Cardiogenetics

47 pages, 643 KiB

Open AccessReview

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

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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 Genetics)

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15 pages, 1546 KiB

Open AccessReview

Brugada Syndrome: Channelopathy and/or Cardiomyopathy

by Michele Ciabatti, Pasquale Notarstefano, Chiara Zocchi, Giacomo Virgili, Fulvio Bellocci, Iacopo Olivotto and Maurizio Pieroni

Cardiogenetics 2025, 15(2), 17; https://doi.org/10.3390/cardiogenetics15020017 - 13 Jun 2025

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Abstract

Brugada syndrome (BrS) has been traditionally considered a pure electrical disorder without an underlying structural substrate. However, early ECG studies showed the presence of depolarization abnormalities in this condition, while many studies based on advanced imaging have suggested the presence of subtle structural [...] Read more.

Brugada syndrome (BrS) has been traditionally considered a pure electrical disorder without an underlying structural substrate. However, early ECG studies showed the presence of depolarization abnormalities in this condition, while many studies based on advanced imaging have suggested the presence of subtle structural alterations. On the other hand, electrophysiological study (EPS) and electroanatomic mapping (EAM) techniques have provided important data regarding right ventricular functional and structural arrhythmic substrate. More recently, histology and immunology shed light on the possible role of fibrotic and inflammatory substrates in BrS. Notably, a significant overlap between electro anatomical and structural features in BrS and arrhythmogenic cardiomyopathy has been proposed. In this review, we summarized the physio pathological pathways and substrate underlying BrS. A deeper knowledge of the structural abnormalities involved in the pathogenesis of this disease could improve our diagnostic and prognostic approach, while novel findings regarding the role of inflammation and immune activation could potentially lead to new therapeutic strategies for BrS. Full article

(This article belongs to the Section Rare Disease-Genetic Syndromes)

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8 pages, 186 KiB

Open AccessArticle

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

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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, 765 KiB

Open AccessReview

Novel Perspectives on Genetic Evaluation in Early-Onset Atrial Fibrillation: Clinical Implications and Future Directions

by Angelo Laconi, Tatiana Fancello, Giuliana Solinas and Gavino Casu

Cardiogenetics 2025, 15(2), 15; https://doi.org/10.3390/cardiogenetics15020015 - 30 May 2025

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Abstract

Background: Early-onset atrial fibrillation (AF) exhibits distinct clinical and genetic profiles compared to AF in older adults. The increasing detection of AF among younger patients—often in the absence of traditional risk factors—has raised interest in the genetic determinants underlying the condition. This review [...] Read more.

Background: Early-onset atrial fibrillation (AF) exhibits distinct clinical and genetic profiles compared to AF in older adults. The increasing detection of AF among younger patients—often in the absence of traditional risk factors—has raised interest in the genetic determinants underlying the condition. This review aims to synthesize current evidence on the genetic architecture of early-onset AF, assess the clinical utility of genetic testing, and discuss future directions for integrating genetic insights into personalized management strategies. Methods: We conducted a comprehensive analysis of recent studies, including genome-wide association studies and targeted sequencing efforts, that examined rare pathogenic variants and polygenic risk scores in early-onset AF. The review also considers emerging data on atrial cardiomyopathy and evaluates current guideline recommendations for genetic testing. Results: Data indicate that rare variants, particularly in genes such as TTN, LMNA, and KCNQ1, play a significant role in early-onset AF, with evidence suggesting an association between these mutations and adverse clinical outcomes. Polygenic risk scores further complement traditional risk factors, providing a more nuanced risk stratification. Despite these advances, challenges remain in the interpretation of variants of uncertain significance, cost-effectiveness, and the need for interdisciplinary collaboration in clinical implementation. Conclusions: Integrating genetic evaluation into the diagnostic and management framework of early-onset AF holds promise for improved risk stratification and personalized therapy. Future large-scale, multi-ethnic studies and ongoing refinement of genetic risk models are essential to overcome current limitations and enhance the clinical applicability of genetic testing in this rapidly evolving field. Full article

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

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16 pages, 554 KiB

Open AccessSystematic Review

Pathophysiological Bases and Clinical Uses of Metalloproteases in Cardiovascular Disease: A Scoping Review

by Laura Manuela Olarte Bermúdez, Camila Karduss Preciado, Julián Manuel Espitia Ángel, Ana María Santos Granados, Julio Cesar Martínez Lozano, Carlos Alberto Pacheco Cuentas and Diana Marcela Díaz Quijano

