Single-center five-year outcomes after interventional edge-to-edge repair of the mitral valve

Background: The MitraClip procedure was established as a therapeutic alternative to mitral valve surgery for symptomatic patients with severe mitral regurgitation (MR) at prohibitive surgical risk. In this study, the aim was to evaluate 5-year outcomes after MitraClip.Methods: Consecutive patients undergoing the MitraClip system were prospectively included. All patients underwent clinical follow-up and transthoracic echocardiography.Results: Two hundred sixty-five patients (age: 81.4 ± 8.1 years, 46.7% female, logistic EuroSCORE: 19.7 ± 16.7%) with symptomatic MR (60.5% secondary MR [sMR]). Although high procedural success of 91.3% was found, patients with primary MR (pMR) had a higher rate of procedural failure (sMR: 3.1%, pMR: 8.6%; p = 0.04). Five years after the MitraClip procedure, the majority of patients presented with reduced symptoms and improved functional capacity (functional NYHA class: p = 0.0001; 6 minutes walking test: p = 0.04). Sustained MR reduction (≤ grade 2) was found in 74% of patients, and right ventricular (RV) function was significantly increased (p = 0.03). Systolic pulmonary artery pressure (sPAP) was significantly reduced during follow-up only in sMR patients (p = 0.05, p = 0.3). Despite a pronounced clinical and echocardiographical amelioration and low interventional failure, 5-year mortality was significantly higher in patients with sMR (p = 0.05). The baseline level of creatinine (HR: 0.695), sPAP (HR: 0.96) and mean mitral valve gradient (MVG) (HR: 0.82) were found to be independent predictors for poor functional outcome and mortality.Conclusions: Transcatheter mitral valve repair with the MitraClip system showed low complication rates and sustained MR reduction with improved RV function and sPAP 5 years after the procedure was found in all patients, predominantly in patients with sMR. Despite pronounced functional amelioration with low procedure failure, sMR patients had higher 5-year mortality and worse outcomes. Baseline creatinine, MVG, and sPAP were found to be independent predictors of poor functional outcomes and 5-year mortality

Pulmonary Hypertension in Patients with Chronic Kidney Disease on Dialysis and without Dialysis: Results of the PEPPER-Study

Pulmonary hypertension (PH) is common in patients with dialysis-dependent chronic kidney disease and is an independent predictor of mortality. However, specific hemodynamics of the pulmonary circulation, changes induced by hemodialysis and characterization into pre- or postcapillary PH have not been evaluated in patients with chronic kidney disease. We assessed consecutive patients with end-stage chronic kidney disease in WHO FC≥II with dyspnea unexplained by other causes on hemodialysis (group 1, n = 31) or without dialysis (group 2, n = 31) using right heart catheterization (RHC). In group 1, RHC was performed before and after dialysis. In end-stage chronic kidney disease, prevalence of precapillary PH was 13% (4/31), and postcapillary PH was discovered in 65% (20/31). All four cases of precapillary PH were unmasked after dialysis. In group 2, two cases of precapillary PH were detected (6%), and postcapillary PH was diagnosed in 22 cases (71%). This is the first study examining a large cohort of patients with chronic kidney disease invasively by RHC for the prevalence of PH. The prevalence of precapillary PH was 13% in patients with end-stage kidney disease. That suggests careful screening for precapillary PH in this selected patient population. RHC should be performed after hemodialysis

The imbalance between proliferation and apoptosis contributes to degeneration of aortic valves and bioprostheses

Background: The pathomechanisms underlying aortic valve degeneration are incompletely understood. Therefore, the aim of our work was to assess the quantitative changes of proliferation and apoptosis accompanied by cellular phenotype alternations and matrix secretionin aortic sclerotic and stenotic valves and degenerative bioprostheses, as well as to detect the expression pattern of the rapamycin receptor FKBP12 across these three valve types.Methods: Mild-to-moderate sclerotic and stenotic valves and degenerative bioprostheses from 30 patients (n = 10 per group) were collected at autopsy or by surgery. Ki67+, FKBP12+, alpha-actin+, HSP47+ and TUNEL+ apoptotic cells were analyzed by immunohistochemistry.Results: The main finding was the reduced proliferation and increased apoptosis in stenotic valves (ST) compared to the sclerotic ones (SC) (proliferation: ST: 20.8 ± 2.0% vs. SC: 30.1 ±2.2%, apoptosis: ST: 40.7 ± 5.0% vs. SC: 28.0 ± 5.1%, p < 0.05, respectively). Analogical alternations were found in degenerative bioprostheses (BP) (proliferation: 4.8 ± 2.3%; apoptosis: 13.1 ± 6.8%). Corresponding changes were observed in the valve cellularity (ST: 893 ± 168, SC: 1034 ± 284, BP: 385 ± 179 cells/mm2, p < 0.05, respectively). The FKBP12 signaling was reduced in diseased valves and bioprostheses (ST: 28.1 ± 3.6%, SC: 42.2 ± 3.8%, BP: 5.8 ± 1.9%, p < 0.05, respectively). Further, the augmented alpha-actin expressionwas observed as the degenerative process progressed (ST: 30.3 ± 5.0%, SC: 22.6 ± 2.7%, BP:8.7 ± 4.0%, p < 0.05, respectively), followed by the upregulation of HSP47 (ST: 22.6 ± 2.8%,SC: 15.4 ± 2.1%, BP: 3.4 ± 1.0%, p < 0.05, respectively) and consecutive matrix accumulation.Conclusions: The imbalance between proliferation and apoptosis with cellular phenotypical shift and subsequent matrix secretion may contribute to aortic valve stenosis and bioprosthesis degeneration. The identification of FKBP12 expression may implicate potential therapeutic strategies

