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Annals of Nutrition & Metabolism 2022Dilated cardiomyopathy (DCM) is the most common form of heart muscle disease characterized by progressive dilatation and ventricular dysfunction. Metabolomics is an... (Review)
Review
BACKGROUND
Dilated cardiomyopathy (DCM) is the most common form of heart muscle disease characterized by progressive dilatation and ventricular dysfunction. Metabolomics is an emerging and powerful discipline that provides a global information on the phenotype of mammalian systems via the study of endogenous and exogenous metabolites in cells, tissues, and biofluids. These studies aid in the identification of biomarkers to prevent diseases in later life or help to early detect onset of diseases as well as aiding in the elucidation of disease mechanisms.
SUMMARY
Metabolomics provides a unique opportunity to discover novel biomarkers for DCM. This review demonstrates evidence of metabolite-based biomarkers useful for predicting, diagnosing, and monitoring therapeutic interventions of DCM. Key metabolites identified as potential biomarkers for diagnosing DCM include acylcarnitines, succinic acid, malate, methylhistidine, aspartate, methionine, and phenylalanine. In terms of differentiating DCM from ischemic cardiomyopathy, potential biomarkers including 1-pyrroline-2-carboxylate, norvaline, lysophosphatidylinositol (16:0/0:0), phosphatidylglycerol, fatty acid esters of hydroxy fatty acid, and phosphatidylcholine were identified. Acylcarnitines, isoleucine and linoleic acid, and tryptophan were the main biomarkers to monitor treatment response to DCM. Mapping metabolites to metabolic pathways revealed dysregulation of branch-chain amino acid, glycolysis, tricarboxylic acid cycle, and triacylglycerol and pentose phosphate metabolism, which have the therapeutic potential for DCM. This review shows several limitations including the use of small sample sizes, lack of interpretation of age and sex differences in most studies, and the fact that studies have so far been limited to case-control study designs.
KEY MESSAGES
Metabolites have close proximity to disease phenotype. With recent advances in metabolomics field, potential biomarkers for DCM have been identified based on studies using different biological and metabolomics technologies. However, multicenter studies with larger populations that will lead to validation of these identified biomarkers to enable their clinical translation and utilization are still needed.
Topics: Animals; Biomarkers; Cardiomyopathy, Dilated; Case-Control Studies; Female; Humans; Linoleic Acid; Male; Mammals; Metabolomics
PubMed: 35472668
DOI: 10.1159/000524722 -
JACC. Clinical Electrophysiology Jul 2023
Topics: Humans; Cardiomyopathy, Dilated; Prognosis; Arrhythmias, Cardiac
PubMed: 37438046
DOI: 10.1016/j.jacep.2023.01.005 -
Science Translational Medicine Jul 2022Dilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well as thinning and enlargement of left ventricular chambers. These characteristics...
Dilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well as thinning and enlargement of left ventricular chambers. These characteristics eventually lead to heart failure. Current standards of care do not target the underlying molecular mechanisms associated with genetic forms of heart failure, driving a need to develop novel therapeutics for DCM. To identify candidate therapeutics, we developed an in vitro DCM model using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) deficient in B-cell lymphoma 2 (BCL2)-associated athanogene 3 (BAG3). With these BAG3-deficient iPSC-CMs, we identified cardioprotective drugs using a phenotypic screen and deep learning. From a library of 5500 bioactive compounds and siRNA validation, we found that inhibiting histone deacetylase 6 (HDAC6) was cardioprotective at the sarcomere level. We translated this finding to a BAG3 cardiomyocyte-knockout (BAG3) mouse model of DCM, showing that inhibiting HDAC6 with two isoform-selective inhibitors (tubastatin A and a novel inhibitor TYA-018) protected heart function. In BAG3 and BAG3 mice, HDAC6 inhibitors improved left ventricular ejection fraction and reduced left ventricular diameter at diastole and systole. In BAG3 mice, TYA-018 protected against sarcomere damage and reduced expression. Based on integrated transcriptomics and proteomics and mitochondrial function analysis, TYA-018 also enhanced energetics in these mice by increasing expression of targets associated with fatty acid metabolism, protein metabolism, and oxidative phosphorylation. Our results demonstrate the power of combining iPSC-CMs with phenotypic screening and deep learning to accelerate drug discovery, and they support developing novel therapies that address underlying mechanisms associated with heart disease.
Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis Regulatory Proteins; Cardiomyopathy, Dilated; Deep Learning; Disease Models, Animal; Heart Failure; Histone Deacetylase Inhibitors; Mice; Myocytes, Cardiac; Stroke Volume; Ventricular Function, Left
PubMed: 35857625
DOI: 10.1126/scitranslmed.abl5654 -
BMC Endocrine Disorders Jun 2021Thyrotoxicosis is the state of thyroid hormone excess. But, in sub-Saharan Africa (SSA), specifically Northern Ethiopia, scientific evidence about thyrotoxicosis and its...
BACKGROUND
Thyrotoxicosis is the state of thyroid hormone excess. But, in sub-Saharan Africa (SSA), specifically Northern Ethiopia, scientific evidence about thyrotoxicosis and its cardiac complications like dilated cardiomyopathy is limited. Therefore, this study aimed to explore the thyrotoxicosis presentation and management and identify factors associated with dilated cardiomyopathy in a tertiary hospital in Northern Ethiopia.
METHODS
An institution-based cross-sectional study was conducted in Ayder Comprehensive Specialized Hospital from 2017 to 2018. Data from 200 thyrotoxicosis cases were collected using a structured questionnaire. After describing variables, logistic regression was conducted to identify independent predictors of dilated cardiomyopathy. Statistical significance was declared at p < 0.05.
RESULTS
Mean age at presentation of thyrotoxicosis was 45 years and females accounted for 89 % of the cases. The most frequent etiology was multinodular toxic goiter (51.5 %). As well, the most common symptoms and signs were palpitation and goiter respectively. Thyroid storm occurred in 6 % of the cases. Out of 89 patients subjected to echocardiography, 35 (39.3 %) of them had dilated cardiomyopathy. And, the odds of dilated cardiomyopathy were higher in patients who had atrial fibrillation (AOR = 15.95, 95 % CI:5.89-38.16, p = 0.001) and tachycardia (AOR = 2.73, 95 % CI:1.04-7.15, p = 0.040). All patients took propylthiouracil and 13.0 % of them experienced its side effects. Concerning β-blockers, propranolol was the most commonly (78.5 % of the cases) used drug followed by atenolol (15.0 %). Six patients underwent surgery.
CONCLUSIONS
In developing countries like Ethiopia, patients with thyrotoxicosis have no access to methimazole which is the first-line anti-thyroid drug. Besides, they greatly suffer from dilated cardiomyopathy (due to late presentation) and side effects of propylthiouracil. Therefore, we recommend that patients should get adequate health information about thyrotoxicosis and anti-thyroid drugs including their side effects. Additionally, hospitals and other concerned bodies should also avail of TSH tests and methimazole at an affordable cost. Furthermore, community awareness about iodized salt and iodine-rich foods should be enhanced.
Topics: Adolescent; Adult; Antithyroid Agents; Cardiomyopathy, Dilated; Cross-Sectional Studies; Developing Countries; Ethiopia; Female; Goiter, Nodular; Humans; Iodine; Male; Methimazole; Middle Aged; Sodium Chloride, Dietary; Thyrotoxicosis; Young Adult
PubMed: 34182968
DOI: 10.1186/s12902-021-00796-5 -
Immunobiology Nov 2021Dilated cardiomyopathy (DCM) is a condition involving dilation of cardiac chambers, which results in contraction impairment. Besides invasive and non-invasive diagnostic... (Review)
Review
BACKGROUND
Dilated cardiomyopathy (DCM) is a condition involving dilation of cardiac chambers, which results in contraction impairment. Besides invasive and non-invasive diagnostic procedures, cardiac biomarkers are of great importance in both diagnosis and prognosis of the disease. These biomarkers are categorized into three groups based on their site; cardiomyocyte biomarkers, microenvironmental biomarkers and macroenvironmental biomarkers.
