Fibrosis in Atrial Fibrillation – Role of Reactive Species and MPO

Atrial fibrosis with enhanced turnover and deposition of matrix proteins leads to inhomogeneous atrial electrical conduction and gives rise to electrical reentry circuits resulting in atrial fibrillation. The multifactorial pathogenesis of atrial fibrosis involves resident cardiac cells as well as infiltrating leukocytes, both generating and sequestering matrix metalloproteinases (MMPs), a key enzyme family involved in fibrosis. A growing body of evidence points toward an important role of reactive oxygen species (ROS) in the release and activation of pro-MMPs and the stimulation of pro-fibrotic cascades. Myeloperoxidase (MPO), a bactericidal enzyme released from activated polymorphonuclear neutrophils (PMN) is not only associated with a variety of cardiovascular diseases, but has also been shown to be mechanistically linked to atrial fibrosis and fibrillation. MPO catalyzes the generation of reactive species like hypochlorous acid, which affect intracellular signaling cascades in various cells and advance activation of pro-MMPs and deposition of atrial collagen resulting in atrial arrhythmias. Thus, inflammatory mechanisms effectively promote atrial structural remodeling and importantly contribute to the initiation and perpetuation of atrial fibrillation

Clinical outcomes through 12 months in patients with degenerative mitral regurgitation treated with the MitraClip® device in the ACCESS-EUrope Phase I trial†

n/

RAD51C – a new human cancer susceptibility gene for sporadic squamous cell carcinoma of the head and neck (HNSCC)

INTRODUCTION: Head and neck squamous cell carcinomas (HNSSCs) are one of the leading causes of cancer-associated death worldwide. Although certain behavioral risk factors are well recognized as tumor promoting, there is very little known about the presence of predisposing germline mutations in HNSCC patients. METHODS: In this study, we analyzed 121 individuals with HNSCCs collected at our institution for germline alterations in the newly identified cancer susceptibility gene RAD51C. RESULTS: Sequencing of all exons and the adjacent introns revealed five distinct heterozygous sequence deviations in RAD51C in seven patients (5.8%). A female patient without any other risk factors carried a germline mutation that disrupted the canonical splice acceptor site of exon 5 (c.706-2A>G). CONCLUSIONS: As there are only a few publications in the literature identifying germline mutations in head and neck cancer patients, our results provide the first indication that paralogs of RAD51, recently described as mutated in breast and ovarian cancer patients, might also be candidates for genetic risk factors in sporadic squamous cell carcinomas of the head and neck

COX-2 mRNA Expression is Significantly Increased in Acid-exposed Compared to Nonexposed Squamous Epithelium in Gastroesophageal Reflux Disease

Background: Little is known about the role of cyclooxygenase (COX)-2 in gastroesophageal reflux disease (GERD) and the development of Barrett's metaplasia. The objectives of this study were to further analyze COX-2 mRNA expression in patients with GERD compared to Barrett's esophagus (BE) and Barrett's cancer (BC). Methods: Tissue samples from 110 patients with GERD (n = 43), BE (n = 20), and BC (n = 47) were obtained in routine upper GI endoscopy. Expression levels of COX-2 were measured by quantitative real-time reverse trancriptase polymerase chain reaction (RT-PCR). Also, 24-h pH monitoring was performed in all patients of the GERD study group and the DeMeester composite score was used to match COX-2 mRNA expression with the severity of acid exposure in the lower esophagus. Results: COX-2 mRNA is progressively upregulated within the metaplasia-dysplasia-adenocarcinoma (MDA) sequence (p = 0.001). COX-2 levels of the squamous epithelium in the distal esophagus from patients with GERD and a pathologic mean DeMeester score (>14.72) were significantly higher than in patients with normal DeMeester scores (p = 0.01). Conclusion: In summary our findings suggest that alterations in COX-2 mRNA expression occur independently of endoscopic or histologic signs of GERD in the acid-exposed squamous epithelium of the distal esophagus. However, this early COX-2 increase in GERD is further upregulated within the MDA sequence for yet unknown reason

A heart team’s perspective on interventional mitral valve repair: Percutaneous clip implantation as an important adjunct to a surgical mitral valve program for treatment of high-risk patients

ObjectiveSurgical mitral valve repair carries an elevated perioperative risk in the presence of severely reduced ventricular function and relevant comorbidities. We sought to assess the feasibility of catheter-based mitral valve repair using a clip-based percutaneous edge-to-edge repair system in selected patients at high surgical risk with mitral regurgitation grade 3 or worse.MethodsBetween 2002 and January 2011, 202 consecutive patients without prior mitral valve surgery (age 75 ± 9 years; 63% were male) with symptomatic functional (65%), degenerative (27%), or mixed (8%) mitral regurgitation were treated with a percutaneous clip system for approximation of the anterior and posterior mitral leaflets. Risk for mitral valve surgery was considered high in terms of a mean logistic European System for Cardiac Operative Risk Evaluation of 44% (range, 21%–54%). Preprocedural left ventricular ejection fraction was 35% or less in 36% of patients. An interdisciplinary heart team of cardiologists and cardiac surgeons discussed all patients.ResultsPercutaneous clip implantation was successful in 186 patients (92%). Patients were treated with 1 clip (n = 125; 62%), 2 clips (n = 64; 32%), or 3 or more clips (n = 7; 3%). Reduction in mitral regurgitation from pre- to postprocedure was significant (P < .0001) and remained stable within the first 12 months in the majority of patients. Thirty-day mortality was 3.5% (7/202 patients). Hospital stay was 12 ± 10 days, and median intensive care unit stay was 1 day (range, 0–45 days). Eleven patients required surgical valve repair/replacement at a median of 38 days (0–468 days) after percutaneous clip implantation.ConclusionsClip-based percutaneous mitral valve repair is a safe, low-risk, and effective therapeutic option in symptomatic patients with a high risk for surgery and does not exclude later surgical repair

