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Heart Failure Reviews Jul 2022Dilated cardiomyopathy (DCM) is an umbrella term entailing a wide variety of genetic and non-genetic etiologies, leading to left ventricular systolic dysfunction and... (Review)
Review
Dilated cardiomyopathy (DCM) is an umbrella term entailing a wide variety of genetic and non-genetic etiologies, leading to left ventricular systolic dysfunction and dilatation, not explained by abnormal loading conditions or coronary artery disease. The clinical presentation can vary from asymptomatic to heart failure symptoms or sudden cardiac death (SCD) even in previously asymptomatic individuals. In the last 2 decades, there has been striking progress in the understanding of the complex genetic basis of DCM, with the discovery of additional genes and genotype-phenotype correlation studies. Rigorous clinical work-up of DCM patients, meticulous family screening, and the implementation of advanced imaging techniques pave the way for a more efficient and earlier diagnosis as well as more precise indications for implantable cardioverter defibrillator implantation and prevention of SCD. In the era of precision medicine, genotype-directed therapies have started to emerge. In this review, we focus on updates of the genetic background of DCM, characteristic phenotypes caused by recently described pathogenic variants, specific indications for prevention of SCD in those individuals and genotype-directed treatments under development. Finally, the latest developments in distinguishing athletic heart syndrome from subclinical DCM are described.
Topics: Cardiomyopathy, Dilated; Death, Sudden, Cardiac; Humans; Phenotype; Precision Medicine; Ventricular Dysfunction, Left
PubMed: 34263412
DOI: 10.1007/s10741-021-10139-0 -
Immunity Sep 2021Cardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2...
Cardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2) macrophages. Herein, we identified an essential role for CCR2 macrophages in the chronically failing heart. Depletion of CCR2 macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2 macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4)-dependent pathway that controlled growth factor expression. These findings establish a role for tissue-resident macrophages in adaptive cardiac remodeling and implicate mechanical sensing in cardiac macrophage activation.
Topics: Animals; Cardiomyopathy, Dilated; Humans; Macrophage Activation; Macrophages; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; Myocardium; Troponin T; Ventricular Remodeling
PubMed: 34320366
DOI: 10.1016/j.immuni.2021.07.003 -
Circulation Research May 2022There is increasing evidence regarding the prevalence of genetic cardiomyopathies, for which arrhythmias may be the first presentation. Ventricular and atrial... (Review)
Review
There is increasing evidence regarding the prevalence of genetic cardiomyopathies, for which arrhythmias may be the first presentation. Ventricular and atrial arrhythmias presenting in the absence of known myocardial disease are often labelled as idiopathic, or lone. While ventricular arrhythmias are well-recognized as presentation for arrhythmogenic cardiomyopathy in the right ventricle, the scope of arrhythmogenic cardiomyopathy has broadened to include those with dominant left ventricular involvement, usually with a phenotype of dilated cardiomyopathy. In addition, careful evaluation for genetic cardiomyopathy is also warranted for patients presenting with frequent premature ventricular contractions, conduction system disease, and early onset atrial fibrillation, in which most detected genes are in the cardiomyopathy panels. Sudden death can occur early in the course of these genetic cardiomyopathies, for which risk is not adequately tracked by left ventricular ejection fraction. Only a few of the cardiomyopathy genotypes implicated in early sudden death are recognized in current indications for implantable cardioverter defibrillators which otherwise rely upon a left ventricular ejection fraction ≤0.35 in dilated cardiomyopathy. The genetic diagnoses impact other aspects of clinical management such as exercise prescription and pharmacological therapy of arrhythmias, and new therapies are coming into clinical investigation for specific genetic cardiomyopathies. The expansion of available genetic information and implications raises new challenges for genetic counseling, particularly with the family member who has no evidence of a cardiomyopathy phenotype and may face a potentially negative impact of a genetic diagnosis. Discussions of risk for both probands and relatives need to be tailored to their numeric literacy during shared decision-making. For patients presenting with arrhythmias or cardiomyopathy, extension of genetic testing and its implications will enable cascade screening, intervention to change the trajectory for specific genotype-phenotype profiles, and enable further development and evaluation of emerging targeted therapies.
