Abstract
Aims
Cell therapy trials using cardiac-resident progenitor cells (CPCs) and bone marrow-derived mesenchymal stem/progenitor cells (BMCs) in patients after myocardial infarction have provided ...encouraging results. Exosomes, nanosized extracellular vesicles of endosomal origin, figure prominently in the bioactivities of these cells. However, a head-to-head comparison of exosomes from the two cell types has not been performed yet.
Methods and results
CPCs and BMCs were derived from cardiac atrial appendage specimens and sternal bone marrow, respectively, from patients (n = 20; age, 69.9 ± 10.9) undergoing heart surgery for aortic valve disease and/or coronary artery disease. Vesicles were purified from cell conditioned media by centrifugation/filtration and ultracentrifugation. Vesicle preparations were predominantly composed of exosomes based on particle size and marker expression (CD9, CD63, CD81, Alix, and TSG-101). CPC-secreted exosomes prevented staurosporine-induced cardiomyocyte apoptosis more effectively than BMC-secreted exosomes. In vivo, CPC-secreted exosomes reduced scar size and improved ventricular function after permanent coronary occlusion in rats more efficiently than BMC-secreted exosomes. Both types of exosomes stimulated blood vessel formation. CPC-secreted exosomes, but not BMC-derived exosomes, enhanced ventricular function after ischaemia/reperfusion. Proteomics profiling identified pregnancy-associated plasma protein-A (PAPP-A) as one of the most highly enriched proteins in CPC vs. BMC exosomes. The active form of PAPP-A was detected on CPC exosome surfaces. These vesicles released insulin-like growth factor-1 (IGF-1) via proteolytic cleavage of IGF-binding protein-4 (IGFBP-4), resulting in IGF-1 receptor activation, intracellular Akt and ERK1/2 phosphorylation, decreased caspase activation, and reduced cardiomyocyte apoptosis. PAPP-A knockdown prevented CPC exosome-mediated cardioprotection both in vitro and in vivo.
Conclusion
These results suggest that CPC-secreted exosomes may be more cardioprotective than BMC-secreted exosomes, and that PAPP-A–mediated IGF-1 release may explain the benefit. They illustrate a general mechanism whereby exosomes may function via an active protease on their surface, which releases a ligand in proximity to the transmembrane receptor bound by the ligand.
Objectives The purpose of this article is to report early and mid-term outcomes of the ACCESS-EU study (ACCESS-Europe A Two-Phase Observational Study of the MitraClip System in Europe), a European ...prospective, multicenter, nonrandomized post-approval study of MitraClip therapy (Abbott Vascular, Inc., Santa Clara, California). Background MitraClip has been increasingly performed in Europe after approval; the ACCESS-EU registry provides a snapshot of the real-world clinical demographic data and outcomes. Methods A total of 567 patients with significant mitral valve regurgitation (MR) underwent MitraClip therapy at 14 European sites. Mean logistic European System for Cardiac Operative Risk Evaluation at baseline was 23.0 ± 18.3; 84.9% patients were in New York Heart Association functional class III or IV, and 52.7% of patients had an ejection fraction ≤40%. Results The MitraClip implant rate was 99.6%. A total of 19 patients (3.4%) died within 30 days after the MitraClip procedure. The Kaplan-Meier survival at 1 year was 81.8%. Intensive care unit and hospital length of stay was 2.5 ± 6.5 days and 7.7 ± 8.2 days, respectively. Single leaflet device attachment was reported in 27 patients (4.8%). There were no MitraClip device embolizations. Thirty-six subjects (6.3%) required mitral valve surgery within 12 months after the MitraClip implant procedure. There was improvement in the severity of MR at 12 months, compared with baseline (p < 0.0001), with 78.9% of patients free from MR, severity of >2+ at 12 months. At 12 months, 71.4% of patients had New York Heart Association functional class II or class I. Six-min-walk-test improved 59.5 ± 112.4 m, and Minnesota-living-with-heart-failure score improved 13.5 ± 20.5 points. Conclusions In the real-world, post-approval experience in Europe, patients undergoing the MitraClip therapy are high-risk, elderly patients, mainly affected by functional MR. In this patient population, the MitraClip procedure is effective with low rates of hospital mortality and adverse events.
