Showing papers by "Suzanne Oparil published in 2006"

Feasibility of Treating Prehypertension with an Angiotensin-Receptor Blocker

Abstract: Background Prehypertension is considered a precursor of stage 1 hypertension and a predictor of excessive cardiovascular risk. We investigated whether pharmacologic treatment of prehypertension prevents or postpones stage 1 hypertension. Methods Participants with repeated measurements of systolic pressure of 130 to 139 mm Hg and diastolic pressure of 89 mm Hg or lower, or systolic pressure of 139 mm Hg or lower and diastolic pressure of 85 to 89 mm Hg, were randomly assigned to receive two years of candesartan (Atacand, AstraZeneca) or placebo, followed by two years of placebo for all. When a participant reached the study end point of stage 1 hypertension, treatment with antihypertensive agents was initiated. Both the candesartan group and the placebo group were instructed to make changes in lifestyle to reduce blood pressure throughout the trial. Results A total of 409 participants were randomly assigned to candesartan, and 400 to placebo. Data on 772 participants (391 in the candesartan group and 381 in the placebo group; mean age, 48.5 years; 59.6 percent men) were available for analysis. During the first two years, hypertension developed in 154 participants in the placebo group and 53 of those in the candesartan group (relative risk reduction, 66.3 percent; P<0.001). After four years, hypertension had developed in 240 participants in the placebo group and 208 of those in the candesartan group (relative risk reduction, 15.6 percent; P<0.007). Serious adverse events occurred in 3.5 percent of the participants assigned to candesartan and 5.9 percent of those receiving placebo. Conclusions Over a period of four years, stage 1 hypertension developed in nearly two thirds of patients with untreated prehypertension (the placebo group). Treatment of prehypertension with candesartan appeared to be well tolerated and reduced the risk of incident hypertension during the study period. Thus, treatment of prehypertension appears to be feasible. (ClinicalTrials.gov number, NCT00227318.)

Salt sensitivity, a determinant of blood pressure, cardiovascular disease and survival.

Abstract: High dietary sodium has been adduced as a cause of hypertension and its target organ damage for millennia; yet careful observations using sophisticated techniques have revealed only a weak relationship between sodium intake/excretion and blood pressure in the general population Further, studies of the effects of dietary sodium reduction on blood pressure have revealed minimal achieved reductions in blood pressure, no relationship between the magnitude of reduction in sodium intake/excretion and the blood pressure effect, and no evidence of an effect of sodium reduction on death or cardiovascular events While blood pressure in the population as a whole is only modestly responsive to alterations in sodium intake, some individuals manifest large blood pressure changes in response to acute or chronic salt depletion or repletion, and are termed "salt sensitive" Salt sensitivity and resistance have a large variety of determinants, including genetic factors, race/ethnicity, age, body mass and diet (overall diet quality, macro- and micronutrient content), as well as associated disease states, eg hypertension, diabetes and renal dysfunction Salt sensitivity can be modulated by improving the quality of the diet, eg the DASH diet reduced salt sensitivity by increasing the slope of the pressure-natriuresis curve Mechanisms that appear to contribute to salt sensitivity include blunted activity of the renin-angiotensin-aldosterone system, deficiency in atrial natriuretic peptide expression, and blunted arterial baroreflex sensitivity Salt sensitivity in both normotensive and hypertensive persons has been associated with increased cardiovascular disease events and reduced survival Increased attention to strategies that reduce salt sensitivity, ie improvement in diet quality and weight loss, particularly in high risk persons, is urgently needed

Dominant negative mutation of the TGF-β receptor blocks hypoxia-induced pulmonary vascular remodeling

Abstract: The present study utilized a novel transgenic mouse model that expresses an inducible dominant negative mutation of the transforming growth factor (TGF)-β type II receptor (DnTGFβRII mouse) to test...

Efficacy and safety of irbesartan/HCTZ combination therapy as initial treatment for rapid control of severe hypertension.

Abstract: Severe hypertension is difficult to control. This prospective, randomized, double-blind, active-controlled, multicenter trial compared efficacy and safety of once-daily irbesartan/hydrochlorothiazide (HCTZ) combination therapy with irbesartan monotherapy in severe hypertension. Patients who were untreated or uncontrolled on monotherapy (seated diastolic blood pressure [BP] ≥110 mm Hg) received fixed-dose irbesartan 150 mg/HCTZ 12.5 mg combination therapy for 7 weeks, force-titrated to irbesartan 300 mg/HCTZ 25 mg at week 1 (n=468); or irbesartan 150 mg monotherapy, force-titrated to 300 mg at week 1 (n=269). Significantly more patients on combination therapy achieved seated diastolic BP <90 mm Hg at week 5 (primary end point) compared with monotherapy recipients (47.2% vs 33.2%; P=.0005). Likewise, significantly more patients attained goals per the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) (<140/90 mm Hg) at week 5 (34.6% vs 19.2%, respectively; P<.0001), while the mean difference between combination and monotherapy in seated diastolic BP and seated systolic BP was 4.7 mm Hg and 9.7 mm Hg (P<.0001). Greater and more rapid BP reduction with irbesartan/HCTZ was achieved without additional side effects.

