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BMC Cardiovascular Disorders Jul 2022The pathogenic mechanism of dilated cardiomyopathy (DCM) remains to be defined. This study aimed to identify hub genes and immune cells that could serve as potential...
BACKGROUND
The pathogenic mechanism of dilated cardiomyopathy (DCM) remains to be defined. This study aimed to identify hub genes and immune cells that could serve as potential therapeutic targets for DCM.
METHODS
We downloaded four datasets from the Gene Expression Omnibus (GEO) database: GSE141910, GSE3585, GSE42955 and GSE79962. Weighted gene coexpression network analysis (WGCNA) and differential expression analysis were performed to identify gene panels related to DCM. Meanwhile, the CIBERSORT algorithm was used to estimate the immune cells in DCM tissues. Multiple machine learning approaches were used to screen the hub genes and immune cells. Finally, the diagnostic value of the hub genes was assessed by receiver operating characteristic (ROC) analysis. An experimental mouse model of dilated cardiomyopathy was used to validate the bioinformatics results.
RESULTS
FRZB and EXT1 were identified as hub biomarkers, and the ROC curves suggested an excellent diagnostic ability of the above genes for DCM. In addition, naive B cells were upregulated in DCM tissues, while eosinophils, M2 macrophages, and memory CD4 T cells were downregulated in DCM tissues. The increase in two hub genes and naive B cells was validated in animal experiments.
CONCLUSION
These results indicated that FRZB and EXT1 could be used as promising biomarkers, and eosinophils, M2 macrophages, resting memory CD4 T cells and naive B cells may also affect the occurrence of DCM.
Topics: Animals; Biomarkers; Cardiomyopathy, Dilated; Gene Expression Profiling; Gene Regulatory Networks; Mice; RNA-Seq
PubMed: 35850644
DOI: 10.1186/s12872-022-02759-7 -
Journal of the American Heart... Jun 2020
Topics: Cardiomyopathy, Dilated; Child; Genetic Testing; Humans; Pedigree; Retrospective Studies
PubMed: 32458723
DOI: 10.1161/JAHA.120.016910 -
Journal of the American Heart... Apr 2021Background Inherited cardiomyopathies display variable penetrance and expression, and a component of phenotypic variation is genetically determined. To evaluate the...
Background Inherited cardiomyopathies display variable penetrance and expression, and a component of phenotypic variation is genetically determined. To evaluate the genetic contribution to this variable expression, we compared protein coding variation in the genomes of those with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Methods and Results Nonsynonymous single-nucleotide variants (nsSNVs) were ascertained using whole genome sequencing from familial cases of HCM (n=56) or DCM (n=70) and correlated with echocardiographic information. Focusing on nsSNVs in 102 genes linked to inherited cardiomyopathies, we correlated the number of nsSNVs per person with left ventricular measurements. Principal component analysis and generalized linear models were applied to identify the probability of cardiomyopathy type as it related to the number of nsSNVs in cardiomyopathy genes. The probability of having DCM significantly increased as the number of cardiomyopathy gene nsSNVs per person increased. The increase in nsSNVs in cardiomyopathy genes significantly associated with reduced left ventricular ejection fraction and increased left ventricular diameter for individuals carrying a DCM diagnosis, but not for those with HCM. Resampling was used to identify genes with aberrant cumulative allele frequencies, identifying potential modifier genes for cardiomyopathy. Conclusions Participants with DCM had more nsSNVs per person in cardiomyopathy genes than participants with HCM. The nsSNV burden in cardiomyopathy genes did not correlate with the probability or manifestation of left ventricular measures in HCM. These findings support the concept that increased variation in cardiomyopathy genes creates a genetic background that predisposes to DCM and increased disease severity.
Topics: Adult; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Echocardiography; Female; Genomics; Genotype; Heart Ventricles; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Stroke Volume; Ventricular Function, Left
PubMed: 33764162
DOI: 10.1161/JAHA.120.019944 -
Journal of Veterinary Cardiology : the... Apr 2022Cardiomyopathies such as dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are common in large breed dogs and carry an overall poor prognosis.... (Review)
Review
Cardiomyopathies such as dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are common in large breed dogs and carry an overall poor prognosis. Research shows that these diseases have strong breed predilections, and selective breeding has historically been recommended to reduce the disease prevalence in affected breeds. Treatment of these diseases is typically palliative and aimed at slowing disease progression and managing clinical signs of heart failure as they develop. The discovery of specific genetic mutations underlying cardiomyopathies, such as the striatin mutation in Boxer arrhythmogenic right ventricular cardiomyopathy and the pyruvate dehydrogenase kinase 4 and titin mutations in Doberman Pinschers, has strengthened our ability to screen and selectively breed individuals in an attempt to produce unaffected offspring. The discovery of these disease-linked mutations has also opened avenues for the development of gene therapies, including gene transfer and genome-editing approaches. This review article discusses the known genetics of cardiomyopathies in dogs, reviews existing gene therapy strategies and the status of their development in canines, and discusses ongoing challenges in the clinical translation of these technologies for treating heart disease. While challenges remain in using these emerging technologies, the exponential growth of the gene therapy field holds great promise for future clinical applications.
