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1.
Familial Dilated Cardiomyopathy and Sudden Cardiac Arrest: New Association with a SCN5A Mutation.
Rico, Y, Ramis, MF, Massot, M, Torres-Juan, L, Pons, J, Fortuny, E, Ripoll-Vera, T, González, R, Peral, V, Rossello, X, et al
Genes. 2021;(12)
Abstract
Dilated cardiomyopathy (DCM) has significant morbidity and mortality. Familial transmission is reported in 20-35% of cases, highlighting the role of genetics in this disorder. We present an interesting family in which the index case is a 64-year-old woman who survived a sudden cardiac arrest. She presented left ventricular dilatation and dysfunction, which indicated the presence of DCM, as well as a history of DCM and sudden arrest in her family (mother and sister). Genetic testing identified a heterozygous mutation c.74A > G missense change that causes an amino acid, p.Glu25Gly, change in the N-terminal domain of the SCN5A protein. After performing an exhaustive family medical history, we found that this previously not described mutation segregated within the family. All relatives with the DCM phenotype were carriers, whereas none of the noncarriers showed signs of heart disease, so this mutation is the most likely cause of the disease. This is the first time that a variant in the N-terminal domain of SCN5A has been associated with DCM.
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Risk Stratification in Patients With Nonisquemic Dilated Cardiomyopathy. The Role of Genetic Testing.
Peña-Peña, ML, Monserrat, L
Revista espanola de cardiologia (English ed.). 2019;(4):333-340
Abstract
Dilated cardiomyopathy is inherited in nearly 50% of cases. More than 90 genes have been associated with this disease, which is one of the main causes of heart transplant and has been associated with an increased risk of sudden cardiac death. Risk stratification in these patients continues to be challenging. The identification of the specific etiology of the disease is very useful for the early detection of mutation carriers. Genetic study often provides prognostic information and can determine the therapeutic approach. Wide phenotypic variability is observed depending on the mutated gene, the type of mutation, and the presence of additional genetic and environmental factors.
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A novel DMD splicing mutation found in a family responsible for X-linked dilated cardiomyopathy with hyper-CKemia.
Tang, J, Song, X, Ji, G, Wu, H, Sun, S, Lu, S, Li, Y, Zhang, C, Zhang, H
Medicine. 2018;(24):e11074
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Abstract
This study was aimed to detect a new mutation responsible for X-linked dilated cardiomyopathy with hyper-CKemia.We studied a proband who presented with cardiac symptoms with hyper-CKemia, but no clinical skeletal involvement in physical examination, laboratory tests, electromyography, echocardiography, and magnetic resonance imaging (MRI) of cardiac muscles. Muscle biopsy for histopathology and immunohistochemistry for accessing sarcolemma changes. The next-generation sequencing and bioinformatics analysis were performed on the patient and Sanger sequencing was confirmed on the other 6 unaffected families.The clinic investigations illustrated a dilated cardiomyopathy. Histopathology and immunohistochemistry showed dystrophic changes and an obvious reduction of dystrophin-N and δ-sarcoglycan, respectively. One hemizygous splicing pathogenic mutation c.31 + 1G > C of exon 1 in the DMD gene (chrX33229398, NM_00 4006) was finally identified in the patient and his nephew, but it was carried in his mother and sister.A novel small mutation was identified at the first exon-intron boundary splicing site by next-generation sequencing and bioinformatics analysis.
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Network Analysis of Se-and Zn-related Proteins in the Serum Proteomics Expression Profile of the Endemic Dilated Cardiomyopathy Keshan Disease.
