Identification of potent, selective P2Y-purinoceptor agonists: structure-activity relationships for 2-thioether derivatives of adenosine 5'-triphosphate

Study of P2-purinoceptor subtypes has been difficult due to the lack of potent and selective ligands. With the goal of developing high affinity P2-purinoceptor-selective agonists, we have synthesized a series of analogues of adenine nucleotides modified on the purine ring as chain-extended 2-thioethers or as N6-methyl-substituted compounds. Chemical functionality incorporated in the thioether moiety included cyanoalkyl, nitroaromatic, amino, thiol, cycloalkyl, n-alkyl, and olefinic groups. Apparent affinity of the compounds for P2Y-purinoceptors was established by measurement of P2Y-purinoceptor-promoted phospholipase C activity in turkey erythrocyte membranes and relaxation of carbachol-contracted smooth muscle in three different preparations (guinea pig taenia coil, rabbit aorta, and rabbit mesenteric artery). Activity at P2X-purinoceptors was established by measurement of contraction of rabbit saphenous artery and of the guinea pig vas deferens and urinary bladder. All 11 of the 2-thioethers of ATP stimulated the production of inositol phosphates with K0.5 values of 1.5–770 nM, with an (aminophenyl)ethyl derivative being most potent. Two adenosine diphosphate analogues were equipotent to the corresponding ATP analogues. Adenosine monophosphate analogues were full agonists, although generally 4 orders of magnitude less potent. ATP 2-thioethers displayed pD2 values in the range of 6–8 in smooth muscle assay systems for activity at P2Y-receptors. There was a significant correlation for the 2-thioether compounds between the pK0.5 values for inositol phosphate production and the pD2 values for relaxation mediated via the P2Y-purinoceptors in the guinea pig taenia coli, but not for the vascular P2Y-receptors or for the P2X-receptors. At P2X-receptors, no activity was observed in the rabbit saphenous artery, but variable degrees of activity were observed in the guinea pig vas deferens and bladder depending on distal substituents of the thioether moiety. N6-Methyl-ATP was inactive at P2X-receptors, and approximately equipotent to ATP at taenia coli P2Y-receptors. This suggested that hybrid N6-methyl and 2-thioether ATP derivatives might be potent and selective for certain P2Y-receptors, as was shown for one such derivative, N6-methyl-2-(5-hexenylthio)-ATP

Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes

Background: The objective of this cross-sectional study was to explore the relationship of detectable C-peptide secretion in type 1 diabetes to clinical features and to the genetic architecture of diabetes. Methods: C-peptide was measured in an untimed serum sample in the SDRNT1BIO cohort of 6076 Scottish people with clinically diagnosed type 1 diabetes or latent autoimmune diabetes of adulthood. Risk scores at loci previously associated with type 1 and type 2 diabetes were calculated from publicly available summary statistics. Results: Prevalence of detectable C-peptide varied from 19% in those with onset before age 15 and duration greater than 15 years to 92% in those with onset after age 35 and duration less than 5 years. Twenty-nine percent of variance in C-peptide levels was accounted for by associations with male gender, late age at onset and short duration. The SNP heritability of residual C-peptide secretion adjusted for gender, age at onset and duration was estimated as 26%. Genotypic risk score for type 1 diabetes was inversely associated with detectable C-peptide secretion: the most strongly associated loci were the HLA and INS gene regions. A risk score for type 1 diabetes based on the HLA DR3 and DQ8-DR4 serotypes was strongly associated with early age at onset and inversely associated with C-peptide persistence. For C-peptide but not age at onset, there were strong associations with risk scores for type 1 and type 2 diabetes that were based on SNPs in the HLA region but not accounted for by HLA serotype. Conclusions: Persistence of C-peptide secretion varies widely in people clinically diagnosed as type 1 diabetes. C-peptide persistence is influenced by variants in the HLA region that are different from those determining risk of early-onset type 1 diabetes. Known risk loci for diabetes account for only a small proportion of the genetic effects on C-peptide persistence

Implantation of Mouse Embryonic Stem Cell-Derived Cardiac Progenitor Cells Preserves Function of Infarcted Murine Hearts

Stem cell transplantation holds great promise for the treatment of myocardial infarction injury. We recently described the embryonic stem cell-derived cardiac progenitor cells (CPCs) capable of differentiating into cardiomyocytes, vascular endothelium, and smooth muscle. In this study, we hypothesized that transplanted CPCs will preserve function of the infarcted heart by participating in both muscle replacement and neovascularization. Differentiated CPCs formed functional electromechanical junctions with cardiomyocytes in vitro and conducted action potentials over cm-scale distances. When transplanted into infarcted mouse hearts, CPCs engrafted long-term in the infarct zone and surrounding myocardium without causing teratomas or arrhythmias. The grafted cells differentiated into cross-striated cardiomyocytes forming gap junctions with the host cells, while also contributing to neovascularization. Serial echocardiography and pressure-volume catheterization demonstrated attenuated ventricular dilatation and preserved left ventricular fractional shortening, systolic and diastolic function. Our results demonstrate that CPCs can engraft, differentiate, and preserve the functional output of the infarcted heart

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Emerging role for bone marrow derived mesenchymal stem cells in myocardial regenerative therapy

Current treatments for ischemic cardiomyopathy are aimed toward minimizing the deleterious consequences of diseased myocardium. The possibility of treating heart failure by generating new myocardium and vascular tissue has been an impetus toward recent stem cell research. Mesenchymal stem cells (MSC), also referred to as marrow stromal cells, differentiate into a wide variety of lineages, including myocardial and endothelial cells. The multi-lineage potential of MSCs, their ability to elude detection by the host immune system, and their relative ease of expansion in culture make MSCs a very promising source of stem cells for transplantation. In addition, emerging experimental results with MSCs offer novel mechanistic insights into cardiac regenerative therapy in general. Here we review the characterization of MSCs, animal and human trials studying MSCs in cardiomyogenesis and vasculogenesis in postinfarct myocardium, routes of delivery, and potential mechanisms of stem cell repair

Intracoronary Imaging and Physiology to Guide PCI: Are We Ready for a Class I Guideline Recommendation?

