Cardiogenetics

15 pages, 1448 KiB

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

Viewed by 721

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 Biomarkers)

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13 pages, 634 KiB

Open AccessEditor’s ChoiceReview

Review of p.(Val429Met), a Variant of LDLR That Is Associated with Familial Hypercholesterolemia

by Eric F. Jotch and Mark S. Kindy

Cardiogenetics 2024, 14(4), 170-182; https://doi.org/10.3390/cardiogenetics14040013 - 29 Sep 2024

Viewed by 866

Abstract

Patients affected by familial hypercholesterolemia possess elevated low-density lipoprotein cholesterol and therefore have greater risk for cardiovascular disease. About 90% of familial hypercholesterolemia cases are associated with aberrant LDLR. Over 3500 LDLR variants have been identified, 15% of which are considered “pathogenic.” [...] Read more.

Patients affected by familial hypercholesterolemia possess elevated low-density lipoprotein cholesterol and therefore have greater risk for cardiovascular disease. About 90% of familial hypercholesterolemia cases are associated with aberrant LDLR. Over 3500 LDLR variants have been identified, 15% of which are considered “pathogenic.” Given the genetic diversity of LDLR variants, specific variants rarely receive attention. However, investigators have proposed the critical evaluation of individual variants as a method to clarify knowledge and to resolve discrepancies in the literature. This article reviews p.(Val429Met) (rs28942078) in the areas of pathology, epidemiology, lipid-lowering therapy, and genetic testing. The p.(Val429Met) variant is associated with a missense point substitution in exon 9 of chromosome 19. Biochemical studies have found severely reduced low-density lipoprotein receptor protein in autologous and heterologous expression systems. Additionally, there are inconsistencies regarding the functional classification of p.(Val429Met). Considered to be of European origin, p.(Val429Met) is found in extant populations due to founder effects. Evidence from clinical trials have also demonstrated variable responses to newer lipid-lowering therapies in patients with a p.(Val429Met) variant. Proper clinical detection and adequate genetic testing have been shown to greatly improve outcomes. Future research may be aimed at resolving discrepancies to better comprehend the implications of familial hypercholesterolemia. Full article

(This article belongs to the Section Molecular Genetics)

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17 pages, 1594 KiB

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

Viewed by 1659

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, 1525 KiB

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

Viewed by 1048

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 KiB

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

Viewed by 2727

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 KiB

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 1 | Viewed by 2040

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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15 pages, 6096 KiB

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

Viewed by 2033

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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13 pages, 568 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Risk of Cardiac Arrhythmias in Patients with Late-Onset Pompe Disease—Results from a Long Follow-Up in a Group of 12 Patients and Review of Literature

by Alberto Palladino, Luigia Passamano, Marianna Scutifero, Salvatore Morra, Esther Picillo, Andrea Antonio Papa, Gerardo Nigro and Luisa Politano

Cardiogenetics 2024, 14(1), 38-50; https://doi.org/10.3390/cardiogenetics14010003 - 12 Feb 2024

Viewed by 1997

Abstract

Background. Pompe disease is a rare, severe, autosomal recessive genetic disorder caused by GAA gene mutations, which cause α-1,4-glucosidase enzyme deficiency. There are two forms of Pompe disease based on the age of onset, the infantile and the adult form (LOPD). Cardiac [...] Read more.

