Research

8 pages, 249 KiB

Open AccessArticle

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 - 09 May 2022

Cited by 3 | Viewed by 2914

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)

12 pages, 1034 KiB

Open AccessArticle

Genetic Diagnostics Contribute to the Risk Stratification for Major Arrhythmic Events in Pediatric Patients with Long QT Syndrome Type 1–3

by Tobias Burkard, Dominik Sebastian Westphal, Franziska Markel, Roman Antonin Gebauer, Gabriele Hessling and Cordula Maria Wolf

Cardiogenetics 2022, 12(1), 90-101; https://doi.org/10.3390/cardiogenetics12010009 - 21 Feb 2022

Viewed by 2957

Abstract

Long QT syndrome (LQTS) is an inherited arrhythmic disorder associated with sudden cardiac death (SCD). This study aimed to identify the clinical and molecular genetic risk factors that contribute to major arrhythmic events (MAEs) in patients with genetically confirmed childhood onset LQTS 1–3. [...] Read more.

Long QT syndrome (LQTS) is an inherited arrhythmic disorder associated with sudden cardiac death (SCD). This study aimed to identify the clinical and molecular genetic risk factors that contribute to major arrhythmic events (MAEs) in patients with genetically confirmed childhood onset LQTS 1–3. This study was a retrospective double-center study. An MAE was defined as the occurrence of SCD, aborted SCD, appropriate implantable cardioverter defibrillator discharge, or sustained ventricular tachycardia. During a median follow-up of 4.6 years (range 0.1–24.3 years), MAEs occurred in 18 (17.8%) of 101 patients diagnosed with LQTS at a median of 7.7 years (range 0.0–18.0 years) despite the use of beta-blockers in 91.6% of patients at the last follow-up. A multivariate analysis identified a genetic diagnosis of LQTS2 and LQTS3 and variants within the KCNH2 S5-loop-S6 pore region as independent risk factors for MAEs, independent of the QTc value or a history of syncope detected from a univariate analysis. MAEs occur frequently in childhood onset LQTS despite beta-blocker treatment. A detailed molecular genetic diagnosis can contribute to the arrhythmia risk stratification and optimize the use of preventive measures in this vulnerable patient population. Full article

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

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11 pages, 868 KiB

Open AccessArticle

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 - 04 Jan 2022

Cited by 1 | Viewed by 2863

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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8 pages, 1001 KiB

Open AccessArticle

Understanding the Function of a Locus Using the Knowledge Available at Single-Nucleotide Polymorphisms

by Majid Nikpay, Sepehr Ravati, Robert Dent and Ruth McPherson

Cardiogenetics 2021, 11(4), 255-262; https://doi.org/10.3390/cardiogenetics11040024 - 07 Dec 2021

Cited by 2 | Viewed by 2325

Abstract

Understanding the function of a locus is an issue in molecular biology. Although numerous molecular data have been generated in the last decades, it remains difficult to grasp how these data are related at a locus. In this study, we describe an analytical [...] Read more.

Understanding the function of a locus is an issue in molecular biology. Although numerous molecular data have been generated in the last decades, it remains difficult to grasp how these data are related at a locus. In this study, we describe an analytical workflow that can solve this problem using the knowledge available at the single-nucleotide polymorphism (SNP) level. The underlying algorithm uses SNPs as connectors to link biological entities and identify correlations between them through a joint bioinformatics/statistics approach. We demonstrate its application in finding the mechanism whereby a mutation causes a phenotype and in revealing the path whereby a gene is regulated and impacts a phenotype. We translate our workflow into publicly available shell scripts. Our approach provides a basic framework to solve the information overload problem in biology surrounding the annotation of a locus and is a step toward repurposing GWAS data for new applications. Full article

