Cardiogenetics

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Open AccessReview

The Novel Role of Epigenetics in Primary Prevention of Cardiovascular Diseases

by Claudio Napoli, Amelia Casamassimi, Vincenzo Grimaldi, Concetta Schiano, Teresa Infante, Alberto Zullo, Maria Lourdes Montesano, Laura Auriemma, Francesco Paolo De Luca, Gustavo De Iorio, Louis J. Ignarro and Francesco Paolo Mancini

Cardiogenetics 2012, 2(1), e12; https://doi.org/10.4081/cardiogenetics.2012.e12 - 19 Nov 2012

Cited by 3 | Viewed by 1

Abstract

A great deal of evidences indicate that impaired fetal growth and in utero exposure to risk factors, especially maternal hypercholesterolemia, may be relevant for human pathophysiological signs of atherosclerosis and subsequent development of cardiovascular disease (CVD) during different life stages. Despite the underlying [...] Read more.

A great deal of evidences indicate that impaired fetal growth and in utero exposure to risk factors, especially maternal hypercholesterolemia, may be relevant for human pathophysiological signs of atherosclerosis and subsequent development of cardiovascular disease (CVD) during different life stages. Despite the underlying mechanisms of fetal programming are still unknown, epigenetics has been suggested as one of the possible explanations for the associations between intrauterine risk factors and CVD development. Indeed, a lot of translational studies support the hypothesis that epigenetic changes are related to increased CVD risk although it is still not possible to establish a direct causality in humans. Notably, epigenetic modifications can be reversible through therapeutic approaches employing histone deacetylase inhibitors, histone acetyltransferase inhibitors and commonly used drugs like statins. Thus, the whole comprehension of these mechanisms will provide in the next future the rationale for the development of novel tools to be used in the primary prevention and therapy of CVD. Full article

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Open AccessViewpoint

Restrictive Cardiomyopathy and Hypertrophic Cardiomyopathy Overlap: The Importance of the Phenotype

by Juan Pablo Kaski, Elena Biagini, Massimo Lorenzini, Claudio Rapezzi and Perry Elliott

Cardiogenetics 2012, 2(1), e10; https://doi.org/10.4081/cardiogenetics.2012.e10 - 19 Oct 2012

Cited by 2 | Viewed by 1

Abstract

Restrictive cardiomyopathy (RCM) is defined on the basis of the haemodynamic finding of restrictive ventricular physiology. However, restrictive ventricular pathophysiology is also a feature of other subtypes of cardiomyopathy, including hypertrophic cardiomyopathy (HCM). Clinically and aetiologically, there is an overlap between RCM and [...] Read more.

Restrictive cardiomyopathy (RCM) is defined on the basis of the haemodynamic finding of restrictive ventricular physiology. However, restrictive ventricular pathophysiology is also a feature of other subtypes of cardiomyopathy, including hypertrophic cardiomyopathy (HCM). Clinically and aetiologically, there is an overlap between RCM and HCM with restrictive physiology. However, the clinical distinction between these two entities can be an important pointer towards the underlying aetiology. This review highlights the importance of the recognition of the clinical phenotype as the first step in the classification of cardiomyopathies. Full article

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Open AccessPerspective

Recent Advances in Cardiovascular Research: Systems Biology

by Raffaella D'Alessandro and Joseph Sepe

Cardiogenetics 2012, 2(1), e9; https://doi.org/10.4081/cardiogenetics.2012.e9 - 17 Oct 2012

Viewed by 1

Abstract

The authors describe different bioinformatic approaches to cardiovascular research, focusing on: (i) the complexity of cardiovascular diseases; (ii) how does systems biology work and its application to cardiology; (iii) new systems research in cardiology; (iv) clinical cardiological practice; (v) perspectives and limitations of [...] Read more.

The authors describe different bioinformatic approaches to cardiovascular research, focusing on: (i) the complexity of cardiovascular diseases; (ii) how does systems biology work and its application to cardiology; (iii) new systems research in cardiology; (iv) clinical cardiological practice; (v) perspectives and limitations of systems biology in cardiology. Full article

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Open AccessArticle

Compound Heterozygous SCN5A Gene Mutations in Aasymptomatic Brugada Syndrome Child

by Elena Sommariva, Matteo Vatta, Yutao Xi, Simone Sala, Tomohiko Ai, Jie Cheng, Carlo Pappone, Maurizio Ferrari and Sara Benedetti

Cardiogenetics 2012, 2(1), e11; https://doi.org/10.4081/cardiogenetics.2012.e11 - 17 Sep 2012

Cited by 4 | Viewed by 1

Abstract

Loss-of-function mutations in the SCN5A gene, encoding the cardiac Nav1.5 sodium channel, have been previously associated with Brugada syndrome (BrS). Despite the low prevalence of the disease, we identified a patient carrying two SCN5A mutations. We aimed at establishing a correlation between genotype, [...] Read more.

