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Recent Advancements in Primary Cardiomyopathies
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Recent Advancements in Primary Cardiomyopathies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 27586

Special Issue Editors

Prof. Dr. Raffaella Lombardi

E-Mail Website
Guest Editor
Department of Advanced Biomedical Sciences, Federico II University of Naples, 80131 Naples, Italy
Interests: hereditary cardiomyopathies; induced pluripotent stem cells; molecular biology; genetics and genomics; biomarkers
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Suet Nee Chen

E-Mail Website
Guest Editor
Molecular Genetics, Cardiovascular Institute, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA
Interests: genetics; animal models; cardiomyopathies; induced pluripotent stem cell derived cardiomyocytes; transcriptomics; molecular pathways
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Kalliopi Pilichou

E-Mail Website
Guest Editor
Department of Cardiac-Thoracic-Vascular Sciences and Public Health, Università degli Studi di Padova, Padua, Italy
Interests: Cardiovascular genetics; molecular mechanisms of inherited cardiomyopathies; animal models; gene expression; lncRNAs; miRNAs

Special Issue Information

Dear Colleagues,

Cardiomyopathies are primary diseases of the myocardium, commonly genetically transmitted. The most common forms are hypertrophic (HCM), dilated (DCM), and arrhythmogenic cardiomyopathy (ACM).

Cardiomyopathies are leading causes of sudden cardiac death (SCD), particularly among the young. However, early diagnosis of affected individuals remains challenging and a resolutive therapy is still lacking, as current treatments can only control the symptoms but not prevent or rescue the phenotype. Genetics, genomics, and basic science studies in cellular and animal models allow delineating the genetic bases and the molecular mechanisms implicated in the pathogenesis of cardiomyopathies in order to develop novel diagnostic tools and more specific therapies.

The purpose of this Special Issue is to review the scientific bases of non-ischemic cardiomyopathies. We will focus on progresses in the current understanding of onset and natural history of these conditions. Furthermore, we will discuss advancements in genetics and genomics, and the most recent discoveries on biomarkers and novel therapeutic targets.

Prof. Dr. Raffaella Lombardi
Prof. Dr. Suet Nee Chen
Prof. Dr. Kalliopi Pilichou
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Arrhythmogenesis 
  • Genetics 
  • Genomics 
  • Epigenetics 
  • Inflammation 
  • Biomarkers 
  • Animal models 
  • Induced pluripotent stem cells 
  • Mechanotransduction 
  • Novel therapeutic targets

Related Special Issue

Published Papers (17 papers)

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Editorial

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4 pages, 150 KiB  
Editorial
Editorial of Special Issue “Genetics and Molecular Pathogenesis of Non-Ischemic Cardiomyopathies”
by Raffaella Lombardi and Suet Nee Chen
Int. J. Mol. Sci. 2020, 21(24), 9398; https://doi.org/10.3390/ijms21249398 - 10 Dec 2020
Cited by 2 | Viewed by 1455
Abstract
This editorial aims to summarize the eight scientific papers published in the Special Issue “Genetics and Molecular Pathogenesis of Non-ischemic Cardiomyopathies” [...] Full article
(This article belongs to the Special Issue Genetics and Molecular Pathogenesis of Non-ischemic Cardiomyopathies)

