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Aims: To investigate whether manganese-enhancedmagnetic resonance imagingcan assess functional pancreatic beta-cellmass in people with type 1 diabetes mellitus.Methods: In a prospective case–controlstudy, 20 people with type 1 diabetesmellitus (10 with low (≥50 pmol/L) and 10 with very low (concentrations) and 15 healthy volunteers underwent manganese-enhancedmagnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescanreproducibility was performed in 10 participants.Results: Mean pancreatic manganese uptake was 31 ± 6 mL/100 g of tissue/minin healthy volunteers (median 32 [interquartile range 23–36]years, 6 women),falling to 23 ± 4 and 13 ± 5 mL/100 g of tissue/min (p ≤ 0.002 for both) in peoplewith type1 diabetes mellitus (52 [44–61]years, 6 women) and low or very lowplasma C-peptideconcentrations respectively. Pancreatic manganese uptakecorrelated strongly with plasma C-peptideconcentrations in people with type1diabetes mellitus (r = 0.73, p < 0.001) but not in healthy volunteers (r = −0.054,p = 0.880). There were no statistically significant correlations between manganeseuptake and age, body-massindex, or glycated haemoglobin. There was strongintra-observer(mean difference: 0.31 (limits of agreement −1.42 to 2.05) mL/100 gof tissue/min; intra-classcorrelation, ICC = 0.99), inter-observer(−1.23 (−5.74 to3.27) mL/100 g of tissue/min; ICC = 0.85) and scan-rescan(−0.72 (−2.9 to 1.6)mL/100 g of tissue/min; ICC = 0.96) agreement for pancreatic manganese uptake.Conclusions: Manganese-enhancedmagnetic resonance imaging provides a potentialreproducible non-invasivemeasure of functional beta-cellmass in people with type1 diabetes mellitus. This holds major promise for investigating type 1 diabetes, monitoringdisease progression and assessing novel immunomodulatory interventions.

Arterial calcification is an important hallmark of cardiovascular disease and shares many similarities with skeletal mineralisation. The bone-specific protein osteocalcin (OCN) is an established marker of vascular smooth muscle cell (VSMC) osteochondrogenic trans-differentiation and a known regulator of glucose metabolism. However, the role of OCN in controlling arterial calcification is unclear. We hypothesised that OCN regulates calcification in VSMCs and sought to identify the underpinning signalling pathways. Immunohistochemistry revealed OCN co-localisation with VSMC calcification in human calcified carotid artery plaques. Additionally, 3 mM phosphate treatment stimulated OCN mRNA expression in cultured VSMCs (1.72 fold; p

Aims This study examined the effect of experimentally‐induced hypoglycaemia on measures of myocardial blood flow and myocardial injury in adults with, and without, type 1 diabetes. Methods In a prospective, randomised, open‐label, blinded, endpoint cross‐over study, 17 young adults with type 1 diabetes with no cardiovascular risk factors, and 10 healthy non‐diabetic volunteers, underwent hyperinsulinaemic‐euglycaemic (blood glucose 4.5–5.5 mmol/L) and hypoglycaemic (2.2–2.5 mmol/L) clamps. Myocardial blood flow was assessed using transthoracic echocardiography Doppler coronary flow reserve (CFR) and myocardial injury using plasma high‐sensitivity cardiac troponin I (hs‐cTnI) concentration. Results During hypoglycaemia, coronary flow reserve trended non‐significantly lower in those with type 1 diabetes than in the non‐diabetic participants (3.54 ± 0.47 vs. 3.89 ± 0.89). A generalised linear mixed‐model analysis examined diabetes status and euglycaemia or hypoglycaemia as factors affecting CFR. No statistically significant difference in CFR was observed for diabetes status (p = .23) or between euglycaemia and hypoglycaemia (p = .31). No changes in hs‐cTnI occurred during hypoglycaemia or in the recovery period (p = .86). Conclusions A small change in CFR was not statistically significant in this study, implying hypoglycaemia may require more than coronary vasomotor dysfunction to cause harm. Further larger studies are required to investigate this putative problem., Hypoglycaemia may require more than coronary vasomotor dysfunction to mediate harm