PURPOSE OF REVIEW: Over the last decade, there has been a plethora of evidence to support the utilization of intravascular coronary imaging and physiological assessment to guide percutaneous coronary interventions (PCI). While there is a class I recommendation for the use of coronary physiology to guide PCI, the use of intravascular coronary imaging remains a class IIa recommendation. Herein, we aimed to review the recent scientific evidence from major trials highlighting the consideration for a future class I guideline recommendation for the use of intracoronary imaging. RECENT FINDINGS: The benefits of intravascular ultrasound (IVUS) and optical coherence tomography (OCT) to guide and optimize PCI have been demonstrated in several large trials. These trials have demonstrated that IVUS reduces major adverse cardiovascular events. Similarly, intracoronary physiology has been demonstrated to be an important tool to guide revascularization decision-making and been associated with a lower incidence of death, non-fatal myocardial infarction, and repeat revascularization compared with angiography alone. With existing clinical outcomes data on the benefit of intracoronary physiology and imaging-guided PCI as well as forthcoming data from ongoing trials regarding the use of these modalities, the interventional cardiology community is bound to transition from routine PCI to precision-, image-, and physiology-guided PCI

Ferumoxytol MRA for transcatheter aortic valve replacement planning with renal insufficiency.

BackgroundComputed tomography angiography (CTA) is the test of choice for pre-procedure imaging of transcatheter aortic valve replacement (TAVR) candidates. The iodinated contrast required, however, increases the risk of renal dysfunction in patients with pre-existing renal failure. Ferumoxytol is a magnetic resonance imaging (MRI) contrast agent that can be used with renal failure. Its long vascular resonance time allows gated MRA sequences that approach CTA in image quality. We present respiratory and cardiac gated MRA enabled by ferumoxytol that can be post-processed in an analogous fashion to CTA.MethodsSeven patients with renal failure presenting for TAVR were imaged with respiratory and cardiac gated MRA at 3T using ferumoxtyol for contrast. Aortic annulus, root and peripheral access dimensions were calculated in a fashion identical to that used for CTA. Of these, 6 patients underwent a TAVR procedure and 5 had intraoperative valve assessment with transesophageal echocardiograph (TEE) using standard clinical protocols that employed both two- and three-dimensional techniques.ResultsGood correlation between MRA aortic annulus measurements and those from TEE were shown in 5 patients with mean annulus area of 392.4mm2 (290-470 range) versus 374.1mm2 (285-440 range), with a pairwise correlation coefficient of 0.92, p=0.029. All patients received Sapien valve implants (one 20mm, three 23mm, and two 26mm valves). Access decisions were guided by MRA with no complications. Annulus sizing resulted in no greater than trace/mild aortic regurgitation in all patients.ConclusionsFerumoxytol MRA is a safe alternative to CTA in patients with renal failure for pre-TAVR analysis of the aortic root and peripheral access

Evolution of Veterans Affairs Transcatheter Aortic Valve Replacement Program: The First 100 Patients.

BackgroundTranscatheter aortic valve replacement (TAVR) is a widely established alternative to surgery in intermediate- and high-risk patients. TAVR program development within the Veterans Affairs (VA) system has been previously described. However, national TAVR registries do not capture VA outcomes data, and few data have been reported regarding TAVR outcomes at lower-volume federal institutions. The study aim was to demonstrate the evolution of a successful VA TAVR program.MethodsA retrospective analysis was performed of the first 100 TAVR patients at San Francisco VA Medical Center. Mortality and major complications were evaluated.ResultsBetween 25th November 2013 and 31st August 2016, a total of 100 TAVR procedures was performed at the authors' institution. The mean patient age was 79.7 ± 8.7 years. Patients underwent TAVR via percutaneous-transfemoral (n = 90), surgical cutdown-transfemoral (n = 8), or transapical (n = 2) approaches. The valve systems employed were Edwards SAPIEN (n = 16), SAPIEN XT (n = 31), SAPIEN 3 (n = 23), and Medtronic CoreValve (n = 16) and CoreValve Evolut R (n = 14). The overall device success was 96%. TAVR-in-TAVR was required in the remaining 4% of patients, and was successful. All-cause procedural mortality was 1%. Complications included tamponade (1%), stroke (2%), temporary hemodialysis (1%), vascular injuries requiring intervention (4%), and permanent pacemaker implantation (14%). There were no conversions to surgical aortic valve replacement. Twenty-two (22%) patients had mild, two (2%) had moderate, and none (0%) had severe paravalvular leakage. The post-procedure aortic valve gradient by echocardiography was 8.6 ± 4.5 mmHg. Follow up was 100% complete and survival was 99%, 93%, and 89% at one, six, and 12 months, respectively.ConclusionsSuccessful outcomes were demonstrated for a VA TAVR program that compared favorably with benchmarks established by the National Transcatheter Valve Therapies Registry. These results provide a necessary transparency of TAVR outcomes at a federal institution