Background. Pompe disease is a rare, severe, autosomal recessive genetic disorder caused by GAA gene mutations, which cause α-1,4-glucosidase enzyme deficiency. There are two forms of Pompe disease based on the age of onset, the infantile and the adult form (LOPD). Cardiac involvement, previously recognized only in infantile cases, is now also reported in adults. Cardiomyopathy remains an exceptional finding while heart rhythm disorders appear to be more frequent. Methods. We retrospectively evaluated cardiac involvement in 12 patients with late-onset Pompe disease (LOPD) followed for an overall period of 143 years (mean 12.7 ± 7.7) using ECG, Holter ECG, and echocardiography. Results. The mean age of patients (M8:F4) at the first visit was 40.7 ± 16.1 (range 14–63) and 53.7 ± 16.9 (range 21–76) at last visit. Conduction delay was present in three patients; one patient developed ascending aorta ectasia but had a history of hypertension, and one patient showed right heart enlargement on echocardiography, probably due to pulmonary hypertension. No patient died during the FU, nor developed cardiomyopathy. Ectopic supraventricular beats and repeated episodes of ablation-resistant atrial fibrillation were observed in only one patient (8.3%) who required PMK implantation. Conclusions. Benefitting from the long follow-up, this study allows us to state that primary myocardial involvement is rare in patients with LOPD, while rhythm disorders are more frequent and require monitoring to avoid the risk of possible life-threatening complications. Full article

(This article belongs to the Section Rare Disease-Neuromuscular Diseases)

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12 pages, 664 KiB

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

Viewed by 3373

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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19 pages, 1471 KiB

Open AccessEditor’s ChoiceReview

From Natural History to Contemporary Management of Aortic Diseases: A State-of-the-Art Review of Thoracic Aortic Aneurysm

by Yuliya Paulenka, Christopher Lee, Mays Tawayha, Sam Dow, Kajal Shah, Stanislav Henkin and Wassim Mosleh

Cardiogenetics 2023, 13(4), 154-172; https://doi.org/10.3390/cardiogenetics13040015 - 29 Nov 2023

Viewed by 2846

Abstract

Thoracic aortic aneurysms (TAAs) are commonly seen in cardiovascular practice. Acquired and genetic conditions contribute to TAA formation. The natural history of genetically mediated TAA underscores the importance of early detection, regular monitoring, and prompt treatment to prevent complications, including dissection or rupture. [...] Read more.

Thoracic aortic aneurysms (TAAs) are commonly seen in cardiovascular practice. Acquired and genetic conditions contribute to TAA formation. The natural history of genetically mediated TAA underscores the importance of early detection, regular monitoring, and prompt treatment to prevent complications, including dissection or rupture. The prognosis is poor in the event of acute dissection, with high rates of in-hospital mortality. Healthcare providers need to remain vigilant in their efforts to identify and surveil TAA to reduce the risk of complications. In this manuscript, we review the natural history of TAA, discuss the most common causes leading to the development of TAA, assess the value and limitations of diagnostic modalities, and review the management and long-term surveillance of patients with aortic disease. Full article

(This article belongs to the Special Issue Advanced Research on Inherited Aortic Diseases)

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18 pages, 5312 KiB

Open AccessEditor’s ChoiceArticle

Functional Characterization of the A414G Loss-of-Function Mutation in HCN4 Associated with Sinus Bradycardia

by Arie O. Verkerk and Ronald Wilders

Cardiogenetics 2023, 13(3), 117-134; https://doi.org/10.3390/cardiogenetics13030012 - 4 Aug 2023

Cited by 1 | Viewed by 2681

Abstract

Patients carrying the heterozygous A414G mutation in the HCN4 gene, which encodes the HCN4 protein, demonstrate moderate to severe bradycardia of the heart. Tetramers of HCN4 subunits compose the ion channels in the sinus node that carry the hyperpolarization-activated ‘funny’ current (I_f [...] Read more.