Women and hypertension: what did we learn from the Women's Health Initiative?

Abstract: The Women's Health Initiative (WHI) provides valuable data on blood pressure (BP) and on the prevalence, treatment, and control of hypertension in the largest multiethnic, best characterized cohort of postmenopausal women ever studied, including 98,705 women aged 50 to 79 years. Hypertension prevalence was high (38% overall) and directly related to age. Major determinants of hypertension prevalence included black race, history of cardiovascular disease (CVD), and concomitant CVD risk factors of physical inactivity, overweight/obesity, and excess alcohol consumption. Menopausal hormone treatment had little effect on BP. BP control rates declined dramatically with age. Interestingly, participants who were insured by Medicaid had significantly higher treatment rates and tended to have better BP control than those with Medicare only, perhaps reflecting differences in drug coverage and/or age. Inadequate intensity of antihypertensive treatment contributed to poor BP control: approximately 60% of participants were treated with a single drug; 30% with 2 drugs; <10% with 3 or more drugs, and the number of medications used was similar across age groups despite the age-related increase in the severity of hypertension. This treatment pattern is inconsistent with current treatment guidelines, which stress the need for 2 or more antihypertensive medications to control BP in most older hypertensive patients. The take-home message from WHI is that more effective strategies, including more efficient and cost-effective systems of healthcare delivery, are needed to control BP and prevent CVD morbidity and mortality in older women, a group characterized by severe, treatment-resistant hypertension and high risk for CVD events.

Incidence and Predictors of Angioedema in Elderly Hypertensive Patients at High Risk for Cardiovascular Disease: A Report From the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Abstract: Angioedema is a rare, potentially life-threatening condition that has been associated with angiotensin-converting enzyme inhibitors since their introduction in the 1980s. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the largest antihypertensive study conducted to date, randomized 42,418 participants to a diuretic (chlorthalidone), a calcium channel blocker (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), or an alpha-blocker (doxazosin). Patients who developed angioedema were compared for baseline characteristics and changes in antihypertensive drug administration. Fifty-three participants developed angioedema during active follow-up: 55% were black, 60% men, and 70% were assigned to lisinopril (including 62% of black participants with angioedema), 15% to chlorthalidone, 9% to doxazosin, and 6% to amlodipine. Six percent occurred within a day of randomization and 23% within the first week. Over half did not have an increase in their assigned (blinded) antihypertensive drug before angioedema onset; 3 (6%) had a dose increase within a week before onset. One patient died following an angioedema episode. The occurrence of angioedema in the angiotensin-converting enzyme inhibitor arm corresponds with previously reported angioedema-angiotensin-converting enzyme inhibitor associations.

Metabolite ligands of estrogen receptor-β reduce primate coronary hyperreactivity

Abstract: Previous reports showed that 17beta-estradiol implants attenuate in vivo coronary hyperreactivity (CH), characterized by long-duration vasoconstrictions (in coronary angiographic experiments), in menopausal rhesus monkeys. Prolonged Ca2+ contraction signals that correspond with CH in coronary vascular muscle cells (VMC) to the same dual-constrictor stimulus, serotonin + the thromboxane analog U-46619, in estrogen-deprived VMC were suppressed by >72 h in 17beta-estradiol. The purpose of this study was to test whether an endogenous estrogen metabolite with estrogen receptor-beta (ER-beta) binding activity, estriol (E3), suppresses in vivo and in vitro CH. E3 treatment in vivo for 4 wk significantly attenuated the angiographically evaluated vasoconstrictor response to intracoronary serotonin + U-46619 challenge. In vitro treatment of rhesus coronary VMC for >72 h with nanomolar E3 attenuated late Ca2+ signals. This reduction of late Ca2+ signals also appeared after >72 h of treatment with subnanomolar 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), an endogenous dihydrotestosterone metabolite with ER-beta binding activity. R,R-tetrahydrochrysene, a selective ER-beta antagonist, significantly blocked the E3- and 3beta-Adiol-mediated attenuation of late Ca2+ signal increases. ER-beta and thromboxane-prostanoid receptor (TPR) were coexpressed in coronary arteries and aorta. In vivo E3 treatment attenuated aortic TPR expression. Furthermore, in vitro treatment with E3 or 3beta-Adiol downregulated TPR expression in VMC, which was blocked for both agonists by pretreatment with R,R-tetrahydrochrysene. E3- and 3beta-Adiol-mediated reduction in persistent Ca2+ signals is associated with ER-beta-mediated attenuation of TPR expression and may partly explain estrogen benefits in coronary vascular muscle.