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

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11 pages, 1269 KiB

Open AccessCommunication

Pathogenic Intronic Splice-Affecting Variants in MYBPC3 in Three Patients with Hypertrophic Cardiomyopathy

by Katherine A. Wood, Jamie M. Ellingford, James Eden, Huw B. Thomas, Raymond T. O’Keefe, Claire Hopton and William G. Newman

Cardiogenetics 2021, 11(2), 73-83; https://doi.org/10.3390/cardiogenetics11020009 - 02 Jun 2021

Cited by 1 | Viewed by 4702

Abstract

Genetic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in MYBPC3 affecting canonical splice site dinucleotides are a well-characterised cause of HCM, only recently has work begun to investigate the pathogenicity of more deeply intronic [...] Read more.

Genetic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in MYBPC3 affecting canonical splice site dinucleotides are a well-characterised cause of HCM, only recently has work begun to investigate the pathogenicity of more deeply intronic variants. Here, we present three patients with HCM and intronic splice-affecting MYBPC3 variants and analyse the impact of variants on splicing using in vitro minigene assays. We show that the three variants, a novel c.927-8G>A variant and the previously reported c.1624+4A>T and c.3815-10T>G variants, result in MYBPC3 splicing errors. Analysis of blood-derived patient RNA for the c.3815-10T>G variant revealed only wild type spliced product, indicating that mis-spliced transcripts from the mutant allele are degraded. These data indicate that the c.927-8G>A variant of uncertain significance and likely benign c.3815-10T>G should be reclassified as likely pathogenic. Furthermore, we find shortcomings in commonly applied bioinformatics strategies to prioritise variants impacting MYBPC3 splicing and re-emphasise the need for functional assessment of variants of uncertain significance in diagnostic testing. Full article

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

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Review

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15 pages, 2489 KiB

Open AccessReview

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 - 01 Apr 2022

Cited by 2 | Viewed by 3842

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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17 pages, 767 KiB

Open AccessReview

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 - 04 Feb 2022

Cited by 4 | Viewed by 4966

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 AccessReview

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 - 02 Feb 2022

Cited by 4 | Viewed by 3943

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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12 pages, 275 KiB

Open AccessReview

An Overview of Therapy Guidelines for Cardiac Arrest and the Potential Benefits of Hemoglobin-Based Oxygen Carriers

by Brian M. Wollocko, Bardia Papian-Gorji, Winston Yen, Urooj Zahid, Nilank Shah, Kenneth Steier and Hanna Wollocko

Cardiogenetics 2022, 12(1), 37-48; https://doi.org/10.3390/cardiogenetics12010004 - 20 Jan 2022

Viewed by 2985

Abstract

Currently, there is an unmet therapeutic need for the medical management of cardiac arrest, as is evident from the high mortality rate associated with this condition. These dire outcomes can be attributed to the severe nature and poor prognosis of this disorder. However, [...] Read more.

Currently, there is an unmet therapeutic need for the medical management of cardiac arrest, as is evident from the high mortality rate associated with this condition. These dire outcomes can be attributed to the severe nature and poor prognosis of this disorder. However, the current treatment modalities, while helping to augment survival, are limited and do not offer adequate improvements to outcomes. Treatment modalities are particularly lacking when considering the underlying pathophysiology of the metabolic phase of cardiac arrest. In this study, we explore the three phases of cardiac arrest and assess the factors related to positive clinical outcomes and survival for these events. Furthermore, we evaluate the present guidelines for resuscitation and recovery, the issues related to ischemia and tissue reperfusion, and the benefit of oxygen-delivery therapeutic methods including blood transfusion therapy and synthetic hemoglobins (HBOCs). The current therapy protocols are limited specifically by the lack of an efficient method of oxygen delivery to address the metabolic phase of cardiac arrest. In this article, we investigate the next generation of HBOCs and review their properties that make them attractive for their potential application in the treatment of cardiac arrest. These products may be a viable solution to address complications associated with ischemia, reperfusion injury, and organ damage. Full article