Patients carrying the heterozygous A414G mutation in the HCN4 gene, which encodes the HCN4 protein, demonstrate moderate to severe bradycardia of the heart. Tetramers of HCN4 subunits compose the ion channels in the sinus node that carry the hyperpolarization-activated ‘funny’ current (I_f), also named the ‘pacemaker current’. I_f plays an essential modulating role in sinus node pacemaker activity. To assess the mechanism by which the A414G mutation results in sinus bradycardia, we first performed voltage clamp measurements on wild-type (WT) and heterozygous mutant HCN4 channels expressed in Chinese hamster ovary (CHO) cells. These experiments were performed at physiological temperature using the amphotericin-perforated patch-clamp technique. Next, we applied the experimentally observed mutation-induced changes in the HCN4 current of the CHO cells to I_f of the single human sinus node cell model developed by Fabbri and coworkers. The half-maximal activation voltage V_1/2 of the heterozygous mutant HCN4 current was 19.9 mV more negative than that of the WT HCN4 current (p < 0.001). In addition, the voltage dependence of the heterozygous mutant HCN4 current (de)activation time constant showed a −11.9 mV shift (p < 0.001) compared to the WT HCN4 current. The fully-activated current density, the slope factor of the activation curve, and the reversal potential were not significantly affected by the heterozygous A414G mutation. In the human sinus node computer model, the cycle length was substantially increased, almost entirely due to the shift in the voltage dependence of steady-state activation, and this increase was more prominent under vagal tone. The introduction of a passive atrial load into the model sinus node cell further reduced the beating rate, demonstrating that the bradycardia of the sinus node was even more pronounced by interactions between the sinus node and atria. In conclusion, the experimentally identified A414G-induced changes in I_f can explain the clinically observed sinus bradycardia in patients carrying the A414G HCN4 gene mutation. Full article

(This article belongs to the Section Molecular Genetics)

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14 pages, 1610 KiB

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 5 | Viewed by 6818

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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17 pages, 4516 KiB

Open AccessEditor’s ChoiceReview

Diagnosis and Treatment of Obstructive Hypertrophic Cardiomyopathy

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

Cardiogenetics 2023, 13(2), 75-91; https://doi.org/10.3390/cardiogenetics13020008 - 15 May 2023

Cited by 2 | Viewed by 6808

Abstract

Left ventricular outflow obstruction (LVOTO) and diastolic dysfunction are the main pathophysiological characteristics of hypertrophic cardiomyopathy (HCM)LVOTO, may be identified in more than half of HCM patients and represents an important determinant of symptoms and a predictor of worse prognosis. This review aims [...] Read more.

Left ventricular outflow obstruction (LVOTO) and diastolic dysfunction are the main pathophysiological characteristics of hypertrophic cardiomyopathy (HCM)LVOTO, may be identified in more than half of HCM patients and represents an important determinant of symptoms and a predictor of worse prognosis. This review aims to clarify the LVOTO mechanism in, diagnosis of, and therapeutic strategies for patients with obstructive HCM. Full article

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

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14 pages, 295 KiB

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 5 | Viewed by 4756

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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14 pages, 4753 KiB

Open AccessEditor’s ChoiceArticle

Sex Differences in Fatty Acid Metabolism and Blood Pressure Response to Dietary Salt in Humans

by Jeanne A. Ishimwe, Jane F. Ferguson and Annet Kirabo

Cardiogenetics 2023, 13(1), 33-46; https://doi.org/10.3390/cardiogenetics13010005 - 3 Mar 2023

Cited by 1 | Viewed by 3518

Abstract

Salt sensitivity is a trait in which high dietary sodium (Na⁺) intake causes an increase in blood pressure (BP). We previously demonstrated that in the gut, elevated dietary Na⁺ causes dysbiosis. The mechanistic interplay between excess dietary Na⁺-induced [...] Read more.

Salt sensitivity is a trait in which high dietary sodium (Na⁺) intake causes an increase in blood pressure (BP). We previously demonstrated that in the gut, elevated dietary Na⁺ causes dysbiosis. The mechanistic interplay between excess dietary Na⁺-induced alteration in the gut microbiome and sex differences is less understood. The goal of this study was to identify novel metabolites in sex differences and blood pressure in response to a high dietary Na⁺ intake. We performed stool and plasma metabolomics analysis and measured the BP of human volunteers with salt intake above or below the American Heart Association recommendations. We also performed RNA sequencing on human monocytes treated with high salt in vitro. The relationship between BP and dietary Na⁺ intake was different in women and men. Network analysis revealed that fatty acids as top subnetworks differentially changed with salt intake. We found that women with high dietary Na⁺ intake have high levels of arachidonic acid related metabolism, suggesting a role in sex differences of the blood pressure response to Na⁺. The exposure of monocytes to high salt in vitro upregulates the transcription of fatty acid receptors and arachidonic acid-related genes. These findings provide potentially novel insights into metabolic changes underlying gut dysbiosis and inflammation in salt sensitivity of BP. Full article