Topics: Animals; Arrhythmogenic Right Ventricular Dysplasia; Cardiomyopathies; Cardiomyopathy, Dilated; Dog Diseases; Dogs; Heart Failure; Mutation
PubMed: 34147413
DOI: 10.1016/j.jvc.2021.05.003 -
Circulation. Heart Failure Aug 2022Alcohol is often cited to be a common cause of cardiomyopathy and heart failure. However, in most available population-based studies, a modest-to-moderate alcohol... (Review)
Review
Alcohol is often cited to be a common cause of cardiomyopathy and heart failure. However, in most available population-based studies, a modest-to-moderate alcohol consumption has been associated with favorable effects on the cardiovascular system, including a lowered risk of heart failure, compared with no alcohol consumption. Available genetic epidemiological data have not supported a causal association between alcohol consumption and heart failure risk, suggesting that alcohol may not be a common cause of heart failure in the community. Data linking alcohol intake with cardiomyopathy risk are sparse, and the concept of alcoholic cardiomyopathy stems mainly from case series of selected patients with dilated cardiomyopathy, where a large proportion reported a history of excessive alcohol intake. This state-of-the-art paper addresses the current knowledge of the epidemiology of alcoholic cardiomyopathy and the role of alcohol intake in patients with non-alcohol-related heart failure. It also offers directions to future research in the area. The review questions the validity of current clinical teaching in the area. It is not well known how much alcohol is needed to cause disease, and the epidemiological pathways linking alcohol consumption to cardiomyopathy and heart failure are not well understood. Until more evidence becomes available, caution is warranted before labeling patients as having alcoholic cardiomyopathy due to a risk of neglecting other contributors, such as genetic causes of cardiomyopathy. In non-alcohol-related heart failure, it is unknown whether total abstinence is improving outcomes (compared with moderate drinking). Ideally, randomized clinical trials are needed to answer this question.
Topics: Alcohol Drinking; Cardiomyopathy, Alcoholic; Cardiomyopathy, Dilated; Consensus; Ethanol; Heart Failure; Humans
PubMed: 35593142
DOI: 10.1161/CIRCHEARTFAILURE.121.009459 -
Naunyn-Schmiedeberg's Archives of... Jul 2023Dilated cardiomyopathy (DCM) is the major cause of heart failure and has a poor prognosis. The accumulating evidence points to an essential role of the inflammatory...
Dilated cardiomyopathy (DCM) is the major cause of heart failure and has a poor prognosis. The accumulating evidence points to an essential role of the inflammatory component in the process of DCM. Inhibitors of sodium-glucose cotransporter 2 (SGLT2) are widely used to treat heart failure patients due to their cardiac benefits. However, their role in DCM remains unclear. We used the doxorubicin (Dox)-induced DCM model for our study. The SGLT2 inhibitor dapagliflozin (Dapa) improved cardiac function in mice treated with doxorubicin and attenuated the activation of the nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome pathway and the expression of inflammatory factors. In addition, dapagliflozin suppresses NLRP3 activation by decreasing p38-dependent toll-like receptor 4 (TLR4) expression. In our study, dagliflozin improves cardiac function in DCM by inhibiting the activity of the NLRP3 inflammasome.
Topics: Mice; Animals; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Cardiomyopathy, Dilated; Diabetic Cardiomyopathies; Heart Failure
PubMed: 36749400
DOI: 10.1007/s00210-023-02409-5 -
Biological Research Jun 2023Dilated cardiomyopathy (DCM) is a primary myocardial disease, leading to heart failure and excessive risk of sudden cardiac death with rather poorly understood...
