Acute Myocardial Infarction-Like Events in Related Patients With a Desmoplakin-Associated Arrhythmogenic Cardiomyopathy
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SUBMITTER: Singh S
PROVIDER: S-EPMC8571794 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundArrhythmogenic cardiomyopathy (AC) is one of the leading causes for sudden cardiac death (SCD). Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of AC. However, the specific etiology in individual families remains largely unknown.MethodsA 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmids containing the mutation and wild type (WT) were constructed. Real-time PCR, western-blot and immunofluorescence were performed to detect the functional change due to the mutation.ResultsThe proband, a 56-year-old female, presented with recurrent palpitations and syncope. An ICD was implanted due to her family history of SCD/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant (c.832delG) in Desmoplakin (DSP) among 5 family members. The variant led to frame-shift and premature termination, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of AC. HEK293T cells transfected with mutant plasmids expressed truncated DSP mRNA and protein, upregulation of nuclear junction plakoglobin (JUP) and downregulation of ?-catenin, when compared with WT.ConclusionWe infer that the novel c.832delG variant in DSP was associated with AC in this family, likely through Wnt/?-catenin signaling pathway.
| S-EPMC7011609 | biostudies-literature
Project description:BackgroundVisfatin is an adipokine that related with the inflammation in atherosclerosis and the destabilization of atherosclerotic plaque. The aim of this study was to observe the relationship between visfatin and major adverse cardiovascular events (MACEs) in acute myocardial infarction (AMI) patients.MethodsWe enrolled a total of 238 patients (183 AMI and 55 control) who underwent coronary angiography. Patients with AMI were followed for an average of 19.3?months and 159 patients were finally included in the study.ResultsIt was observed patients with AMI had higher serum visfatin levels than controls. The total incidence of MACEs was 11.32% (18/159) in AMI patients. After calculation of the Youden index, the best cut-off value of visfatin on the curve of receiver-operating characteristic was 8.799?ng/mL for predicting the occurrence of MACEs. The occurrence of MACEs was elevated in high-visfatin group (?8.799?ng/mL) compared with low-visfatin group (?8.799?ng/mL). The time to MACEs was correlated with visfatin (HR?=?1.235, 95%CI 1.051-1.451, P?=?0.01) and high-visfatin group had an earlier time to MACEs and a shorter time of cumulative survival.ConclusionsIncreased serum visfatin levels were observed in AMI patients, and correlated with an earlier onset and higher incidence of MACEs.
| S-EPMC7275306 | biostudies-literature
Project description:Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder with variable genetic etiologies. Here we focused on understanding the precise molecular pathology of a single clinical variant in DSP, the gene encoding desmoplakin. We initially identified a novel missense desmoplakin variant (p.R451G) in a patient diagnosed with biventricular ACM. An extensive single-family ACM cohort was assembled, revealing a pattern of coinheritance for R451G desmoplakin and the ACM phenotype. An in vitro model system using patient-derived induced pluripotent stem cell lines showed depressed levels of desmoplakin in the absence of abnormal electrical propagation. Molecular dynamics simulations of desmoplakin R451G revealed no overt structural changes, but a significant loss of intramolecular interactions surrounding a putative calpain target site was observed. Protein degradation assays of recombinant desmoplakin R451G confirmed increased calpain vulnerability. In silico screening identified a subset of 3 additional ACM-linked desmoplakin missense mutations with apparent enhanced calpain susceptibility, predictions that were confirmed experimentally. Like R451G, these mutations are found in families with biventricular ACM. We conclude that augmented calpain-mediated degradation of desmoplakin represents a shared pathological mechanism for select ACM-linked missense variants. This approach for identifying variants with shared molecular pathologies may represent a powerful new strategy for understanding and treating inherited cardiomyopathies.
| S-EPMC6675562 | biostudies-literature
Project description:The case of a 49-year-old man with acute onset of heart failure is presented. The initial work-up showed a dilated cardiomyopathy with severely reduced left ventricular ejection fraction. In the differential diagnostic process, hypertensive, ischaemic, and valvular aetiologies were discarded. Subsequently, a cardiac magnetic resonance revealed global hypokinesis and inferior and anterior subepicardial fibrosis. Once differential diagnoses of subepicardial fibrosis (myocarditis, sarcoidosis, and Chagas disease) were discarded, a genetic panel was performed, resulting in a heterozygous mutation of desmoplakin (DSP) gene c.6697_6698del. A left-dominant DSP arrhythmogenic cardiomyopathy mutation was diagnosed. Structural myocardial abnormalities and ventricular arrhythmias characterize arrhythmogenic cardiomyopathy. Up to 50% of cases are associated with mutations in DSP genes (JUP, DSP, and PKP2). DSP is the fundamental component of the desmosome structure and provides structural support through intercellular adhesion. Therefore, when frequent differential diagnoses are discarded, genetic studies for dilated cardiomyopathy and DSP mutation should be considered.