(This article belongs to the Section Biomarkers)

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9 pages, 1766 KiB

Open AccessEditor’s ChoiceReview

Moderately Prolonged QTc in Computer-Assessed ECG, Random Variation or Significant Risk Factor? A Literature Review

by Jan Hysing, Charlotte Gibbs, Øystein Lunde Holla, Jacob Thalamus and Kristina H. Haugaa

Cardiogenetics 2022, 12(3), 261-269; https://doi.org/10.3390/cardiogenetics12030025 - 8 Sep 2022

Cited by 2 | Viewed by 3770

Abstract

Most ECGs in European hospitals are recorded with equipment giving computer measured intervals and interpretation of the recording. In addition to measurements of interval and QRS axis, this interpretation frequently provides the Bazett’s-corrected QTc time. The introduction of computer-corrected QTc revealed QTc prolongation [...] Read more.

Most ECGs in European hospitals are recorded with equipment giving computer measured intervals and interpretation of the recording. In addition to measurements of interval and QRS axis, this interpretation frequently provides the Bazett’s-corrected QTc time. The introduction of computer-corrected QTc revealed QTc prolongation to be a frequent condition among medical patients. Nevertheless, the finding is frequently overlooked by the treating physician. The authors combine experience from a local hospital with a review of the current literature in this field in order to elucidate the importance of this risk factor both as congenital long QT syndrome and as acquired QT prolongation. Full article

(This article belongs to the Special Issue Cardiogenetics: Feature Papers 2022)

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6 pages, 3610 KiB

Open AccessEditor’s ChoiceCase Report

Identification of Single-Nucleotide Polymorphisms in ZNF469 in a Patient with Aortoiliac Aneurysmal Disease

by Adam Wolf, Faria Khimani and Mohanakrishnan Sathyamoorthy

Cardiogenetics 2022, 12(3), 212-217; https://doi.org/10.3390/cardiogenetics12030020 - 28 Jun 2022

Cited by 2 | Viewed by 3363

Abstract

Thoracic aortic aneurysms and dissections often have inter-related pathologies that are increasingly recognized to have a genetic basis. A patient with a vascular history consisting of a spontaneous aorto-iliac dissection and thoracic aortic aneurysm belonged to a family with a significant self-reported history [...] Read more.

Thoracic aortic aneurysms and dissections often have inter-related pathologies that are increasingly recognized to have a genetic basis. A patient with a vascular history consisting of a spontaneous aorto-iliac dissection and thoracic aortic aneurysm belonged to a family with a significant self-reported history of aneurysmal disease. Suspecting a genetic component, genetic investigation was undertaken. Three variants of unknown significance were found in the ZNF469 gene, which is responsible for the production of a collagen-related zinc finger protein involved in multiple aspects of the development and regulation of major extracellular matrix components. This is the first report to associate this gene with vasculopathy, and further investigation by our group is underway to understand the role it plays in the development of aneurysmal diseases. Full article

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

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8 pages, 249 KiB

Open AccessEditor’s ChoiceArticle

Genetic Screening of a Large Panel of Genes Associated with Cardiac Disease in a Spanish Heart Transplanted Cohort

by Elías Cuesta-Llavona, Rebeca Lorca, Beatriz Díaz-Molina, José L. Lambert-Rodríguez, Julián R. Reguero, Sara Iglesias, Belén Alonso, Alejandro Junco-Vicente, Vanesa Alonso, Eliecer Coto and Juan Gómez

Cardiogenetics 2022, 12(2), 198-205; https://doi.org/10.3390/cardiogenetics12020018 - 9 May 2022

Cited by 3 | Viewed by 3639

Abstract

In this study we performed a next generation sequencing of 210 genes in 140 patients with cardiac failure requiring a heart transplantation. We identified a total of 48 candidate variants in 47 patients. Forty-three patients (90%) presented a single variant, and fourpatients (10%) [...] Read more.