Aim: Ischaemia-reperfusion injury (IRI) causes impaired endothelial function and is a major component of the adverse effects of reperfusion following myocardial infarction. Rotigaptide increases gap junction conductance via connexin-43. We tested the hypothesis that rotigaptide reduces experimental myocardial infarction size and ameliorates endothelial IRI in humans. Methods: Myocardial infarction study: porcine myocardial infarction was achieved by catheter-induced occlusion of the left anterior descending artery. In a randomized double-blind study, rotigaptide (n = 9) or placebo (n = 10) was administered intravenously as a 10 min bolus prior to reperfusion and continuously during 2 h of reperfusion. Myocardial infarction size (IS) was assessed as proportion of the area at risk (AAR). Human translational study: forearm IRI was induced in the presence or absence of intra-arterial rotigaptide. In a randomized double-blind study, forearm arterial blood flow was measured at rest and during intra-arterial infusion of acetylcholine (5–20 μg min–1; n = 11) or sodium nitroprusside (2–8 mg min–1; n = 10) before and after intra-arterial infusion of placebo or rotigaptide, and again following IRI. Results: Myocardial infarction study: Rotigaptide treatment was associated with a reduction of infarct size (IS/AAR[%]: 18.7 ± 4.1 [rotigaptide] vs. 43.6 ± 4.2 [placebo], P = 0.006). Human translational study: Endothelium-dependent vasodilatation to acetylcholine was attenuated after ischaemia-reperfusion in the presence of placebo (P = 0.007), but not in the presence of rotigaptide (P = NS). Endothelium-independent vasodilatation evoked by sodium nitroprusside was unaffected by IRI or rotigaptide (P = NS). Conclusions: Rotigaptide reduces myocardial infarction size in a porcine model and protects from IRI-related endothelial dysfunction in man. Rotigaptide may have therapeutic potential in the treatment of myocardial infarction.

Summary Background With advancing liver disease and the development of portal hypertension, there are major alterations in somatic and visceral blood flow. Using phase-contrast magnetic resonance angiography, we characterised alterations in blood flow within the hepatic, splanchnic and extra-splanchnic circulations of patients with established liver cirrhosis. Aims To compare blood flow in splanchnic and extra-splanchnic circulations in patients with varying degrees of cirrhosis and healthy controls. Methods In a single-centre prospective study, 21 healthy volunteers and 19 patients with established liver disease (Child's stage B and C) underwent electrocardiogram-gated phasecontrast-enhanced 3T magnetic resonance angiography of the aorta, hepatic artery, portal vein, superior mesenteric artery, and the renal and common carotid arteries. Results In comparison to healthy volunteers, resting blood flow in the descending thoracic aorta was increased by 43% in patients with liver disease (4.31 ± 1.47 vs. 3.31 ± 0.80 L/min, P = 0.011). While portal vein flow was similar (0.83 ± 0.38 vs. 0.77 ± 0.35 L/min, P = 0.649), hepatic artery flow doubled (0.50 ± 0.46 vs. 0.25 ± 0.15 L/min, P = 0.021) and consequently total liver blood flow increased by 30% (1.33 ± 0.84 vs. 1.027 ± 0.5 L/min, P = 0.043). In patients with liver disease, superior mesenteric artery flow was threefold higher (0.65 ± 0.35 vs. 0.22 ± 0.13 L/min, P < 0.001), while total renal blood flow was reduced by 40% (0.37 ± 0.14 vs. 0.62 ± 0.22 L/min, P < 0.001) and total carotid blood flow unchanged (0.62 ± 0.20 vs. 0.65 ± 0.13 L/min, P = 0.315). Conclusions Rather than a generalised systemic hyperdynamic circulation, liver disease is associated with dysregulated splanchnic vasodilatation and portosystemic shunting that, while inducing a high cardiac output, causes compensatory extra-splanchnic vasoconstriction - the ‘splanchnic steal’ phenomenon. These circulatory disturbances may underlie many of the manifestations of advanced liver disease.

LY is funded by a Wellcome Trust-GSK Translational Medicine and Therapeutics (TMAT) Studentship and a Raymond and Beverley Sackler Fellowship. IW is a British Heart Foundation Senior Clinical Fellow and both JC and IW are supported by the Cambridge NIHR Biomedical Research Centre. Funding for the two studies (NCT01762774 and NCT02006537) was provided by GSK. Partial funding for study 1 was provided by the Innovate UK Stratified Medicines programme (ERICA Consortium).

Air pollution is now recognized as an important independent risk factor for cardiovascular morbidity and mortality and may be responsible for up to 3 million premature deaths each year worldwide. The mechanisms underlying the observed effects are poorly understood but are likely to be multifactorial. Here, we review the acute and chronic effects of air pollution exposure on the cardiovascular system and discuss how these effects may explain the observed increases in cardiovascular morbidity and mortality.