Loss-of-function mutations in the SCN5A gene, encoding the cardiac Nav1.5 sodium channel, have been previously associated with Brugada syndrome (BrS). Despite the low prevalence of the disease, we identified a patient carrying two SCN5A mutations. We aimed at establishing a correlation between genotype, clinical phenotype and in vitro sodium current. A 3-year-old boy presented with right bundle branch block and ST-segment elevation. Genetic analysis and electrophysiology studies in transfected HEK293 cells were performed to identify possibly disease-causing variants and assess their effect on sodium channel function. Two SCN5A variants were identified: a new frameshift deletion causing premature truncation of the putative protein (c.3258_3261del4) and a missense substitution (p.F1293S). In vitro studies revealed that the truncated mutant did not produce functional channels and decreased total sodium current when co-expressed with p.F1293S channels compared to p.F1293S alone. In addition, p.F1293S channels presented with a steep slope of steady-state activation voltagedependency, which was shifted towards more positive potentials by the co-expression with the truncated channel. p.F1293S channels also showed shift towards more positive potentials of the steady-state inactivation both alone and co-expressed with the deletion mutant. Our data identified a severe reduction of sodium channel current associated with two distinct SCN5A changes. However, all mutation carriers were asymptomatic and BrS electrocardiogram was observed only transiently in the compound heterozygous subject. These observations underline the difficulty of genotype/ phenotype correlations in BrS patients and support the idea of a polygenic disorder, where different mutations and variants can contribute to the clinical phenotype. Full article

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Open AccessCase Report

An Unusual Case of Familial Hypertrophic Cardiomyopathy with Left Ventricular Systolic Dysfunction: A Still Unsolved Diagnosis

by Elena Biagini, Chiara Pazzi, Stefania Rosmini, Ornella Leone, Domenico A. Coviello and Claudio Rapezzi

Cardiogenetics 2012, 2(1), e8; https://doi.org/10.4081/cardiogenetics.2012.e8 - 01 Aug 2012

Viewed by 1

Abstract

A 35-year-old woman was referred to our centre for clinical management of hypertrophic cardiomyopathy (HCM) with left ventricular (LV) systolic dysfunction (end-stage evolution). She was recently diagnosed elsewhere because of palpitations. Her 7-year-old daughter underwent familiar screening and she was diagnosed with classic [...] Read more.

A 35-year-old woman was referred to our centre for clinical management of hypertrophic cardiomyopathy (HCM) with left ventricular (LV) systolic dysfunction (end-stage evolution). She was recently diagnosed elsewhere because of palpitations. Her 7-year-old daughter underwent familiar screening and she was diagnosed with classic HCM. She was completely asymptomatic without extracardiac or systemic manifestations. During the following years, they both experienced a similar clinical course with worsening dyspnoea and progressive deterioration of LV systolic function. They both underwent heart transplantation, the mother at the age of 47 and the daughter at the age of 23, respectively. Many diagnostic hypotheses, including sarcomeric HCM, Anderson-Fabry disease, glycogen storage diseases and mitochondrial cardiomyopathies have been taken into account. The diagnostic work-up included serial electrocardiogram and echocardiographic assessments, pathologic evaluation of the explanted hearts and genetic analysis of 8 sarcomeric and 3 metabolic genes. Even if a shared HCM phenotype (LV systolic dysfunction in two first-degree female family members associated with a likely autosomal dominant inheritance and absence of extracardiac or multisystemic manifestations) could support a temptative diagnosis of sarcomeric HCM, a definitive diagnosis could not be reached, due to the lack of genetic analysis to confirm such diagnosis. Full article

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Open AccessBook Review

Inherited Cardiac Disease

by Philippe Charron

Cardiogenetics 2012, 2(1), br1; https://doi.org/10.4081/cardiogenetics.2012.br1 - 28 Jun 2012

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Abstract

Major advances have been achieved over the two last decades in the field of genetic cardiovascular diseases, not only through increased recognition and understanding of underlying molecular defects but also through rapid translation of knowledge into clinical practice [...] Full article

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Open AccessArticle

Transcriptional Regulation of Cardiac Genes Balance Pro- and Anti-Hypertrophic Mechanisms in Hypertrophic Cardiomyopathy

by Nina Gennebäck, Gerhard Wikström, Urban Hellman, Jane-Lise Samuel, Anders Waldenström and Stellan Mörner

Cardiogenetics 2012, 2(1), e5; https://doi.org/10.4081/cardiogenetics.2012.e5 - 22 Jun 2012

Cited by 1 | Viewed by 1

Abstract

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy. HCM is often hereditary, but our knowledge of the mechanisms leading from mutation to phenotype is incomplete. The transcriptional expression patterns in the myocar - dium of HCM patients may contribute to understanding [...] Read more.

