Vascular Consequences of Prehypertension

Prehypertension, defined as systolic blood pressure between 120-139 mm Hg and/or diastolic blood pressure between 80-89 mm Hg, is a common condition that affects ~30% of the US adult population. It is increasingly recognized that prehypertension is not only an independent risk factor for the development of clinical hypertension (blood pressure ≥ 140/90 mm Hg), but also cardiovascular disease and its clinical consequences, such as myocardial infarction, stroke, and congestive heart failure. The increased cardiovascular risk associated with prehypertension may be mediated, at least in part, by vascular endothelial dysfunction, a critical etiological event in the pathogenesis and progression of atherosclerotic vascular disease. However, the impact of blood pressure in the prehypertensive range on the vascular endothelium is currently unclear. Accordingly, the purpose of this dissertation was to determine: 1) if prehypertension is associated with impaired nitric oxide (NO)-mediated endothelium-dependent vasodilation; 2) whether endothelin (ET)-1 vasoconstrictor tone is elevated in prehypertensive adults; and, if so, 3) whether the increase in ET-1-mediated vasoconstriction contributes to endothelial vasodilator dysfunction in prehypertensive adults. To address these aims, venous occlusion plethysmography was used to measure forearm blood flow responses to intra-arterial acetylcholine, sodium nitroprusside, and selective and non-selective ET-1 receptor blockade in normotensive and prehypertensive adults. In addition, forearm blood flow responses to acetylcholine were determined with concomitant endothelial NO synthase inhibition and selective ET-1 receptor blockade. The results of these studies indicate that: 1) prehypertension is associated with impaired NO-mediated endothelium-dependent vasodilation; 2) ET-1 vasoconstrictor tone is greater in prehypertensive compared with normotensive adults; and 3) the elevation in ET-1-mediated vasoconstriction contributes to impaired endothelium-dependent vasodilation with prehypertension. Collectively, these findings demonstrate that blood pressure in the prehypertensive range, independent of other cardiovascular risk factors, is associated with impaired endothelial vasomotor function. Reduced NO-mediated endothelium-dependent vasodilation and elevated ET-1-mediated vasoconstrictor tone represent an atherogenic endothelial phenotype that may contribute to the elevated risk of clinical hypertension and acute vascular events in prehypertensive adults

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)