Cross-talk between different cell types plays central roles both in cardiac homeostasis and in adaptive responses of the heart to stress. Cardiomyocytes (CMs) send biological messages to the other ...cell types present in the heart including endothelial cells (ECs) and fibroblasts. In turn, CMs receive messages from these cells. Recent evidence has now established that exosomes, nanosized secreted extracellular vesicles, are crucial mediators of such messages. CMs, ECs, cardiac fibroblasts, and cardiac progenitor cells (CPCs) release exosomes carrying nonrandom subsets of proteins, lipids, and nucleic acids present in their cells of origin. Exosomes secreted from CMs are internalized by fibroblasts and regulate gene expression in these cells as well as in ECs. CPC-derived exosomes protect CMs against apoptosis while also stimulating angiogenesis. They are rich in cardioprotective and proangiogenic microRNAs such as miR-146, miR-210, and miR-132. When injected into infracted hearts in vivo, CPC-derived exosomes reduce infarct size and improve cardiac function. Thus, exosomes are emerging both as key mediators of intercellular communication in the heart and as therapeutic candidates for heart disease.
Abstract Aim We compared the time to initiation of cardiopulmonary resuscitation (CPR) by lay responders and/or first responders alerted either via Short Message Service (SMS) or by using a mobile ...application-based alert system (APP). Methods The Ticino Registry of Cardiac Arrest collects all data about out-of-hospital cardiac arrests (OHCAs) occurring in the Canton of Ticino. At the time of a bystander’s call, the EMS dispatcher sends one ambulance and alerts the first-responders network made up of police officers or fire brigade equipped with an automatic external defibrillator, the so called “traditional” first responders, and − if the scene was considered safe − lay responders as well. We evaluated the time from call to arrival of traditional first responders and/or lay responders when alerted either via SMS or the new developed mobile APP. Results Over the study period 593 OHCAs have occurred. Notification to the first responders network was sent via SMS in 198 cases and via mobile APP in 134 cases. Median time to first responder/lay responder arrival on scene was significantly reduced by the APP-based system (3.5 2.8-5.2) compared to the SMS-based system (5.6 4.2-8.5 min, p 0.0001). The proportion of lay responders arriving first on the scene significantly increased (70% vs. 15%, p<0.01) with the APP. Earlier arrival of a first responder or of a lay responder determined a higher survival rate. Conclusions The mobile APP system is highly efficient in the recruitment of first responders, significantly reducing the time to the initiation of CPR thus increasing survival rates.
Cell therapy has been evaluated to enhance heart function after injury. Delivered cells mostly act via paracrine mechanisms, including secreted growth factors, cytokines, and vesicles, such as ...exosomes (Exo). Intramyocardial injection of cardiac-resident progenitor cells (CPC)-derived Exo reduced scarring and improved cardiac function after myocardial infarction in rats. Here, we explore a clinically relevant approach to enhance the homing process to cardiomyocytes (CM), which is crucial for therapeutic efficacy upon systemic delivery of Exo. By overexpressing exosomal CXCR4, we increased the efficacy of plasmatic injection of cardioprotective Exo-CPC by increasing their bioavailability to ischemic hearts. Intravenous injection of Exo
significantly reduced infarct size and improved left ventricle ejection fraction at 4 weeks compared to Exo
(
< 0.01). Hemodynamic measurements showed that Exo
improved dp/dt min, as compared to Exo
and PBS group. In vitro, Exo
was more bioactive than Exo
in preventing CM death. This in vitro effect was independent from SDF-1α, as shown by using AMD3100 as specific CXCR4 antagonist. We showed, for the first time, that systemic administration of Exo derived from CXCR4-overexpressing CPC improves heart function in a rat model of ischemia reperfusion injury These data represent a substantial step toward clinical application of Exo-based therapeutics in cardiovascular disease.
In an era of catheter-based structural heart disease and left-side electrophysiologic interventions, transseptal puncture (TSP) is probably the most common transcatheter procedure. Experienced ...interventional cardiologists and electrophysiologists may safely perform TSP using fluoroscopic guidance alone. However, at present TSP is usually the first step in complex percutaneous catheter-based structural heart disease procedures and necessitate a precise site-specific TSP. Thus, in these procedures most interventional cardiologists perform TSP under fluoroscopic and two- or three-dimensional transesophageal echocardiographic guidance. The EchoNavigator system may provide a solution by fusing fluoroscopic and transesophageal echocardiographic images. In this review, the authors describe advantages and limitations of this new imaging system in guiding TSP and suggest specific echocardiographic-fluoroscopic fusion imaging perspectives that may facilitate TSP, making it potentially easier and safer.