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy. HCM is often hereditary, but our knowledge of the mechanisms leading from mutation to phenotype is incomplete. The transcriptional expression patterns in the myocar - dium of HCM patients may contribute to understanding the mechanisms that drive and stabilize the hypertrophy. Cardiac myectomies/biopsies from 8 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 5 controls were studied with whole genome Illumina microarray gene expression (detecting 18 189 mRNA). When comparing HOCM myocardium to controls, there was significant transcriptional down-regulation of the MYH6, EGR1, APOB and FOS genes, and significant transcriptional up-regulation of the ACE2, JAK2, NPPA (ANP), APOA1 and HDAC5 genes. The transcriptional regulation revealed both pro- and anti-hypertrophic mechanisms. The pro-hypertrophic response was explained by the transcriptional down-regulation of MYH6, indicating that the switch to the fetal gene program is maintained, and the transcriptional up-regulation of JAK2 in the JAK-STAT pathway. The anti-hypertrophic response was seen as a transcriptional down-regulation of the immediate early genes (IEGs), FOS and EGR1, and a transcriptional up-regulation of ACE2 and HDAC5. This can be interpreted as a transcriptional endogenous protection system in the heart of the HOCM patients, neither growing nor suppressing the already hypertrophic myocardium. Full article

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Open AccessArticle

Combined Use of In Silico and In Vitro Splicing Assays for Interpretation of Genomic Variants of Unknown Significance in Cardiomyopathies and Channelopathies

by Hervé Crehalet, Gilles Millat, Juliette Albuisson, Véronique Bonnet, Isabelle Rouvet, Robert Rousson and Dominique Bozon

Cardiogenetics 2012, 2(1), e6; https://doi.org/10.4081/cardiogenetics.2012.e6 - 05 Jun 2012

Cited by 11 | Viewed by 1

Abstract

The identification of molecular anomalies in patients with inherited arrhythmias or cardiomyopathies is a multi challenge due to: i) the number of genes involved; ii) the number of polymorphisms and the fact that most mutations are private; and iii) the variable degree of [...] Read more.

The identification of molecular anomalies in patients with inherited arrhythmias or cardiomyopathies is a multi challenge due to: i) the number of genes involved; ii) the number of polymorphisms and the fact that most mutations are private; and iii) the variable degree of penetrance which complicates family segregation study. Consequently, a number of unclassified variants (UV) are found in patients’ DNA and some (outside the canonical GT/AG) may affect splicing. Mutational screening on the most prevalent genes involved in arrythmias syndromes or in cardiomyopathies was performed on a cohort made up of 740 unrelated French index probands. To identify splice variants among the identified UVs, a combination of available in silico and in vitro tools were used since transcript is not available. Using this approach, 10 previously identified UVs were reclassified as disease-causing mutations and, more precisely, as haploinsufficiency mutations rather than dominant-negative mutations. Most of them (7 of 10) were observed in MYBPC3. Our study highlighted the importance of the combined use of in silico and in vitro splicing assays to improve the prediction of the functional impact of identified genetic variants. The primary challenge now, with new sequencing technologies, is to distinguish between background polymorphisms and pathogenic mutations. Since splice site mutations can account for almost 50% of disease-causing mutations, recognizing them from among other variations is essential. Full article

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Open AccessViewpoint

Idiopathic Restrictive Cardiomyopathy - Perspectives from Genetics Studies. Is It Time to Redefine These Disorders?

by Ajay Bahl, Uma Nahar Saikia and Madhu Khullar

Cardiogenetics 2012, 2(1), e4; https://doi.org/10.4081/cardiogenetics.2012.e4 - 30 May 2012

Cited by 1 | Viewed by 1

Abstract

Idiopathic restrictive cardiomyopathy (IRC) is a rare form of heart muscle disease. Genetic studies have revealed that in about half the cases, IRC forms part of the hereditary sarcomeric contractile protein disease spectrum. Mutations in several sarcomere protein encoding genes are detected in [...] Read more.