Research

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12 pages, 1509 KiB  
Article
Identification of SCN5a p.C335R Variant in a Large Family with Dilated Cardiomyopathy and Conduction Disease
by Farbod Sedaghat-Hamedani, Sabine Rebs, Ibrahim El-Battrawy, Safak Chasan, Tobias Krause, Jan Haas, Rujia Zhong, Zhenxing Liao, Qiang Xu, Xiaobo Zhou, Ibrahim Akin, Edgar Zitron, Norbert Frey, Katrin Streckfuss-Bömeke and Elham Kayvanpour
Int. J. Mol. Sci. 2021, 22(23), 12990; https://doi.org/10.3390/ijms222312990 - 30 Nov 2021
Cited by 15 | Viewed by 1879
Abstract
Introduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional [...] Read more.
Introduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (SCN5a) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with Xenopus oocytes and iPSC-CMs were performed. Results: A SCN5a variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating TTN variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the SCN5a variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with Xenopus oocytes showed a loss of function in SCN5a p.C335R. Na+ channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (SCN5a p.C335R and TTNtv) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The SCN5a p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., SCN5a p.C335R and TTNtv) increases the severity of the DCM phenotype. Full article
(This article belongs to the Special Issue Recent Advancements in Primary Cardiomyopathies)
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15 pages, 2605 KiB  
Article
In Experimental Dilated Cardiomyopathy Heart Failure and Survival Are Adversely Affected by a Lack of Sexual Interactions
by Ranjana Tripathi, Ryan D. Sullivan, Tai-Hwang M. Fan, Radhika M. Mehta, Inna P. Gladysheva and Guy L. Reed
Int. J. Mol. Sci. 2020, 21(15), 5450; https://doi.org/10.3390/ijms21155450 - 30 Jul 2020
Cited by 4 | Viewed by 3723
Abstract
Nearly one in three people in the U.S. will develop heart failure (HF), characterized by fluid retention (edema) in the lungs and elsewhere. This leads to difficult breathing, deterioration of physical capacity, restriction of normal activities and death. There is little data about [...] Read more.
Nearly one in three people in the U.S. will develop heart failure (HF), characterized by fluid retention (edema) in the lungs and elsewhere. This leads to difficult breathing, deterioration of physical capacity, restriction of normal activities and death. There is little data about the safety and effects of sexual interactions in patients with HF. We tested whether a lack of sexual interactions affected pathophysiological outcomes in a pre-clinical mouse model of dilated cardiomyopathy that recapitulates the progressive stages of human HF. Male mice were randomly given access to, or deprived from, sexual interactions with female mice, which were confirmed by videography and generation of offspring. Cohousing with access to sexual interactions markedly prolonged survival, while cohousing without access to sexual activity did not. Sexual interactions improved systolic function, reduced HF-associated edema, altered transcription of heart contractile protein genes and decreased plasma testosterone levels. To determine whether testosterone levels contributed to survival, testosterone levels were experimentally reduced. Reduction of testosterone levels significantly prolonged survival. Taken together, in mice with dilated cardiomyopathy, sexual activity altered cardiac contractile gene transcription, improved systolic function, reduced edema and prolonged survival which may be in part due to lower testosterone levels. Full article
(This article belongs to the Special Issue Genetics and Molecular Pathogenesis of Non-ischemic Cardiomyopathies)
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15 pages, 3096 KiB  
Article
A microRNA Expression Profile as Non-Invasive Biomarker in a Large Arrhythmogenic Cardiomyopathy Cohort
by Maria Bueno Marinas, Rudy Celeghin, Marco Cason, Riccardo Bariani, Anna Chiara Frigo, Joanna Jager, Petros Syrris, Perry M. Elliott, Barbara Bauce, Gaetano Thiene, Domenico Corrado, Cristina Basso and Kalliopi Pilichou
Int. J. Mol. Sci. 2020, 21(4), 1536; https://doi.org/10.3390/ijms21041536 - 24 Feb 2020
Cited by 22 | Viewed by 3924
Abstract
Arrhythmogenic Cardiomyopathy (AC) is a clinically and genetically heterogeneous myocardial disease. Half of AC patients harbour private desmosomal gene variants. Although microRNAs (miRNAs) have emerged as key regulator molecules in cardiovascular diseases and their involvement, correlated to phenotypic variability or to non-invasive biomarkers, [...] Read more.
Arrhythmogenic Cardiomyopathy (AC) is a clinically and genetically heterogeneous myocardial disease. Half of AC patients harbour private desmosomal gene variants. Although microRNAs (miRNAs) have emerged as key regulator molecules in cardiovascular diseases and their involvement, correlated to phenotypic variability or to non-invasive biomarkers, has been advanced also in AC, no data are available in larger disease cohorts. Here, we propose the largest AC cohort unbiased by technical and biological factors. MiRNA profiling on nine right ventricular tissue, nine blood samples of AC patients, and four controls highlighted 10 differentially expressed miRNAs in common. Six of these were validated in a 90-AC patient cohort independent from genetic status: miR-122-5p, miR-133a-3p, miR-133b, miR-142-3p, miR-182-5p, and miR-183-5p. This six-miRNA set showed high discriminatory diagnostic power in AC patients when compared to controls (AUC-0.995), non-affected family members of AC probands carrying a desmosomal pathogenic variant (AUC-0.825), and other cardiomyopathy groups (Hypertrophic Cardiomyopathy: AUC-0.804, Dilated Cardiomyopathy: AUC-0.917, Brugada Syndrome: AUC-0.981, myocarditis: AUC-0.978). AC-related signalling pathways were targeted by this set of miRNAs. A unique set of six-miRNAs was found both in heart-tissue and blood samples of AC probands, supporting its involvement in disease pathogenesis and its possible role as a non-invasive AC diagnostic biomarker. Full article
(This article belongs to the Special Issue Genetics and Molecular Pathogenesis of Non-ischemic Cardiomyopathies)
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Review