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

12 pages, 461 KiB

Open AccessReview

Nanoparticle-Based Modification of the DNA Methylome: A Therapeutic Tool for Atherosclerosis?

by Ana Cristina Márquez-Sánchez, Lino Sánchez-Segura, Gertrud Lund and Silvio Zaina

Cardiogenetics 2022, 12(1), 12-23; https://doi.org/10.3390/cardiogenetics12010002 - 06 Jan 2022

Viewed by 2768

Abstract

Cardiovascular epigenomics is a relatively young field of research, yet it is providing novel insights into gene regulation in the atherosclerotic arterial wall. That information is already pointing to new avenues for atherosclerosis (AS) prevention and therapy. In parallel, advances in nanoparticle (NP) [...] Read more.

Cardiovascular epigenomics is a relatively young field of research, yet it is providing novel insights into gene regulation in the atherosclerotic arterial wall. That information is already pointing to new avenues for atherosclerosis (AS) prevention and therapy. In parallel, advances in nanoparticle (NP) technology allow effective targeting of drugs and bioactive molecules to the vascular wall. The partnership of NP technology and epigenetics in AS is just beginning and promises to produce novel exciting candidate treatments. Here, we briefly discuss the most relevant recent advances in the two fields. We focus on AS and DNA methylation, as the DNA methylome of that condition is better understood in comparison with the rest of the cardiovascular disease field. In particular, we review the most recent advances in NP-based delivery systems and their use for DNA methylome modification in inflammation. We also address the promises of DNA methyltransferase inhibitors for prevention and therapy. Furthermore, we emphasize the unique challenges in designing therapies that target the cardiovascular epigenome. Lastly, we touch the issue of human exposure to industrial NPs and its impact on the epigenome as a reminder of the undesired effects that any NP-based therapy must avoid to be apt for secondary prevention of AS. Full article

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

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27 pages, 3895 KiB

Open AccessReview

Pathogenesis, Diagnosis and Risk Stratification in Arrhythmogenic Cardiomyopathy

by Maria Teresa Florio, Filomena Boccia, Erica Vetrano, Marco Borrelli, Thomas Gossios and Giuseppe Palmiero

Cardiogenetics 2021, 11(4), 263-289; https://doi.org/10.3390/cardiogenetics11040025 - 08 Dec 2021

Viewed by 3348

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease associated with sudden cardiac death (SCD). It is most frequently caused by mutations in genes encoding desmosomal proteins. However, there is growing evidence that ACM is not exclusively a desmosome disease but rather appears [...] Read more.

Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease associated with sudden cardiac death (SCD). It is most frequently caused by mutations in genes encoding desmosomal proteins. However, there is growing evidence that ACM is not exclusively a desmosome disease but rather appears to be a disease of the connexoma. Fibroadipose replacement of the right ventricle (RV) had long been the hallmark of ACM, although biventricular involvement or predominant involvement of the left ventricle (LD-ACM) is increasingly found, raising the challenge of differential diagnosis with arrhythmogenic dilated cardiomyopathy (a-DCM). A-DCM, ACM, and LD-ACM are increasingly acknowledged as a single nosological entity, the hallmark of which is electrical instability. Our aim was to analyze the complex molecular mechanisms underlying arrhythmogenic cardiomyopathies, outlining the role of inflammation and autoimmunity in disease pathophysiology. Secondly, we present the clinical tools used in the clinical diagnosis of ACM. Focusing on the challenge of defining the risk of sudden death in this clinical setting, we present available risk stratification strategies. Lastly, we summarize the role of genetics and imaging in risk stratification, guiding through the appropriate patient selection for ICD implantation. Full article

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

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25 pages, 860 KiB

Open AccessReview

MicroRNAs: From Junk RNA to Life Regulators and Their Role in Cardiovascular Disease

by Federica Amodio, Martina Caiazza, Fabio Fimiani, Paolo Calabrò and Giuseppe Limongelli

Cardiogenetics 2021, 11(4), 230-254; https://doi.org/10.3390/cardiogenetics11040023 - 29 Nov 2021

Cited by 1 | Viewed by 3003

Abstract

MicroRNAs (miRNAs) are single-stranded small non-coding RNA (18–25 nucleotides) that until a few years ago were considered junk RNA. In the last twenty years, they have acquired more importance thanks to the understanding of their influence on gene expression and their role as [...] Read more.

