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Genetics and Treatment of Dilated Cardiomyopathy

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A special issue of Journal of Cardiovascular Development and Disease (ISSN 2308-3425).

Deadline for manuscript submissions: closed (30 June 2017) | Viewed by 33266

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Special Issue Editor

Prof. Dr. Xiaolei Xu

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Guest Editor

Department of Biochemistry and Molecular Biology, and Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA
Interests: cardiomyopathy; sarcomere; zebrafish; modifying screen; animal models; genome editing

Special Issue Information

Dear Colleagues,

JCDD launches a Special Issue on “Genetics and Treatment of Dilated Cardiomyopathy”. Idiopathic dilated cardiomyopathy (DCM) is a heritable, progressive disorder that ultimately leads to heart failure. The identification of many causative genes and key pathological pathways opens the door to new therapeutic strategies. However, the development of effective therapy is significantly hindered by the heterogeneous nature of DCM, manifesting as both locus heterogeneity, i.e., mutations in different genes result in DCM, and phenotypic variation, i.e., individuals with the same causative mutation could exhibit highly variable phenotypes. Therefore, strategies that enable the categorization of DCM into different types and development of individualized medicine tailored for different DCM types are needed. The advent of genomic tools and the integration of in vitro and in vivo models offer new research opportunities to identify the remaining causative genes, to pinpoint underlying mechanisms and to identify effective therapies.

Prof. Dr. Xiaolei Xu
Guest Editor

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. Journal of Cardiovascular Development and Disease is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

Dilated cardiomyopathy
Genetics
Genetic modifiers
Mutagenesis screen
Individualized medicine
Drug repurposing
Animal models
Heterogeneity

Published Papers (6 papers)

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Research

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1568 KiB

Open AccessArticle

Insights from Second-Line Treatments for Idiopathic Dilated Cardiomyopathy

by Marco Luciani and Federica Del Monte

J. Cardiovasc. Dev. Dis. 2017, 4(3), 12; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd4030012 - 23 Aug 2017

Cited by 3 | Viewed by 6119

Abstract

Background: Dilated cardiomyopathy (DCM) is an independent nosographic entity characterized by left ventricular dilatation and contractile dysfunction leading to heart failure (HF). The idiopathic form of DCM (iDCM) occurs in the absence of coronaropathy or other known causes of DCM. Despite being different from other forms of HF for demographic, clinical, and prognostic features, its current pharmacological treatment does not significantly diverge. Methods: In this study we performed a Pubmed library search for placebo-controlled clinical investigations and a post-hoc analysis recruiting iDCM from 1985 to 2016. We searched for second-line pharmacologic treatments to reconsider drugs for iDCM management and pinpoint pathological mechanisms. Results: We found 33 clinical studies recruiting a total of 3392 patients of various durations and sizes, as well as studies that tested different drug classes (statins, pentoxifylline, inotropes). A metanalysis was unfeasible, although a statistical significance for changes upon treatment for molecular results, morphofunctional parameters, and clinical endpoints was reported. Statins appeared to be beneficial in light of their pleiotropic effects; inotropes might be tolerated more for longer times in iDCM compared to ischemic patients. General anti-inflammatory therapies do not significantly improve outcomes. Metabolic and growth modulation remain appealing fields to be investigated. Conclusions: The evaluation of drug effectiveness based on direct clinical benefit is an inductive method providing evidence-based insights. This backward approach sheds light on putative and underestimated pathologic mechanisms and thus therapeutic targets for iDCM management. Full article

(This article belongs to the Special Issue Genetics and Treatment of Dilated Cardiomyopathy)