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14 pages, 783 KiB  
Review
Mitochondrial a Kinase Anchor Proteins in Cardiovascular Health and Disease: A Review Article on Behalf of the Working Group on Cellular and Molecular Biology of the Heart of the Italian Society of Cardiology
by Roberta Paolillo, Stefania D’Apice, Gabriele Giacomo Schiattarella, Pietro Ameri, Domenica Borzacchiello, Daniele Catalucci, Cristina Chimenti, Lia Crotti, Sebastiano Sciarretta, Daniele Torella, Antonio Feliciello and Cinzia Perrino
Int. J. Mol. Sci. 2022, 23(14), 7691; https://doi.org/10.3390/ijms23147691 - 12 Jul 2022
Cited by 2 | Viewed by 2031
Abstract
Second messenger cyclic adenosine monophosphate (cAMP) has been found to regulate multiple mitochondrial functions, including respiration, dynamics, reactive oxygen species production, cell survival and death through the activation of cAMP-dependent protein kinase A (PKA) and other effectors. Several members of the large family [...] Read more.
Second messenger cyclic adenosine monophosphate (cAMP) has been found to regulate multiple mitochondrial functions, including respiration, dynamics, reactive oxygen species production, cell survival and death through the activation of cAMP-dependent protein kinase A (PKA) and other effectors. Several members of the large family of A kinase anchor proteins (AKAPs) have been previously shown to locally amplify cAMP/PKA signaling to mitochondria, promoting the assembly of signalosomes, regulating multiple cardiac functions under both physiological and pathological conditions. In this review, we will discuss roles and regulation of major mitochondria-targeted AKAPs, along with opportunities and challenges to modulate their functions for translational purposes in the cardiovascular system. Full article
(This article belongs to the Special Issue Recent Advancements in Primary Cardiomyopathies)
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13 pages, 1121 KiB  
Review
Pushing the Limits of Medical Management in HCM: A Review of Current Pharmacological Therapy Options
by Cristian Stătescu, Ștefana Enachi, Carina Ureche, Laura Țăpoi, Larisa Anghel, Delia Șalaru, Carmen Pleșoianu, Mădălina Bostan, Dragoș Marcu, Mircea Ovanez Balasanian and Radu Andy Sascău
Int. J. Mol. Sci. 2021, 22(13), 7218; https://doi.org/10.3390/ijms22137218 - 5 Jul 2021
Cited by 6 | Viewed by 4335
Abstract
Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiac disease with a highly variable phenotypic expression, ranging from asymptomatic to drug refractory heart failure (HF) presentation. Pharmacological therapy is the first line of treatment, but options are currently limited to nonspecific medication like [...] Read more.
Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiac disease with a highly variable phenotypic expression, ranging from asymptomatic to drug refractory heart failure (HF) presentation. Pharmacological therapy is the first line of treatment, but options are currently limited to nonspecific medication like betablockers or calcium channel inhibitors, with frequent suboptimal results. While being the gold standard practice for the management of drug refractory HCM patients, septal reduction therapy (SRT) remains an invasive procedure with associated surgical risks and it requires the expertise of the operating centre, thus limiting its accessibility. It is therefore with high interest that researchers look for pharmacological alternatives that could provide higher rates of success. With new data gathering these past years as well as the development of a new drug class showing promising results, this review provides an up-to-date focused synthesis of existing medical treatment options and future directions for HCM pharmacological treatment. Full article
(This article belongs to the Special Issue Recent Advancements in Primary Cardiomyopathies)
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25 pages, 1279 KiB  
Review
CMR-Based Risk Stratification of Sudden Cardiac Death and Use of Implantable Cardioverter–Defibrillator in Non-Ischemic Cardiomyopathy
by Laura Keil, Céleste Chevalier, Paulus Kirchhof, Stefan Blankenberg, Gunnar Lund, Kai Müllerleile and Christina Magnussen
Int. J. Mol. Sci. 2021, 22(13), 7115; https://doi.org/10.3390/ijms22137115 - 1 Jul 2021
Cited by 13 | Viewed by 4952
Abstract
Non-ischemic cardiomyopathy (NICM) is one of the most important entities for arrhythmias and sudden cardiac death (SCD). Previous studies suggest a lower benefit of implantable cardioverter–defibrillator (ICD) therapy in patients with NICM as compared to ischemic cardiomyopathy (ICM). Nevertheless, current guidelines do not [...] Read more.
