Editorial

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Open AccessEditorial

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249398 - 10 Dec 2020

Cited by 2 | Viewed by 1427

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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15 pages, 2605 KiB

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155450 - 30 Jul 2020

Cited by 4 | Viewed by 3639

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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041536 - 24 Feb 2020

Cited by 22 | Viewed by 3767

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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26 pages, 1081 KiB

Open AccessReview

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186682 - 12 Sep 2020

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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

Open AccessReview

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186615 - 10 Sep 2020

Cited by 19 | Viewed by 7916

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

Open AccessReview

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176434 - 03 Sep 2020

Cited by 6 | Viewed by 2298

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

Open AccessReview

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176320 - 31 Aug 2020

Cited by 18 | Viewed by 3818

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

Open AccessReview

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165865 - 15 Aug 2020

Cited by 7 | Viewed by 2688

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

Open AccessOpinion

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176013 - 21 Aug 2020

Cited by 12 | Viewed by 2503

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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