Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

Background Changes in the myocardium in acute ischemia are dynamic and complex and the characteristics of myocardial tissue on cardiovascular magnetic resonance (CMR) in the acute setting are not fully defined. We investigated changes in edema and late gadolinium enhancement (LGE) with serial imaging early after acute MI, relating these to global and segmental myocardial function at 6 months. Methods and Results CMR scans were performed on 30 patients with ST elevation MI (STEMI) treated by primary PCI at each of 4 time points: 12-48 hours (24H); 5-7 days (1W); 14-17 days (2W); and 6 months (6M). All patients showed edema at 24H. The mean volume of edema (% LV) was 37 ± 16 at 24H and 39 ± 17 at 1W with a reduction to 24 ± 13 (P < 0.01) by 2W. Myocardial segments with edema also had increased signal on LGE at 24H (kappa = 0.77; P < 0.001). The volume of LGE decreased significantly between 24H and 6M (27 ± 15 % vs. 22 ± 12 %; P = 0.002). Of segments showing LGE at 24H, 50% showed resolution by six months. In segments with such a reduction in LGE, 65% also showed improved wall motion (P < 0.0001). The area of LGE measured at 6M correlated more strongly with troponin at 48h (r = 0.9; P < 0.01) than LGE at 24H (r = 0.7). The difference in LGE between 24H and 6M had profound effects on the calculation of salvage index (26 ± 21 % at 24H vs. 42 ± 23 % at 6M; P = 0.02). Conclusions Myocardial edema is maximal and constant over the first week post MI, providing a stable window for the retrospective evaluation of area at risk. By contrast, myocardial areas with high signal intensity in LGE images recede over time with corresponding recovery of function, indicating that acutely detected LGE does not necessarily equate with irreversible injury and may severely underestimate salvaged myocardium.

Background-The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) plays a pivotal role in maintaining endothelial function in experimental vascular disease models and in humans. Augmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a potential therapeutic strategy in vascular disease states. We sought to determine the mechanisms relating exogenous BH4 to human vascular function and to determine oral BH4 pharmacokinetics in both plasma and vascular tissue in patients with coronary artery disease. Methods and Results-Forty-nine patients with coronary artery disease were randomized to receive low-dose (400 mg/d) or high-dose (700 mg/d) BH4 or placebo for 2 to 6 weeks before coronary artery bypass surgery. Vascular function was quantified by magnetic resonance imaging before and after treatment, along with plasma BH4 levels. Vascular superoxide, endothelial function, and BH4 levels were determined in segments of saphenous vein and internal mammary artery. Oral BH4 treatment significantly augmented BH4 levels in plasma and in saphenous vein (but not internal mammary artery) but also increased levels of the oxidation product dihydrobiopterin (BH2), which lacks endothelial nitric oxide synthase cofactor activity. There was no effect of BH4 treatment on vascular function or superoxide production. Supplementation of human vessels and blood with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with predominant BH2 uptake by vascular tissue. Conclusions-Oral BH4 treatment augments total biopterin levels in patients with established coronary artery disease but has no net effect on vascular redox state or endothelial function owing to systemic and vascular oxidation of BH4. Alternative strategies are required to target BH4-dependent endothelial function in established vascular disease states. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00423280.

SUMMARY:Our purpose was to use multiple inflow pulsed ASL to investigate whether hemodynamic AAT information is sensitive to hemispheric asymmetry in acute ischemia. The cohorts included 15 patients with acute minor stroke or TIA and 15 age-matched controls. Patients were scanned by using a stroke MR imaging protocol at a median time of 74 hours. DWI lesion volumes were small and functional impairment was low; however, perfusion abnormalities were evident. Prolonged AAT values were more likely to reside in the affected hemisphere (significant when compared with controls, P Ͻ .048). An advantage of this ASL technique is the ability to use AAT information in addition to CBF to characterize ischemia. ABBREVIATIONS:AAT ϭ arterial arrival time; ASL ϭ arterial spin-labeling; AUH ϭ area under the histogram; CBF ϭ cerebral blood flow; DSC ϭ dynamic susceptibility contrast; DWI ϭ diffusionweighted imaging; FMRIB ϭ Functional MRI of the Brain; GRASE ϭ gradient and spin-echo; ICA ϭ internal carotid artery; MCA ϭ middle cerebral artery; NIHSS ϭ National Institutes of Health Stroke Scale; PASL ϭ pulsed arterial spin-labeling; TIA ϭ transient ischemic attack A SL is a noninvasive MR imaging technique capable of providing perfusion information without the use of gadolinium-based contrast agents. ASL relies on contrast by magnetically labeling blood water and detecting the signal intensity as a tracer bolus; it has shown promise in clinical studies involving acute stroke 1,2 and ICA occlusion. 3,4 The shortcomings of the ASL techniques include the following: 1) limited brain coverage, 2) low signal intensity-to-noise ratio, and 3) accounting for delays in AAT (the time duration for blood to move from tagging to imaging locations). The current study attempts to address each of these issues.An acute cerebrovascular event may increase the AAT by the following mechanisms: Labeled blood must travel via either collateral pathways of the circle of Willis or secondary collateral pathways, such as those that are provided by leptomeningeal vessels. Labeled blood that remains in the largevessel intravascular space at the time of imaging, due to an insufficient postlabel delay as in continuous ASL or an insufficient TI as in pulsed ASL, will affect the CBF image.2 A recent ICA occlusion study highlighted the relevance of AAT in clinical perfusion ASL. 5 The goal in the current study is to demonstrate the clinical utility of a whole-brain 3D-GRASE-PASL implementation with multiple-inflow periods to derive maps of CBF and AAT in patients with minor stroke/TIA. Analogous to hemodynamic timing parameters used in DSC perfusion for acute stroke diagnosis, AAT maps, hypothetically, can be used to characterize the extent of perfusion abnormalities. TechniqueMR imaging data were collected on a 3T scanner (Tim Trio; Siemens, Erlangen, Germany) with a 12-channel head receive coil in a 2-cohort study: 1) 15 patients with acute minor stroke or TIA, and 2) 15 agematched controls. Carotid Doppler sonography was performed on patients only. Relevant sequen...