Topics: Atrial Fibrillation; Cardiomyopathies; Cardiomyopathy, Dilated; Death, Sudden; Death, Sudden, Cardiac; Humans; Stroke Volume; Ventricular Function, Left
PubMed: 35617362
DOI: 10.1161/CIRCRESAHA.122.319835 -
International Journal of Molecular... Nov 2021With the development and advancement of next-generation sequencing (NGS), genetic analysis is becoming more accessible. High-throughput genetic studies using NGS have... (Review)
Review
With the development and advancement of next-generation sequencing (NGS), genetic analysis is becoming more accessible. High-throughput genetic studies using NGS have contributed to unraveling the association between cardiomyopathy and genetic background, as is the case with many other diseases. Rare variants have been shown to play major roles in the pathogenesis of cardiomyopathy, which was empirically recognized as a monogenic disease, and it has been elucidated that the clinical course of cardiomyopathy varies depending on the causative genes. These findings were not limited to dilated and hypertrophic cardiomyopathy; similar trends were reported one after another for peripartum cardiomyopathy (PPCM), cancer therapy-related cardiac dysfunction (CTRCD), and alcoholic cardiomyopathy (ACM). In addition, as the association between clinical phenotypes and the causative genes becomes clearer, progress is being made in elucidating the mechanisms and developing novel therapeutic agents. Recently, it has been suggested that not only rare variants but also common variants contribute to the development of cardiomyopathy. Cardiomyopathy and genetics are approaching a new era, which is summarized here in this overview.
Topics: Cardiomyopathies; Cardiomyopathy, Alcoholic; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Mutation; Phenotype
PubMed: 34830403
DOI: 10.3390/ijms222212522 -
American Journal of Human Genetics Feb 2022To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using...
To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.
Topics: Age of Onset; Cardiomyopathy, Dilated; Case-Control Studies; Child; Cohort Studies; Exome; Female; Gene Expression Profiling; Gene Expression Regulation; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Genotype; Humans; Inheritance Patterns; Male; Phenotype; Practice Guidelines as Topic; Exome Sequencing
PubMed: 35026164
DOI: 10.1016/j.ajhg.2021.12.006 -
Journal of Animal Science Jun 2020Dilated cardiomyopathy (DCM) has been in the literature and news because of the recent opinion-based journal articles and public releases by regulatory agencies. DCM is... (Review)
Review
Dilated cardiomyopathy (DCM) has been in the literature and news because of the recent opinion-based journal articles and public releases by regulatory agencies. DCM is commonly associated with a genetic predisposition in certain dog breeds and can also occur secondary to other diseases and nutritional deficiencies. Recent communications in veterinary journals have discussed a potential relationship between grain-free and/or novel protein diets to DCM, citing a subjective increase in DCM in dog breeds that are not known to have a genetic predisposition for the disease. This literature review describes clinical presentations of DCM, common sequelae, treatment and preventative measures, histopathologic features, and a discussion of the varied etiological origins of the disease. In addition, current literature limitations are addressed, in order to ascertain multiple variables leading to the development of DCM. Future studies are needed to evaluate one variable at a time and to minimize confounding variables and speculation. Furthermore, to prevent sampling bias with the current FDA reports, the veterinary community should be asked to provide information for all cases of DCM in dogs. This should include cases during the same time period, regardless of the practitioner's proposed etiology, due to no definitive association between diets with specific characteristics, such as, but not limited to, grain-free diets and those containing legumes, novel protein diets, and those produced by small manufacturers to DCM in dogs. In summary, in order to determine if certain ingredients, categories of diets, or manufacturing processes are related to an increased risk of DCM, further studies investigating these variables are necessary.
