Abstract Background Sphingosine-1-phosphate (S1P) is a constituent of high-density lipoproteins (HDL) that contributes to their beneficial effects. We have shown decreased HDL-S1P in coronary artery ...disease (CAD) but its functional relevance remains unclear. Objectives This study investigated the functional consequences of reduced HDL-S1P content in CAD and tested if increasing it may improve or restore HDL function. Methods Human HDL from healthy and CAD subjects, as well as mouse HDL, were isolated by ultracentrifugation. HDL-S1P-dependent activation of cell-signaling pathways and induction of vasodilation were examined in vitro and in isolated arteries using native and S1P-loaded HDL, S1P receptor antagonists, and S1P-blocking antibodies. Results HDL-S1P-dependent signaling was clearly impaired and S1P content reduced in CAD-HDL as compared to healthy HDL. Both healthy and CAD-HDL could be efficiently and equally well loaded with S1P from cellular donors and plasma. S1P-loading greatly improved HDL signaling and vasodilatory potential in pre-contracted arteries and completely corrected the defects inherent to CAD-HDL. HDL-S1P content and uptake was reduced by oxidation and was lower in HDL3 than HDL2 . Loading with S1P in vitro and in vivo fully replenished the virtually absent S1P content of apolipoprotein M-deficient HDL and restored their defective signaling. Infusion of erythrocyte-associated C17-S1P in mice led to its rapid and complete uptake by HDL providing a means to directly S1P-load HDL in vivo. Conclusions Reduced HDL-S1P content contributes to HDL dysfunction in CAD. It can be efficiently increased by S1P-loading in vitro and in vivo, providing a novel approach to correcting HDL dysfunction in CAD.
Summary Although remote ischemic pre-conditioning (RIPC) reduced infarct size in animal experiments and proof-of-concept clinical trials, recent phase III trials failed to confirm cardioprotection ...during cardiac surgery. Here, we characterized the kinetic properties of humoral factors that are released after RIPC, as well as the signal transduction pathways that were responsible for cardioprotection in an ex vivo model of global ischemia reperfusion injury. Venous blood from 20 healthy volunteers was collected at baseline and 5 min, 30 min, 1 h, 6 h, and daily from 1 to 7 days after RIPC (3 × 5/5 min upper-limb ischemia/reperfusion). Plasma-dialysates (cut-off: 12 to 14 kDa; dilution: 1:20) were infused into Langendorff-perfused mouse hearts subjected to 20/120 min global ischemia/reperfusion. Infarct size and phosphorylation of signal transducer and activator of transcription (STAT)3, STAT5, extracellular-regulated kinase 1/2 and protein kinase B were determined. In a subgroup of plasma-dialysates, an inhibitor of STAT3 (Stattic) was used in mouse hearts. Perfusion with baseline-dialysate resulted in an infarct size of 39% of ventricular mass (interquartile range: 36% to 42%). Perfusion with dialysates obtained 5 min to 6 days after RIPC significantly reduced infarct size by ∼50% and increased STAT3 phosphorylation beyond that with baseline-dialysate. Inhibition of STAT3 abrogated these effects. These results suggest that RIPC induces the release of cardioprotective, dialyzable factor(s) within 5 min, and that circulate for up to 6 days. STAT3 is activated in murine myocardium by RIPC-induced human humoral factors and is causally involved in cardioprotection.
Summary Background Remote ischaemic preconditioning has been associated with reduced risk of myocardial injury after coronary artery bypass graft (CABG) surgery. We investigated the safety and ...efficacy of this procedure. Methods Eligible patients were those scheduled to undergo elective isolated first-time CABG surgery under cold crystalloid cardioplegia and cardiopulmonary bypass at the West-German Heart Centre, Essen, Germany, between April, 2008, and October, 2012. Patients were prospectively randomised to receive remote ischaemic preconditioning (three cycles of 5 min ischaemia and 5 min reperfusion in the left upper arm after induction of anaesthesia) or no ischaemic preconditioning (control). The primary endpoint was myocardial injury, as reflected by the geometric mean area under the curve (AUC) for perioperative concentrations of cardiac troponin I (cTnI) in serum in the first 72 h after CABG. Mortality was the main safety endpoint. Analysis was done in intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov , number NCT01406678. Findings 329 patients were enrolled. Baseline characteristics and perioperative data did not differ between groups. cTnI AUC was 266 ng/mL over 72 h (95% CI 237–298) in the remote ischaemic preconditioning group and 321 ng/mL (287–360) in the control group. In the intention-to-treat population, the ratio of remote ischaemic preconditioning to control for cTnI AUC was 0·83 (95% CI 0·70–0·97, p=0·022). cTnI release remained lower in the per-protocol analysis (0·79, 0·66–0·94, p=0·001). All-cause mortality was assessed over 1·54 (SD 1·22) years and was lower with remote ischaemic preconditioning than without (ratio 0·27, 95% CI 0·08–0·98, p=0·046). Interpretation Remote ischaemic preconditioning provided perioperative myocardial protection and improved the prognosis of patients undergoing elective CABG surgery. Funding German Research Foundation.