Inhibition of Rac1 GTPase Decreases Vascular Oxidative Stress, Improves Endothelial Function, and Attenuates Atherosclerosis Development in Mice

Aims: Oxidative stress and inflammation contribute to atherogenesis. Rac1 GTPase regulates pro-oxidant NADPH oxidase activity, reactive oxygen species (ROS) formation, actin cytoskeleton organization and monocyte adhesion. We investigated the vascular effects of pharmacological inhibition of Rac1 GTPase in mice. Methods and Results: We treated wild-type and apolipoprotein E-deficient (ApoE−/−) mice with Clostridium sordellii lethal toxin (LT), a Rac1 inhibitor, and assessed vascular oxidative stress, expression and activity of involved proteins, endothelial function, macrophage infiltration, and atherosclerosis development. LT-treated wild-type mice displayed decreased vascular NADPH oxidase activity and ROS production. Therapeutic LT doses had no impact on behavior, food intake, body weight, heart rate, blood pressure, vascular and myocardial function, differential blood count, and vascular permeability. ApoE−/− mice were fed a cholesterol-rich diet and were treated with LT or vehicle. LT treatment led to decreased aortic Rac1 GTPase activity, NADPH oxidase activity and ROS production, but had no impact on expression and membrane translocation of NADPH oxidase subunits and RhoA GTPase activity. LT-treated mice showed improved aortic endothelium-dependent vasodilation, attenuated atherosclerotic lesion formation and reduced macrophage infiltration of atherosclerotic plaques. Concomitant treatment of cholesterol-fed ApoE−/− mice with LT, the specific synthetic Rac1 inhibitor NSC 23766 or simvastatin comparably reduced aortic Rac1 activity, NADPH oxidase activity, oxidative stress, endothelial dysfunction, atherosclerosis development, and macrophage infiltration. Conclusions: These findings identify an important role of the small GTPase Rac1 in atherogenesis and provide a potential target for anti-atherosclerotic therapy

CAD increases the long noncoding RNA PUNISHER in small extracellular vesicles and regulates endothelial cell function via vesicular shuttling

Long noncoding RNAs (lncRNAs) have emerged as biomarkers and regulators of cardiovascular disease. However, the expression pattern of circulating extracellular vesicle (EV)-incorporated lncRNAs in patients with coronary artery disease (CAD) is still poorly investigated. A human lncRNA array revealed that certain EV-lncRNAs are significantly dysregulated in CAD patients. Circulating small EVs (sEVs) from patients with (n = 30) or without (n = 30) CAD were used to quantify PUNISHER (also known as AGAP2-antisense RNA 1 [AS1]), GAS5, MALAT1, and H19 RNA levels. PUNISHER (p = 0.002) and GAS5 (p = 0.02) were significantly increased in patients with CAD, compared to non-CAD patients. Fluorescent labeling and quantitative real-time PCR of sEVs demonstrated that functional PUNISHER was transported into the recipient cells. Mechanistically, the RNA-binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNPK), interacts with PUNISHER, regulating its loading into sEVs. Knockdown of PUNISHER abrogated the EV-mediated effects on endothelial cell (EC) migration, proliferation, tube formation, and sprouting. Angiogenesis-related gene profiling showed that the expression of vascular endothelial growth factor A (VEGFA) RNA was significantly increased in EV recipient cells. Protein stability and RNA immunoprecipitation indicated that the PUNISHER-hnRNPK axis regulates the stability and binding of VEGFA mRNA to hnRNPK. Loss of PUNISHER in EVs abolished the EV-mediated promotion of VEGFA gene and protein expression. Intercellular transfer of EV-incorporated PUNISHER promotes a pro-angiogenic phenotype via a VEGFA-dependent mechanism

Impact of pulmonary vein isolation on obstructive sleep apnea in patients with atrial fibrillation

Background: Obstructive sleep apnea (OSA) has been identified as associated with the onset and propagation of atrial fibrillation (AF) and predicts recurrences of AF after pulmonary vein isolation (PVI). Vice versa, it has never been investigated whether PVI influences OSA. However, it has been controversial whether a restored atrial function can affect the course of OSA. There­fore, we have assessed whether PVI procedure modulates the prevalence and severity of OSA. Methods and Results: We included 23 individuals with AF that were assigned to undergo PVI into this study. Patients were 65 ± 7 years old, obese (BMI 29.9 ± 5.4 kg/m2), white (100%) and had a normal left ventricular function (LVEF 64 ± 9%). Polygraphic assessment was carried out before and 6 months after PVI. The prevalence of OSA, defined as an apnea-hypopnea index (AHI) ≥ 5 per hour of sleep, was 74% before PVI compared to 70% 6 months after the procedure (p > 0.05). Severity of OSA did not differ (AHI before vs. after: 18 ± 18/h vs. 15 ± 17/h, p > 0.05) as well as further polygraphic parameters did not differ before and after the procedure. Conclusions: Prevalence and severity of OSA are not affected by PVI in patients suffering from AF.