Abstract Objectives The objective of this meta-analysis of randomized trials was to evaluate if the administration of furosemide with matched hydration using the RenalGuard System reduces ...contrast-induced acute kidney injury (CI-AKI) in patients undergoing interventional procedures. Background CI-AKI is a serious complication following angiographic procedures and a powerful predictor of unfavorable early and long-term outcomes. Methods Online databases were searched up to October 1, 2016, for randomized controlled trials. The primary outcome was the incidence of CI-AKI, and the secondary outcomes were need for renal replacement therapy, mortality, stroke, and adverse events. Results A total of four trials (n = 698) published between 2011 and 2016 were included in the analysis and included patients undergoing percutaneous coronary procedures and transcatheter aortic valve replacement. RenalGuard therapy was associated with a lower incidence of CI-AKI compared with control treatment (27 of 348 7.76% patients vs. 75 of 350 21.43% patients; odds ratio OR: 0.31; 95% confidence interval CI: 0.19 to 0.50; I2 = 4%; p < 0.00001) and with a lower need for renal replacement therapy (2 of 346 0.58% patients vs. 12 of 348 3.45% patients; OR: 0.19; 95% CI: 0.05 to 0.76; I2 = 0%; p = 0.02). No major adverse events occurred in patients undergoing RenalGuard therapy. Conclusions The main finding of this meta-analysis is that furosemide with matched hydration by the RenalGuard System may reduce the incidence of CI-AKI in high-risk patients undergoing percutaneous coronary intervention or transcatheter aortic valve replacement. However, further independent high-quality randomized trials should elucidate the effectiveness and safety of this prophylactic intervention in interventional cardiology.
During the last ten years, transcatheter aortic valve implantation (TAVI) has become a reliable and valid alternative treatment for elderly patients with severe symptomatic aortic valve stenosis ...requiring valve replacement and being at high or intermediate surgical risk. While common femoral arteries are the access site of choice in the vast majority of TAVI patients, in up to 15-20% of TAVI candidates this route might be precluded due to the presence of diffuse atherosclerotic disease, tortuosity or small vessel diameter. Therefore, in order to achieve an antegrade or retrograde implant, several alterative access routes have been described, namely trans-axillary, trans-aortic, trans-apical, trans-carotid, trans-septal, and trans-caval. The aim of this paper is to give a concise overview on vascular access sites for TAVI, with a particular focus on patient's selection criteria, imaging, technical aspects, and clinical outcome.
This report describes the 12-month outcomes of the a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe (ACCESS-EU postapproval study of MitraClip therapy) ...with respect to preprocedural left ventricular ejection fraction (LVEF). Transcatheter deployment of the MitraClip device may be considered for patients who are not suitable for conventional surgery. A total of 567 patients with significant mitral regurgitation (MR) underwent MitraClip therapy. Of those, 393 had functional MR (FMR) and were subdivided by preprocedural LVEF (A: 10% to 20%, B: >20% to 30%, C: >30% to 40%, D: >40%). Procedural safety and efficacy and treatment outcomes including MR grade, New York Heart Association (NYHA) functional class, 6-minute walk test, and the Minnesota Living with Heart Failure Questionnaire were analyzed at baseline, 30 days, and 12 months. Baseline mean logistic EuroSCORE was 25 ± 19; 87% of patients were in NYHA classes III or IV (A: 96%, B: 83%, C: 90%, D: 86%). There was no incidence of death or stroke intraprocedurally. Eleven patients died within 30 days with no differences among subgroups. Kaplan–Meier survival at 12 months was 81.8% (A: 71%, B: 79%, C: 87%, D: 86%). There was a significant improvement in MR severity at 30 days and 12 months (p <0.0001). At 12 months, all subgroups experienced similar improvements in NYHA class, 6-minute walk test, and Minnesota Living with Heart Failure Questionnaire. This real-world registry reports promising results of MitraClip therapy in patients with FMR. In conclusion, the low rates of hospital mortality and adverse events in patients with FMR—even in patients with severely reduced LVEF—provide additional evidence of substantial benefits after MitraClip implantation.
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