Colin Cunnington

Effects of High-Dose Modified-Release Nicotinic Acid on Atherosclerosis and Vascular Function: A Randomized, Placebo-Controlled, Magnetic Resonance Imaging Study

OBJECTIVESnOur aim was to determine the effects of high-dose (2 g) nicotinic acid (NA) on progression of atherosclerosis and measures of vascular function.nnnBACKGROUNDnNA raises high-density lipoprotein cholesterol (HDL-C) and reduces low-density lipoprotein cholesterol and is widely used as an adjunct to statin therapy in patients with coronary artery disease. Although changes in plasma lipoproteins suggest potential benefit, there is limited evidence of the effects of NA on disease progression when added to contemporary statin treatment.nnnMETHODSnWe performed a double-blind, randomized, placebo-controlled study of 2 g daily modified-release NA added to statin therapy in 71 patients with low HDL-C (<40 mg/dl) and either: 1) type 2 diabetes with coronary heart disease; or 2) carotid/peripheral atherosclerosis. The primary end point was the change in carotid artery wall area, quantified by magnetic resonance imaging, after 1 year.nnnRESULTSnNA increased HDL-C by 23% and decreased low-density lipoprotein cholesterol by 19%. At 12 months, NA significantly reduced carotid wall area compared with placebo (adjusted treatment difference: -1.64 mm(2) [95% confidence interval: -3.12 to -0.16]; p = 0.03). Mean change in carotid wall area was -1.1 +/- 2.6 mm(2) for NA versus +1.2 +/- 3.0 mm(2) for placebo. In both the treatment and placebo groups, larger plaques were more prone to changes in size (r = 0.4, p = 0.04 for placebo, and r = -0.5, p = 0.02 for NA).nnnCONCLUSIONSnIn statin-treated patients with low HDL-C, high-dose modified-release NA, compared with placebo, significantly reduces carotid atherosclerosis within 12 months. (Oxford Niaspan Study: Effects of Niaspan on Atherosclerosis and Endothelial Function; NCT00232531).

Altered Plasma Versus Vascular Biopterins in Human Atherosclerosis Reveal Relationships Between Endothelial Nitric Oxide Synthase Coupling, Endothelial Function, and Inflammation

Background— Tetrahydrobiopterin (BH4) is a key regulator of endothelial nitric oxide synthase (eNOS) activity and coupling. However, the extent to which vascular and/or systemic BH4 levels are altered in human atherosclerosis and the importance of BH4 bioavailability in determining endothelial function and oxidative stress remain unclear. We sought to define the relationships between plasma and vascular biopterin levels in patients with coronary artery disease and to determine how BH4 levels affect endothelial function, eNOS coupling, and vascular superoxide production. Methods and Results— Samples of saphenous veins and internal mammary arteries were collected from 219 patients with coronary artery disease undergoing coronary artery bypass grafting. We determined plasma and vascular levels of biopterins, vasomotor responses to acetylcholine, and vascular superoxide production in the presence and absence of the eNOS inhibitor NG-nitro-l-arginine methyl ester. High vascular BH4 was associated with greater vasorelaxations to acetylcholine (P<0.05), whereas high plasma BH4 was associated with lower vasorelaxations in response to acetylcholine (P<0.05). Furthermore, an inverse association was observed between plasma and vascular biopterins (P<0.05 for both saphenous veins and internal mammary arteries). High vascular (but not plasma) BH4 was associated with reduced total and NG-nitro-l-arginine methyl ester–inhibitable superoxide, suggesting improved eNOS coupling. Finally, plasma but not vascular biopterin levels were correlated with plasma C-reactive protein levels (P<0.001). Conclusions— An inverse association exists between plasma and vascular biopterins in patients with coronary artery disease. Vascular but not plasma BH4 is an important determinant of eNOS coupling, endothelium-dependent vasodilation, and superoxide production in human vessels, whereas plasma biopterins are a marker of systemic inflammation.

Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models

Mitochondrial aldehyde dehydrogenase-2 (ALDH-2) is involved in preconditioning pathways, but its role in remote ischaemic preconditioning (rIPC) is unknown. We investigated its role in animal and human models of rIPC. (i) In a rabbit model of myocardial infarction, rIPC alone reduced infarct size [69xa0±xa05.8xa0% (nxa0=xa011) to 40xa0±xa06.5xa0% (nxa0=xa012), Pxa0=xa00.019]. However, rIPC protection was lost after pre-treatment with the ALDH-2 inhibitor cyanamide (62xa0±xa07.6xa0% controls, nxa0=xa010, versus 61xa0±xa06.9xa0% rIPC after cyanamide, nxa0=xa010, Pxa0>xa00.05). (ii) In a forearm plethysmography model of endothelial ischaemia–reperfusion injury, 24 individuals of Asian ethnic origin underwent combined rIPC and ischaemia–reperfusion (IR). 11 had wild-type (WT) enzyme and 13 carried the Glu504Lys (ALDH2*2) polymorphism (rendering ALDH-2 functionally inactive). In WT individuals, rIPC protected against impairment of response to acetylcholine (Pxa0=xa00.9), but rIPC failed to protect carriers of Glu504Lys polymorphism (Pxa0=xa00.004). (iii) In a second model of endothelial IR injury, 12 individuals participated in a double-blind placebo-controlled crossover study, receiving the ALDH-2 inhibitor disulfiram 600xa0mg od or placebo for 48xa0h prior to assessment of flow-mediated dilation (FMD) before and after combined rIPC and IR. With placebo, rIPC was effective with no difference in FMD before and after IR (6.18xa0±xa01.03xa0% and 4.76xa0±xa00.93xa0% Pxa0=xa00.1), but disulfiram inhibited rIPC with a reduction in FMD after IR (7.87xa0±xa01.27xa0% and 3.05xa0±xa00.53xa0%, Pxa0=xa00.001). This study demonstrates that ALDH-2 is involved in the rIPC pathway in three distinct rabbit and human models. This has potential implications for future clinical studies of remote conditioning.

Impaired Endothelial Responses in Apparently Healthy Young People Associated With Subclinical Variation in Blood Pressure and Cardiovascular Phenotype

BACKGROUNDnA phenomenon of endothelial impairment, independent of classical cardiovascular risk factors, has been observed in young people. We identified subjects with persistently reduced, or declining, endothelial function during adolescence and early adulthood, without apparent cardiovascular risk, and investigated the clinical relevance of this finding.nnnMETHODSnEndothelial vasomotor responses were assessed by brachial artery flow-mediated dilatation (FMD) at age 15 years in 47 subjects (22 males) who returned for a repeated measurement at age 25. Subjects underwent quantification of left ventricular mass (LVM) and function by cardiovascular magnetic resonance, central arterial stiffness by applanation tonometry, and common carotid artery intima-media thickness using ultrasound on their visit at age 25.nnnRESULTSnIndividuals with low average FMD over 10-year period, although normotensive, had 5 mm Hg higher systolic blood pressure and, significantly greater LVM (73.48 ± 7.73 vs. 56.25 ± 9.54 g/m(2), P = 0.0001), carotid intima-media thickness (cIMT) (0.53 ± 0.06 vs. 0.47 ± 0.04 mm, P = 0.03), and pulse wave velocity (5.97 ± 0.63 vs. 5.29 ± 0.59 m/s, P = 0.02) than those with higher endothelial responses. Subjects with the greatest decline in FMD over 10 years had a significant increase in mean arterial pressure but similar cardiovascular phenotype.nnnCONCLUSIONnPersistently reduced, or declining, endothelial function during adolescence, in the absence of overt cardiovascular disease, is a sensitive early marker associated with subclinical changes in blood pressure (BP) and an adverse cardiovascular phenotype. The findings highlight the potential importance of endothelial responses during adolescence in primary prevention strategies for hypertension.

Adenosine Receptor Activation in the “Trigger” Limb of Remote Pre-Conditioning Mediates Human Endothelial Conditioning and Release of Circulating Cardioprotective Factor(s)

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