Dilated cardiomyopathy (DCM) is a primary myocardial disease, leading to heart failure and excessive risk of sudden cardiac death with rather poorly understood pathophysiology. In 2015, Parvari's group identified a recessive mutation in the autophagy regulator, PLEKHM2 gene, in a family with severe recessive DCM and left ventricular non-compaction (LVNC). Fibroblasts isolated from these patients exhibited abnormal subcellular distribution of endosomes, Golgi apparatus, lysosomes and had impaired autophagy flux. To better understand the effect of mutated PLEKHM2 on cardiac tissue, we generated and characterized induced pluripotent stem cells-derived cardiomyocytes (iPSC-CMs) from two patients and a healthy control from the same family. The patient iPSC-CMs showed low expression levels of genes encoding for contractile functional proteins (α and β-myosin heavy chains and 2v and 2a-myosin light chains), structural proteins integral to heart contraction (Troponin C, T and I) and proteins participating in Ca pumping action (SERCA2 and Calsequestrin 2) compared to their levels in control iPSC-derived CMs. Furthermore, the sarcomeres of the patient iPSC-CMs were less oriented and aligned compared to control cells and generated slowly beating foci with lower intracellular calcium amplitude and abnormal calcium transient kinetics, measured by IonOptix system and MuscleMotion software. Autophagy in patient's iPSC-CMs was impaired as determined from a decrease in the accumulation of autophagosomes in response to chloroquine and rapamycin treatment, compared to control iPSC-CMs. Impairment in autophagy together with the deficiency in the expression of NKX2.5, MHC, MLC, Troponins and CASQ2 genes, which are related to contraction-relaxation coupling and intracellular Ca signaling, may contribute to the defective function of the patient CMs and possibly affect cell maturation and cardiac failure with time.
Topics: Humans; Calcium; Cardiomyopathy, Dilated; Cell Differentiation; Induced Pluripotent Stem Cells; Mutation; Myocytes, Cardiac
PubMed: 37349842
DOI: 10.1186/s40659-023-00442-5 -
Journal of the American College of... Sep 2022
Topics: Cardiomyopathy, Dilated; Genetic Testing; Humans
PubMed: 36109107
DOI: 10.1016/j.jacc.2022.07.010 -
Journal of Translational Medicine Oct 2023Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse...
BACKGROUND
Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most common form of autosomal dominant DCM. LMNA DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate LMNA DCM. However, it is unknown whether these candidates could serve as potential therapeutic targets especially in long term efficacy.
METHODS
We evaluated 14 potential candidates including Lmna gene products (Lamin A and Lamin C), key signaling pathways (Tgfβ/Smad, mTor and Fgf/Mapk), calcium handling, proliferation regulators and modifiers of LINC complex function in a cardiac specific Lmna DCM model. Positive candidates for improved cardiac function were further assessed by survival analysis. Suppressive roles and mechanisms of these candidates in ameliorating Lmna DCM were dissected by comparing marker gene expression, Tgfβ signaling pathway activation, fibrosis, inflammation, proliferation and DNA damage. Furthermore, transcriptome profiling compared the differences between Lamin A and Lamin C treatment.
RESULTS
Cardiac function was restored by several positive candidates (Smad3, Yy1, Bmp7, Ctgf, aYAP1, Sun1, Lamin A, and Lamin C), which significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. Importantly, Lamin A treatment improved but could not reproduce long term survival, and Lamin A administration to healthy hearts itself induced DCM. Mechanistically, we identified this lapse as caused by a dose-dependent toxicity of Lamin A, which was independent from its maturation.
CONCLUSIONS
In vivo candidate evaluation revealed that supplementation of Lamin C or knockdown of Sun1 significantly suppressed Lmna DCM and achieve prolonged survival. Conversely, Lamin A supplementation did not rescue long term survival and may impart detrimental cardiotoxicity risk. This study highlights a potential of advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.
Topics: Humans; Cardiomyopathy, Dilated; Lamin Type A; Cardiomyopathies; Fibrosis; Inflammation; Transforming Growth Factor beta; Mutation
PubMed: 37840136
DOI: 10.1186/s12967-023-04542-4 -
European Journal of Heart Failure Jul 2020The term dilated cardiomyopathy (DCM) defines a heterogeneous group of cardiac disorders, which are characterized by left ventricular or biventricular dilatation and... (Review)
Review
The term dilated cardiomyopathy (DCM) defines a heterogeneous group of cardiac disorders, which are characterized by left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment. In approximately one third of cases, DCM is familial with a genetic pathogenesis and various patterns of inheritance. Although the electrocardiogram (ECG) has been considered traditionally non-specific in DCM, the recently acquired knowledge of the genotype-phenotype correlations provides novel opportunities to identify patterns and abnormalities that may point toward specific DCM subtypes. A learned ECG interpretation in combination with an appropriate use of other ECG-based techniques including ambulatory ECG monitoring, exercise tolerance test and imaging modalities, such as echocardiography and cardiovascular magnetic resonance, may allow the early identification of specific genetic or acquired forms of DCM. Furthermore, ECG abnormalities may reflect the severity of the disease and provide a useful tool in risk stratification and management. In the present review, we discuss the current role of the ECG in the diagnosis and management of DCM. We describe various clinical settings where the appropriate use and interpretation of the ECG can provide invaluable clues, contributing to the important role of this basic tool as cardiovascular medicine evolves.
Topics: Cardiomyopathy, Dilated; Echocardiography; Electrocardiography; Heart Failure; Humans; Risk Assessment
PubMed: 32243666
DOI: 10.1002/ejhf.1815