Treatment of isolated systolic hypertension in diabetes mellitus type 2.

Abstract: Age-related arterial stiffness is more pronounced in diabetics compared to non-diabetics, which could explain the prevalence of isolated systolic hypertension (ISH, systolic blood pressure > or =140 mmHg and diastolic blood pressure <90 mmHg) being approximately twice that of the general population without diabetes. Large-scale interventional outcome trials have also shown that diabetics usually have higher pulse pressure and higher systolic blood pressure than non-diabetics. Advanced glycation end-product formation has been implicated in vascular and cardiac complications of diabetes including loss of arterial elasticity, suggesting possibilities for new therapeutic options. With increasing age, there is a shift to from diastolic to systolic blood pressure and pulse pressure as predictors of cardiovascular disease. This may affect drug treatment as different antihypertensive drugs may have differential effects on arterial stiffness that can be dissociated from their effects on blood pressure. While thiazide diuretics are associated with little or no change in arterial stiffness despite a robust antihypertensive effect, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and calcium-channel blockers have been shown to reduce arterial stiffness. However, combination therapy is nearly always necessary to obtain adequate blood pressure control in diabetics. There are no randomized controlled trials looking specifically at treatment of ISH in diabetics. Recommendations regarding treatment of ISH in diabetes mellitus type 2 are based on extrapolation from studies in non-diabetics, post-hoc analyses and prespecified subgroup analysis in large-scale studies, and metaanalysis. These analyses have clearly demonstrated that blood pressure lowering in ISH confers improved prognosis and reduced cardiovascular and renal outcomes in both diabetics and non-diabetics.

Eplerenone prevents adverse cardiac remodelling induced by pressure overload in atrial natriuretic peptide-null mice

Abstract: 1. Atrial natriuretic peptide (ANP)-null mice (Nppa(-/-)) exhibit cardiac hypertrophy at baseline and adverse cardiac remodelling in response to transverse aortic constriction (TAC)-induced pressure overload stress. Previous studies have suggested that natriuretic peptides could potentially oppose mineralocorticoid signalling at several levels, including suppression of adrenal aldosterone production, inhibition of mineralocorticoid receptor (MR) activation or suppression of MR-mediated production of pro-inflammatory factors. Thus, we hypothesized that the MR blocker eplerenone would prevent the exaggerated left ventricular (LV) remodelling/fibrosis and dysfunction after TAC in Nppa(-/-). 2. In the present study, Nppa(-/-) and wild-type Nppa(+/+) mice fed eplerenone- or vehicle (oatmeal)-supplemented chow since weaning were subjected to TAC or sham operation. The daily dose of eplerenone administered was approximately 200 mg/kg. At 1 week after TAC, LV size and function were evaluated by echocardiogram and LV cross-sections were stained with picrosirius red for collagen volume measurement. Total RNA was extracted from the LV for real-time polymerase chain reaction analysis of osteopontin. 3. Eplerenone had no effect on baseline hypertrophy observed in sham-operated Nppa(-/-) compared with Nppa(+/+) mice. Eplerenone attenuated the TAC-induced increase in LV weight in both genotypes and completely prevented LV dilation, systolic dysfunction and interstitial collagen deposition seen in Nppa(-/-) mice after TAC. However, serum aldosterone levels were lower in Nppa(-/-) compared with Nppa(+/+) wild types. No interaction between eplerenone and genotype in osteopontin mRNA levels was observed. 4. Eplerenone prevents adverse cardiac remodelling related to pressure overload in ANP-deficient mice, mainly due to an antifibrotic effect. The mechanism whereby ANP deficiency leads to excess hypertrophy, fibrosis and early failure following TAC is increased profibrotic signals resulting from excess or unopposed MR activation, rather than increased levels of aldosterone.

Beta-blockers as sub-optimal treatment for hypertension: time for first-line therapy revision?

Abstract: Recent evidence provides growing support to earlier observations by Messerli et al. [1] that beta‐blockers might not offer optimal cardiovascular protection for patients with uncomplicated essentia...