AIMS
In this review, an overview of characteristics, epidemiology, etiology and clinical manifestations of DCM is provided. In addition, the most important biomarkers, of all three categories, and their diagnostic and prognostic values are discussed.
CONCLUSION
Considering the association of DCM with conditions such as infections and autoimmunity, which are prevalent among the population, introducing efficient diagnostic tools is of high value for the early detection of DCM to prevent its severe complications. The three discussed classes of biomarkers are potential candidates for the detection of DCM. However, further studies are necessary in this regard.
Topics: Animals; Biomarkers; Cardiomyopathy, Dilated; Cellular Microenvironment; Disease Management; Disease Susceptibility; Genetic Predisposition to Disease; Heart Function Tests; Humans; Inflammation Mediators; Myocytes, Cardiac; Prognosis
PubMed: 34784575
DOI: 10.1016/j.imbio.2021.152153 -
Current Heart Failure Reports Oct 2020This review aims to give an update on recent findings related to the cardiac splicing factor RNA-binding motif protein 20 (RBM20) and RBM20 cardiomyopathy, a form of... (Review)
Review
PURPOSE OF REVIEW
This review aims to give an update on recent findings related to the cardiac splicing factor RNA-binding motif protein 20 (RBM20) and RBM20 cardiomyopathy, a form of dilated cardiomyopathy caused by mutations in RBM20.
RECENT FINDINGS
While most research on RBM20 splicing targets has focused on titin (TTN), multiple studies over the last years have shown that other splicing targets of RBM20 including Ca/calmodulin-dependent kinase IIδ (CAMK2D) might be critically involved in the development of RBM20 cardiomyopathy. In this regard, loss of RBM20 causes an abnormal intracellular calcium handling, which may relate to the arrhythmogenic presentation of RBM20 cardiomyopathy. In addition, RBM20 presents clinically in a highly gender-specific manner, with male patients suffering from an earlier disease onset and a more severe disease progression. Further research on RBM20, and treatment of RBM20 cardiomyopathy, will need to consider both the multitude and relative contribution of the different splicing targets and related pathways, as well as gender differences.
Topics: Cardiomyopathy, Dilated; DNA; DNA Mutational Analysis; Humans; Mutation; Myocytes, Cardiac; RNA-Binding Proteins
PubMed: 32789749
DOI: 10.1007/s11897-020-00475-x -
JACC. Cardiovascular Imaging Apr 2022The aim of this study is to examine the prognostic value of T1 mapping and the extracellular volume (ECV) fraction in patients with dilated cardiomyopathy (DCM).
OBJECTIVES
The aim of this study is to examine the prognostic value of T1 mapping and the extracellular volume (ECV) fraction in patients with dilated cardiomyopathy (DCM).
BACKGROUND
Patients with DCM with functional left ventricular remodeling have poorer prognoses. Noninvasive assessment of myocardial fibrosis using T1 mapping and the ECV fraction may improve risk stratification of patients with DCM; however, this has not yet been systematically evaluated.
METHODS
A total of 659 consecutive patients with DCM (498 men; 45 ± 15 years) who underwent cardiac magnetic resonance with T1 mapping and late gadolinium enhancement (LGE) imaging with a 1.5-T magnetic resonance scanner were enrolled in this study. Primary endpoints were cardiac-related death and heart transplantation. Secondary endpoints were hospitalization for heart failure, ventricular arrhythmias, and implantable cardioverter-defibrillator or cardiac resynchronization therapy implantation. Survival estimates were calculated by Kaplan-Meier curves with the log-rank test.