Topics: Animals; Breeding; Cardiomyopathy, Dilated; Diet; Dog Diseases; Dogs; Edible Grain
PubMed: 32542359
DOI: 10.1093/jas/skaa155 -
Journal of Internal Medicine Oct 2019Dilated cardiomyopathy (DCM) is characterized by left ventricular dilatation and, consecutively, contractile dysfunction. The causes of DCM are heterogeneous. DCM often... (Review)
Review
Dilated cardiomyopathy (DCM) is characterized by left ventricular dilatation and, consecutively, contractile dysfunction. The causes of DCM are heterogeneous. DCM often results from myocarditis, exposure to alcohol, drugs or other toxins and metabolic or endocrine disturbances. In about 35% of patients, genetic mutations can be identified that usually involve genes responsible for cytoskeletal, sarcomere and nuclear envelope proteins. Due to its heterogeneity, a detailed diagnostic work-up is necessary to identify the specific underlying cause and exclude other conditions with phenotype overlap. Patients with DCM show typical systolic heart failure symptoms, but, with progress of the disease, diastolic dysfunction is present as well. Depending on the underlying pathology, DCM patients also become apparent through arrhythmias, thromboembolic events or cardiogenic shock. Disease progression and prognosis are mostly driven by disease severity and reverse remodelling within the heart. The worst prognosis is seen in patients with lowest ejection fractions or severe diastolic dysfunction, leading to terminal heart failure with subsequent need for left ventricular assist device implantation or heart transplantation. Guideline-based heart failure medication and device therapy reduces the frequency of heart failure hospitalizations and improves survival.
Topics: Age of Onset; Cardiomyopathy, Dilated; Diagnosis, Differential; Disease Progression; Heart Function Tests; Humans; Incidence; Mutation; Phenotype; Prevalence; Prognosis; Risk Factors
PubMed: 31132311
DOI: 10.1111/joim.12944 -
Theranostics 2021Mitochondrial dysfunction facilitates heart failure development forming a therapeutic target, but the mechanism involved remains unclear. We studied whether the Hippo...
Mitochondrial dysfunction facilitates heart failure development forming a therapeutic target, but the mechanism involved remains unclear. We studied whether the Hippo signaling pathway mediates mitochondrial abnormalities that results in onset of dilated cardiomyopathy (DCM). Mice with DCM due to overexpression of Hippo pathway kinase Mst1 were studied. DCM phenotype was evident in adult animals but contractile dysfunction was identified as an early sign of DCM at 3 weeks postnatal. Electron microscopy, multi-omics and biochemical assays were employed. In 3-week and adult DCM mouse hearts, cardiomyocyte mitochondria exhibited overt structural abnormalities, smaller size and greater number. RNA sequencing revealed comprehensive suppression of nuclear-DNA (nDNA) encoded gene-sets involved in mitochondria turnover and all aspects of metabolism. Changes in cardiotranscriptome were confirmed by lower protein levels of multiple mitochondrial proteins in DCM heart of both ages. Mitochondrial DNA-encoded genes were also downregulated; due apparently to repression of nDNA-encoded transcriptional factors. Lipidomics identified remodeling in cardiolipin acyl-chains, increased acylcarnitine content but lower coenzyme Q10 level. Mitochondrial dysfunction was featured by lower ATP content and elevated levels of lactate, branched-chain amino acids and reactive oxidative species. Mechanistically, inhibitory YAP-phosphorylation was enhanced, which was associated with attenuated binding of transcription factor TEAD1. Numerous suppressed mitochondrial genes were identified as YAP-targets. Hippo signaling activation mediates mitochondrial damage by repressing mitochondrial genes, which causally promotes the development of DCM. The Hippo pathway therefore represents a therapeutic target against mitochondrial dysfunction in cardiomyopathy.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cardiomyopathies; Cardiomyopathy, Dilated; China; Hippo Signaling Pathway; Humans; Male; Mice; Mice, Transgenic; Mitochondria; Myocytes, Cardiac; Signal Transduction; Transcription Factors
PubMed: 34522223
DOI: 10.7150/thno.62302 -
Circulation. Genomic and Precision... Apr 2020The hypothesis of the Dilated Cardiomyopathy Precision Medicine Study is that most dilated cardiomyopathy has a genetic basis. The study returns results to probands and,...