Non-ischemic cardiomyopathy (NICM) is one of the most important entities for arrhythmias and sudden cardiac death (SCD). Previous studies suggest a lower benefit of implantable cardioverter–defibrillator (ICD) therapy in patients with NICM as compared to ischemic cardiomyopathy (ICM). Nevertheless, current guidelines do not differentiate between the two subgroups in recommending ICD implantation. Hence, risk stratification is required to determine the subgroup of patients with NICM who will likely benefit from ICD therapy. Various predictors have been proposed, among others genetic mutations, left-ventricular ejection fraction (LVEF), left-ventricular end-diastolic volume (LVEDD), and T-wave alternans (TWA). In addition to these parameters, cardiovascular magnetic resonance imaging (CMR) has the potential to further improve risk stratification. CMR allows the comprehensive analysis of cardiac function and myocardial tissue composition. A range of CMR parameters have been associated with SCD. Applicable examples include late gadolinium enhancement (LGE), T1 relaxation times, and myocardial strain. This review evaluates the epidemiological aspects of SCD in NICM, the role of CMR for risk stratification, and resulting indications for ICD implantation. Full article
(This article belongs to the Special Issue Recent Advancements in Primary Cardiomyopathies)
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22 pages, 595 KiB  
Review
The Mystery of Diabetic Cardiomyopathy: From Early Concepts and Underlying Mechanisms to Novel Therapeutic Possibilities
by Petra Grubić Rotkvić, Zrinka Planinić, Ana-Marija Liberati Pršo, Jozica Šikić, Edvard Galić and Luka Rotkvić
Int. J. Mol. Sci. 2021, 22(11), 5973; https://doi.org/10.3390/ijms22115973 - 1 Jun 2021
Cited by 25 | Viewed by 3824
Abstract
Diabetic patients are predisposed to diabetic cardiomyopathy, a specific form of cardiomyopathy which is characterized by the development of myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis that develops independently of concomitant macrovascular and microvascular diabetic complications. Its pathophysiology is multifactorial and poorly understood and [...] Read more.
Diabetic patients are predisposed to diabetic cardiomyopathy, a specific form of cardiomyopathy which is characterized by the development of myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis that develops independently of concomitant macrovascular and microvascular diabetic complications. Its pathophysiology is multifactorial and poorly understood and no specific therapeutic guideline has yet been established. Diabetic cardiomyopathy is a challenging diagnosis, made after excluding other potential entities, treated with different pharmacotherapeutic agents targeting various pathophysiological pathways that need yet to be unraveled. It has great clinical importance as diabetes is a disease with pandemic proportions. This review focuses on the potential mechanisms contributing to this entity, diagnostic options, as well as on potential therapeutic interventions taking in consideration their clinical feasibility and limitations in everyday practice. Besides conventional therapies, we discuss novel therapeutic possibilities that have not yet been translated into clinical practice. Full article
(This article belongs to the Special Issue Recent Advancements in Primary Cardiomyopathies)
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34 pages, 679 KiB  
Review
Molecular Epidemiology of Mitochondrial Cardiomyopathy: A Search Among Mitochondrial and Nuclear Genes
by Cristina Mazzaccara, Bruno Mirra, Ferdinando Barretta, Martina Caiazza, Barbara Lombardo, Olga Scudiero, Nadia Tinto, Giuseppe Limongelli and Giulia Frisso
Int. J. Mol. Sci. 2021, 22(11), 5742; https://doi.org/10.3390/ijms22115742 - 27 May 2021
Cited by 16 | Viewed by 3397
Abstract
Mitochondrial Cardiomyopathy (MCM) is a common manifestation of multi-organ Mitochondrial Diseases (MDs), occasionally present in non-syndromic cases. Diagnosis of MCM is complex because of wide clinical and genetic heterogeneity and requires medical, laboratory, and neuroimaging investigations. Currently, the molecular screening for MCM is [...] Read more.