Idiopathic restrictive cardiomyopathy (IRC) is a rare form of heart muscle disease. Genetic studies have revealed that in about half the cases, IRC forms part of the hereditary sarcomeric contractile protein disease spectrum. Mutations in several sarcomere protein encoding genes are detected in 33-66% of cases. Among these, the mutations most commonly involve TNNI3 and MYH7. There is a disproportionately high incidence of TNNI3 mutations in patients with restrictive physiology. De novo mutations are also frequently seen in this group of patients. IRC and hypertrophic cardiomyopathy (HCM) with restrictive phenotype reflect the same or very similar disorders with different names due to arbitrary cut offs in the left ventricular wall thickness rather than two separate distinct diseases. HCM with restrictive physiology should be considered part of a continuous spectrum with IRC. This is because patients with HCM with restrictive phenotype bear far greater clinical and genetic resemblance to IRC than to rest of the HCM cohort. Full article

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Open AccessArticle

Targeted Capture and Massively Parallel Sequencing in Pediatric Cardiomyopathy: Development of Novel Diagnostics

by Muhammad Tariq, Thanh-Tam Le, Patrick Putnam, Steven Kindel, Mehdi Keddache and Stephanie M. Ware

Cardiogenetics 2012, 2(1), e7; https://doi.org/10.4081/cardiogenetics.2012.e7 - 14 May 2012

Viewed by 1

Abstract

Pediatric cardiomyopathy is a genetically heterogeneous disease associated with significant morbidity. Although identification of underlying etiology is important for management, therapy, and screening of at risk family members, molecular diagnosis is difficult due to the large number of causative genes, the high rate [...] Read more.

Pediatric cardiomyopathy is a genetically heterogeneous disease associated with significant morbidity. Although identification of underlying etiology is important for management, therapy, and screening of at risk family members, molecular diagnosis is difficult due to the large number of causative genes, the high rate of private mutations, and cost. In this study, we aimed to define the genetic basis of pediatric cardiomyopathy and test a novel diagnostic tool using a custom targeted microarray coupled to massively parallel sequencing. Three patients with cardiomyopathy were screened using a custom NimbleGen sequence capture array containing 110 genes and providing 99.9% coverage of the exons of interest. The sensitivity and specificity was over 99% as determined by comparison to long-range polymerase chain reaction (PCR)- based massively parallel sequencing, Sanger sequencing of missense variants, and single nucleotide polymorphisms genotyping using the Illumina Infinium Omni1 array. Overall, 99.73% of the targeted regions were captured and sequenced at over 10x coverage, allowing reliable mutation calling in all patients. Analysis identified a total of 165 non-synonymous coding single nucleotide polymorphisms (cSNPs) of which 89 were unique and 14 were novel. On average, each patient had 4 cSNPs predicted to be pathogenic. In conclusion, we report a cardiomyopathy sequencing array that allows simultaneous assessment of 110 genes. Comparison of targeted sequence capture versus PCR-based enrichment methods demonstrates that the former is more sensitive and efficient. Array-based sequence capture technology followed by massively parallel sequencing is promising as a robust and comprehensive tool for genetic screening of cardiomyopathy. These results provide important information about genetic architecture and indicate that improved annotation of variants and interpretation of clinical significance, particularly in cases with multiple rare variants, are important for clinical practice. Full article

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Open AccessCase Report

A New Clonal Chromosomal Aberration (47, XY, +21) in Atrial Myxoma from an Elderly Male Patient

by Ewa Stępień, Grzegorz Grudzień, Marek Andres, Małgorzata Jakóbczyk, Dorota Czapczak, Przemysław Kapusta, Wiesław Frasik, Tomasz Myrdko and Jerzy Sadowski

Cardiogenetics 2012, 2(1), e3; https://doi.org/10.4081/cardiogenetics.2012.e3 - 16 Feb 2012

Cited by 1 | Viewed by 1

Abstract

Myxomas are the most common primary cardiac tumors, with an estimated incidence of 0.5 per million per year. Familial myxoma constitutes 10% of all myxomas, among these tumors, one in ten is part of Carney complex - an autosomal dominant syndrome, which are [...] Read more.

