A Novel Circulating MicroRNA for the Detection of Acute Myocarditis.

BACKGROUND: The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis. METHODS: To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls. RESULTS: We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level. CONCLUSIONS: After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.).

Feasibility and safety of transfemoral sheathless portico aortic valve implantation: Preliminary results in a single center experience.

BACKGROUND: Feasibility of transfemoral (TF) transcathteter aortic valve replacement (TAVR) is limited by the smallest diameter, the calcification and tortuosity of the iliofemoral access vessels. The use of the Portico system without delivery sheath results in significantly lower profile delivery system compared to standard technique. We herein report our single center experience, feasibility and safety of such an approach. METHODS: The Portico valve was implanted sheathless in 81 high-risk patients with severe aortic stenosis utilizing percutaneous femoral access. Mean minimal diameter of the ileo-femoral arterial access was 7.06 ± 1.89 mm. In most cases a multidetector computed tomography was performed before the intervention to assess the feasibility of vascular access and for aortic annulus measurements. The vascular access site was preclosed using two ProGlide suture systems. RESULTS: Device implantation was successful 98.7% of patients. Valve recapturing and repositioning as well as valve-in-valve deployment was performed in only one case (1.2%). There were no infarctions, 2 strokes (2.4%) and 2 acute kidney failure (2.4%), 1 major vascular complication1 (1.2%) 4 major bleedings (4.9%), 11 conductions disturbances and relative pace-maker implantations (14.2%). The mean gradient decreased from 42.3 ± 17 to 6.3 ± 2.78 mm Hg. Paravalvular regurgitation as assessed by TTE at discharge was absent or trivial in 19 patients, mild in 60 and moderate 1. Thirty-day mortality was 2.4%. CONCLUSIONS: Sheathless use of the Portico valve is feasible and appears to be safe, with excellent rates of complications and mortality in the short-term. Such an approach has the potential to further expand feasibility of TF TAVR to patients with severe peripheral arterial disease. Feasibility in patients with smaller femoral access and more challenging anatomy has to be proven in further studies. © 2017 Wiley Periodicals, Inc.

FIMICS: A panel of long noncoding RNAs for cardiovascular conditions.

Cardiovascular disorders such as heart failure are leading causes of mortality. Patient stratification via identification of novel biomarkers could improve management of cardiovascular diseases of complex etiologies. Long-noncoding RNAs (lncRNAs) are highly tissue-specific in nature and have emerged as important biomarkers in human diseases. In this study, we aimed to identify cardiac-enriched lncRNAs as potential biomarkers for cardiovascular conditions. Deep RNA sequencing and quantitative PCR identified differentially expressed lncRNAs between failing and non-failing hearts. An independent dataset was used to evaluate the enrichment of lncRNAs in normal hearts. We identified a panel of 2906 lncRNAs, named FIMICS, that were either cardiac-enriched or differentially expressed between failing and non-failing hearts. Expression of lncRNAs in blood samples differentiated patients with myocarditis and acute myocardial infarction. We hereby present the FIMICS panel, a readily available tool to provide insights into cardiovascular pathologies and which could be helpful for diagnosis, monitoring and prognosis purposes.

Erysipelothrix rhusiopathiae infection by geese to human transmission.

Erysipelothrix rhusiopathiae transmission to human is often occupation-related, but in most cases, a detailed case history is missing. This case report is based on an interdisciplinary approach and includes a thorough medical record. A 58-year-old laboratory technician working on geese necropsy cut open her glove at a rib fragment of a goose and subsequently noticed a slowly progressive, reddish skin alteration in the particular region of the hand. Bacteriological investigations on the geese revealed septicaemia due to E. rhusiopathiae and therefore substantiated the diagnosis of the patient. The infectious agent could not be cultured from the patient; however, antibiotic susceptibility testing was performed using the goose isolate. An entire follow-up until full recovery of the patient was conducted. Zoonotic infections possibly have a significant impact on certain occupations. This case report analyses a rare but important zoonotic infection to create awareness of this in physicians caring for human patients.

Clinical Presentation and Laboratory Findings in Men Versus Women with Myocarditis.

