Dapper-1 is essential for Wnt5a induced cardiomyocyte hypertrophy by regulating the Wnt/PCP pathway

AbstractThe Wnt signaling pathway was identified as crucial mediator of cardiomyocyte hypertrophy. In this study we found that activation of non-canonical Wnt signaling by Wnt5a stimulates protein synthesis and enlargement of cardiomyocyte surface area. These hypertrophic features were inhibited in Dapper-1 (Dpr1) depleted cells. On the molecular level, we observed inhibition of the non-canonical Wnt/planar-cell-polarity (PCP) pathway denoted by reduction of c-jun-n-terminal-kinase (JNK) phosphorylation. Upstream of JNK, increased protein levels of the Wnt/PCP trans-membrane receptor van-Gogh-like-2 (Vangl2) were observed along with an enrichment of Vangl2 in perinuclear located vesicles. The findings suggest that Dpr1 is essential for execution of the Wnt/PCP pathway and regulation of the Vangl2/JNK axis. Depletion of Dpr1 inhibits non-canonical Wnt signaling induced cardiomyocyte hypertrophy by blocking Wnt/PCP signaling

Multi-omics assessment of dilated cardiomyopathy using non-negative matrix factorization

Dilated cardiomyopathy (DCM), a myocardial disease, is heterogeneous and often results in heart failure and sudden cardiac death. Unavailability of cardiac tissue has hindered the comprehensive exploration of gene regulatory networks and nodal players in DCM. In this study, we carried out integrated analysis of transcriptome and methylome data using nonnegative matrix factorization from a cohort of DCM patients to uncover underlying latent factors and covarying features between whole-transcriptome and epigenome omics datasets from tissue biopsies of living patients. DNA methylation data from Infinium HM450 and mRNA Illumina sequencing of n = 33 DCM and n = 24 control probands were filtered, analyzed and used as input for matrix factorization using R NMF package. Mann-Whitney U test showed 4 out of 5 latent factors are significantly different between DCM and control probands (P<0.05). Characterization of top 10% features driving each latent factor showed a significant enrichment of biological processes known to be involved in DCM pathogenesis, including immune response (P = 3.97E-21), nucleic acid binding (P = 1.42E-18), extracellular matrix (P = 9.23E-14) and myofibrillar structure (P = 8.46E-12). Correlation network analysis revealed interaction of important sarcomeric genes like Nebulin, Tropomyosin alpha-3 and ERC-protein 2 with CpG methylation of ATPase Phospholipid Transporting 11A0, Solute Carrier Family 12 Member 7 and Leucine Rich Repeat Containing 14B, all with significant P values associated with correlation coefficients >0.7. Using matrix factorization, multiomics data derived from human tissue samples can be integrated and novel interactions can be identified. Hypothesis generating nature of such analysis could help to better understand the pathophysiology of complex traits such as DCM

Incidental finding of a giant intracardiac angioma infiltrating both ventricles in a 35-year-old woman: a case report

Background: Primary cardiac tumors are rare and often asymptomatic or present with unspecific symptoms. Benign cardiac tumors of vascular origin are especially rare, with only few existing data in the literature. Case presentation: A 35-year-old Caucasian female patient presented to our department with an asymptomatic giant intracardiac angioma infiltrating both ventricles. Evaluation of this tumor involved electrocardiography, echocardiography, cardiac magnetic resonance imaging, coronary angiography, an open myocardial biopsy, and histological examination of the resected specimen. Because our patient was asymptomatic, she was managed conservatively with regular follow-up. We discuss the treatment options available in comparison with similar cases. Conclusion: Diagnosis and therapy of benign cardiac tumors, especially of asymptomatic lesions, can be a challenge. There is no evidence available to help in the management of such patients. An extensive evaluation is needed with different imaging modalities, and case-specific decisions should be made that involve experts in cardiology, cardio-oncology, and heart surgery

Staged cardiovascular magnetic resonance for differential diagnosis of Troponin T positive patients with low likelihood for acute coronary syndrome