Myxomas are the most common primary cardiac tumors, with an estimated incidence of 0.5 per million per year. Familial myxoma constitutes 10% of all myxomas, among these tumors, one in ten is part of Carney complex - an autosomal dominant syndrome, which are related to some mutations in the PRKAR1A gene. We report a case of 75-year-old man with sporadic cardiac myxoma of a 4-cm large tumor, arising from the left side of the atrial septum and causing a severe left ventricle inflow obstruction. Cytogenetic analysis confirmed by fluorescence in situ hybridization method (FISH), demonstrated a numerical aberration in atrial myxoma cells: 47, XY, +21. Flow cytometry analysis demonstrated that a quarter of tumors cells were hematopoietic progenitor cells (CD34+) and that a similar number were endothelial specific neovascular cells (CD31+). These finding suggest that, hematopoietic progenitor cells may play an important role in the histogenesis of cardiac myxomas and the karyotype aberrations have an impact on sporadic tumor genesis. Nevertheless, genetic screening for sporadic (non-familial) cardiac myxomas is not recommended. Full article

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Open AccessBrief Report

Cardiac Electrical System Involvement in Alström Syndrome: Uncommon Causes of Dilated Cardiomyopathies

by Richard J. Czosek, Paula Goldenberg, Erin M. Miller, Robert Spicer, Jeffrey A. Towbin and Stephanie M. Ware

Cardiogenetics 2012, 2(1), e2; https://doi.org/10.4081/cardiogenetics.2012.e2 - 20 Jan 2012

Cited by 1 | Viewed by 2

Abstract

Alström syndrome is a rare autosomal recessive disorder with dilated cardiomyopathy in 60% of patients. Despite the frequency of cardiac involvement in Alström syndrome, conduction system abnormalities or arrhythmias have not been characterized previously. We report two siblings with Alström syndrome with conduction [...] Read more.

Alström syndrome is a rare autosomal recessive disorder with dilated cardiomyopathy in 60% of patients. Despite the frequency of cardiac involvement in Alström syndrome, conduction system abnormalities or arrhythmias have not been characterized previously. We report two siblings with Alström syndrome with conduction system involvement with left bundle branch block on electrocardiogram (ECG). One patient had first degree atrioventricular block in addition to bundle branch block and underwent pacemaker implantation. This same patient developed intra-atrial reentry tachycardia requiring anti-arrhythmic medication and eventual trans-catheter ablation. The second patient developed atrial and ventricular arrhythmias and underwent placement of a bi-ventricular defibrillator. These findings suggest that cardiac conduction system involvement and clinical arrhythmia may be significant yet under-recognized complications in patients with Alström syndrome. Patients should be routinely screened with ECG and Holter monitoring in addition to echocardiographic assessment and a cardiologist experienced with cardiomyopathy should be an integral part of the care team. Full article

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Open AccessArticle

Novel SCN5A Mutation Associated with Idiopathic Ventricular Fibrillation Due to Subclinical Brugada Syndrome

by Juan Jiménez-Jáimez, Miguel Álvarez-López, Luis Tercedor-Sánchez, Pablo Santiago, Maria Algarra, Rocio Peñas, Francisca Valverde and Rafael Melgares-Moreno

Cardiogenetics 2012, 2(1), e1; https://doi.org/10.4081/cardiogenetics.2012.e1 - 20 Dec 2011

Abstract

Idiopathic ventricular fibrillation can be caused by subclinical channelopathies such as Brugada syndrome. Our objective is to study the clinical behaviour of a new SCN5A mutation found in a woman with idiopathic ventricular fibrillation. A 53-year-old woman presented with multiple episodes of ventricular [...] Read more.

Idiopathic ventricular fibrillation can be caused by subclinical channelopathies such as Brugada syndrome. Our objective is to study the clinical behaviour of a new SCN5A mutation found in a woman with idiopathic ventricular fibrillation. A 53-year-old woman presented with multiple episodes of ventricular fibrillation, a structurally normal heart and normal baseline electrocardiogram. Genetic testing included KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 and KCNJ2 and identified a mutation in SCN5A (D1816fs/g98747-98748insT). We studied 15 immediate family members by means of electrocardiogram, echocardiogram, flecainide challenge test and genetic study. Eight subjects had the mutation. The flecainide challenge test was positive for Brugada syndrome in two subjects in the case group and none in the control group. The PR and QRS intervals on the baseline electrocardiogram were longer in the case group. The left atrial volume indexed to body surface was higher in the case group, likely due to the fact that two patients with the mutation had atrial fibrillation and none had it in the control group. The D1816fs/g98747-98748insT mutation in SCN5A may be associated with idiopathic ventricular fibrillation and Brugada syndrome with a broad phenotypic spectrum and incomplete penetrance. Genetic testing may be useful to identify the etiology of idiopathic ventricular fibrillation in patients with a negative thorough clinical evaluation. Full article

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Cardiogenetics, Volume 2, Issue 1 (December 2012) – 13 articles

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