Wang, S, Lv, Y, Wang, Y, Du, P, Tan, W, Lammi, MJ, Guo, X
Biological trace element research. 2018;(1):40-48
Abstract
Keshan disease (KD) is an endemic cardiomyopathy with high mortality. Selenium (Se) and zinc (Zn) deficiencies are closely related to KD. The molecular mechanism of KD pathogenesis is still unclear. There are only few studies on the interaction of trace elements and proteins associated with the pathogenesis of KD. In this study, isobaric tags for relative and absolute quantitation (iTRAQ)-coupled two-dimensional liquid chromatography tandem mass spectrometry (2DLC-MS/MS) technique analysis was used to analyze the differential expression of proteins from serum samples. Comparative Toxicogenomics Database (CTD) was used to screen Se- and Zn-associated proteins. Then, pathway and network analyses of Se- and Zn-associated proteins were constituted by Cytoscape ClueGO and GeneMANIA plugins. One hundred and five differentially expressed proteins were obtained by 2DLC-MS/MS, among them 19 Se- and 3 Zn-associated proteins. Fifty-two pathways were identified from ClueGO and 1 network from GeneMANIA analyses. The results showed that Se-associated proteins STAT3 and MAPK1 and Zn-associated proteins HIF1A and PARP1, the proteins involved in HIF-1 signaling pathway and apoptosis pathway, may play significant roles in the pathogenesis of KD. The approach of this study would be also beneficial for further dissecting molecular mechanism of other trace element-associated disease.
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5.
Genetics of Dilated Cardiomyopathy.
Fu, Y, Eisen, HJ
Current cardiology reports. 2018;(11):121
Abstract
PURPOSE OF REVIEW Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and systolic function and is the most common among all cardiomyopathies. Familial DCM makes up a significant portion of cases, and approximately 40 genes are identified as involved in the pathogenesis of heart failure, each affecting a specific part of cellular mechanisms. The purpose of this review is to summarize recent findings and the current understanding of the most common gene mutations identified associated with DCM. RECENT FINDINGS Next-generation sequencing is a comprehensive gene analysis technique used to discover more mutation variants and also to learn about the impact of mutations in relationship to clinical presentations. A variety of techniques are utilized to study different gene mutations, such as genotype-phenotype association analysis or whole-exome sequencing, to understand the natural history of diseases. For certain genetic abnormalities, information is helpful in developing potential therapeutic treatment targeting mutations. More treatment options are hopeful with the understanding of specific genetic mutations and their pathogenic mechanism. It also suggests the importance of genetic assessment and counseling for family members of an affected patient, in order to provide potential early diagnosis and better clinical management of DCM.
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Interventions for preventing and treating cardiac complications in Duchenne and Becker muscular dystrophy and X-linked dilated cardiomyopathy.
Bourke, JP, Bueser, T, Quinlivan, R
The Cochrane database of systematic reviews. 2018;(10):CD009068
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Abstract
BACKGROUND The dystrophinopathies include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XLDCM). In recent years, co-ordinated multidisciplinary management for these diseases has improved the quality of care, with early corticosteroid use prolonging independent ambulation, and the routine use of non-invasive ventilation signficantly increasing survival. The next target to improve outcomes is optimising treatments to delay the onset or slow the progression of cardiac involvement and so prolong survival further. OBJECTIVES To assess the effects of interventions for preventing or treating cardiac involvement in DMD, BMD, and XLDCM, using measures of change in cardiac function over six months. SEARCH METHODS On 16 October 2017 we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE and Embase, and on 12 December 2017, we searched two clinical trials registries. We also searched conference proceedings and bibliographies. SELECTION CRITERIA We considered only randomised controlled trials (RCTs), quasi-RCTs and randomised cross-over trials for inclusion. In the Discussion, we reviewed open studies, longitudinal observational studies and individual case reports but only discussed studies that adequately described the diagnosis, intervention, pretreatment, and post-treatment states and in which follow-up lasted for at least six months. DATA COLLECTION AND ANALYSIS Two authors independently reviewed the titles and abstracts identified from the search and performed data extraction. All three authors assessed risk of bias independently, compared results, and decided which trials met the inclusion criteria. They assessed the