Purpose Transcatheter aortic valve implantation (TAVI) results in the dislodgement of debris with risk of cerebral lesions or stroke. The EMBOL-X protection device (Edwards Lifesciences, Irvine, CA) ...is positioned within the ascending aorta to capture such debris. Description Between July 2012 and April 2014 we randomly assigned 30 high-risk patients to undergo transaortic TAVI with the SAPIEN XT prosthesis (Edwards Lifesciences) combined with either the EMBOL-X device (group-1, n = 14) or without (group-2, n = 16). Periprocedural cerebral lesions were assessed by diffusion-weighted magnetic resonance imaging (DW-MRI) at baseline and within 7 days post-procedurally. Evaluation New foci of restricted diffusion on cerebral DW-MRI were found in 69% in group-2 and 50% in group-1. Lesion size was smaller in patients treated with the EMBOL-X device than in those without (88 ± 60 vs 168 ± 217 mm3 , p = 0.27, t = 1.2, degrees of freedom = 10). Transaortic TAVI patients treated with the EMBOL-X device had significantly smaller lesion volumes in the supply region of the middle cerebral artery (33 ± 29 vs 76 ± 67 mm3 , p = 0.04). There were no neurologic events after transaortic TAVI. Conclusions The intraaortic protection device seems to reduce both the incidence and the volume of new cerebral lesions ( ClinicalTrials.gov number, NCT01735513 ).
Sustained Benefits in Vascular Function Through Flavanol-Containing Cocoa in Medicated Diabetic Patients: A Double-Masked, Randomized, Controlled Trial Jan Balzer, Tienush Rassaf, Christian Heiss, ...Petra Kleinbongard, Thomas Lauer, Marc Merx, Nicole Heussen, Heidrun B. Gross, Carl L. Keen, Hagen Schroete, Malte Kelm Controlled clinical trials evaluating effects of the consumption of flavanol-containing cocoa on endothelial function in diabetic patients are missing. The aim of this double-masked, randomized, controlled study was to examine the vasculoprotective impact of flavanol-containing cocoa intake in diabetic patients. A single ingestion of flavanol-containing cocoa was dose-dependently associated with significant acute increases in flow-mediated dilation (FMD), and the 30-day, thrice-daily consumption of flavanol-containing cocoa increased baseline FMD by 30%. Acute and chronic changes were accompanied by increases in plasma flavanol metabolites. These data demonstrate improvements of endothelial function after the regular consumption of flavanol-containing cocoa in patients with type 2 diabetes.
Remote ischemic conditioning (RIC) induces the release of circulating cardioprotective factors and attenuates myocardial ischemia/reperfusion injury. Evidence for such humoral cardioprotective ...factor(s) is derived from transfer with plasma (derivatives) from one individual undergoing RIC to another individual’s heart, even across species. With transfer into an isolated perfused heart, only a single plasma (derivative) sample can be studied with infarct size as endpoint, and therefore the comparison of samples before and after RIC or between RIC and placebo is hampered by the inter-individual variation of infarct sizes in isolated perfused hearts. We therefore developed a preparation of cardiomyocytes from a single mouse heart, where aliquots of the same heart can undergo hypoxia/reoxygenation (H/R) with exposure to buffer, RIC, or placebo samples without or with pharmacological blockade. To validate this approach, we used plasma dialysates taken before and after RIC from patients undergoing coronary bypass grafting who had experienced protection by RIC (troponin release ↓ by 28% vs placebo). The cardiomyocyte bioassay had little variation after H/R with buffer (mean ± standard deviation; 7% ± 2% viable cells) and demonstrated preserved viability after RIC (15% ± 5% vs 6% ± 3% before). For comparison, infarct size in isolated mouse hearts after global ischemia and reperfusion was 22% ± 14% of left ventricular mass after versus 42% ± 14% before RIC. Stattic, an inhibitor of signal transducer and activator of transcription (STAT)3 protein, abrogated protection in the cardiomyocytes. We have thus established a cardiomyocyte bioassay to analyze RIC’s protection which minimizes inter-individual variation and the use of animals.
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