-
Journal of Cardiac Failure Dec 2023A diagnosis of Lamin proteins A and C cardiomyopathy (LMNA-CM) not only impacts disease prognosis, but also leads to specific guideline-recommended treatment options for... (Review)
Review
BACKGROUND
A diagnosis of Lamin proteins A and C cardiomyopathy (LMNA-CM) not only impacts disease prognosis, but also leads to specific guideline-recommended treatment options for these patients. This etiology is fundamentally different from other genetic causes of dilated CM.
METHODS AND RESULTS
LMNA-CM often presents early in the third to fourth decades and there is an age-dependent penetrance of nearly 90% among those with a positive genotype for LMNA-CM. Oftentimes, electrical abnormalities with either conduction disturbances and/or either atrial or ventricular arrhythmias manifest before there is imaging evidence of left ventricular dysfunction. Given these subtle early findings, cardiac magnetic resonance provides helpful guidance regarding patterns of enhancement associated with LMNA-CM, often before there is significant left ventricular dilation and/or a decrease in the ejection fraction and could be used for further understanding of risk stratification and prognosis of asymptomatic genotype-positive individuals. Among symptomatic patients with LMNA-CM, approximately one-quarter of individuals progress to needing advanced heart failure therapies such as heart transplantation.
CONCLUSIONS
In the era of precision medicine, increased recognition of clinical findings associated with LMNA-CM and increased detection by genetic testing among patients with idiopathic nonischemic CM is of increasing importance. Not only does a diagnosis of LMNA-CM have implications for management and risk stratification, but new gene-based therapies continue to be evaluated for this group. Clinicians must be aware not only of the general indications for genetic testing in arrhythmogenic and dilated cardiomyopathies and of when to suspect LMNA-CM, but also of the clinical trials underway targeted toward the different genetic cardiomyopathies.
Topics: Humans; Heart Failure; Mutation; Cardiomyopathies; Arrhythmias, Cardiac; Cardiomyopathy, Dilated; Lamin Type A
PubMed: 37659618
DOI: 10.1016/j.cardfail.2023.08.016 -
European Journal of Cardiovascular... Apr 2020Dilated cardiomyopathy (DCM) in children is an important cause of severe heart failure and carries a poor prognosis. Adults with heart failure are at increased risk of... (Comparative Study)
Comparative Study
BACKGROUND
Dilated cardiomyopathy (DCM) in children is an important cause of severe heart failure and carries a poor prognosis. Adults with heart failure are at increased risk of anxiety and depression and such symptoms predict adverse clinical outcomes such as mortality. In children with DCM, studies examining these associations are scarce.
AIMS
We studied whether in children with DCM: (1) the level of emotional and behavioral problems was increased as compared to normative data, and (2) depressive and anxiety problems were associated with the combined risk of death or cardiac transplantation.
METHODS
To assess emotional and behavioral problems in children with DCM, parents of 68 children, aged 1.5-18 years (6.9±5.7 years), completed the Child Behavior Checklist.
RESULTS
Compared to normative data, more young children (1.5-5 years) with DCM had somatic complaints (24.3% vs. 8.0%; p < .001), but fewer had externalizing problems (5.4% vs. 17.0%; p = .049). Overall internalizing problems did not reach significance. Compared to normative data, more older children (6-18 years) showed internalizing problems (38.7% vs. 17.0%; p = .001), including depressive (29.0% vs. 8.0%; p < .001) and anxiety problems (19.4% vs. 8.0%; p = .023), and somatic complaints (29.0% vs. 8.0%; p < .001). Anxiety and depressive problems, corrected for heart failure severity, did not predict the risk of death or cardiac transplantation.
CONCLUSION
Children of 6 years and older showed more depressive and anxiety problems than the normative population. Moreover, in both age groups, somatic problems were common. No association with outcome could be demonstrated.