certainty of evidence using GRADE criteria. MAIN RESULTS We included five studies (N = 205) in the review; four studies included participants with DMD only, and one study included participants with DMD or BMD. All studied different interventions, and meta-analysis was not possible. We found no studies for XLDCM. None of the trials reported cardiac function as improved or stable cardiac versus deteriorated.The randomised first part of a two-part study of perindopril (N = 28) versus placebo (N = 27) in boys with DMD with normal heart function at baseline showed no difference in the number of participants with a left ventricular ejection fraction (LVEF%) of less than 45% after three years of therapy (n = 1 in each group; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.07 to 15.77). This result is uncertain because of study limitations, indirectness and imprecision. In a non-randomised follow-up study, after 10 years, more participants who had received placebo from the beginning had reduced LVEF% (less than 45%). Adverse event rates were similar between the placebo and treatment groups (low-certainty evidence).A study comparing treatment with lisinopril versus losartan in 23 boys newly diagnosed with Duchenne cardiomyopathy showed that after 12 months, both were equally effective in preserving or improving LVEF% (lisinopril 54.6% (standard deviation (SD) 5.19), losartan 55.2% (SD 7.19); mean difference (MD) -0.60% CI -6.67 to 5.47: N = 16). The certainty of evidence was very low because of very serious imprecision and study limitations (risk of bias). Two participants in the losartan group were withdrawn due to adverse events: one participant developed an allergic reaction, and a second exceeded the safety standard with a fall in ejection fraction greater than 10%. Authors reported no other adverse events related to the medication (N = 22; very low-certainty evidence).A study comparing idebenone versus placebo in 21 boys with DMD showed little or no difference in mean change in cardiac function between the two groups from baseline to 12 months; for fractional shortening the mean change was 1.4% (SD 4.1) in the idebenone group and 1.6% (SD 2.6) in the placebo group (MD -0.20%, 95% CI -3.07 to 2.67, N = 21), and for ejection fraction the mean change was -1.9% (SD 9.8) in the idebenone group and 0.4% (SD 5.5) in the placebo group (MD -2.30%, 95% CI -9.18 to 4.58, N = 21). The certainty of evidence was very low because of study limitations and very serious imprecision. Reported adverse events were similar between the treatment and placebo groups (low-certainty evidence).A multicentre controlled study added eplerenone or placebo to 42 patients with DMD with early cardiomyopathy but preserved left ventricular function already established on ACEI or ARB therapy. Results showed that eplerenone slowed the rate of decline of magnetic resonance (MR)-assessed left ventricular circumferential strain at 12 months (eplerenone group median 1.0%, interquartile range (IQR) 0.3 to -2.2; placebo group median 2.2%, IQR 1.3 to -3.1%; P = 0.020). The median decline in LVEF over the same period was also less in the eplerenone group (-1.8%, IQR -2.9 to 6.0) than in the placebo group (-3.7%, IQR -10.8 to 1.0; P = 0.032). We downgraded the certainty of evidence to very low for study limitations and serious imprecision. Serious adverse events were reported in two patients given placebo but none in the treatment group (very low-certainty evidence).A randomised placebo-controlled study of subcutaneous growth hormone in 16 participants with DMD or BMD showed an increase in left ventricular mass after three months' treatment but no significant improvement in cardiac function. The evidence was of very low certainty due to imprecision, indirectness, and study limitations. There were no clinically significant adverse events (very low-certainty evidence).Some studies were at risk of bias, and all were small. Therefore, although there is some evidence from non-randomised data to support the prophylactic use of perindopril for cardioprotection ahead of detectable cardiomyopathy, and for lisinopril or losartan plus eplerenone once cardiomyopathy is detectable, this must be considered of very low certainty. Findings from non-randomised studies, some of which have been long term, have led to the use of these drugs in daily clinical practice. AUTHORS' CONCLUSIONS Based on the available evidence from RCTs, early treatment with ACE inhibitors or ARBs may be comparably beneficial for people with a dystrophinopathy; however, the certainty of evidence is very low. Very low-certainty evidence indicates that adding eplerenone might give additional benefit when early cardiomyopathy is detected. No clinically meaningful effect was seen for growth hormone or idebenone, although the certainty of the evidence is also very low.
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Whole exome sequencing identifies a KCNJ12 mutation as a cause of familial dilated cardiomyopathy.