Objectives: Understanding sex differences in myocarditis is crucial to improve clinical care. We sought to investigate sex differences focusing on clinical presentation and laboratory parameters. Methods: From 2011 to 2018, 77 patients were diagnosed with myocarditis according to European Society of Cardiology (ESC) criteria with available clinical, laboratory, and cardiac magnetic resonance imaging data. First, we investigated sex differences of clinical and laboratory parameters in the entire cohort of 77 patients. Second, we focused on patients with acute myocarditis (n = 51) defined as recent symptom onset (≤10 days). Results: Myocarditis was present in 63 men (82%) and 14 women (18%). While men most frequently presented with chest pain (78%), a considerable amount of women presented with dyspnea as the only symptom (40%). Within the entire cohort, only creatinine kinase (CK) was higher in men versus women (364 ± 286 vs. 147 ± 148 U/L, p = 0.007), while in patients with acute myocarditis both CK and myoglobin (Mb) were higher in men versus women (CK: 327 ± 223 vs. 112 ± 65 U/L, p = 0.004 and Mb: 111 ± 126 vs. 25 ± 29 µg/L, p = 0.04). No sex differences were found for high-sensitivity troponin T, C-reactive protein, and NT-probrain natriuretic peptide. Conclusions: This is the first study reporting sex differences in clinical presentation and routine laboratory parameters in myocarditis. While clinical presentation appeared to be subtle in women with dyspnea being the only presenting symptom of myocarditis in a considerable part, men typically complained of chest pain. Similarly to observations in myocardial infarction, atypical symptoms and underdiagnosis may be a cause for under-representation of women in cohorts of myocarditis.

Myoglobin for Detection of High-Risk Patients with Acute Myocarditis.

There is an unmet need for accurate and practical screening to detect myocarditis. We sought to test the hypothesis that the extent of acute myocarditis, measured by late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR), can be estimated based on routine blood markers. A total of 44 patients were diagnosed with acute myocarditis and included in this study. There was strong correlation between myoglobin and LGE (rs = 0.73 [95% CI 0.51; 0.87], p < 0.001), while correlation was weak between LGE and TnT-hs (rs = 0.37 [95% CI 0.09; 0.61], p = 0.01). Receiver operating curve (ROC) analysis determined myoglobin ≥ 87 µg/L as cutoff to identify myocarditis (92% sensitivity, 80% specificity). The data were reproduced in an established model of coxsackievirus B3 myocarditis in mice (n = 26). These data suggest that myoglobin is an accurate marker of acute myocarditis. Graphical Abstract Receiver operating curve analysis determined myoglobin ≥ 87 µg/L as cutoff to identify myocarditis and these data were reproduced in an established model of coxsackievirus B3 myocarditis in mice: CMRI, cardiac magnetic resonance imaging; Mb, myoglobin; LGE, late gadolinium enhancement; ROC, receiver operating curve analysis.

Virome Sequencing in Patients With Myocarditis.

BACKGROUND: Polymerase chain reaction analyses of cardiac tissues have detected viral sequences in up to 67% of cases of myocarditis. However, viruses have not been implicated in giant cell myocarditis (GCM). Furthermore, efforts to detect viruses implicated in myocarditis have been unsuccessful in more accessible samples such as peripheral blood. METHODS: We used Virome Capture Sequencing for Vertbrate Viruses (VirCapSeq-VERT), a method that simultaneously screens for all known vertebrate viruses, to investigate viruses in 33 patients with myocarditis. We investigated peripheral blood mononuclear cells (n=24), plasma (n=27), endomyocardial biopsies (n=2), and cardiac tissue samples from explanted hearts (n=13). RESULTS: Nine patients (27%) had GCM and 4 patients (13%) had fulminant myocarditis. We found the following viruses in the blood of patients with myocarditis: Epstein Barr virus (n=11, 41%), human pegivirus (n=1, 4%), human endogenous retrovirus K (n=27, 100%), and anellovirus (n=15, 56%). All tissue samples from fulminant myocarditis (n=2) and GCM (n=13) contained human endogenous retrovirus K. CONCLUSIONS: No nucleic acids from viruses previously implicated in myocarditis or other human illnesses were detected in relevant amounts in cardiac tissue samples from GCM or in blood samples from other types of myocarditis. These findings do not exclude a role for viral infection in GCM but do suggest that if viruses are implicated, the mechanism is likely to be indirect rather than due to cytotoxic infection of myocardium.