Cardiogenetics 2025, 15(2), 14; https://doi.org/10.3390/cardiogenetics15020014 - 29 May 2025

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Abstract

(1) Objective: Cardiovascular diseases (CVD) are one of the main entities responsible for the progressive increase in morbidity and mortality worldwide. Some of the biomarkers involved in these processes are matrix metalloproteases (MMPs) and disintegrants and metalloproteases (ADAMS), produced by multiple tissues and [...] Read more.

(1) Objective: Cardiovascular diseases (CVD) are one of the main entities responsible for the progressive increase in morbidity and mortality worldwide. Some of the biomarkers involved in these processes are matrix metalloproteases (MMPs) and disintegrants and metalloproteases (ADAMS), produced by multiple tissues and whose main function is the excessive degradation of the extracellular matrix (ECM). The aim of this study is to describe the existing literature on the role of MMP in the pathophysiology of CVD and its usefulness in clinical practice for the diagnostic and therapeutic approach. (2) Methods: A systematic exploratory review of the literature was carried out according to the guidelines of the Joanna Briggs Institute. The information was collected from the PubMed/Medline and Embase databases, using the search strategy “cardiovascular disease” AND “Metalloprotease”. (3) Results: Thirty eight papers that mainly mention 17 types of MMPs were included. Pathologies such as atherosclerosis, coagulation diseases, atrial fibrillation, ischemic heart disease, heart failure, hypertension, dyslipidemias, congenital cyanotic heart disease and Takotsubo cardiomyopathy were identified. (4) Conclusions: The stimulation or inhibition of these biomolecules could generate positive and/or negative effects, which impact the development and prognosis of the disease. Furthermore, they can be potential biomarkers for new diagnostic and even therapeutic approaches in the future. Full article

(This article belongs to the Topic Biomarkers in Cardiovascular Disease—Chances and Risks, 2nd Volume)

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9 pages, 9384 KiB

Open AccessCase Report

Cardiac Phenotype Associated with Two Heterozygous LMNA Variants

by Aura Siikjärvi, Krista Heliö, Tiina Heliö and Miia Holmström

Cardiogenetics 2025, 15(2), 13; https://doi.org/10.3390/cardiogenetics15020013 - 1 May 2025

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Abstract

Background: Laminopathies are a heterogenous group of heritable diseases caused by variants in the Lamin A/C gene (LMNA). They manifest as cardiac and muscular myopathies, lipodystrophies, neuropathies, and progeria. Cardiac manifestations include dilated cardiomyopathy and arrhythmias. Case presentation: A Finnish woman [...] Read more.

Background: Laminopathies are a heterogenous group of heritable diseases caused by variants in the Lamin A/C gene (LMNA). They manifest as cardiac and muscular myopathies, lipodystrophies, neuropathies, and progeria. Cardiac manifestations include dilated cardiomyopathy and arrhythmias. Case presentation: A Finnish woman in her 40s who was found to carry two heterozygous likely pathogenic (LP) variants in LMNA, c.1003C>T p.Arg335Trp and c.1303C>T p.Arg435Cys. She was diagnosed with dilated cardiomyopathy and received cardiac resynchronization therapy with a defibrillator. Conclusions: Double heterozygous LMNA variants are exceedingly rare. Even though the patient presented with two LP variants, the age of onset was typical, and the phenotype was not markedly more severe than in those with only one LP variant. Full article

(This article belongs to the Section Rare Disease-Genetic Syndromes)

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13 pages, 1096 KiB

Open AccessArticle

The Influence of Genotype on the Cardiopulmonary Test Response in Patients Affected by Hypertrophic Cardiomyopathy

by Maria Felicia Gagliardi, Gabriella Malfatto, Claudia Baratto, Alessia Giglio, Valeria Rella, Paolo Cerea, Davide Mariani, Sabrina Salerno, Silvia Ravaro, Silvia Castelletti, Gerardina Fratianni, Chiara Alberio, Matteo Pedrazzini, Mariam Khujadze, Luigi P. Badano, Denisa Muraru, Gianfranco Parati, Franco Cecchi, Sergio Caravita and Lia Crotti

Cardiogenetics 2025, 15(2), 12; https://doi.org/10.3390/cardiogenetics15020012 - 29 Apr 2025

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Abstract

In hypertrophic cardiomyopathy (HCM), the presence of pathogenic/likely pathogenic (P/LP) disease-causing genetic variants may indicate a worse prognosis. Few data exist on the effects of these genetic variants on cardiopulmonary exercise test (CPET) performance in HCM patients. We analysed asymptomatic and slightly symptomatic [...] Read more.