| S-EPMC10567658 | biostudies-literature
Project description:BackgroundMutations in desmoplakin (DSP), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of DSP cardiomyopathy have been limited to small case series.MethodsClinical and genetic data were collected on 107 patients with pathogenic DSP mutations and 81 patients with pathogenic plakophilin 2 (PKP2) mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed.ResultsDSP and PKP2 cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with DSP (55% versus 0% for PKP2, P<0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with DSP versus 40% for PKP2 (P<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for DSP cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with DSP (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with DSP. Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with DSP and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 DSP cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias for DSP cases (P<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for PKP2 cases (P<0.001) but was poorly associated for DSP cases (P=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both DSP (80%) and PKP2 (91%) groups (P=non-significant).ConclusionsDSP cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.
| S-EPMC7286080 | biostudies-literature
Project description:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy primarily of the right ventricle characterized through fibrofatty replacement of cardiomyocytes. The genetic etiology in ARVC patients is most commonly caused by dominant inheritance and high genetic heterogeneity. Though histological examinations of ARVC affected human myocardium reveals fibrolipomatous replacement, the molecular mechanisms leading to loss of cardiomyocytes are largely unknown. We therefore analyzed the transcriptomes of 6 ARVC specimen derived from heart transplantation candidates and compared our findings to 6 non-failing donor hearts (NF) which could not be transplanted for technical reasons. In addition, we compared our findings to 7 hearts from patients with idiopathic dilated cardiomyopathy. From each heart left (LV) and right ventricular (RV) myocardial samples were analyzed by Affymetrix HG-U133 Plus 2.0 arrays, adding up to six sample groups. Unsupervised cluster analyses of the six sample groups revealed a clear separation of NF and cardiomyopathy samples. However, in contrast to the other samples, unsupervised cluster analyses revealed no distinct expression pattern in LV and RV samples from ARVC-hearts. We further identified differentially expressed transcripts using t-tests and found transcripts separating diseased and NF ventricular myocardium. Of note, in failing myocardium only about 15-16% of the genes are commonly regulated compared to NF samples. In addition both cardiomyopathies are clearly distinct on the transcriptome level. Comparison of the expression patterns between the failing RV and LV using a paired t-test revealed a lack of major differences between LV and RV gene expression in ARVC hearts. Microarrays were used to elucidate the differences between non-failing control hearts and those, suffering from arrhythmogenic right ventricular cardiomyopathy (ARVC).
2011-11-30 | E-GEOD-29819 | biostudies-arrayexpress
Project description:ImportancePatients who survive acute myocardial infarction (AMI) have a high risk of subsequent major cardiovascular events. Efforts to identify risk factors for recurrence have primarily focused on the period immediately following AMI admission.ObjectivesTo identify risk factors and develop and evaluate a risk model that predicts 1-year cardiovascular events after AMI.Design, setting, and participantsProspective cohort study. Patients with AMI (n?=?4227), aged 18 years or older, discharged alive from 53 acute-care hospitals across China from January 1, 2013, to July 17, 2014. Patients were randomly divided into samples: training (50% [2113 patients]), test (25% [1057 patients]), and validation (25% [1057 patients]). Risk factors were identified by a Cox model with Markov chain Monte Carlo simulation and further evaluated by latent class analysis. Analyses were conducted from May 1, 2017, to January 21, 2018.Main outcomes and measuresMajor cardiovascular events, including recurrent AMI, stroke, heart failure, and death, within 1 year after discharge for the index AMI hospitalization.ResultsThe mean (SD) age of the cohort was 60.8 (11.8) years and 994 of 4227 patients (23.5%) were female. Common comorbidities included hypertension (2358 patients [55.8%]), coronary heart disease (1798 patients [42.5%]), and dyslipidemia (1290 patients [30.5%]). One-year event rates were 8.1% (95% CI, 6.91%-9.24%), 9.0% (95% CI, 7.22%-10.70%), and 6.4% (95% CI, 4.89%-7.85%) for the training, test, and validation samples, respectively. Nineteen risk factors comprising 15 unique variables (age, education, prior AMI, prior ventricular tachycardia or fibrillation, hypertension, angina, prearrival medical assistance, >4 hours from onset of symptoms to admission, ejection fraction, renal dysfunction, heart rate, systolic blood pressure, white blood cell count, blood glucose, and in-hospital complications) were identified. In the training, test, and validation samples, respectively, the risk model had C statistics of 0.79 (95% CI, 0.75-0.83), 0.73 (95% CI, 0.68-0.78), and 0.77 (95% CI, 0.70-0.83) and a predictive range of 1.2% to 33.9%, 1.2% to 37.9%, and 1.3% to 34.3%. The C statistic was 0.69 (95% CI, 0.65-0.74) for the latent class model in the training data. The risk model stratified 11.3%, 81.0%, and 7.7% of patients to high-, average-, and low-risk groups, with respective probabilities of 0.32, 0.06, and 0.01 for 1-year events.Conclusions and relevanceNineteen risk factors were identified, and a model was developed and evaluated to predict risk of 1-year cardiovascular events after AMI. This may aid clinicians in identifying high-risk patients who would benefit most from intensive follow-up and aggressive risk factor reduction.