Concomitant mitral regurgitation in patients with low-gradient aortic stenosis: an analysis from the German Aortic Valve Registry

Background: Patients with severe aortic stenosis (AS) frequently presented mitral regurgitation (MR), which may interfere with the standard echocardiographic measurements of mean pressure gradient (MPG), flow velocity, and aortic valve area (AVA). Aims: Herein we investigated the prevalence and severity of MR in patients with severe AS and its role on the accuracy of the standard echocardiographic parameters of AS quantification. Methods: Of all patients with severe AS undergoing transcatheter or surgical aortic valve replacement enrolled in the German Aortic Registry from 2011 to 2017, 119,641 were included in this study. The population was divided based on the values of left ventricular ejection fraction ([LVEF] > 50%, LVEF 31-50%, and LVEF <= 30%] and AVA (0.80 to <= 1.00 cm(2), 0.60 to < 0.80 cm(2), 0.40 to < 0.60 cm(2), and 0.20 to < 0.40 cm(2)). Results: Overall, 77,890 (65%) patients with mild to-moderate and 4262 (4%) with severe MR were compared with 37,489 (31%) patients without MR. Patients with mild-to-moderate and severe MR presented significantly lower mPG (Delta mPG [95%CI] - 1.694 mmHg [- 2.123 to - 1.265], p 50%: AVA 0.80 to 1.00 cm(2); LVEF 31-50%: AVA 0.60 to 0.80 cm(2)). Conclusions: In patients with severe AS, concomitant MR is common, contributes to the onset of a low-gradient AS pattern, and affects the diagnostic accuracy of flow-dependent AVA measurements. In this setting, a multimodality, AVA-centric approach should be implemented

Meta-analysis of extracorporeal membrane oxygenation in combination with intra-aortic balloon pump vs. extracorporeal membrane oxygenation only in patients with cardiogenic shock due to acute myocardial infarction

BackgroundIncidence and mortality of cardiogenic shock (CS) in patients with acute myocardial infarction (AMI) remain high despite substantial therapy improvements in acute percutaneous coronary intervention over the last decades. Unloading the left ventricle in patients with Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can be performed by using an intra-aortic balloon pumps’ (IABP) afterload reduction, which might be especially beneficial in AMI patients with CS.ObjectiveThe objective of this meta-analysis was to assess the effect of VA-ECMO + IABP vs. VA-ECMO treatment on the mortality of patients with CS due to AMI.MethodsA systematic literature search was performed using EMBASE, COCHRANE, and MEDLINE databases. Studies comparing the effect of VA-ECMO + IABP vs. VA-ECMO on mortality of patients with AMI were included. Meta-analyses were performed to analyze the effect of the chosen treatment on 30-day/in-hospital mortality.ResultsTwelve studies were identified by the literature search, including a total of 5,063 patients, 81.5% were male and the mean age was 65.9 years. One thousand one hundred and thirty-six patients received treatment with VA-ECMO in combination with IABP and 2,964 patients received VA-ECMO treatment only. The performed meta-analysis showed decreased mortality at 30-days/in-hospital after VA-ECMO + IABP compared to VA-ECMO only for patients with cardiogenic shock after AMI (OR 0.36, 95% CI 0.30–0.44, P≤0.001). Combination of VA-ECMO + IABP was associated with higher rates of weaning success (OR 0.29, 95% CI 0.16–0.53, P &lt; 0.001) without an increase of vascular access complications (OR 0.85, 95% CI 0.35–2.08, P = 0.72).ConclusionIn this meta-analysis, combination therapy of VA-ECMO + IABP was superior to VA-ECMO only therapy in patients with CS due to AMI. In the absence of randomized data, these results are hypothesis generating only

Thioredoxin-interacting protein regulates protein disulfide isomerases and endoplasmic reticulum stress

The endoplasmic reticulum (ER) is responsible for protein folding, modification, and trafficking. Accumulation of unfolded or misfolded proteins represents the condition of ER stress and triggers the unfolded protein response (UPR), a key mechanism linking supply of excess nutrients to insulin resistance and type 2 diabetes in obesity. The ER harbors proteins that participate in protein folding including protein disulfide isomerases (PDIs). Changes in PDI activity are associated with protein misfolding and ER stress. Here, we show that thioredoxin-interacting protein (Txnip), a member of the arrestin protein superfamily and one of the most strongly induced proteins in diabetic patients, regulates PDI activity and UPR signaling. We found that Txnip binds to PDIs and increases their enzymatic activity. Genetic deletion of Txnip in cells and mice led to increased protein ubiquitination and splicing of the UPR regulated transcription factor X-box-binding protein 1 (Xbp1s) at baseline as well as under ER stress. Our results reveal Txnip as a novel direct regulator of PDI activity and a feedback mechanism of UPR signaling to decrease ER stress