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Open AccessArticle

Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy

by Pamela A. Long, Jared M. Evans and Timothy M. Olson

J. Cardiovasc. Dev. Dis. 2017, 4(3), 11; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd4030011 - 08 Aug 2017

Cited by 37 | Viewed by 6342

Abstract

Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. DCM typically remains clinically silent until adulthood, yet symptomatic disease can develop in childhood. We sought to identify the genetic basis of pediatric DCM in 15 sporadic and three affected-siblings cases, comprised of 21 affected children (mean age, five years) whose parents had normal echocardiograms (mean age, 39 years). Twelve underwent cardiac transplantation and five died with severe heart failure. Parent-offspring whole exome sequencing (WES) data were filtered for rare, deleterious, de novo and recessive variants. In prior work, we reported de novo mutations in TNNT2 and RRAGC and compound heterozygous mutations in ALMS1 and TAF1A among four cases in our cohort. Here, de novo mutations in established DCM genes—RBM20, LMNA, TNNT2, and PRDM16—were identified among five additional cases. The RBM20 mutation was previously reported in familial DCM. An identical unreported LMNA mutation was identified in two unrelated cases, both harboring gene-specific defects in cardiomyocyte nuclear morphology. Collectively, WES had a 50% diagnostic yield in our cohort, providing an explanation for pediatric heart failure and enabling informed family planning. Research is ongoing to discover novel DCM genes among the remaining families. Full article

(This article belongs to the Special Issue Genetics and Treatment of Dilated Cardiomyopathy)

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Open AccessArticle

Breast Cancer Clinical Trial of Chemotherapy and Trastuzumab: Potential Tool to Identify Cardiac Modifying Variants of Dilated Cardiomyopathy

by Daniel J. Serie, Julia E. Crook, Brian M. Necela, Bianca C. Axenfeld, Travis J. Dockter, Gerardo Colon-Otero, Edith A. Perez, E. Aubrey Thompson and Nadine Norton

J. Cardiovasc. Dev. Dis. 2017, 4(2), 6; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd4020006 - 04 May 2017

Cited by 5 | Viewed by 4366

Abstract

Doxorubicin and the ERBB2 targeted therapy, trastuzumab, are routinely used in the treatment of HER2+ breast cancer. In mouse models, doxorubicin is known to cause cardiomyopathy and conditional cardiac knock out of Erbb2 results in dilated cardiomyopathy and increased sensitivity to doxorubicin-induced cell death. In humans, these drugs also result in cardiac phenotypes, but severity and reversibility is highly variable. We examined the association of decline in left ventricular ejection fraction (LVEF) at 15,204 single nucleotide polymorphisms (SNPs) spanning 72 cardiomyopathy genes, in 800 breast cancer patients who received doxorubicin and trastuzumab. For 7033 common SNPs (minor allele frequency (MAF) > 0.01) we performed single marker linear regression. For all SNPs, we performed gene-based testing with SNP-set (Sequence) Kernel Association Tests: SKAT, SKAT-O and SKAT-common/rare under rare variant non-burden; rare variant optimized burden and non-burden tests; and a combination of rare and common variants respectively. Single marker analyses identified seven missense variants in OBSCN (p = 0.0045–0.0009, MAF = 0.18–0.50) and two in TTN (both p = 0.04, MAF = 0.22). Gene-based rare variant analyses, SKAT and SKAT-O, performed very similarly (ILK, TCAP, DSC2, VCL, FXN, DSP and KCNQ1, p = 0.042–0.006). Gene-based tests of rare/common variants were significant at the nominal 5% level for OBSCN as well as TCAP, DSC2, VCL, NEXN, KCNJ2 and DMD (p = 0.044–0.008). Our results suggest that rare and common variants in OBSCN, as well as in other genes, could have modifying effects in cardiomyopathy. Full article

(This article belongs to the Special Issue Genetics and Treatment of Dilated Cardiomyopathy)