Non-steroidal anti-inflammatory drug use in acute myopericarditis: 12-month clinical follow-up.

Objective: Clinical data on the effect of non-steroidal anti-inflammatory drugs (NSAIDs) in myopericarditis are limited. Since NSAIDs are standard therapy in pericarditis, we retrospectively investigated their safety in myopericarditis. Methods: In a retrospective case-control study, we identified 60 patients with myopericarditis from September 2010 to August 2017. Diagnosis was based on clinical criteria, elevated high-sensitivity troponin T and cardiac magnetic resonance imaging (CMR). All patients received standard heart failure therapy if indicated. Twenty-nine patients (62%) received NSAIDs (acetylsalicylic acid: n=7, average daily dose =1300 mg or ibuprofen: n=22, average daily dose =1500 mg) for an average duration of 4 weeks. To create two cohorts with similar baseline conditions, 15 patients were excluded. Three months after diagnosis, 29 patients were re-evaluated by CMR to measure late gadolinium enhancement (LGE). Results: Baseline characteristics of those treated with or without NSAIDs were similar. Mean age was 34 (±13) years, 6 (13%) were women. Mean left ventricular ejection fraction (LVEF) was 56% (±5). 82 % of the patients (14 of 17) treated with NSAIDs experienced a decrease in LGE at 3 months, while it was only 58 % (7 of 12) of those without NSAIDs (p=0.15). At 12-month follow-up, one of the patients treated without NSAIDs experienced polymorphic ventricular tachycardia (VT) with cardiac arrest, while one of the patients with NSAIDs experienced non-sustained VT. Conclusions: This is the first case-control study demonstrating that NSAIDs are safe in patients with myopericarditis and preserved LVEF. Our data suggest that this drug class should be tested prospectively in a large randomised clinical trial.

Systematic use of cardiac magnetic resonance imaging in MINOCA led to a five-fold increase in the detection rate of myocarditis: a retrospective study.

BACKGROUND: Systematic work-up of patients with myocardial infarction and non-obstructive coronary artery disease (MINOCA) using cardiac magnetic resonance imaging (CMR) led to a more than six-fold increase in the detection rate of myocarditis. In this study, we expanded on our prior two-year analysis by including preceding and subsequent years. METHODS: We performed a retrospective chart review of patients with angina-like symptoms and elevated high-sensitivity troponin T (TnT-hs ≥14 ng/l) but without significant coronary artery disease, from 2011 to 2017. Patients underwent CMR to test for myocarditis. From 2011 to 2015, only patients with elevated TnT-hs, no significant coronary artery disease and moderate to high clinical likelihood of suffering from myocarditis, underwent CMR. In 2016 and 2017, CMR images were obtained from all patients with MINOCA, independent of the clinical likelihood that patients were suffering from myocarditis. RESULTS: A total of 556 patients who underwent CMR (70.5% male, 57 ± 17 years, with an average left ventricular ejection fraction of 51 ± 15%) qualified for inclusion in this study’s analysis. From 2011 to 2015, 240 CMR examinations were performed, with the number increasing to 316 between 2016 and 2017. In total, myocarditis was diagnosed in 76 out of the 556 patients (13.7%). Between 2011 and 2015, the detection rate of myocarditis was 12.7 per 100,000 hospitalisations and increased 4.9-fold (p <0.0001), to 62.5 per 100,000 hospitalisations, between 2016 and 2017. CONCLUSION: A novel diagnostic algorithm led to an average 4.9-fold increase in the rate of myocarditis detection in our hospital over the two subsequent years. This highlights that myocarditis continues to be underdiagnosed when CMR is not systematically used in patients with MINOCA.  .

Real-world procedural and 30-day outcome using the Portico transcatheter aortic valve prosthesis: A large single center cohort.

