Cardiogenetics

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

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

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

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

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

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

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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8 pages, 563 KiB

Open AccessReview

Brugada Syndrome and GPD1L: Definite Genotype-Phenotype Association?

by Andrea Greco, Estefanía Martínez-Barrios, José Cruzalegui, Sergi Cesar, Fredy Chipa, Nuria Díez-Escuté, Patricia Cerralbo, Irene Zschaeck, Paula Loredo, Georgia Sarquella-Brugada and Oscar Campuzano

Cardiogenetics 2025, 15(1), 9; https://doi.org/10.3390/cardiogenetics15010009 - 14 Mar 2025

Abstract

The GPD1L gene encodes a small cytoplasmic protein that is involved in the regulation of sodium currents. Alterations in this gene have been associated with Brugada syndrome. This rare arrhythmogenic syndrome is characterized by a typical electrocardiographic pattern, incomplete penetrance, variable expressivity, and [...] Read more.

The GPD1L gene encodes a small cytoplasmic protein that is involved in the regulation of sodium currents. Alterations in this gene have been associated with Brugada syndrome. This rare arrhythmogenic syndrome is characterized by a typical electrocardiographic pattern, incomplete penetrance, variable expressivity, and risk of sudden cardiac death. To date, few families with a clinical diagnosis of Brugada syndrome caused by a rare alteration in the GPD1L gene have been reported worldwide. The increase in data focused on genetic variants allows us to improve the interpretation of their role in Brugada syndrome. In our study, we have compiled the GPD1L variants reported so far in patients with a definitive clinical diagnosis or suspected Brugada syndrome. We performed an exhaustive update and interpretation of each variant following the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Our results showed that none of the variants described to date can be classified as truly harmful in Brugada syndrome. Despite this fact, more clinical and genetic data are needed to definitively rule out the GPD1L gene as a cause of Brugada syndrome. In summary, to date, there is insufficient evidence to conclude a definitive association between GPD1L and Brugada syndrome. Full article

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

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20 pages, 1254 KiB

Open AccessReview

Genetic Implications of Fatty Tissue for the Development of Ventricular Arrhythmias

by Raluca Sirbu Prisecaru, Oana Purcar and Ioan Manitiu

Cardiogenetics 2025, 15(1), 8; https://doi.org/10.3390/cardiogenetics15010008 - 14 Mar 2025

Abstract

Ventricular arrhythmias are a common disorder, and sometimes the etiology remains unclear. Present data support cardiac fatty tissue’s potential role as a substrate for ventricular arrhythmias. Diagnosing fatty tissue based on imaging markers and histopathological evidence is often challenging. Data about the influence [...] Read more.

Ventricular arrhythmias are a common disorder, and sometimes the etiology remains unclear. Present data support cardiac fatty tissue’s potential role as a substrate for ventricular arrhythmias. Diagnosing fatty tissue based on imaging markers and histopathological evidence is often challenging. Data about the influence of individual and multiple genetic variants on epicardial adipose tissue volume remain limited. In this review, we aimed to provide a comprehensive overview of the current understanding of the genetic basis of fatty tissue and its contribution to the pathogenesis of ventricular arrhythmias and to discuss the relationship between certain genetic variants and the development of ventricular arrhythmia. Full article

(This article belongs to the Section Education in Cardiogenetics)

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27 pages, 22222 KiB

Open AccessReview

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

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 Disease-Neuromuscular Diseases)

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12 pages, 1474 KiB

Open AccessArticle

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

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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10 pages, 1181 KiB

Open AccessArticle

Electrocardiogram May Fail to Identify Proportion of High-Risk Individuals: Analysis of Series of 50 Sudden Death Cases

by Mariela Salar-Alcaraz, Pablo Peñafiel-Verdú, Francisco J. Castro-García, Francisco A. Pastor-Quirante, Carmen Muñoz-Esparza, José M. López-Ayala, Juan Martínez-Sánchez, Juan J. Sánchez-Muñoz, Arcadi García-Alberola, María Sabater-Molina and Juan R. Gimeno-Blanes

Cardiogenetics 2025, 15(1), 5; https://doi.org/10.3390/cardiogenetics15010005 - 10 Feb 2025

Abstract

Background: An electrocardiogram (ECG) is an essential and easily available diagnostic test in the management of cardiomyopathies and channelopathies. Different strategies based on ECG have been recommended for general population and athlete screening. Objectives: The purpose of this study was to explore the [...] Read more.

Background: An electrocardiogram (ECG) is an essential and easily available diagnostic test in the management of cardiomyopathies and channelopathies. Different strategies based on ECG have been recommended for general population and athlete screening. Objectives: The purpose of this study was to explore the value of the ECG for the diagnosis of sudden cardiac death (SCD) cases. Methods: ECGs from 50 (aged 37.6 ± 19.9 years, 37 men) resuscitated cardiac arrest (26, 52%) and SCD cases (24, 48%) were analyzed. Relevant medical history and results from clinical tests were reviewed. ECG findings were compared with the final diagnosis. Results: Final ECG classification was as follows: 9 (18%) normal, 15 (30%) unspecific, 14 (28%) suggestive, and 12 (24%) diagnostic. Amongst 13 hypertrophic cardiomyopathy patients, ECGs were diagnostic in 6 (46%) and suggestive in 1 (8%). Arrhythmogenic right ventricular cardiomyopathy was diagnosed in seven patients, two (28%) with suggestive ECG. Dilated cardiomyopathy was diagnosed in four patients, two (50%) with suggestive ECG. Six patients had Brugada syndrome: four (66%) had diagnostic ECGs, and two (33%) had suggestive ECG. Long QT syndrome was diagnosed in four cases; only one (25%) had a diagnostic ECG. Three patients had other cardiomyopathies. After the complete study, 13 (26%) patients remained with a non-conclusive diagnosis; their ECGs were unspecific or normal. Conclusion: ECG can be unspecific or normal in an important percentage of SCD cases (48%). Furthermore, a significant proportion of SCD cases after a comprehensive study remain without a definite diagnosis (26%). These findings should be considered when planning SCD preventive strategies. Full article

