International Journal of Molecular Sciences

Editorial

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4 pages, 150 KiB

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://doi.org/10.3390/ijms21249398 - 10 Dec 2020

Cited by 2 | Viewed by 1721

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

Open AccessArticle

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 2253

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

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://doi.org/10.3390/ijms21155450 - 30 Jul 2020

Cited by 5 | Viewed by 4113

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://doi.org/10.3390/ijms21041536 - 24 Feb 2020

Cited by 27 | Viewed by 4425

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

Open AccessReview

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 4 | Viewed by 2557

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

Open AccessReview

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 7 | Viewed by 4925

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

Open AccessReview

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 16 | Viewed by 5729

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

Open AccessReview

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 31 | Viewed by 4557

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

Open AccessReview

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 18 | Viewed by 3933

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

Open AccessReview

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 7 | Viewed by 3409

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

Open AccessReview

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 20 | Viewed by 3779

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

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://doi.org/10.3390/ijms21186682 - 12 Sep 2020

Cited by 18 | Viewed by 3672

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://doi.org/10.3390/ijms21186615 - 10 Sep 2020

Cited by 22 | Viewed by 9074

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://doi.org/10.3390/ijms21176434 - 3 Sep 2020

Cited by 7 | Viewed by 2675

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://doi.org/10.3390/ijms21176320 - 31 Aug 2020

Cited by 19 | Viewed by 4421

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://doi.org/10.3390/ijms21165865 - 15 Aug 2020

Cited by 8 | Viewed by 3163

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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Other

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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://doi.org/10.3390/ijms21176013 - 21 Aug 2020

Cited by 15 | Viewed by 2918

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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