Topics: Adolescent; Anxiety Disorders; Cardiomyopathy, Dilated; Child; Child Behavior; Child, Preschool; Female; Heart Failure; Heart Transplantation; Humans; Infant; Male; Problem Behavior
PubMed: 31552760
DOI: 10.1177/1474515119876148 -
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. Genomic and Precision... Apr 2024Dilated cardiomyopathy (DCM) is a common heart muscle disorder of nonischemic etiology associated with heart failure development and the risk of malignant ventricular... (Review)
Review
Dilated cardiomyopathy (DCM) is a common heart muscle disorder of nonischemic etiology associated with heart failure development and the risk of malignant ventricular arrhythmias and sudden cardiac death. A tailored approach to risk stratification and prevention of sudden cardiac death is required in genetic DCM given its variable presentation and phenotypic severity. Currently, advances in cardiogenetics have shed light on disease mechanisms, the complex genetic architecture of DCM, polygenic contributors to disease susceptibility and the role of environmental triggers. Parallel advances in imaging have also enhanced disease recognition and the identification of the wide spectrum of phenotypes falling under the DCM umbrella. Genotype-phenotype associations have been also established for specific subtypes of DCM, such as (desmoplakin) or (filamin-C) cardiomyopathy but overall, they remain elusive and not readily identifiable. Also, despite the accumulated knowledge on disease mechanisms, certain aspects remain still unclear, such as which patients with DCM are at risk for disease progression or remission after treatment. Imagenetics, that is, the combination of imaging and genetics, is expected to further advance research in the field and contribute to precision medicine in DCM management and treatment. In the present article, we review the existing literature in the field, summarize the established knowledge and emerging data on the value of genetics and imaging in establishing genotype-phenotype associations in DCM and in clinical decision making for DCM patients.
Topics: Humans; Cardiomyopathy, Dilated; Precision Medicine; Death, Sudden, Cardiac; Arrhythmias, Cardiac; Genetic Association Studies
PubMed: 38415367
DOI: 10.1161/CIRCGEN.123.004301 -
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 -
Scientific Reports May 2022Dilated cardiomyopathy (DCM) is a primary myocardial disease of unclear mechanism and poor prevention. The purpose of this study is to explore the potential molecular...
Dilated cardiomyopathy (DCM) is a primary myocardial disease of unclear mechanism and poor prevention. The purpose of this study is to explore the potential molecular mechanisms and targets of DCM via bioinformatics methods and try to diagnose and prevent disease progression early. We screened 333 genes differentially expressed between DCM and normal heart samples from GSE141910, and further used Weighted correlation network analysis to identify 197 DCM-related genes. By identifying the key modules in the protein-protein interaction network and Least Absolute Shrinkage and Selection Operator regression analysis, seven hub DCM genes (CX3CR1, AGTR2, ADORA3, CXCL10, CXCL11, CXCL9, SAA1) were identified. Calculating the area under the receiver's operating curve revealed that these 7 genes have an excellent ability to diagnose and predict DCM. Based on this, we built a logistic regression model and drew a nomogram. The calibration curve showed that the actual incidence is basically the same as the predicted incidence; while the C-index values of the nomogram and the four external validation data sets are 0.95, 0.90, 0.96, and 0.737, respectively, showing excellent diagnostic and predictive ability; while the decision curve indicated the wide applicability of the nomogram is helpful for clinicians to make accurate decisions.
Topics: Cardiomyopathy, Dilated; Computational Biology; Humans; Nomograms; Protein Interaction Maps; Regression Analysis
PubMed: 35618744
DOI: 10.1038/s41598-022-13135-y -
International Journal of Cardiology Mar 2024Dilated cardiomyopathy (DCM) is a leading cause of heart failure. Cuproptosis is involved in various diseases, although its role in DCM is still unclear. Here, this...
BACKGROUND
Dilated cardiomyopathy (DCM) is a leading cause of heart failure. Cuproptosis is involved in various diseases, although its role in DCM is still unclear. Here, this study aims to investigate the feasibility of using genes related to cuproptosis as diagnostic biomarkers for DCM and the association of their expression with immune infiltration and drug target in cardiac tissue.
METHODS
Gene expression data from nonfailure (NF) and DCM samples were retrieved from the GEO database. Cuproptosis scores were calculated using single-sample gene set enrichment analysis (ssGSEA). Weighted gene co-expression network analysis (WGCNA) was used to screen key modules associated with DCM and cuproptosis. Random forest and least absolute shrinkage and selection operator (LASSO) were applied to identify signature genes. Finally, immune cell infiltration was assessed using ssGSEA. mRNA-miRNA-lncRNA regulatory networks and chemical-drug regulatory networks based on signature genes were analyzed by Cytoscape.
RESULTS
8 modules were aggregated by WGCNA, among which MEblue was significantly associated with cuproptosis scores and DCM. A diagnostic model made up of six signature genes including SEPTIN1, CLEC11A, ISG15, P3H3, SDSL, and INKA1 was selected. Furthermore, immune infiltration studies showed significant differences between DCM and NF. Drugs networks and ceRNA regulatory network based on six signature genes were successfully constructed.
CONCLUSION
Six signature genes (SEPTIN1, CLEC11A, ISG15, P3H3, SDSL, and INKA1) were identified as novel diagnostic biomarkers in DCM. In addition, the expression of these genes was associated with immune cell infiltration, suggesting that cuproptosis may be involved in the immune regulation of DCM.