Is There a New Treatment for Hypertensive Disease in the Horizon?: Role of Soluble Guanylate Cyclase

Abstract: Left ventricular hypertrophy (LVH) and fibrosis have received special attention as possible therapeutic targets in preventing cardiovascular complications of hypertension. Suppression of neurohormonal factors that predispose to target organ damage, in addition to blood pressure (BP) reduction, seems to be of importance in modulating cardiac remodeling and fibrosis in hypertensive heart disease. In the normal heart, the effects of endogenous hypertrophic/profibrotic factors, including angiotensin II (Ang II), aldosterone, and inflammatory cytokines, such as transforming growth factor-β, growth factors, and catecholamines, are balanced by the action of growth-inhibiting/antifibrotic factors, including NO, natriuretic peptides, and bradykinin. Previous studies have shown that atrial natriuretic peptide (ANP) modulates cardiac hypertrophy and fibrosis in response to a variety of hemodynamic stresses.1–3 In the setting of hypertension or in the absence of the counterregulatory effects of ANP signaling, as in the ANP null ( Nppa −/−) or heterozygous ( Nppa +/−) mouse or the mouse lacking natriuretic peptide type A receptors ( Npr −/−), the unopposed profibrotic/hypertrophic factors predominate, and …

The question of whether diabetes and its cardiovascular risks can be prevented: a realistic DREAM?

Abstract: Type 2 diabetes mellitus is currently evolving as a worldwide health problem associated with excess morbidity and mortality related primarily to cardiovascular problems. As the global prevalence of type 2 diabetes is rapidly increasing, prevention of the disease and the risks it carries is considered a key objective in developed as well as in developing countries. Hypertension and dyslipidemia are common entities and bear a significant part of the cardiovascular risk within the diabetic population. Conversely, arterial hypertension is a clinical entity in which insulin resistance is common, and type 2 diabetes may precede the development of hypertension by several years. Besides lifestyle changes, recent studies have suggested that inhibition of the renin–angiotensin system (RAS) may prevent diabetes development in people with cardiovascular disease or hypertension (1–3). Also, alternative pharmacological treatments in subjects at risk of developing diabetes have proven their efficacy in placebo-controlled clinical trials, including antidiabetic drugs such as metformin, acarbose and troglitazone, or antiobesity agents such as orlistat (1). In the hypertensive population, research over the years has suggested that thiazide diuretics as well as beta-blockers, alone or in combination, might precipitate the development or worsen type 2 diabetes mellitus (2,3). However, while antihypertensive agents such as diuretics or beta-blockers may impair insulin resistance or worsen glucose tolerance, other antihypertensives such as angiotensinconverting enzyme (ACE) inhibitors or calcium antagonists were found to be associated with neutral or even slightly positive metabolic effects. The potential mechanisms underlying the beneficial effects of inhibitors of the RAS on glucose tolerance and insulin sensitivity are complex and probably manifold (2,3). For example, they may improve blood flow and microcirculation in skeletal muscles and, thereby, enhance insulin and glucose delivery to the insulin-sensitive tissues, facilitate insulin signaling at the cellular level, and also improve insulin secretion from the beta cells (2,3). Several recent large-scale clinical studies have demonstrated, as a secondary objective, that inhibition of the RAS delays type 2 diabetes development. These studies include CAPPP (Captopril Prevention Project), HOPE (Heart Outcomes Prevention Evaluation), ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), LIFE (Losartan Intervention For Endpoint reduction in hypertension study), SCOPE (Study on Cognition and Prognosis in the Elderly), and VALUE (Valsartan Antihypertensive Long-term Use Evaluation), where consistent reductions in the incidence of type 2 diabetes were reported in hypertensive patients treated with either an ACE inhibitor or an angiotensin II receptor antagonist for 3–6 years, compared with a thiazide diuretic and/or beta-adrenoceptor antagonist or even a placebo. The relative risk reduction for diabetes development ranged between 14% and 30% in the different studies (2,3). In the recently published DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) trial (4–6), people with impaired fasting glucose or impaired glucose tolerance were randomized to ramipril (15 mg/day) or a placebo alternatively with rosiglitazone (8 mg/day) or a placebo in a 262 factorial design. The overriding objective of the DREAM trial was to learn if ramipril or rosiglitazone could reduce the number of cases of diabetes, as well as to identify novel risk factors for diabetes. Overall, in DREAM, 5269 participants, without cardiovascular disease but with impaired fasting glucose levels (after an 8-h fast) or impaired Blood Pressure. 2006; 15: 260–262