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.

Abstract-Offspring born to mothers with hypertensive pregnancy have higher childhood blood pressure. We hypothesized this relates to prenatally programmed differences in the underlying vascular pathophysiology of the offspring and that these would be most apparent in those born preterm because of severe hypertension. We carried out a 20-year follow-up study of 71 subjects born preterm, 19 to a hypertensive pregnancy and 52 to a normotensive pregnancy. Findings were compared with 38 subjects born at term to uncomplicated pregnancies. Peripheral and central blood pressures were measured, and then central arterial stiffness was assessed by carotid-femoral pulse wave velocity using applanation tonometry. Ultrasound was used to assess flow-mediated endothelial-dependent and independent brachial artery responses and common carotid artery intima-media thickness. Key Words: blood pressure Ⅲ preeclampsia Ⅲ endothelial function Ⅲ fetal programming Ⅲ prematurity D e novo onset hypertension affects 5% to 7% of all pregnancies 1 and is manifest as a spectrum of hypertensive complications ranging from gestational hypertension to severe preeclampsia. 2 Hypertensive pregnancy has 3,4 emerged as an independent risk factor for premature maternal cardiovascular disease, 1,5,6 and recently offspring of hypertensive pregnancies have also been found to be at greater risk of higher blood pressure in childhood 7-11 and stroke in later life. 12 Furthermore, the risk to the offspring is graded and greatest in those whose mothers had more severe hypertensive signs, such as early onset hypertension or preeclampsia. 12 Severe hypertensive pregnancy is commonly associated with premature delivery and intrauterine growth restriction. 13 Prematurity and growth restriction, in turn, have been independently linked with hypertension and cardiovascular complications in the offspring, 14 -16 and it is postulated that this is mediated through intrauterine conditions adversely affecting the development of the offspring vascular system. 17 Interestingly, despite both prematurity and intrauterine growth restriction leading to the same clinical sequelae of hypertension, the persistent underlying vascular phenotype appears to vary with, for example, only the term intrauterine growthrestricted offspring exhibiting endothelial dysfunction. 15,18 -20 Better understanding of the long-term changes in vascular pathophysiology related to different pregnancy complications may allow novel primary cardiovascular prevention strategies targeted at key aspects of vascular function. 21

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...