MicroRNAs (miRNAs) are single-stranded small non-coding RNA (18–25 nucleotides) that until a few years ago were considered junk RNA. In the last twenty years, they have acquired more importance thanks to the understanding of their influence on gene expression and their role as negative regulators at post-transcriptional level, influencing the stability of messenger RNA (mRNA). Approximately 5% of the genome encodes miRNAs which are responsible for regulating numerous signaling pathways, cellular processes and cell-to-cell communication. In the cardiovascular system, miRNAs control the functions of various cells, such as cardiomyocytes, endothelial cells, smooth muscle cells and fibroblasts, playing a role in physiological and pathological processes and seeming also related to variations in contractility and hereditary cardiomyopathies. They provide a new perspective on the pathophysiology of disorders such as hypertrophy, fibrosis, arrhythmia, inflammation and atherosclerosis. MiRNAs are differentially expressed in diseased tissue and can be released into the circulation and then detected. MiRNAs have become interesting for the development of new diagnostic and therapeutic tools for various diseases, including heart disease. In this review, the concept of miRNAs and their role in cardiomyopathies will be introduced, focusing on their potential as therapeutic and diagnostic targets (as biomarkers). Full article

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

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18 pages, 1593 KiB

Open AccessFeature PaperReview

Constraints in Clinical Cardiology and Personalized Medicine: Interrelated Concepts in Clinical Cardiology

by Katerina G. Lourida and George E. Louridas

Cardiogenetics 2021, 11(2), 50-67; https://doi.org/10.3390/cardiogenetics11020007 - 10 May 2021

Cited by 1 | Viewed by 4272

Abstract

Systems biology is established as an integrative computational analysis methodology with practical and theoretical applications in clinical cardiology. The integration of genetic and molecular components of a disease produces interacting networks, modules and phenotypes with clinical applications in complex cardiovascular entities. With the [...] Read more.

Systems biology is established as an integrative computational analysis methodology with practical and theoretical applications in clinical cardiology. The integration of genetic and molecular components of a disease produces interacting networks, modules and phenotypes with clinical applications in complex cardiovascular entities. With the holistic principle of systems biology, some of the features of complexity and natural progression of cardiac diseases are approached and explained. Two important interrelated holistic concepts of systems biology are described; the emerging field of personalized medicine and the constraint-based thinking with downward causation. Constraints in cardiovascular diseases embrace three scientific fields related to clinical cardiology: biological and medical constraints; constraints due to limitations of current technology; and constraints of general resources for better medical coverage. Systems healthcare and personalized medicine are connected to the related scientific fields of: ethics and legal status; data integration; taxonomic revisions; policy decisions; and organization of human genomic data. Full article

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

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9 pages, 906 KiB

Open AccessCase Report

Pharmacogenomics of Pediatric Cardiac Arrest: Cisplatin Treatment Worsened by a Ryanodine Receptor 2 Gene Mutation

by Angela Maggio, Sandra Mastroianno, Giuseppe Di Stolfo, Stefano Castellana, Pietro Palumbo, Maria Pia Leone, Anita Spirito, Domenico Rosario Potenza, Saverio Ladogana, Marco Castori, Massimo Carella, Massimo Villella and Mauro Pellegrino Salvatori

Cardiogenetics 2022, 12(1), 80-88; https://doi.org/10.3390/cardiogenetics12010007 - 07 Feb 2022

Cited by 1 | Viewed by 2691

Abstract

In thelast few decades, the roles of cardio-oncology and cardiovascular geneticsgained more and more attention in research and daily clinical practice, shaping a new clinical approach and management of patients affected by cancer and cardiovascular disease. Genetic characterization of patients undergoing cancer treatment [...] Read more.