In hypertrophic cardiomyopathy (HCM), the presence of pathogenic/likely pathogenic (P/LP) disease-causing genetic variants may indicate a worse prognosis. Few data exist on the effects of these genetic variants on cardiopulmonary exercise test (CPET) performance in HCM patients. We analysed asymptomatic and slightly symptomatic HCM patients (NYHA I-II) whose genetic analysis and CPET were available; at baseline, left ventricular function was normal and severe left ventricular outflow trait obstruction was excluded. Out of 120 HCM patients, we excluded 13 carrying variants of uncertain significance; of the remaining 107 patients, 54 were genotype negative [gene (−)], and 53 had a P/LP variant in sarcomeric genes [gene (+)]. Patients in the two groups had similar NYHA class, cardiovascular risk factors and echocardiographic characteristics. Gene (+) patients showed a lower peak VO₂% and O₂ pulse % (p < 0.05). Moreover, among gene (+), patients with P/LP variants in the so called “thin-filament” genes (TNNT2, TPM1 and MYL3) had the poorest CPET results. In asymptomatic or slightly symptomatic HCM patients with similar echocardiographic characteristics, exercise tolerance is affected by the genetic background. Indeed, exercise capacity is poorer in gene (+) compared to gene (−) patients and those carrying P/LP variants in “thin-filament” genes show the worst performance. Full article

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

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15 pages, 2701 KiB

Open AccessSystematic 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

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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 Inherited Heart Disease-Children)

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13 pages, 419 KiB

Open AccessArticle

Medical Therapy Versus Percutaneous Coronary Intervention in Patients with Myocardial Bridging from a National Population-Based Cohort Study: The Use of Big Data Analytics

by Chayakrit Krittanawong, Song Peng Ang, Fernando Alexis Padilla, Yusuf Kamran Qadeer, Zhen Wang, Nicola Gaibazzi, Samin K. Sharma, Carl J. Lavie, Hartzell V. Schaff and Ernst R. Schwarz

Cardiogenetics 2025, 15(2), 10; https://doi.org/10.3390/cardiogenetics15020010 - 9 Apr 2025

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Abstract

Myocardial Bridging (MB) is typically a benign congenital coronary anomaly. MB can infrequently result in complications such as myocardial ischemia, arrhythmias, and sudden cardiac death. Recent studies suggest an underlying genetic component for MB involving DES, FBN1, SCN2B, or NOTCH1 [...] Read more.

Myocardial Bridging (MB) is typically a benign congenital coronary anomaly. MB can infrequently result in complications such as myocardial ischemia, arrhythmias, and sudden cardiac death. Recent studies suggest an underlying genetic component for MB involving DES, FBN1, SCN2B, or NOTCH1. The role of percutaneous coronary intervention (PCI) in managing MB, compared to optimal medical therapy (OMT), remains uncertain. Our study used the National Inpatient Sample (NIS) Database to identify patients aged 18 or older with myocardial bridging who were managed with PCI versus medical therapy. We compared the outcomes between both groups including in-hospital mortality, the trend of management of MB and other in-hospital outcomes or complications. Our results showed no statistically significant difference between both subgroups when comparing in-hospital mortality and secondary outcomes of cardiac arrest and the development of an acute kidney injury (AKI). Patients with myocardial bridging treated with PCI had a higher risk of developing cardiogenic shock, requiring LVAD, and requiring the use of intra-aortic balloon pump (IABP) compared to the medical therapy subgroup. Our study suggests the decision to perform PCI in myocardial bridging patients should be individualized such as in patients with refractory symptoms despite medical therapy or those with known high-risk features. Full article

(This article belongs to the Special Issue Gene Therapy in Cardiovascular Genetics)

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Cardiogenetics, Volume 15, Issue 2 (June 2025) – 9 articles

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