Background The comparative effects of antihypertensive therapy on cerebral hemodynamics in the contest of cognitive decline related to hypertension are unknown. Objectives To compare antihypertensive medicationsthat modulate the renin angiotensin system in cerebral hemodynamic and cognitive effects in hypertensive individuals with executive dysfunction. Design double-blind randomized clinical trial. Setting Community-dwelling Participants Subjects were ≥60 years with hypertension and executive dysfunction. Intervention lisinopril, candesartan, or hydrochlorothiazide for 1 year Measurements Cerebral blood flow velocity (Transcranial Doppler ultrasonography during rest, sitting, standing, hypercapnia, and hypocapnia), cognition and blood pressure were measured at baseline, 6 and 12 months. Linear mixed models were used to compare the3 groups. Results Of the 53 enrolled, 47 had successful insonation (mean age=72 years; 70% white; 57% women). There was a tendency for increased blood flow velocity (BFV) in the candesartan groupcompared to a decline in the lisinopril or HCTZ groups (between group p-value =0.57). This was significant in those with relative low BFV at baseline (

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BackgroundPrior evidence suggests that the renin angiotensin system and antihypertensives that inhibit this system play a role in cognitive, central vascular, and endothelial function. Our objective is to conduct a double-blind randomized controlled clinical trial, the antihypertensives and vascular, endothelial, and cognitive function (AVEC), to compare 1 year treatment of 3 antihypertensives (lisinopril, candesartan, or hydrochlorothiazide) in their effect on memory and executive function, cerebral blood flow, and central endothelial function of seniors with hypertension and early objective evidence of executive or memory impairments.Methods/DesignThe overall experimental design of the AVEC trial is a 3-arm double blind randomized controlled clinical trial. A total of 100 community eligible individuals (60 years or older) with hypertension and early cognitive impairment are being recruited from the greater Boston area and randomized to lisinopril, candesartan, or hydrochlorothiazide ("active control") for 12 months. The goal of the intervention is to achieve blood pressure control defined as SBP < 140 mm Hg and DBP < 90 mm Hg. Additional antihypertensives are added to achieve this goal if needed. Eligible participants are those with hypertension, defined as a blood pressure 140/90 mm Hg or greater, early cognitive impairment without dementia defined (10 or less out of 15 on the executive clock draw test or 1 standard deviation below the mean on the immediate memory subtest of the repeatable battery for the assessment of neuropsychological status and Mini-Mental-Status-exam >20 and without clinical diagnosis of dementia or Alzheimer's disease). Individuals who are currently receiving antihypertensives are eligible to participate if the participants and the primary care providers are willing to taper their antihypertensives. Participants undergo cognitive assessment, measurements of cerebral blood flow using Transcranial Doppler, and central endothelial function by measuring changes in cerebral blood flow in response to changes in end tidal carbon dioxide at baseline (off antihypertensives), 6, and 12 months. Our outcomes are change in cognitive function score (executive and memory), cerebral blood flow, and carbon dioxide cerebral vasoreactivity.DiscussionThe AVEC trial is the first study to explore impact of antihypertensives in those who are showing early evidence of cognitive difficulties that did not reach the threshold of dementia. Success of this trial will offer new therapeutic application of antihypertensives that inhibit the renin angiotensin system and new insights in the role of this system in aging.Trial RegistrationClinicaltrials.gov NCT00605072

Higher levels of aldosterone may be associated with decreased cerebrovascular function in hypertension. Those with higher aldosterone levels may benefit the most from lowering blood pressure. The role of aldosterone in brain health warrants further investigation in a larger trial.

With the widespread use of blood pressure medications, it has become extremely difficult to assess the effects of elevated blood pressure on physiological and pathological phenomena without the confounding effects of antihypertensives. In both observational studies and randomized clinical trials, attempts to account for the antihypertensive effects have ranged from overly simplified dichotomous measures (either on or not on treatment) to tedious formulas that, in most instances, cannot be calculated in the population studied. Here, we propose a novel yet simple measurement index that not only takes into consideration whether an individual is on treatment but also accounts for the number and doses of each antihypertensive medication taken. We are suggesting that this measure maybe superior to the dichotomous measure and can be used to prospectively assess changes in blood pressure treatment. The developed measure was used in an ongoing trial, the Antihypertensive and Vascular, Endothelial, and Cognitive Function, to evaluate the burden of antihypertensive treatment before and after the intervention. The Antihypertensive and Vascular, Endothelial, and Cognitive Function Trial is a double-blind, randomized clinical trial examining the cognitive effects of antihypertensive medications among older adults with mild cognitive impairment. As part of the research protocol, participants were tapered off their usual antihypertensive medications and started on one of the study medications (lisinopril, candesartan, or hydrochlorothiazide; step 2: nifedipine XL; and step 3: metoprolol). This new measure of the antihypertensive load was used to monitor the drug burden of the participants during different phases of the trial. We define the antihypertensive load as the sum of the ratio of the current daily dosage divided by the maximum recommended daily dosage for each medication. The maximum daily dosage of each agent as indicated for hypertension was obtained from the drug database. A similar but more complex drug burden index has been developed for other drug classes. 1(1) Antihypertensive load ϭ antihypertensive medications prescribed daily dosage maximum daily dosage Using this antihypertensive load index, we are monitoring the drug burden of the participants and evaluating whether achieving blood pressure control is associated with increased antihypertensive burden during the study period. So far we have enrolled and randomized 34 individuals, 26 of whom were receiving antihypertensives (mean age: 70 years; 65% women; 27% blacks; antihypertensive load: 0.60Ϯ0.09; controlled to below 140/ 90 mm Hg [58%]). Overall, the antihypertensive load decreased in our sample to 0.55Ϯ0.13, although we achieved a 100% control rate. Of particular interest, among the 15 participants who were controlled when they entered the study, their load significantly decreased from 0.50 to 0.25 (Mann-Whitney test Pϭ0.034), although they remained controlled. In comparison, using the dichotomous measure (treated or not) or the number of antihypertensive...