(This article belongs to the Section Sport Cardiology)

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12 pages, 627 KiB

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

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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9 pages, 414 KiB

Open AccessEditor’s ChoiceArticle

Contribution of Rare and Common APOE Variants to Familial Hypercholesterolemia in Spanish Cohort

by Lorena M. Vega-Prado, Daniel Vázquez-Coto, Francisco Villazón, Lorena Suárez-Gutiérrez, Ceferino Martínez-Faedo, Edelmiro Menéndez-Torre, María Riestra, Silvia González-Martínez, Gala Gutiérrez-Buey, Claudia García-Lago, Juan Gómez, Victoria Alvarez, Helena Gil, Rebeca Lorca and Eliecer Coto

Cardiogenetics 2025, 15(1), 3; https://doi.org/10.3390/cardiogenetics15010003 - 27 Jan 2025

Abstract

Our aim was to determine whether rare APOE pathogenic variants (PV) and the common e2/e3/e4 polymorphism were associated with the risk of familial hypercholesterolemia (FH). A total of 431 patients who met the inclusion criteria for FH were next-generation sequenced for the main [...] Read more.

Our aim was to determine whether rare APOE pathogenic variants (PV) and the common e2/e3/e4 polymorphism were associated with the risk of familial hypercholesterolemia (FH). A total of 431 patients who met the inclusion criteria for FH were next-generation sequenced for the main candidate genes (LDLR, APOB, PCSK9, APOE, LDLRAP1). A total of 139 patients (32%) had a pathogenic variant, including 3 with APOE p.Leu167del. Among the PV-negatives (n = 292), one was homozygous for APOE-e2 and showed a combined phenotype of high low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs). A total of 165 population controls were also genotyped for the APOE polymorphism. PV-negative patients showed a significantly higher frequency of APOE-e3e4/e4e4 compared to PV-positives (p = 0.006) and to population controls (p = 0.0002, OR = 2.63, 95% CI = 1.57–4.40). APOE-e4e4 patients had significantly higher mean LDL-C compared to the other genotypes (p = 0.047). In conclusion, APOE pathogenic variants were a rare cause of FH in our population, and the APOE-e4 allele was a significant risk factor for being diagnosed with familial hypercholesterolemia in the absence of a pathogenic variant involved in FH. In particular, the APOE-e4e4 genotype was associated with higher LDL-C levels compared to the other genotypes. Full article

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

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18 pages, 1710 KiB

Open AccessReview

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

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 KiB

Open AccessReview

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

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 Disease-Genetic Syndromes)

26 pages, 2427 KiB

Open AccessReview

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

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 Biomarkers)

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7 pages, 547 KiB

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 1

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 Inherited Aortic Disease)

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10 pages, 1326 KiB

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

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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7 pages, 1981 KiB

Open AccessCase Report

Ballooning and Bursting of Barrels and Pipes: A Rare Case of Suspected Vascular Ehlers–Danlos Disease

by Ogechi Agogbuo, Sri Harsha Kanuri, Luis Salinas, Mohamed Goweba, Khashayar Vahdat, Oscar Chastian and Larry Frase

Cardiogenetics 2024, 14(4), 204-210; https://doi.org/10.3390/cardiogenetics14040016 - 6 Nov 2024

Abstract

Vascular Ehler–Danlos disease (vEDS), a rare subtype of a rare disease, is a life-threatening disease, with an increased risk for spontaneous vascular or visceral rupture. These patients have fatal complications ranging from vascular aneurysms, dissection, and rupture of systemic vessels to frequent thromboembolic [...] Read more.

Vascular Ehler–Danlos disease (vEDS), a rare subtype of a rare disease, is a life-threatening disease, with an increased risk for spontaneous vascular or visceral rupture. These patients have fatal complications ranging from vascular aneurysms, dissection, and rupture of systemic vessels to frequent thromboembolic events, the common causes of death in these individuals with a shortened life span. In the present case, a 28-year-old male with history of shoulder dislocations and spontaneous colon perforation presented to the primary care clinic with right lower extremity swelling and pain. His history includes presentation to the emergency department with left lower leg swelling with compartment syndrome one year prior. A CT angiogram of lower extremities and abdomen revealed acute arterial extravasation of the left posterior tibial artery, indicating a ruptured aneurysm along with aneurysms of the splenic artery and left common iliac artery. He was treated with a saphenous vein graft, but was associated with post-operative complications that necessitated below-knee amputation. CT angiogram of his right leg revealed occlusion of the anterior tibial and peroneal arteries with aneurysms, and, ultimately, he was referred to a tertiary care center for aneurysm embolization. This case report emphasizes the frequent vascular complications encountered in vascular EDS patients, and thus advocates for close and regular monitoring for early referral and surgical management of their vascular anomalies. Finally, genetic counseling and screening of asymptomatic family members should be routinely implemented in these patients. Full article

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

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