In thelast few decades, the roles of cardio-oncology and cardiovascular geneticsgained more and more attention in research and daily clinical practice, shaping a new clinical approach and management of patients affected by cancer and cardiovascular disease. Genetic characterization of patients undergoing cancer treatment can support a better cardiovascular risk stratification beyond the typical risk factors, suchas contractile function and QT interval duration, uncovering a possible patient’s concealed predisposition to heart failure, life threatening arrhythmias and sudden death. Specifically, an integrated cardiogenetic approach in daily oncological clinical practice can ensure the best patient-centered healthcare model, suggesting, also the adequate cardiac monitoring timing and alternative cancer treatments, reducing drug-related complications. We report the case of a 14-month-old girl affected by neuroblastoma, treated by cisplatin, complicated by cardiac arrest. We described the genetic characterization of a Ryanodine receptor 2 (RYR2) gene mutation and subsequent pharmacogenomic approach to better shape the cancer treatment. Full article

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

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6 pages, 2095 KiB

Open AccessCase Report

Azygos Vein ICD Lead Implantation Lowers Defibrillation Threshold in a Patient with Hypertrophic Cardiomyopathy

by Giovanni Quarta, Paola Ferrari, Andrea Giammarresi, Giovanni Malanchini, Cristina Leidi, Michele Senni and Paolo De Filippo

Cardiogenetics 2021, 11(4), 185-190; https://doi.org/10.3390/cardiogenetics11040019 - 07 Oct 2021

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Abstract

A 14-year-old boy with hypertrophic cardiomyopathy (HCM) diagnosed at the age of 1 year and with massive left ventricular hypertrophy suffered an episode of ventricular fibrillation during mild effort. He underwent a dual-chamber implantable cardioverter defibrillator (ICD) implantation. The defibrillation threshold testing (DFT) [...] Read more.

A 14-year-old boy with hypertrophic cardiomyopathy (HCM) diagnosed at the age of 1 year and with massive left ventricular hypertrophy suffered an episode of ventricular fibrillation during mild effort. He underwent a dual-chamber implantable cardioverter defibrillator (ICD) implantation. The defibrillation threshold testing (DFT) was ineffective. Subcutaneous multi-coli arrays tunneled into the left postero-lateral position and connected to the superior vena cava (SVC) port of the dual-chamber ICD were added to increase the myocardial mass involved in the defibrillation shock pathway. A new DFT was unsuccessful. The patient was transferred to our hospital for myectomy. An epicardial defibrillation patch was placed on the left ventricular lateral wall, but again, DFT testing was ineffective using the right ventricular (RV) coil to lateral patch as shock pathway. Another epicardial defibrillation patch was then placed on the inferior wall. In this case, DFT testing was effective with a defibrillation pathway between the two patches and the can. In November 2015, a high shock impedance alarm was recorded through remote monitoring, thus compromising the safety of the ICD shock pathway. The patient underwent the implant of a new trans-venous defibrillation coil lead in the azygos vein. After few months, the patient developed symptomatic severe aortic regurgitation and underwent an aortic valve replacement. During the operation, DFT testing was performed and was successful. Our case illustrates that azygous vein ICD lead implantation is efficacious in HCM with massive hypertrophy and high DFT, and prompts further studies to systematically investigate its efficacy in this particular subgroup of the HCM population. Full article

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

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16 pages, 797 KiB

Open AccessStudy Protocol

A Novel Human Biospecimen Repository for Clinical and Molecular Investigation of Thoracic Aortopathy

by Courtney E. Vujakovich and Benjamin J. Landis

Cardiogenetics 2021, 11(3), 148-163; https://doi.org/10.3390/cardiogenetics11030017 - 18 Sep 2021

Cited by 2 | Viewed by 2775

Abstract

Thoracic aortic aneurysm (TAA) is a heritable aortopathy with significant morbidity and mortality, affecting children and adults. Genetic causes, pathobiological mechanisms, and prognostic markers are incompletely understood. In 2015, the Collaborative Human Aortopathy Repository (CHAR) was created to address these fundamental gaps. Patients [...] Read more.