Despite major advances in antiplatelet therapies, recurrent cardiovascular events remain high after acute coronary syndrome. Furthermore, incremental benefits achieved in the reduction of atherothrombotic events have almost always been at the expense of hemorrhagic side effects. Thrombin is the most potent platelet activating factor known and it makes important interactions with the endothelium and vascular smooth muscle with proinflammatory, proatherogenic effects. Distinct from its activity within the coagulation cascade, thrombin mediates these effects via protease-activated receptor type 1 (PAR-1) in man. This review discusses the role of PAR-1 in the vasculature and the development of novel PAR-1 antagonists. These drugs may provide important antiatherothrombotic effects without attendant bleeding complications and could represent a major breakthrough for the treatment of cardiovascular diseases.

Aims A number of endothelin receptor antagonists (ERAs) are currently in clinical development as potential therapies in states characterized by vasoconstriction, such as systemic hypertension. We investigated the haemodynamic effects of locally and systemically active doses of BMS-193884, an endothelin A (ETA) receptor selective ERA, and its influence on vasoconstriction to endothelin-1 (ET-1) in healthy men. Methods In three separate randomized, placebo-controlled studies, the forearm blood flow (FBF) response to intra-arterial (i.a.) infusion of ET-1 (5 pmol min−1) was assessed during i.a. co-infusion of BMS-193884 (5 and 50 nmol min−1), and at 12 and at 24 h after oral administration of BMS-193884 (50, 100 and 200 mg at 12 h; and 200 mg at 24 h). Data were examined by repeated-measures analysis of variance (anova) with treatment and subject as factors. Results ET-1 caused significant forearm vasoconstriction, attenuated after oral dosing with BMS-193884 (200 mg) at 12 (P

The influence of vasodilators on augmentation index (AIx) offers a simple, rapid and noninvasive method of evaluating vascular function. Glyceryl trinitrate (GTN) is widely used as an endothelium-independent vasodilator, although other nitrates that are shorter acting may have advantages in clinical studies. The aim of this study was to compare the effects of two short-acting nitrates, GTN and amyl nitrite, which have differing pharmacodynamic profiles.Twenty-one healthy volunteers (15 male; mean age 35 years, range 21-56 years) attended on three occasions and received sublingual GTN (0.5 mg for 3 min), inhaled amyl nitrite (0.2 ml inhaled for 30 s), or no treatment in a randomized cross-over design. Haemodynamic responses of AIx, blood pressure and thoracic bioimpedance (heart rate, cardiac index) were assessed by measurement at baseline, every 60 s for the first 5 min, and then every 5 min for a further 55 min.AIx was reduced by amyl nitrite (peak effect -9 +/- 2% at 1 min, P0.002) and GTN (peak effect -12 +/- 3% at 4 min, P0.05). Compared with amyl nitrite, the onset and offset of action of GTN was slower. Amyl nitrite initially increased heart rate by 27 +/- 4% (P0.001) and cardiac index by 13 +/- 3% (P0.001) whereas GTN had no significant effect (P0.05). Neither agent affected blood pressure.GTN causes a slower and more sustained reduction in AIx than amyl nitrite. Although amyl nitrite causes a more rapid fall and recovery in AIx, it induces a reflex tachycardia that may limit interpretation of the initial (1 min) but not later (2 min) changes in AIx. The prolonged offset of GTN suggests that a sufficient washout period must be included when making repeated measures or when assessing the subsequent effects of other agents.

Aims In rodent and primate studies, urotensin II is an extremely potent vasoconstrictor peptide with effects in the central aortic and arterial vasculature as well as on cardiac function. The aim of the present study was to assess systemic haemodynamic responses to intravenous urotensin II infusion in humans. Methods In 10 healthy male volunteers, intravenous urotensin II (3, 30 and 300 pmol min−1) and saline placebo were given on separate occasions in a single-blind randomized manner. Systemic haemodynamics and arterial stiffness were assessed by sphygmomanometry, transthoracic bioimpedance, and pulse wave analysis. Plasma urotensin II immuno-reactivity was measured by radio-immunoassay. Results Intravenous urotensin II infusions were well tolerated with no adverse clinical effects and no electrocardiographic changes. Circulating plasma urotensin II immuno-reactivity increased from baseline of 16 ± 1 to 1460 ± 82 pmol l−1 (mean ± s.e. mean) during infusion of urotensin II at 300 pmol min−1 (P