| S-EPMC6324290 | biostudies-literature
Project description:Background: Stress cardiomyopathy (SCM) is a unique form of LV dysfunction that more often occurs in women. Patients with SCM have a higher Troponin I/B-type natriuretic peptide ratio than AMI, but little is known about other circulating proteins. The goals of this study were to compare plasma proteins in SCM and AMI to learn about the pathophysiology of SCM and also to identify putative biomarkers of SCM. Methods: Blood was drawn in normal controls (n=6), women with AMI (n=12) or women with acute SCM (n=15). Two-week follow up samples were available in AMI (n=4) and SCM patients (n=11). Relative concentrations of 1310 serum proteins were measured in each of the 48 samples using the SOMAscan aptamer based assay. Women with AMI tended to be younger (57.87 ± 16.0 vs. 65.08 ± 9.11 years, p=0.12) and had a higher peak troponin I (AMI 32.03 ± 29.46 vs. SCM 2.68 ± 2.6 ng/mL, p=0.02). No differentially expressed proteins were detected (absolute log2 fold change>1; q<0.05) between AMI and SCM in the acute or recovery phase. In the normal vs. AMI comparison there was differential expression of 35 proteins. In the normal vs. SCM comparison there were 45 proteins with differential expression. Pathway analysis demonstrated activation of complement, coagulation, and inflammation in both AMI and SCM. Conclusions: The acute phase of SCM is characterized by a severe inflammatory response similar to AMI. Despite recovery of LV function in SCM at two weeks, differences in circulating proteins remain in comparison to normal controls.
2017-08-03 | GSE95368 | GEO
Project description:AbstractDesmoplakin (DSP), encoded by the DSP gene, is the main desmosome component and is abundant in the myocardial tissue. There are three DSP isoforms that assume the role of supporting structural stability through intercellular adhesion. It has been found that DSP regulates the transcription of adipogenic and fibrogenic genes, and maintains appropriate electrical conductivity by regulating gap junctions and ion channels. DSP is essential for normal myocardial development and the maintenance of its structural functions. Studies have suggested that DSP gene mutations are associated with a variety of hereditary cardiomyopathy, such as arrhythmia cardiomyopathy, dilated cardiomyopathy (DCM), left ventricular noncompaction, and is also closely associated with the Carvajal syndrome, Naxos disease, and erythro-keratodermia-cardiomyopathy syndrome with skin and heart damage. The structure and function of DSP, as well as the clinical manifestations of DSP-related cardiomyopathy were reviewed in this article.
| S-EPMC8367056 | biostudies-literature
Project description:The early and late ischemic and bleeding clinical outcomes according to baseline platelet count after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) remain unclear. Overall, 10,667 patients from the Cardiovascular Risk and identification of potential high-risk population in AMI (COREA-AMI) I and II registries were classified according to the following universal criteria on baseline platelet counts: (1) moderate to severe thrombocytopenia (platelet < 100 K/?L, n = 101), (2) mild thrombocytopenia (platelet = 100~149 K/?L, n = 631), (3) normal reference (platelet = 150~450 K/?L, n = 9832), and (4) thrombocytosis (platelet > 450 K/?L, n = 103). The primary endpoint was the occurrence of major adverse cardiovascular events (MACE). The secondary outcome was Bleeding Academic Research Consortium (BARC) 2, 3, and 5 bleeding. After adjusting for confounders, the moderate to severe thrombocytopenia (HR, 2.03; 95% CI, 1.49-2.78); p < 0.001), mild thrombocytopenia (HR, 1.15; 95% CI, 1.01-1.34; p = 0.045), and thrombocytosis groups (HR, 1.47; 95% CI, 1.07-2.03; p = 0.019) showed higher 5-year MACE rates than the normal reference. In BARC 2, 3, and 5 bleeding outcomes, the bleedings rates were higher than the normal range in the moderate to severe thrombocytopenia (HR, 2.18; 95% CI, 1.36-3.49; p = 0.001) and mild thrombocytopenia (HR, 1.41; 95% CI, 1.12-1.78; p = 0.004) groups. Patients with AMI had higher 5-year MACE rates after PCI if they had lower- or higher-than-normal platelet counts. Thrombocytopenia revealed higher early and late bleeding rates whereas thrombocytosis showed long-term bleeding trends, although these trends were not statistically significant.
| S-EPMC7589459 | biostudies-literature