<p>Abstract</p> <p>Background</p> <p>Cardiac Troponin-T (cTnT) is a cardio-specific indicator of myocardial necrosis due to ischemic or non-ischemic events. Considering the multiple causes of myocardial injury and treatment consequences there is great clinical need to clarify the underlying reason for cTnT release. We sought to implement acute CMR as a non-invasive imaging method for differential diagnosis of elevated cTnT in chest-pain unit (CPU) patients with non-conclusive symptoms and ECG-changes and a low to intermediate probability for coronary artery disease (CAD).</p> <p>Results</p> <p>CPU patients (n = 29) who had positive cTnT were scanned at 1.5T with a new step-by-step CMR algorithm including cine-, perfusion-, T2-, angiography-and late gadolinium enhancement (LGE) imaging. For comparison patients also underwent echocardiography and coronary angiography if necessary. CMR was conducted successfully in all patients and detected 93% of cTnT releases of unknown cause, without adverse hemodynamic or arrhythmic events. Acute myocardial infarction was detected in 11, pulmonary embolism in 6, myocarditis in 5, renal disease and cardiomyopathy in 2, storage disorder in 1 patient. In 2 patients CMR was unable to reveal the cause of cTnT elevations. Mean CMR scan-time was 35 ± 8 min. In 4 patients, CMR led to immediate coronary angiography with correct prediction of the infarct related artery.</p> <p>Conclusions</p> <p>We implemented a novel CMR algorithm to show the clinical value and practical feasibility of acute CMR in a non-conclusive patient cohort with unclear cTnT elevation. Since this pilot study has shown the feasibility of CMR in CPU patients, further prospective studies are warranted to compare CMR with other imaging modalities.</p

Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial

Objective To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy

Effects of early myocardial reperfusion and perfusion on myocardial necrosis/dysfunction and inflammation in patients with ST-segment and non-ST-segment elevation acute coronary syndrome : results from the PLATelet inhibition and patients Outcomes (PLATO) trial

Aims Restoration of myocardial blood flow and perfusion during percutaneous coronary intervention (PCI) measured using Thrombolysis in Myocardial Infarction (TIMI) flow grade (TFG) and perfusion grade (TMPG) is associated with improved outcomes in acute coronary syndrome (ACS). Associations between TFG/TMPG and changes in biomarkers reflecting myocardial damage/dysfunction and inflammation is unknown. Methods and results Among 2606 patients included, TFG was evaluated in 2198 and TMPG in 1874 with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment ACS (NSTE-ACS). Biomarkers reflecting myocardial necrosis [troponin T (TnT)], myocardial dysfunction [N-terminal prohormone brain natriuretic peptide (NT-proBNP)], inflammation [interleukin-6 (IL-6) and C-reactive protein (CRP)], and oxidative stress/ageing/inflammation [growth differentiation factor-15 (GDF-15)] were measured at baseline, discharge, and 1- and 6-month post-randomization. Associations between TFG/TMPG and changes in biomarker levels were evaluated using the Mann–Whitney–Wilcoxon signed test. In total, 1423 (54.6%) patients had STEMI and 1183 (45.4%) NSTE-ACS. Complete reperfusion after PCI with TFG = 3 was achieved in 1110 (85.3%) with STEMI and in 793 (88.5%) with NSTE-ACS. Normal myocardial perfusion with TMPG = 3 was achieved in 475 (41.6%) with STEMI and in 396 (54.0%) with NSTE-ACS. Levels of TnT, NT-proBNP, IL-6, CRP, and GDF-15 were substantially lower at discharge in patients with complete vs. incomplete TFG and STEMI (P < 0.01). This pattern was not observed for patients with NSTE-ACS. Patients with normal vs. abnormal TMPG and NSTE-ACS had lower levels of NT-proBNP at discharge (P = 0.01). Conclusions Successful restoration of epicardial blood flow in STEMI was associated with less myocardial necrosis/dysfunction and inflammation. Attainment of normal myocardial perfusion was associated with less myocardial dysfunction in NSTE-ACS