RESULTS
During a mean follow-up of 66.3 ± 20.9 months, 122 and 205 patients with DCM reached the primary and secondary endpoints, respectively. The presence of LGE had an association with both of the primary and secondary endpoints observed in the patients with DCM (both P < 0.001). The maximum native T1 (HR: 1.04; 95% CI: 1.02-1.09) and maximum ECV fraction (HR: 1.14; 95% CI: 1.08-1.21) had associations with the primary endpoints in the patients with positive LGE (both P < 0.001), whereas the mean native T1 (HR: 1.13; 95% CI: 1.10-1.36) and mean ECV fraction (HR: 1.32; 95% CI: 1.12-1.53) had the best associations in the patients with negative LGE (all P < 0.001).
CONCLUSIONS
T1 mapping and the ECV fraction had prognostic value in patients with DCM and were particularly important in patients with DCM without LGE. Using a combination of T1 mapping, ECV fraction, and LGE provided optimal risk stratification for patients with DCM.
Topics: Cardiomyopathy, Dilated; Contrast Media; Gadolinium; Humans; Magnetic Resonance Imaging, Cine; Male; Myocardium; Predictive Value of Tests; Prognosis; Stroke Volume
PubMed: 34538631
DOI: 10.1016/j.jcmg.2021.07.023 -
European Journal of Heart Failure Jul 2022
Topics: Cardiomyopathy, Dilated; Heart Failure; Humans; Stroke Volume
PubMed: 35717623
DOI: 10.1002/ejhf.2586 -
Current Heart Failure Reports Oct 2022Myocarditis is a disease caused by inflammation of the heart that can progress to dilated cardiomyopathy, heart failure, and eventually death in many patients. Several... (Review)
Review
PURPOSE OF REVIEW
Myocarditis is a disease caused by inflammation of the heart that can progress to dilated cardiomyopathy, heart failure, and eventually death in many patients. Several etiologies are implicated in the development of myocarditis including autoimmune, drug-induced, infectious, and others. All causes lead to inflammation which causes damage to the myocardium followed by remodeling and fibrosis. This review aims to summarize recent findings in biomarkers for myocarditis and highlight the most promising candidates.
RECENT FINDINGS
Current methods of diagnosing myocarditis, including imaging and endomyocardial biopsy, are invasive, expensive, and often not done early enough to affect progression. Research is being done to find biomarkers of myocarditis that are cost-effective, accurate, and prognostically informative. These biomarkers would allow for earlier screening for myocarditis, as well as earlier treatment, and a better understanding of the disease course for specific patients. Early diagnosis of myocarditis with biomarkers may allow for prompt treatment to improve outcomes in patients.
Topics: Biomarkers; Cardiomyopathy, Dilated; Heart Failure; Humans; Inflammation; Myocarditis; Myocardium
PubMed: 35913661
DOI: 10.1007/s11897-022-00569-8 -
Cells Oct 2021Ventricular arrhythmias contribute significantly to morbidity and mortality in patients with heart failure (HF). Pathomechanisms underlying arrhythmogenicity in patients... (Review)
Review
Ventricular arrhythmias contribute significantly to morbidity and mortality in patients with heart failure (HF). Pathomechanisms underlying arrhythmogenicity in patients with structural heart disease and impaired cardiac function include myocardial fibrosis and the remodeling of ion channels, affecting electrophysiologic properties of ventricular cardiomyocytes. The dysregulation of ion channel expression has been associated with cardiomyopathy and with the development of arrhythmias. However, the underlying molecular signaling pathways are increasingly recognized. This review summarizes clinical and cellular electrophysiologic characteristics observed in dilated cardiomyopathy (DCM) with ionic and structural alterations at the ventricular level. Furthermore, potential translational strategies and therapeutic options are highlighted.
Topics: Animals; Arrhythmias, Cardiac; Cardiomyopathy, Dilated; Electrophysiological Phenomena; Epigenesis, Genetic; Humans; Translational Research, Biomedical; Ventricular Remodeling
PubMed: 34685747
DOI: 10.3390/cells10102767