Topics: Humans; Cardiomyopathy, Dilated; Drug Delivery Systems; MicroRNAs; Databases, Factual; Biomarkers
PubMed: 38168558
DOI: 10.1016/j.ijcard.2023.131702 -
Journal of Biological Regulators and... 2020Mucolipidosis II and III are lysosomal storage diseases caused by pathogenetic mutations in GNPTAB and GNPTG genes which cause an impaired activity of the lysosomal...
Mucolipidosis II and III are lysosomal storage diseases caused by pathogenetic mutations in GNPTAB and GNPTG genes which cause an impaired activity of the lysosomal hydrolase N-acetylglucosamine- 1-phosphotransferase, a key enzyme in the synthesis of the mannose-6-phosphate targeting signals on lysosomal enzymes. Patients with MLII alpha/beta present coarse facial features, cessation of statural growth, important skeletal manifestations, impaired neuromotor development and cardiorespiratory involvement. All children appear to have cardiac involvement, but severe dilated cardiomyopathy is uncommon. In this report we describe the case of an 11-month-old girl who is affected by a MLII. Analysis of the GNPTAB gene identified at a heterozygous level the previously described gene variants c. 2693delA p(Lys898Serfs*13) and c. 2956C>T p(Arg986Cys). Her main clinical features were coarse face with gingival hypertrophy, dysostosis multiplex, recurrent respiratory infection and an early onset of dilated cardiomyopathy, an uncommon feature for MLII. To our knowledge, dilated cardiomyopathy has been previously described in literature in only two cases of MLII and in one patient affected by MLIII.
Topics: Cardiomyopathy, Dilated; Child; Female; Humans; Infant; Mucolipidoses; Mutation; Transferases (Other Substituted Phosphate Groups)
PubMed: 33000604
DOI: No ID Found -
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 Cardiovascular Magnetic... Dec 2023Despite the use of cardiovascular magnetic resonance (CMR) feature tracking (FT) imaging to detect myocardial deformation, the optimal strain index in dilated...
BACKGROUND
Despite the use of cardiovascular magnetic resonance (CMR) feature tracking (FT) imaging to detect myocardial deformation, the optimal strain index in dilated cardiomyopathy (DCM) is unclear. This study aimed to determine whether atrial and biventricular strains can provide the greatest or joint incremental prognostic value in patients with DCM over a long follow-up period.
METHODS
Four hundred-twelve DCM patients were included retrospectively. Comprehensive clinical evaluation and imaging investigations were obtained, including measurements of CMR-FT derived left atrial (LA) reservoir, conduit, booster strain (εs, εe, εa); left ventricular (LV) and right ventricular (RV) global longitudinal, radial, circumferential strain (GLS, GRS, GCS). All patients were followed up for major adverse cardiac events (MACE) including all-cause mortality, heart transplantation, and implantable cardioverter defibrillator discharge. The predictors of MACE were examined with univariable and multivariable Cox regression analysis. Subsequently, nested Cox regression models were built to evaluate the incremental prognostic value of strain parameters. The incremental predictive power of strain parameters was assessed by Omnibus tests, and the model performance and discrimination were evaluated by Harrell C-index and integrated discrimination improvement (IDI) analysis. Patient survival was illustrated by Kaplan-Meier curves and differences were evaluated by log-rank test.
RESULTS
During a median follow-up of 5.0 years, MACE were identified in 149 (36%) patients. LAεe, LVGLS, and RVGLS were the most predictive strain parameters for MACE (AUC: 0.854, 0.733, 0.733, respectively). Cox regression models showed that the predictive value of LAεe was independent from and incremental to LVGLS, RVGLS, and baseline variables (HR 0.74, 95% CI 0.68-0.81, P < 0.001). In reclassification analysis, the addition of LAεe provided the best discrimination of the model (χ 223.34, P < 0.001; C-index 0.833; IDI 0.090, P < 0.001) compared with LVGLS and RVGLS models. Moreover, LAεe with a cutoff of 5.3% further discriminated the survival probability in subgroups of patients with positive LGE or reduced LVEF (all log-rank P < 0.001).
CONCLUSION
LAεe provided the best prognostic value over biventricular strains and added incremental value to conventional clinical predictors for patients with DCM.
Topics: Humans; Prognosis; Cardiomyopathy, Dilated; Retrospective Studies; Magnetic Resonance Imaging, Cine; Predictive Value of Tests; Ventricular Function, Left; Stroke Volume
PubMed: 38057892
DOI: 10.1186/s12968-023-00967-4