Mitochondrial Cardiomyopathy (MCM) is a common manifestation of multi-organ Mitochondrial Diseases (MDs), occasionally present in non-syndromic cases. Diagnosis of MCM is complex because of wide clinical and genetic heterogeneity and requires medical, laboratory, and neuroimaging investigations. Currently, the molecular screening for MCM is fundamental part of MDs management and allows achieving the definitive diagnosis. In this article, we review the current genetic knowledge associated with MDs, focusing on diagnosis of MCM and MDs showing cardiac involvement. We searched for publications on mitochondrial and nuclear genes involved in MCM, mainly focusing on genetic screening based on targeted gene panels for the molecular diagnosis of the MCM, by using Next Generation Sequencing. Here we report twelve case reports, four case-control studies, eleven retrospective studies, and two prospective studies, for a total of twenty-nine papers concerning the evaluation of cardiac manifestations in mitochondrial diseases. From the analysis of published causal mutations, we identified 130 genes to be associated with mitochondrial heart diseases. A large proportion of these genes (34.3%) encode for key proteins involved in the oxidative phosphorylation system (OXPHOS), either as directly OXPHOS subunits (22.8%), and as OXPHOS assembly factors (11.5%). Mutations in several mitochondrial tRNA genes have been also reported in multi-organ or isolated MCM (15.3%). This review highlights the main disease-genes, identified by extensive genetic analysis, which could be included as target genes in next generation panels for the molecular diagnosis of patients with clinical suspect of mitochondrial cardiomyopathies. Full article
(This article belongs to the Special Issue Recent Advancements in Primary Cardiomyopathies)
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18 pages, 575 KiB  
Review
Well-Known and Novel Serum Biomarkers for Risk Stratification of Patients with Non-ischemic Dilated Cardiomyopathy
by Larisa Anghel, Radu Sascău, Ioana Mădălina Zota and Cristian Stătescu
Int. J. Mol. Sci. 2021, 22(11), 5688; https://doi.org/10.3390/ijms22115688 - 26 May 2021
Cited by 5 | Viewed by 2876
Abstract
Non-ischemic dilated cardiomyopathy encompasses a wide spectrum of myocardial disorders, characterized by left ventricular dilatation with systolic impairment and increased risk of sudden cardiac death. In spite of all the therapeutic progress that has been made in recent years, dilated cardiomyopathy continues to [...] Read more.
Non-ischemic dilated cardiomyopathy encompasses a wide spectrum of myocardial disorders, characterized by left ventricular dilatation with systolic impairment and increased risk of sudden cardiac death. In spite of all the therapeutic progress that has been made in recent years, dilated cardiomyopathy continues to be an important cause of cardiac transplant, being associated with an enormous cost burden for health care systems worldwide. Predicting the prognosis of patients with dilated cardiomyopathy is essential to individualize treatment. Late gadolinium enhancement-cardiac magnetic resonance imaging, microvolt T-wave alternans, and genetic testing have emerged as powerful tools in predicting sudden cardiac death occurrence and maximizing patient’s selection. Despite all these new diagnostic modalities, additional tests to complement or replace current tools are required for better risk stratification. Therefore, biomarkers are an easy and important tool that can help to detect patients at risk of adverse cardiovascular events. Additionally, identifying potential biomarkers involved in dilated cardiomyopathy can provide us important information regarding the diagnostic, prognostic, risk stratification, and response to treatment for these patients. Many potential biomarkers have been studied in patients with dilated cardiomyopathy, but only a few have been adopted in current practice. Therefore, the aim of our review is to provide the clinicians with an update on the well-known and novel biomarkers that can be useful for risk stratification of patients with non-ischemic dilated cardiomyopathy. Full article
(This article belongs to the Special Issue Recent Advancements in Primary Cardiomyopathies)
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19 pages, 2921 KiB  
Review
Update on the Diagnostic Pitfalls of Autopsy and Post-Mortem Genetic Testing in Cardiomyopathies
by Simone Grassi, Oscar Campuzano, Mònica Coll, Francesca Cazzato, Georgia Sarquella-Brugada, Riccardo Rossi, Vincenzo Arena, Josep Brugada, Ramon Brugada and Antonio Oliva
Int. J. Mol. Sci. 2021, 22(8), 4124; https://doi.org/10.3390/ijms22084124 - 16 Apr 2021
Cited by 19 | Viewed by 3257