In this study we performed a next generation sequencing of 210 genes in 140 patients with cardiac failure requiring a heart transplantation. We identified a total of 48 candidate variants in 47 patients. Forty-three patients (90%) presented a single variant, and fourpatients (10%) were carriers of two variants. After refining the classification, we identified a pathogenic or likely pathogenic variant in 13 patients (10% of our cohort). In 34 additional cases (25%) the variants were classified as of unknown significance (VUS). In reference to the cause of cardiac failure in the 13 carriers of pathogenic variants, 5 were of dilated non-ischemic cause, 4 hypertrophic and 1 restrictive cardiomyopathy. In the ischemic cases (n = 3) no family history of cardiac disease was recorded, while nineof the non-ischemic had other relatives who were also diagnosed. In conclusion, the NGS of a cardiac transplanted cohort identified a definite or very likely genetic cause in 10% of the cases. Most of them had a family history of cardiac disease, and were thus previously studied as part of a routine screening by a genetic counselor. Pathogenic variants in cases without a family history of cardiac disease were mainly of ischemic origin. Full article

(This article belongs to the Special Issue Cardiogenetics: Feature Papers 2021)

15 pages, 2489 KiB

Open AccessEditor’s ChoiceReview

Left Ventricular Non-Compaction Spectrum in Adults and Children: From a Morphological Trait to a Structural Muscular Disease

by Flavia Fusco, Nunzia Borrelli, Rosaria Barracano, Giovanni Domenico Ciriello, Federica Verrillo, Giancarlo Scognamiglio and Berardo Sarubbi

Cardiogenetics 2022, 12(2), 170-184; https://doi.org/10.3390/cardiogenetics12020016 - 1 Apr 2022

Cited by 2 | Viewed by 4919

Abstract

Left ventricular non-compaction (LVNC) is an extremely heterogeneous disorder with a highly variable clinical presentation, morphologic appearance at imaging testing, and prognosis. It is still unclear whether LVNC should be classified as a separate cardiomyopathy or if it is a mere morphological trait [...] Read more.

Left ventricular non-compaction (LVNC) is an extremely heterogeneous disorder with a highly variable clinical presentation, morphologic appearance at imaging testing, and prognosis. It is still unclear whether LVNC should be classified as a separate cardiomyopathy or if it is a mere morphological trait shared by many phenotypically distinct cardiomyopathies. Moreover, the hypertrabeculated phenotype may be reversible in some cases, possibly reflecting the left ventricular physiological response of the cardiac muscle to chronic overload. The current diagnostic criteria have several limitations, leaving many patients in a grey area. Here, we review the available literature on LVNC in order to provide an overview of the current knowledge on this complex disorder. Full article

(This article belongs to the Special Issue Cardiogenetics: Feature Papers 2021)

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11 pages, 1039 KiB

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 4 | Viewed by 5888

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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17 pages, 767 KiB

Open AccessEditor’s ChoiceReview

Genetics of Heritable Thoracic Aortic Disease

by Efstathios Papatheodorou, Dimitrios Degiannis and Aris Anastasakis

Cardiogenetics 2022, 12(1), 63-79; https://doi.org/10.3390/cardiogenetics12010006 - 4 Feb 2022

Cited by 6 | Viewed by 6056

Abstract

Genetic testing plays an increasing diagnostic and prognostic role in the management of patients with heritable thoracic aortic disease (HTAD). The identification of a specific variant can establish or confirm the diagnosis of syndromic HTAD, dictate extensive evaluation of the arterial tree in [...] Read more.