Aims We investigated the repeatability of the forearm blood flow response to intra-arterial infusion of endothelin-1 (ET-1), assessed by venous occlusion ­plethysmography. Methods In eight healthy men (aged 18–50 years), on four separate occasions, ET-1 (2.5 or 10 pmol min−1) was infused for 120 min via a 27 SWG cannula sited in the brachial artery of the nondominant arm. Each dose level was administered twice on consecutive visits. The dose order was randomized. Results are expressed as percentage change from baseline at 120 min (mean ± s.e. mean). Results ET-1 caused significant vasoconstriction (P

Advances in catheter-based technology have put many innovative techniques at the disposal of the clinical investigator. Intravascular ultrasound (IVUS), in particular, has facilitated the more detailed functional and morphological assessment of the coronary circulation, and will be the major focus of this review. Selective intracoronary drug infusion may be desirable for a number of reasons. When examining in vivo vascular responses, systemic drug administration causes concomitant effects on organs, such as the brain and kidney, and influences neurohumoral reflexes through changes in systemic haemodynamics. Intracoronary infusions have the advantage of assessing the heart and coronary circulation in relative isolation without invoking systemic effects. This is particularly important for the assessment of cardiac and coronary function which is heavily dependent on changes in the systemic vasculature and haemodynamics. In addition, relatively high doses can be administered locally which may be important for the desired physiological or therapeutic effect and may be further facilitated by the use of local drug delivery systems. Finally, combining intracoronary drug administration with coronary sinus catheterization and sampling can further extend the assessment of the coronary circulation to include additional aspects of cardiac metabolism and function. In addition to providing functional information, IVUS provides an invasive method of assessing arterial structure and morphology. Detailed and high-resolution examination of the proximal coronary vasculature is possible with precise and accurate definition of tissue planes [1, 2]. This permits the quantitative assessment of atherosclerotic burden and composition as well as enabling the assessment of systemic therapeutic interventions targeted at reducing atherosclerosis such as lipid-lowering therapy [3, 4].

Aims Following intravenous administration of its prodrug, L-758,298, we assessed the pharmacodynamics of L-754,030, a novel and highly selective NK1 receptor antagonist, by examining systemic haemodynamics and the blood flow responses to intra-arterial substance P infusion. Methods Sixteen healthy male volunteers participated in a double-blind, randomised, placebo controlled crossover trial of L-758 298. Forearm blood flow was measured using venous occlusion plethysmography during intrabrachial substance P infusion (0.125–128 pmol min−1 ). In part 1, eight subjects received substance P infusions before and during placebo, 0.25 mg, 1 mg or 5 mg of L-758 298. In part 2, eight subjects received substance P infusions 24 h after placebo or 1.43 mg of L-758 298. Results L-758 298 caused dose dependent inhibition of substance P induced vasodilatation (P 1400–fold shift in substance P response): 0.00 (−0.49 to +0.49) ml 100 ml−1 min−1, 1.0 (−3.2 to +5.2) mmHg and 1.9 (−5.9 to +9.7) beats min−1, respectively. Twenty-four hours after 1.43 mg of L-758,298, there was ~34–fold shift in response to substance P induced vasodilatation (P

Aims The current studies were designed to characterize the pharmacology, reproducibility and tolerability of the vasodilator response to intra-arterial substance P infusion in the forearm of healthy man. Methods On different occasions, eight healthy male volunteers received brachial artery infusions of substance P at doubling doses ranging from 0.5 to 128 pmol min−1. Blood flow was measured in both arms using venous occlusion plethysmography. Results Substance P induced dose-dependent vasodilatation in the human forearm which had a log-linear relationship to dose. At doses of 1–8 pmol min−1, mean responses were highly reproducible both within and between days. There were no differences between responses to discontinuous doses and continuous doses of substance P. Substance P was generally well tolerated at doses of ≤64 pmol min−1 with no significant alteration in arterial blood pressure or heart rate. Skin oedema in the infused forearm and systemic vasodilatation, manifested by facial flushing and non-infused forearm vasodilatation, occurred at doses of ≥16 pmol min−1. Conclusions Forearm vasodilatation to substance P represents a reproducible and useful model in the assessment of peripheral endothelial cell NK1 receptor function.