BACKGROUND: Published procedural and short-term outcome of the Portico valve for Transcatheter Aortic Valve Implantation (TAVI) is limited. We report a single-center patient series assessing procedural and 30-day outcome of this device. METHODS AND RESULTS: Procedural and 30-day follow-up data were prospectively collected from a consecutive series of 73 patients (80.7±6.9years, 45% male, mean STS score: 4.8±3.9) with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI). Transfemoral access was used in 69 patients (94.5%), whereas in the remainder subclavian access was used. Concomitant interventions were performed in 30% of the patients. At 30days, all-cause mortality and the rate of neurological events were both 2.7%. The rates of non-minor bleeding and major vascular complications were 8.2% and 4.1%, respectively. Clinically significant aortic regurgitation was limited to a single case (1.4%) of moderate regurgitation at discharge, which was reduced to mild at 30days. Overall pacemaker rate after TAVI was 12% and the transprosthetic gradient was 6.9±3.2mmHg. CONCLUSIONS: TAVI using the Portico system was associated with low mortality and a low rate of neurological events at 30days and excellent hemodynamic outcome with no more than mild residual aortic regurgitation.

Cardiac Magnetic Resonance Imaging in Myocarditis Reveals Persistent Disease Activity Despite Normalization of Cardiac Enzymes and Inflammatory Parameters at 3-Month Follow-Up.

BACKGROUND: There is a major unmet need to identify high-risk patients in myocarditis. Although decreasing cardiac and inflammatory markers are commonly interpreted as resolving myocarditis, this assumption has not been confirmed as of today. We sought to evaluate whether routine laboratory parameters at diagnosis predict dynamic of late gadolinium enhancement (LGE) as persistent LGE has been shown to be a risk marker in myocarditis. METHODS AND RESULTS: Myocarditis was diagnosed based on clinical presentation, high-sensitivity troponin T, and cardiac magnetic resonance imaging, after exclusion of obstructive coronary artery disease by angiography. Cardiac magnetic resonance imaging was repeated at 3 months. LGE extent was analyzed with the software GT Volume. Change in LGE >20% was considered significant. Investigated cardiac and inflammatory markers included high-sensitivity troponin T, creatine kinase, myoglobin, N-terminal B-type natriuretic peptide, C-reactive protein, and leukocyte count. Twenty-four patients were enrolled. Absolute levels of cardiac enzymes and inflammatory markers at baseline did not predict change in LGE at 3 months. Cardiac and inflammatory markers had normalized in 21 patients (88%). LGE significantly improved in 16 patients (67%); however, it persisted to a lesser degree in 17 of them (71%) and increased in a small percentage (21%) despite normalization of cardiac enzymes. CONCLUSIONS: This is the first study reporting that cardiac enzymes and inflammatory parameters do not sufficiently reflect LGE in myocarditis. Although a majority of patients with normalizing laboratory markers experienced improved LGE, in a small percentage LGE worsened. These data suggest that cardiac magnetic resonance imaging might add value to currently existing diagnostic tools for risk assessment in myocarditis.

Mutations in PINK1 and Parkin impair ubiquitination of Mitofusins in human fibroblasts.

PINK1 and Parkin mutations cause recessive Parkinson's disease (PD). In Drosophila and SH-SY5Y cells, Parkin is recruited by PINK1 to damaged mitochondria, where it ubiquitinates Mitofusins and consequently promotes mitochondrial fission and mitophagy.Here, we investigated the impact of mutations in endogenous PINK1 and Parkin on the ubiquitination of mitochondrial fusion and fission factors and the mitochondrial network structure. Treating control fibroblasts with mitochondrial membrane potential (Δψ) inhibitors or H(2)O(2) resulted in ubiquitination of Mfn1/2 but not of OPA1 or Fis1. Ubiquitination of Mitofusins through the PINK1/Parkin pathway was observed within 1 h of treatment. Upon combined inhibition of Δψ and the ubiquitin proteasome system (UPS), no ubiquitination of Mitofusins was detected. Regarding morphological changes, we observed a trend towards increased mitochondrial branching in PD patient cells upon mitochondrial stress.For the first time in PD patient-derived cells, we demonstrate that mutations in PINK1 and Parkin impair ubiquitination of Mitofusins. In the presence of UPS inhibitors, ubiquitinated Mitofusin is deubiquitinated by the UPS but not degraded, suggesting that the UPS is involved in Mitofusin degradation.