Genetic testing plays an increasing diagnostic and prognostic role in the management of patients with heritable thoracic aortic disease (HTAD). The identification of a specific variant can establish or confirm the diagnosis of syndromic HTAD, dictate extensive evaluation of the arterial tree in HTAD with known distal vasculature involvement and justify closer follow-up and earlier surgical intervention in HTAD with high risk of dissection of minimal or normal aortic size. Evolving phenotype–genotype correlations lead us towards more precise and individualized management and treatment of patients with HTAD. In this review, we present the latest evidence regarding the role of genetics in patients with HTAD. Full article

(This article belongs to the Special Issue Cardiogenetics: Feature Papers 2021)

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14 pages, 6228 KiB

Open AccessEditor’s ChoiceReview

The Roles of Platelet-Activating Factor and Magnesium in Pathophysiology of Hypertension, Atherogenesis, Cardiovascular Disease, Stroke and Aging

by Nilank Shah, Roshni Sethi, Sachin Shah, Komail Jafri, Jonah Duran, Yong Chang, Chirag Soni and Hanna Wollocko

Cardiogenetics 2022, 12(1), 49-62; https://doi.org/10.3390/cardiogenetics12010005 - 2 Feb 2022

Cited by 5 | Viewed by 4838

Abstract

Hypertension and atherosclerosis are debilitating diseases that affect millions each year. Long-term consequences include but are not limited to stroke, myocardial infarction, and kidney failure. Platelet-activating factor (PAF) is a proinflammatory mediator synthesized from a subclass of phosphatidylcholines that increases platelet activation, leukocyte [...] Read more.

Hypertension and atherosclerosis are debilitating diseases that affect millions each year. Long-term consequences include but are not limited to stroke, myocardial infarction, and kidney failure. Platelet-activating factor (PAF) is a proinflammatory mediator synthesized from a subclass of phosphatidylcholines that increases platelet activation, leukocyte adhesion, infiltration of macrophages, and intracellular lipid accumulation, thereby contributing to atherosclerosis. Magnesium, a key micronutrient and free radical scavenger, is a water-soluble mineral that regulates peripheral vasodilation and calcium, phosphate, and hydroxyapatite homeostasis. Magnesium’s antihypertensive ability stems from its role as a natural calcium antagonist and promoter of vasodilatory mediators, such as nitric oxide. Platelet-activating factor and magnesium share an inverse relationship, and elevated magnesium levels have been shown to have protective effects against plaque formation as well as antihypertensive and antiarrhythmic effects, all of which allow for healthier aging. The purpose of this literature review is to investigate the role of platelet-activating factor and magnesium in the pathophysiology of hypertension, atherosclerosis, cardiovascular disease, stroke, and aging. Since the pathophysiology of the platelet-activating factor biomolecule is underexplored, further research studies are warranted in order to navigate the putative signaling pathways involved in the cardioprotective effects of dietary magnesium as a natural anti-PAF agent. Full article

(This article belongs to the Special Issue Cardiogenetics: Feature Papers 2021)

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13 pages, 2595 KiB

Open AccessEditor’s ChoiceArticle

Cardiovascular Characteristics of Patients with Genetic Variation in Desmoplakin (DSP)

by Nosheen Reza, Alejandro de Feria, Jessica L. Chowns, Lily Hoffman-Andrews, Laura Vann, Jessica Kim, Amy Marzolf and Anjali Tiku Owens

Cardiogenetics 2022, 12(1), 24-36; https://doi.org/10.3390/cardiogenetics12010003 - 6 Jan 2022

Cited by 10 | Viewed by 5301

Abstract

Background: Variants in the desmoplakin (DSP) gene have been recognized in association with the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC) for nearly 20 years. More recently, genetic variation in DSP has also been associated with left-dominant arrhythmogenic cardiomyopathy. Data regarding [...] Read more.

