No abstract

clinicaltrials.gov Identifier: NCT00099788.

Aims  Loss-of-function mutations in ANGPTL3 are associated with beneficial effects on lipid and glucose metabolism and reduced risk of coronary artery disease. Vupanorsen (AKCEA-ANGPTL3-L Rx ) is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits angiopoietin-like 3 (ANGPTL3) protein synthesis. Methods and results  This was a double-blind, placebo-controlled, dose-ranging, Phase 2 study. Patients (N =105) with fasting triglycerides >150 mg/dL (>1.7 mmol/L), type 2 diabetes, and hepatic steatosis were treated for 6 months with 40 or 80 mg every 4 weeks (Q4W), or 20 mg every week (QW) of vupanorsen, or placebo given subcutaneously. The primary efficacy endpoint was per cent change in fasting triglycerides from baseline at 6 months. Median baseline triglycerides were 2.84 mmol/L (252 mg/dL). Significant reductions in triglycerides of 36%, 53%, 47%, and in ANGPTL3 of 41%, 59%, 56%, were observed in the 40 mg Q4W, 80 mg Q4W, and 20 mg QW groups, respectively, compared with 16% reduction in triglycerides and 8% increase in ANGPTL3 in placebo. Compared with placebo, vupanorsen 80 mg Q4W reduced apolipoprotein C-III (58%), remnant cholesterol (38%), total cholesterol (19%), non-high-density lipoprotein cholesterol (HDL-C; 18%), HDL-C (24%), and apolipoprotein B (9%). There was no improvement in glycaemic parameters, or hepatic fat fraction. Treatment with vupanorsen was not associated with clinically significant changes in platelet counts, and the most common adverse events were those at the injection site, which were generally mild. Conclusion  Vupanorsen results in a favourable lipid/lipoprotein profile and provides a potential strategy for residual cardiovascular risk reduction.

MD; for the MERLIN-TIMI 36 InvestigatorsBackground-Ranolazine is a novel antianginal shown in an exploratory analysis in patients with diabetes mellitus and chronic angina to be associated with a decline in hemoglobin A 1c (HbA 1c

Results of this proof-of-concept study revealed that ranolazine improved measures of hemodynamics but that there was no improvement in relaxation parameters. (Ranolazine in Diastolic Heart Failure [RALI-DHF]; NCT01163734).

No abstract

Sympathetic nerves have long been suspected of trophic activity, but the nature of their angiogenic factor has not been determined. Neuropeptide Y (NPY), a sympathetic cotransmitter, is the most abundant peptide in the heart and the brain. It is released during nerve activation and ischemia and causes vasoconstriction and smooth muscle cell proliferation. Here we report the first evidence that NPY is angiogenic. At low physiological concentrations, in vitro, it promotes vessel sprouting and adhesion, migration, proliferation, and capillary tube formation by human endothelial cells. In vivo, in a murine angiogenic assay, NPY is angiogenic and is as potent as a basic fibroblast growth factor. The NPY action is specific and is mediated by Y1 and Y2 receptors. The expression of both receptors is upregulated during cell growth; however, Y2 appears to be the main NPY angiogenic receptor. Its upregulation parallels the NPY-induced capillary tube formation on reconstituted basement membrane (Matrigel); the Y2 agonist mimics the tube-forming activity of NPY, whereas the Y2 antagonist blocks it. Endothelium contains not only NPY receptors but also peptide itself, its mRNA, and the "NPY-converting enzyme" dipeptidyl peptidase IV (both protein and mRNA), which terminates the Y1 activity of NPY and cleaves the Tyr1-Pro2 from NPY to form an angiogenic Y2 agonist, NPY3-36. Endothelium is thus not only the site of action of NPY but also the origin of the autocrine NPY system, which, together with the sympathetic nerves, may be important in angiogenesis during tissue development and repair.

Abstract-Recently, we found that vacuolar proton ATPase (VPATPase) operates in cardiomyocytes as a complementary proton-extruding mechanism. Its activity was increased by preconditioning with resultant attenuation of intracellular acidification during ischemia. In this study, we examined whether VPATPase-mediated proton efflux during metabolic inhibition/recovery may spare Na ϩ overload via Na ϩ -H ϩ exchange, attenuate Na ϩ -Ca 2ϩ exchange, and decrease apoptosis. Neonatal rat cardiomyocytes were subjected to 2-to 3-hour metabolic inhibition with cyanide and 2-deoxyglucose and 24-hour recovery. The effect of VPATPase inhibition by 50 nmol/L bafilomycin A 1 on apoptosis, pH i , and [Ca 2ϩ ] i was studied by flow cytometry with propidium iodide, seminaphthorhodafluor (SNARF)-1-AM, and indo-1-AM staining, respectively. VPATPase inhibition increased the amount of apoptosis measured after 24 hours of recovery and abrogated the protective effect of inhibition of Na