Yuan, HX, Yan, K, Hou, DY, Zhang, ZY, Wang, H, Wang, X, Zhang, J, Xu, XR, Liang, YH, Zhao, WS, et al
Medicine. 2017;(33):e7727
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Abstract
Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation, and is associated with systolic dysfunction and increased action potential duration. Approximately 50% of DCM cases are caused by inherited gene mutations with genetic and phenotypic heterogeneity. Next generation sequencing may be useful in screening unknown mutations in such cases.A family was identified with DCM, in which the affected family members developed heart failure, arrhythmia, and sudden death. Probands and 4 affected family members underwent whole exome sequencing (WES), bioinformatics methods, and gene annotation to identify potentially causative variants. The Sanger sequencing method was used to verify the candidate mutation.WES yielded 2,238,831 variations. KCNJ12 (p.Glu334del) was identified as a candidate mutation, and the heterozygous mutation was verified by Sanger sequencing.Our study emphasizes the application of WES in identifying causative mutations in DCM. This report is the first to describe the KCNJ12 gene as a cause of DCM in patients.
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Natural genetic variation of the cardiac transcriptome in non-diseased donors and patients with dilated cardiomyopathy.
Heinig, M, Adriaens, ME, Schafer, S, van Deutekom, HWM, Lodder, EM, Ware, JS, Schneider, V, Felkin, LE, Creemers, EE, Meder, B, et al
Genome biology. 2017;(1):170
Abstract
BACKGROUND Genetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases. RESULTS Here we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome-wide association signals in two independent cohorts. CONCLUSIONS RNA transcription, splicing, and allele-specific expression are each important determinants of the dilated cardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics.
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QTc prolongation and torsades de pointes due to a coadministration of fluoxetine and amiodarone in a patient with implantable cardioverter-defibrillator: Case report and review of the literature.
Wei, A, Peng, J, Gu, Z, Li, J
Medicine. 2017;(49):e9071
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Abstract
RATIONALE Drug-induced prolongation of the corrected QT interval (QTc) may lead to serious and potentially life-threatening ventricular tachyarrhythmia, such as torsades de pointes (Tdp), which is worthy of clinical attention. Here, we report 1 case of Tdp after a coadministration of fluoxetine and amiodarone. PATIENT CONCERNS A 62-year-old Chinese male who placed with the implanted cardioverter-defibrillator (ICD) appeared the QTc prolongation and Tdp after the concurrent administration of fluoxetine and amiodarone. DIAGNOSES Torsades de pointes (Tdp). INTERVENTIONS The patient was treated with magnesium and potassium immediately. Her ICD-brady pacing mode was reprogrammed to 90 bpm. Meanwhile, both of fluoxetine and amiodarone were discontinued. OUTCOMES The further episodes of Tdp were prevented. After a few days, the QTc gradually decreased without clinically significant arrhythmias. LESSONS The present case demonstrates that a potential drug-drug interaction (DDI) may lead to a life-threatening drug adverse reaction (ADR) especially in special subjects. Therefore, clinicians should closely monitor the electrocardiogram (ECG) when QTc-prolonging agents are given to patients with cardiac abnormalities, and avoid combining 2 QTc-prolonging drugs.
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The Role of Omega-3 Polyunsaturated Fatty Acids in Heart Failure: A Meta-Analysis of Randomised Controlled Trials.
Wang, C, Xiong, B, Huang, J
Nutrients. 2016;(1)
Abstract
Many new clinical trials about the effect of omega-3 polyunsaturated fatty acids (PUFAs) in heart failure (HF) patients have shown inconsistent results. Therefore, a meta-analysis of randomised controlled trials (RCTs) was performed to determine the benefits of omega-3 PUFAs in HF patients. Articles were obtained from PubMed, EMBASE, and the Cochrane Library. RCTs comparing omega-3 PUFAs with placebo for HF were included. Two reviewers independently extracted the data from the selected publications. The I² statistic was used to assess heterogeneity. The pooled mean difference and associated 95% confidence intervals were calculated, and a fixed or random-effects model was used for the meta-analysis. A total of nine RCTs involving 800 patients were eligible for inclusion. Compared with patients taking placebo, HF patients who received omega-3 PUFAs experienced decreased brain natriuretic peptide levels and serum norepinephrine levels. Although the left ventricular ejection fraction (LVEF) and clinical outcomes (Tei index, peak oxygen consumption) did not improve, subgroup analysis showed that the LVEF increased in dilated cardiomyopathy (DCM) patients. Overall, omega-3 PUFA supplements might be beneficial in HF patients, especially in DCM patients, but further studies are needed to confirm these benefits.