Background: Variants in the desmoplakin (DSP) gene have been recognized in association with the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC) for nearly 20 years. More recently, genetic variation in DSP has also been associated with left-dominant arrhythmogenic cardiomyopathy. Data regarding the cardiac phenotypes associated with genetic variation in DSP have been largely accumulated from phenotype-first studies of ARVC. Methods: We aimed to evaluate the clinical manifestations of cardiac disease associated with variants in DSP through a genotype-first approach employed in the University of Pennsylvania Center for Inherited Cardiovascular Disease registry. We performed a retrospective study of 19 individuals with “pathogenic” or “likely pathogenic” variants in DSP identified by clinical genetic testing. Demographics and clinical characteristics were collected. Results: Among individuals with disease-causing variants in DSP, nearly 40% had left ventricular enlargement at initial assessment. Malignant arrhythmias were prevalent in this cohort (42%) with a high proportion of individuals undergoing primary and secondary prevention implantable cardioverter defibrillator implantation (68%) and ablation of ventricular arrhythmias (16%). Probands also experienced end-stage heart failure requiring heart transplantation (11%). Conclusions: Our data suggest DSP cardiomyopathy may manifest with a high burden of heart failure and arrhythmic events, highlighting its importance in the pathogenesis of dilated and arrhythmogenic cardiomyopathies. Targeted strategies for diagnosis and risk stratification for DSP cardiomyopathy should be investigated. Full article

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

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11 pages, 868 KiB

Open AccessEditor’s ChoiceArticle

Transthyretin Gene Variants and Associated Phenotypes in Danish Patients with Amyloid Cardiomyopathy

by Torsten B. Rasmussen, Bertil T. Ladefoged, Anne M. Dybro, Tor S. Clemmensen, Rikke H. Sørensen, Astrid J. Terkelsen, Henning Mølgaard, Henrik Vase and Steen H. Poulsen

Cardiogenetics 2022, 12(1), 1-11; https://doi.org/10.3390/cardiogenetics12010001 - 4 Jan 2022

Cited by 1 | Viewed by 3486

Abstract

Genotyping divides transthyretin cardiac amyloidosis (ATTR-CA) in hereditary (ATTRv) and wild type (ATTRwt) forms. This study investigated the prevalence and clinical presentation of ATTRv in a contemporary cohort of consecutive ATTR-CA patients diagnosed at a tertiary Danish amyloidosis center. Age at diagnosis, clinical- [...] Read more.

Genotyping divides transthyretin cardiac amyloidosis (ATTR-CA) in hereditary (ATTRv) and wild type (ATTRwt) forms. This study investigated the prevalence and clinical presentation of ATTRv in a contemporary cohort of consecutive ATTR-CA patients diagnosed at a tertiary Danish amyloidosis center. Age at diagnosis, clinical- and echocardiographic data, and transthyretin (TTR) genotype were recorded. Relatives of ATTRv patients underwent clinical phenotyping and predictive gene testing. Genetic testing in 102 patients identified four TTR variant carriers: p.Pro63Ser, p.Ala65Ser (n = 2) and p.Val142Ile. The mean age of ATTRv index patients was significantly lower compared to ATTRwt patients: 70.2 ± 1.2 versus 80.0 ± 6.2, p-value: 0.005. Evaluation of ATTRv families identified seven TTR variant carriers with a median age of 65 years (range 48–76) and three were diagnosed with ATTR-CA by DPD-scintigraphy. Family members with ATTR-CA were all asymptomatic and had normal levels of cardiac biomarkers. In conclusion, the prevalence of ATTRv in a contemporary Danish ATTR-CA cohort is 4%. ATTRv index patients were significantly younger age at diagnosis than ATTRwt patients. Non-p.Leu131Met TTR variants have reduced penetrance at the age of 65 years in which approximately half of variant carriers have asymptomatic ATTR-CA with normal LV systolic function and cardiac biomarker analyses. Full article

(This article belongs to the Special Issue Cardiogenetics: Feature Papers 2021)

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