Abstract
Inherited cardiomyopathies are frequent causes of sudden cardiac death (SCD), especially in young patients. Despite at the autopsy they usually have distinctive microscopic and/or macroscopic diagnostic features, their phenotypes may be mild or ambiguous, possibly leading to misdiagnoses or missed diagnoses. In this [...] Read more.
Inherited cardiomyopathies are frequent causes of sudden cardiac death (SCD), especially in young patients. Despite at the autopsy they usually have distinctive microscopic and/or macroscopic diagnostic features, their phenotypes may be mild or ambiguous, possibly leading to misdiagnoses or missed diagnoses. In this review, the main differential diagnoses of hypertrophic cardiomyopathy (e.g., athlete’s heart, idiopathic left ventricular hypertrophy), arrhythmogenic cardiomyopathy (e.g., adipositas cordis, myocarditis) and dilated cardiomyopathy (e.g., acquired forms of dilated cardiomyopathy, left ventricular noncompaction) are discussed. Moreover, the diagnostic issues in SCD victims affected by phenotype-negative hypertrophic cardiomyopathy and the relationship between myocardial bridging and hypertrophic cardiomyopathy are analyzed. Finally, the applications/limits of virtopsy and post-mortem genetic testing in this field are discussed, with particular attention to the issues related to the assessment of the significance of the genetic variants. Full article
(This article belongs to the Special Issue Recent Advancements in Primary Cardiomyopathies)
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26 pages, 1081 KiB  
Review
The Hidden Fragility in the Heart of the Athletes: A Review of Genetic Biomarkers
by Ferdinando Barretta, Bruno Mirra, Emanuele Monda, Martina Caiazza, Barbara Lombardo, Nadia Tinto, Olga Scudiero, Giulia Frisso and Cristina Mazzaccara
Int. J. Mol. Sci. 2020, 21(18), 6682; https://doi.org/10.3390/ijms21186682 - 12 Sep 2020
Cited by 14 | Viewed by 3186
Abstract
Sudden cardiac death (SCD) is a devastating event which can also affect people in apparent good health, such as young athletes. It is known that intense and continuous exercise along with a genetic background that predisposes a person to the risk of fatal [...] Read more.
Sudden cardiac death (SCD) is a devastating event which can also affect people in apparent good health, such as young athletes. It is known that intense and continuous exercise along with a genetic background that predisposes a person to the risk of fatal arrhythmias is a trigger for SCD. Therefore, knowledge of the athlete’s genetic conditions underlying the onset of SCD must be extended, in order to develop new effective prevention and/or therapeutic strategies. Arrhythmic features occur across a broad spectrum of cardiac diseases, sometimes presenting with overlapping phenotypes. The genetic basis of arrhythmogenic disorders has been greatly highlighted in the last 30 years, and has shown marked heterogeneity. The advent of next-generation sequencing has constantly updated our understanding of the genetic basis of arrhythmogenic diseases and is laying the foundation for precision medicine. With the exception of a few clinical cases involving a single athlete showing a highly suspected phenotype for the presence of a heart disease, there are few studies to date that analysed the applicability of genetic testing on cohorts of athletes. This evidence shows that genetic testing can contribute to the diagnosis of up to 13% of athletes; however, the presence of clinical markers is essential. This review aims to provide a reference collection on current knowledge of the genetic basis of sudden cardiac death in athletes and to review updated evidence on the effectiveness of genetic testing in early identification of athletes at risk for SCD. Full article
(This article belongs to the Special Issue Genetics and Molecular Pathogenesis of Non-ischemic Cardiomyopathies)
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47 pages, 16267 KiB  
Review
State of the Art Review on Genetics and Precision Medicine in Arrhythmogenic Cardiomyopathy
by Viraj Patel, Babken Asatryan, Bhurint Siripanthong, Patricia B. Munroe, Anjali Tiku-Owens, Luis R. Lopes, Mohammed Y. Khanji, Alexandros Protonotarios, Pasquale Santangeli, Daniele Muser, Francis E. Marchlinski, Peter A. Brady and C. Anwar A. Chahal
Int. J. Mol. Sci. 2020, 21(18), 6615; https://doi.org/10.3390/ijms21186615 - 10 Sep 2020
Cited by 20 | Viewed by 8212
Abstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterised by ventricular arrhythmia and an increased risk of sudden cardiac death (SCD). Numerous genetic determinants and phenotypic manifestations have been discovered in ACM, posing a significant clinical challenge. Further to this, wider evaluation of family [...] Read more.
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterised by ventricular arrhythmia and an increased risk of sudden cardiac death (SCD). Numerous genetic determinants and phenotypic manifestations have been discovered in ACM, posing a significant clinical challenge. Further to this, wider evaluation of family members has revealed incomplete penetrance and variable expressivity in ACM, suggesting a complex genotype-phenotype relationship. This review details the genetic basis of ACM with specific genotype-phenotype associations, providing the reader with a nuanced perspective of this condition; whilst also proposing a future roadmap to delivering precision medicine-based management in ACM. Full article
(This article belongs to the Special Issue Genetics and Molecular Pathogenesis of Non-ischemic Cardiomyopathies)
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16 pages, 790 KiB  
Review
The Role of MicroRNAs in Arrhythmogenic Cardiomyopathy: Biomarkers or Innocent Bystanders of Disease Progression?
by Maria Bueno Marinas, Rudy Celeghin, Marco Cason, Gaetano Thiene, Cristina Basso and Kalliopi Pilichou
Int. J. Mol. Sci. 2020, 21(17), 6434; https://doi.org/10.3390/ijms21176434 - 3 Sep 2020
Cited by 6 | Viewed by 2379
Abstract
Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease characterized by a progressive fibro-fatty replacement of the working myocardium and by life-threatening arrhythmias and risk of sudden cardiac death. Pathogenic variants are identified in nearly 50% of affected patients mostly in genes encoding for [...] Read more.
Arrhythmogenic cardiomyopathy (AC) is an inherited cardiac disease characterized by a progressive fibro-fatty replacement of the working myocardium and by life-threatening arrhythmias and risk of sudden cardiac death. Pathogenic variants are identified in nearly 50% of affected patients mostly in genes encoding for desmosomal proteins. AC incomplete penetrance and phenotypic variability advocate that other factors than genetics may modulate the disease, such as microRNAs (miRNAs). MiRNAs are small noncoding RNAs with a primary role in gene expression regulation and network of cellular processes. The implication of miRNAs in AC pathogenesis and their role as biomarkers for early disease detection or differential diagnosis has been the objective of multiple studies employing diverse designs and methodologies to detect miRNAs and measure their expression levels. Here we summarize experiments, evidence, and flaws of the different studies and hitherto knowledge of the implication of miRNAs in AC pathogenesis and diagnosis. Full article
(This article belongs to the Special Issue Genetics and Molecular Pathogenesis of Non-ischemic Cardiomyopathies)
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26 pages, 2737 KiB  
Review
Established and Emerging Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy: A Multifaceted Disease
by Shanshan Gao, Deepa Puthenvedu, Raffaella Lombardi and Suet Nee Chen
Int. J. Mol. Sci. 2020, 21(17), 6320; https://doi.org/10.3390/ijms21176320 - 31 Aug 2020
Cited by 18 | Viewed by 3904
Abstract
Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease that manifests with cardiac arrhythmias, syncope, sudden cardiac death, and heart failure in the advanced stages. The pathological hallmark of ACM is a gradual replacement of the myocardium by fibroadiposis, which typically starts from the [...] Read more.
Arrhythmogenic cardiomyopathy (ACM) is a heritable myocardial disease that manifests with cardiac arrhythmias, syncope, sudden cardiac death, and heart failure in the advanced stages. The pathological hallmark of ACM is a gradual replacement of the myocardium by fibroadiposis, which typically starts from the epicardium. Molecular genetic studies have identified causal mutations predominantly in genes encoding for desmosomal proteins; however, non-desmosomal causal mutations have also been described, including genes coding for nuclear proteins, cytoskeleton componentsand proteins involved in excitation-contraction coupling. Despite the poor prognosis, currently available treatments can only partially control symptoms and to date there is no effective therapy for ACM. Inhibition of the canonical Wnt/β-catenin pathway and activation of the Hippo and