Clinical Trials

Growing evidence suggests an association of environmental stress with the development of hypertension and there is strong evidence in normotensive subjects that a greater pressor response to sympathoexcitatory stress is a harbinger of future hypertension. Pharmacological studies have shown that individuals with HTN have a blunted baroreflex sensitivity, and display a greater increase in blood pressure during administration of an alpha-agonist.  Furthermore, exaggerated 24-hour ambulatory blood pressure variability (BPV) is proposed to be a risk factor for the development of cardiovascular disease.  Finally, Beta-2 adrenergic receptor-mediated forearm vasodilator responses to mental stress are blunted in Caucasian subjects at increased risk for hypertension, in African Americans, and in mild hypertension.  We postulate that a relationship exists between these variables, even in normotensive healthy individuals.  We also believe that signs of subclinical metabolic dysfunction exist in healthy individuals and that they may either contribute to or be affected by BPV.  There is also evidence the prematurity at birth and low birth weight are associated with hypertension.  Finally, arterial stiffness may also be related to blood pressure variability and the pressor response.  Therefore the specific aims of this study are:

       1. To examine the relationship between 24-hour ambulatory BPV and baroreflex sensitivity. By measuring the baroreflex control of heart rate during sequential boluses of nitroprusside and phenylephrine, we hypothesize that baroreflex sensitivity will be inversely related to the degree of 24-hour BPV.

       2. To examine the relationship between 24-hour ambulatory BPV and the pressor response to four sympathoexcitatory maneuvers: head-up tilt testing, mental stress, cold pressor test, and isometric handgrip to fatigue.  We hypothesize that greater BPV will predict the pressor response to stress.

       3. To examine the relationship between baroreflex sensitivity and the pressor response/forearm vasodilator response to the three sympathoexcitatory maneuvers.  We hypothesize that individuals with higher baroreflex sensitivity will have a lower pressor response and a lower forearm vasodilator response to sympathoexcitatory stress.

       4. To draw a venous blood sample for future screening of genetic polymorphisms of interest, which may include nitric oxide synthase (NOS), alpha-adrenergic and beta-adrenergic receptor polymorphisms.  We hypothesize that genetic variation in these key regulatory systems might explain some of the differences in baroreflex sensitivity, BPV, the pressor response and forearm vasodilator response to sympathoexcitation.

       5. To examine the relationship between 24-hour ambulatory BPV and the pressor response to sympathoexcitatory maneuvers and insulin resistance, dyslipidemia, and body fat distribution.  We hypothesize that greater BPV will be associated with insulin resistance, dyslipidemia, and increase waist-hip ratio.

       6. To examine the relationship between 24-hour ambulatory BPV and arterial stiffness using measurements of pulse wave velocity.  We hypothesize that greater BPV will be associated with increased pulse wave velocity, an index of arterial stiffness.

       7. To examine the relationship between 24-hour ambulatory BPV and the pressor response to sympathoexcitatory maneuvers with birth weight and post-conceptual age at birth.  We will ask each subject to provide this data based on their birth certificate and/or knowledge of their medical history.

Evidence suggests a relationship between sleep deprivation and cardiovascular disease. Voluntary sleep restriction is common, with 28% of the US adult population reports getting 6 or fewer hours of sleep per night, and those who do are 24% more likely to have cardiovascular disease and have twice the risk of hypertension. Insufficient sleep may conceivably be one of the most common, and most preventable, cardiovascular risk factors. The investigators wish to determine whether 9 nights of modest sleep restriction results in activation of cardiovascular disease mechanisms, thus potentially increasing the risk of cardiovascular disease. The investigators will combine our cardiovascular studies with state-of-the art sleep monitoring and neurocognitive tests to provide unambiguous data on the neurologic effects of sleep restriction. Together, the investigators findings will help explain whether the reduced sleep duration in the general population may be contributing to the current epidemic of cardiovascular disease, and suggest strategies to reduce this risk.

Elevated blood pressure (BP) is an important public health concern. It is highly prevalent, the prevalence may be increasing, and it is a risk factor for several adverse health outcomes, especially coronary heart disease, stroke, heart failure, chronic kidney disease, and decline in cognitive function.  SPRINT will randomize about 9250 participants aged ≥ 55 years with SBP ≥130 mm Hg and at least one additional CVD risk factor. The trial will compare the effects of randomization to a treatment program of an intensive SBP goal with randomization to a treatment program of a standard goal. Target SBP goals are <120 vs <140 mm Hg, respectively, to create a minimum mean difference of 10 mm Hg between the two randomized groups. The primary hypothesis is that CVD event rates will be lower in the intensive arm. Participants will be recruited at approximately 90 clinics within 5 clinical center networks (CCNs) over a 2-year period, and will be followed for 4-6 years.

The proposed work should help move toward the long-term goal of selection of antihypertensive drug therapy based on a patient's genetic make-up. Hypertension (HTN) is the most common chronic disease for which drugs are prescribed, and the most prevalent risk factor for heart attack, stroke, renal failure and heart failure. Responses to antihypertensive drug therapy exhibit considerable interpatient variability, contributing to poor rates of HTN control (currently about 40-50% in the US), and frequent nonadherence and dropout from therapy. We propose to identify genetic predictors of the antihypertensive and adverse metabolic responses to two preferred and pharmacodynamically contrasting drugs, a beta-blocker (metoprolol) and a thiazide diuretic (chlorthalidone) in a sequential monotherapy design in 400 hypertensive individuals. Data collected will include home and clinic blood pressure, blood samples for testing for adverse metabolic effects and other biomarkers, RNA, and DNA and urine sample. We will conduct genome-wide association SNP genotyping and data from the study will be used for replication of findings from the previous PEAR trial, along with new discoveries. The primary aims are to define the genetic determinants of the antihypertensive response and adverse metabolic responses (e.g. changes in glucose, triglycerides and uric acid). The proposed research is significant because genetically-targeted antihypertensive therapy could lead to dramatically higher response rates and fewer adverse effects than the usual trial-and-error approach. This would likely lead to higher rates of HTN control, less need for polypharmacy, reduced health care costs, and improved outcomes.

Hypertension remains a global burden in cardiovascular disease leading to stroke, myocardial infarction, and heart failure. Its myocardial complications result from increased mechanical load on the heart. Under physiological conditions of increased myocardial load and resulting myocardial stretch, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) synthesis and secretion occur contributing to maintenance of optimal cardiorenal and blood pressure homeostasis. However, studies indicate that in subjects with cardiovascular diseases the biological structure of these hormones may be altered, thus reducing their favorable protective activities. New studies indicate that early and moderate hypertension is associated with a derangement of the natriuretic peptide system which is characterized by the lack of activation of biologically active ANP and BNP, while severe hypertension is characterized by cardiac release of altered molecular forms of ANP and BNP that have reduced biological properties and/or enhanced degradation. The broad objective of proposal is to advance the biology and therapeutics of the natriuretic peptides (NPs) with a special focus on the cardiac peptide BNP in human hypertension. Our proposal is based upon the biological properties of BNP (i.e., natriuretic, renin-angiotensin-aldosterone suppressing, vasodilating, anti-fibrotic, anti-hypertrophic and positive lusitropic), its mechanistic role in human hypertension, and thus its potential as an innovative chronic protein therapeutic to enhance the treatment of patients with uncontrolled and or resistant hypertension. Importantly, BNP is an endocrine hormone normally produced by the human heart, and its use as therapeutic agent has been approved in USA for more than a decade and has been proven to be safe.