Variant Interpretation for Dilated Cardiomyopathy: Refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study.
BACKGROUND
The hypothesis of the Dilated Cardiomyopathy Precision Medicine Study is that most dilated cardiomyopathy has a genetic basis. The study returns results to probands and, when indicated, to relatives. While both the American College of Medical Genetics and Genomics/Association for Molecular Pathology and ClinGen's -cardiomyopathy specifications provide relevant guidance for variant interpretation, further gene- and disease-specific considerations were required for dilated cardiomyopathy. To this end, we tailored the ClinGen -cardiomyopathy variant interpretation framework; the specifications implemented for the study are presented here.
METHODS
Modifications were created and approved by an external Variant Adjudication Oversight Committee. After a pilot using 81 probands, further adjustments were made, resulting in 27 criteria (9 modifications of the ClinGen framework and reintroduction of 2 American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria that were deemed not applicable by the ClinGen working group).
RESULTS
These criteria were applied to 2059 variants in a test set of 97 probands. Variants were classified as benign (n=1702), likely benign (n=33), uncertain significance (n=71), likely pathogenic (likely pathogenic; n=12), and pathogenic (P; n=3). Only 2/15 likely pathogenic/P variants were identified in Non-Hispanic African ancestry probands.
CONCLUSIONS
We tailored the ClinGen criteria for our study. Our preliminary data show that 15/97 (15.5%) probands have likely pathogenic/P variants, most of which were identified in probands of Non-Hispanic European ancestry. We anticipate continued evolution of our approach, one that will be informed by new insights on variant interpretation and a greater understanding of the genetic architecture of dilated cardiomyopathy.
CLINICAL TRIAL REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.
Topics: Cardiomyopathy, Dilated; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Genetics, Medical; Genomics; Humans; Mutation; Practice Guidelines as Topic; Precision Medicine; United States
PubMed: 32160020
DOI: 10.1161/CIRCGEN.119.002480 -
Redox Biology Jul 2020Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure, and the underlying mechanism remains largely elusive. Here we investigated whether NLRP3...
Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure, and the underlying mechanism remains largely elusive. Here we investigated whether NLRP3 inflammasome-mediated pyroptosis contributes to non-ischemic DCM and dissected the underlying mechanism. We found that hyper activated NLRP3 inflammasome with pyroptotic cell death of cardiomyocytes were presented in the myocardial tissues of DCM patients, which were negatively correlated with cardiac function. Doxorubicin (Dox)-induced DCM characterization disclosed that NLRP3 inflammasome activation and pyroptosis occurred in Dox-treated heart tissues, but were very marginal in either NLRP3 or caspase-1 mice. Mechanistically, Dox enhanced expressions of NOX1 and NOX4 and induced mitochondrial fission through dynamin-related protein 1 (Drp1) activation, leading to NLRP3 inflammasome-mediated pyroptosis in cardiomyocytes via caspase-1-dependent manner. Conversely, both inhibitions of NOX1 and NOX4 and Drp1 suppressed Dox-induced NLPR3 inflammasome activation and pyroptosis. The alterations of NOX1 and NOX4 expression, Drp1 phosphorylation and mitochondrial fission were validated in DCM patients and mice. Importantly, Dox-induced Drp1-mediated mitochondrial fission and the consequent NLRP3 inflammasome activation and pyroptosis were reversed by NOX1 and NOX4 inhibition in mice. This study demonstrates for the first time that cardiomyocyte pyroptosis triggered by NLRP3 inflammasome activation via caspase-1 causally contributes to myocardial dysfunction progression and DCM pathogenesis.
Topics: Animals; Cardiomyopathy, Dilated; Caspase 1; Humans; Inflammasomes; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis
PubMed: 32273259
DOI: 10.1016/j.redox.2020.101523