Thoracic aortic aneurysm (TAA) is a heritable aortopathy with significant morbidity and mortality, affecting children and adults. Genetic causes, pathobiological mechanisms, and prognostic markers are incompletely understood. In 2015, the Collaborative Human Aortopathy Repository (CHAR) was created to address these fundamental gaps. Patients with thoracic aortopathy, associated genetic diagnoses, or aortic valve disease are eligible for prospective enrollment. Family members and controls are also enrolled. Detailed clinical and family data are collected, and blood and aortic tissue biospecimens are processed for broad usage. A total of 1047 participants were enrolled. The mean age in 834 affected participants was 47 ± 22 (range <1 to 88) years and 580 were male (70%). A total of 156 (19%) were under the age of 21 years. Connective tissue diagnoses such as Marfan syndrome were present in 123 (15%). Unaffected participants included relatives (N = 176) and healthy aorta tissue controls (N = 37). Aortic or aortic valve biospecimens were acquired from over 290 and 110 participants, respectively. RNA and protein were extracted from cultured aortic smooth muscle cells (SMCs) for 90 participants. Over 1000 aliquots of aortic SMCs were cryopreserved. The CHAR’s breadth, robust biospecimen processing, and phenotyping create a unique, multipronged resource to accelerate our understanding of human aortopathy. Full article

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

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7 pages, 598 KiB

Open AccessCase Report

Human SMAD4 Genomic Variants Identified in Individuals with Heritable and Early-Onset Thoracic Aortic Disease

by Shreyas A. Bhave, Dongchuan Guo, Stoyan N. Angelov, Michael J. Bamshad, Deborah A. Nickerson, Dianna M. Milewicz and Mary C. Wallingford

Cardiogenetics 2021, 11(3), 132-138; https://doi.org/10.3390/cardiogenetics11030015 - 18 Aug 2021

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Abstract

Thoracic aortic aneurysms (TAAs) that progress to acute thoracic aortic dissections (TADs) are life-threatening vascular events that have been associated with altered transforming growth factor (TGF) β signaling. In addition to TAA, multiple genetic vascular disorders, including hereditary hemorrhagic telangiectasia (HHT), involve altered [...] Read more.

Thoracic aortic aneurysms (TAAs) that progress to acute thoracic aortic dissections (TADs) are life-threatening vascular events that have been associated with altered transforming growth factor (TGF) β signaling. In addition to TAA, multiple genetic vascular disorders, including hereditary hemorrhagic telangiectasia (HHT), involve altered TGFβ signaling and vascular malformations. Due to the importance of TGFβ, genomic variant databases have been curated for activin receptor-like kinase 1 (ALK1) and endoglin (ENG). This case report details seven variants in SMAD4 that are associated with either heritable or early-onset aortic dissections and compares them to pathogenic exon variants in gnomAD v2.1.1. The TAA and TAD variants were identified through whole exome sequencing of 346 families with unrelated heritable thoracic aortic disease (HTAD) and 355 individuals with early-onset (age ≤ 56 years old) thoracic aortic dissection (ESTAD). An allele frequency filter of less than 0.05% was applied in the Genome Aggregation Database (gnomAD exome v2.1.1) with a combined annotation-dependent depletion score (CADD) greater than 20. These seven variants also have a higher REVEL score (>0.2), indicating pathogenic potential. Further in vivo and in vitro analysis is needed to evaluate how these variants affect SMAD4 mRNA stability and protein activity in association with thoracic aortic disease. Full article

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

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