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Review

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1093 KiB

Open AccessReview

Dystrophic Cardiomyopathy: Complex Pathobiological Processes to Generate Clinical Phenotype

by Takeshi Tsuda and Kristi K. Fitzgerald

J. Cardiovasc. Dev. Dis. 2017, 4(3), 14; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd4030014 - 08 Sep 2017

Cited by 17 | Viewed by 6141

Abstract

Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XL-DCM) consist of a unique clinical entity, the dystrophinopathies, which are due to variable mutations in the dystrophin gene. Dilated cardiomyopathy (DCM) is a common complication of dystrophinopathies, but the onset, progression, and severity of heart disease differ among these subgroups. Extensive molecular genetic studies have been conducted to assess genotype-phenotype correlation in DMD, BMD, and XL-DCM to understand the underlying mechanisms of these diseases, but the results are not always conclusive, suggesting the involvement of complex multi-layers of pathological processes that generate the final clinical phenotype. Dystrophin protein is a part of dystrophin-glycoprotein complex (DGC) that is localized in skeletal muscles, myocardium, smooth muscles, and neuronal tissues. Diversity of cardiac phenotype in dystrophinopathies suggests multiple layers of pathogenetic mechanisms in forming dystrophic cardiomyopathy. In this review article, we review the complex molecular interactions involving the pathogenesis of dystrophic cardiomyopathy, including primary gene mutations and loss of structural integrity, secondary cellular responses, and certain epigenetic and other factors that modulate gene expressions. Involvement of epigenetic gene regulation appears to lead to specific cardiac phenotypes in dystrophic hearts. Full article

(This article belongs to the Special Issue Genetics and Treatment of Dilated Cardiomyopathy)

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Open AccessReview

Midkine’s Role in Cardiac Pathology

by Kathleen C. Woulfe and Carmen C. Sucharov

J. Cardiovasc. Dev. Dis. 2017, 4(3), 13; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd4030013 - 24 Aug 2017

Cited by 14 | Viewed by 3950

Abstract

Midkine (MDK) is a heparin-binding growth factor that is normally expressed in mid-gestational development mediating mesenchymal and epithelial interactions. As organisms age, expression of MDK diminishes; however, in adults, MDK expression is associated with acute and chronic pathologic conditions such as myocardial infarction and heart failure (HF). The role of MDK is not clear in cardiovascular disease and currently there is no consensus if it plays a beneficial or detrimental role in HF. The lack of clarity in the literature is exacerbated by differing roles that circulating and myocardial MDK play in signaling pathways in cardiomyocytes (some of which have yet to be elucidated). Of particular interest, serum MDK is elevated in adults with chronic heart failure and higher circulating MDK is associated with worse cardiac function. In addition, pediatric HF patients have higher levels of myocardial MDK. This review focuses on what is known about the effect of exogenous versus myocardial MDK in various cardiac disease models in an effort to better clarify the role of midkine in HF. Full article

(This article belongs to the Special Issue Genetics and Treatment of Dilated Cardiomyopathy)

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Open AccessReview

Multiple Species Comparison of Cardiac Troponin T and Dystrophin: Unravelling the DNA behind Dilated Cardiomyopathy

by Jennifer England, Siobhan Loughna and Catrin Sian Rutland

J. Cardiovasc. Dev. Dis. 2017, 4(3), 8; https://0-doi-org.brum.beds.ac.uk/10.3390/jcdd4030008 - 07 Jul 2017

Cited by 3 | Viewed by 5818

Abstract

Animals have frequently been used as models for human disorders and mutations. Following advances in genetic testing and treatment options, and the decreasing cost of these technologies in the clinic, mutations in both companion and commercial animals are now being investigated. A recent review highlighted the genes associated with both human and non-human dilated cardiomyopathy. Cardiac troponin T and dystrophin were observed to be associated with both human and turkey (troponin T) and canine (dystrophin) dilated cardiomyopathies. This review gives an overview of the work carried out in cardiac troponin T and dystrophin to date in both human and animal dilated cardiomyopathy. Full article

(This article belongs to the Special Issue Genetics and Treatment of Dilated Cardiomyopathy)

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