopytsya, Olga V. Petyunina, Alexander A. Berezin, Zeljko Obradovic, Lukas Schmidbauer, Michael Lichtenauer and Alexander E. Berezin

Cardiogenetics 2023, 13(1), 15-30; https://doi.org/10.3390/cardiogenetics13010003 - 7 Feb 2023

Cited by 9 | Viewed by 7391

Abstract

Cell-free nuclear (cf-nDNA) and mitochondrial (cf-mDNA) DNA are released from damaged cells in type 2 diabetes mellitus (T2DM) patients, contributing to adverse cardiac remodeling, vascular dysfunction, and inflammation. The purpose of this study was to correlate the presence and type of cf-DNAs with [...] Read more.

Cell-free nuclear (cf-nDNA) and mitochondrial (cf-mDNA) DNA are released from damaged cells in type 2 diabetes mellitus (T2DM) patients, contributing to adverse cardiac remodeling, vascular dysfunction, and inflammation. The purpose of this study was to correlate the presence and type of cf-DNAs with HF in T2DM patients. A total of 612 T2DM patients were prescreened by using a local database, and 240 patients (120 non-HF and 120 HF individuals) were ultimately selected. The collection of medical information, including both echocardiography and Doppler imagery, as well as the assessment of biochemistry parameters and the circulating biomarkers, were performed at baseline. The N-terminal brain natriuretic pro-peptide (NT-proBNP) and cf-nDNA/cf-mtDNA levels were measured via an ELISA kit and real-time quantitative PCR tests, respectively. We found that HF patients possessed significantly higher levels of cf-nDNA (9.9 ± 2.5 μmol/L vs. 5.4 ± 2.7 μmol/L; p = 0.04) and lower cf-mtDNA (15.7 ± 3.3 μmol/L vs. 30.4 ± 4.8 μmol/L; p = 0.001) than those without HF. The multivariate log regression showed that the discriminative potency of cf-nDNA >7.6 μmol/L (OR = 1.07; 95% CI = 1.03–1.12; p = 0.01) was higher that the NT-proBNP (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.04–1.19; p = 0.001) for HF. In conclusion, we independently established that elevated levels of cf-nDNA, originating from NT-proBNP, were associated with HF in T2DM patients. Full article

(This article belongs to the Section Molecular & Translational Genetics)

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11 pages, 1039 KB

Open AccessEditor’s ChoiceArticle

MYH7 Genotype–Phenotype Correlation in a Cohort of Finnish Patients

by Teemu Vepsäläinen, Tiina Heliö, Catalina Vasilescu, Laura Martelius, Sini Weckström, Juha Koskenvuo, Anita Hiippala and Tiina Ojala

Cardiogenetics 2022, 12(1), 122-132; https://doi.org/10.3390/cardiogenetics12010013 - 16 Mar 2022

Cited by 7 | Viewed by 8973

Abstract

Cardiomyopathies (CMPs) are a heterogeneous group of diseases, frequently genetic, affecting the heart muscle. The symptoms range from asymptomatic to dyspnea, arrhythmias, syncope, and sudden cardiac death. This study is focused on MYH7 (beta-myosin heavy chain), as this gene is commonly mutated in [...] Read more.

Cardiomyopathies (CMPs) are a heterogeneous group of diseases, frequently genetic, affecting the heart muscle. The symptoms range from asymptomatic to dyspnea, arrhythmias, syncope, and sudden cardiac death. This study is focused on MYH7 (beta-myosin heavy chain), as this gene is commonly mutated in cardiomyopathy patients. Due to the high combined prevalence of MYH7 variants and severe health outcomes, it is one of the most frequently tested genes in clinical settings. We analyzed the clinical presentation and natural history of 48 patients with MYH7-related cardiomyopathy belonging to a cohort from a tertiary center at Helsinki University Hospital, Finland. We made special reference to three age subgroups (0–1, 1–12, and >12 years). Our results characterize a clinically significant MYH7 cohort, emphasizing the high variability of the CMP phenotype depending on age. We observed a subgroup of infants (0–1 years) with MYH7 associated severe DCM phenotype. We further demonstrate that patients under the age of 12 years have a similar symptom burden compared to older patients. Full article

(This article belongs to the Special Issue Genetic Diagnostics in Inherited Cardiomyopathies)

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