the TGF-β pathways have been implicated in the pathogenesis of ACM. Yet, our understanding of the molecular mechanisms involved in the development of the disease and the cell source of fibroadiposis remains incomplete. Elucidation of the pathogenesis of the disease could facilitate targeted approaches for treatment. In this manuscript we will provide a comprehensive review of the proposed molecular and cellular mechanisms of the pathogenesis of ACM, including the emerging evidence on abnormal calcium homeostasis and inflammatory/autoimmune response. Moreover, we will propose novel hypothesis about the role of epicardial cells and paracrine factors in the development of the phenotype. Finally, we will discuss potential innovative therapeutic approaches based on the growing knowledge in the field. Full article
(This article belongs to the Special Issue Genetics and Molecular Pathogenesis of Non-ischemic Cardiomyopathies)
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16 pages, 1044 KiB  
Review
Current Understanding of the Role of Cytoskeletal Cross-Linkers in the Onset and Development of Cardiomyopathies
by Ilaria Pecorari, Luisa Mestroni and Orfeo Sbaizero
Int. J. Mol. Sci. 2020, 21(16), 5865; https://doi.org/10.3390/ijms21165865 - 15 Aug 2020
Cited by 7 | Viewed by 2750
Abstract
Cardiomyopathies affect individuals worldwide, without regard to age, sex and ethnicity and are associated with significant morbidity and mortality. Inherited cardiomyopathies account for a relevant part of these conditions. Although progresses have been made over the years, early diagnosis and curative therapies are [...] Read more.
Cardiomyopathies affect individuals worldwide, without regard to age, sex and ethnicity and are associated with significant morbidity and mortality. Inherited cardiomyopathies account for a relevant part of these conditions. Although progresses have been made over the years, early diagnosis and curative therapies are still challenging. Understanding the events occurring in normal and diseased cardiac cells is crucial, as they are important determinants of overall heart function. Besides chemical and molecular events, there are also structural and mechanical phenomena that require to be investigated. Cell structure and mechanics largely depend from the cytoskeleton, which is composed by filamentous proteins that can be cross-linked via accessory proteins. Alpha-actinin 2 (ACTN2), filamin C (FLNC) and dystrophin are three major actin cross-linkers that extensively contribute to the regulation of cell structure and mechanics. Hereby, we review the current understanding of the roles played by ACTN2, FLNC and dystrophin in the onset and progress of inherited cardiomyopathies. With our work, we aim to set the stage for new approaches to study the cardiomyopathies, which might reveal new therapeutic targets and broaden the panel of genes to be screened. Full article
(This article belongs to the Special Issue Genetics and Molecular Pathogenesis of Non-ischemic Cardiomyopathies)
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5 pages, 714 KiB  
Opinion
Change the Laminin, Change the Cardiomyocyte: Improve Untreatable Heart Failure
by Camila Hochman-Mendez, Ernesto Curty and Doris A. Taylor
Int. J. Mol. Sci. 2020, 21(17), 6013; https://doi.org/10.3390/ijms21176013 - 21 Aug 2020
Cited by 13 | Viewed by 2563
Abstract
No effective medical treatment exists for heart failure with preserved ejection fraction (HFpEF), accounting for approximately half of all heart failure cases. The elevated passive myocardial stiffness in HFpEF is attributed to a combination of alterations in the extracellular matrix (ECM) collagen content [...] Read more.
No effective medical treatment exists for heart failure with preserved ejection fraction (HFpEF), accounting for approximately half of all heart failure cases. The elevated passive myocardial stiffness in HFpEF is attributed to a combination of alterations in the extracellular matrix (ECM) collagen content and modifications in the sarcomeric protein titin. Here, we propose polylaminin, a biomimetic polymer of laminin, as a promising approach for manipulating the titin isoform shift and phosphorylation in cardiomyocytes. Exploring the pleiotropic effects of polylaminin may be a novel strategy for alleviating symptoms in HFpEF’s multifactorial pathophysiology. Full article
(This article belongs to the Special Issue Genetics and Molecular Pathogenesis of Non-ischemic Cardiomyopathies)
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