Effectiveness of initiating treatment with valsartan/hydrochlorothiazide in patients with stage-1 or stage-2 hypertension.

This prospective, 6-week, multicenter, double-blind study examined the benefits of initiating treatment with combination valsartan/hydrochlorothiazide (HCTZ) compared with initial valsartan monotherapy for 648 patients with stage-1 or stage-2 hypertension (age=52.6+/-10 years; 54% male; baseline blood pressure (BP)=161/98 mm Hg, 32% stage 1). Patients were randomized to valsartan 80 mg (V-low), valsartan 160 mg (V-high) or valsartan/HCTZ 160/12.5 mg (V/HCTZ), and electively titrated after weeks 2 and 4 to the next dosage level (maximum dose valsartan/HCTZ 160/25 mg) if BP remained >140/90 mm Hg. At end of the study, patients initiated with V/HCTZ required less titration steps compared with the initial valsartan monotherapy groups (63 vs 86% required titration by study end, respectively) and reached the target BP goal of <140/90 mm Hg in a shorter period of time (2.8 weeks) (P<0.0001) vs V-low (4.3 weeks) and V-high (3.9 weeks). Initial combination therapy was also associated with higher BP control rates and greater reductions in both systolic and diastolic BP from baseline (63%, -27.7+/-13/-15.1+/-8 mm Hg) compared with V-low (46%, -21.2+/-13/-11.4+/-8 mm Hg, P<0.0001) or V-high (51%, -24.0+/-13/-12.0+/-10 mm Hg, P<0.01). Overall and drug-related AEs were mild to moderate and were similar between V/HCTZ (53.1 and 14.1%, respectively) and the two monotherapy groups, V-low (50.5 and 13.8%) and V-high (50.7 and 11.8%). In conclusion, initiating therapy with a combination of valsartan and low-dose HCTZ results in early, improved BP efficacy with similar tolerability as compared with starting treatment with a low or higher dose of valsartan for patients with stage-1 and stage-2 hypertension.

Rationale for angiotensin II receptor blockers in patients with low-renin hypertension.

African Americans outrank other ethnic groups in the United States in prevalence, early onset, and severity of hypertension. Furthermore, African Americans suffer the highest rates of mortality from cardiovascular, cerebrovascular, and end-stage renal disease. The recently concluded Heart Outcomes Prevention Evaluation (HOPE) study reports that the angiotensin-converting enzyme (ACE) inhibitor ramipril significantly reduced morbidity and mortality in a broad range of patients at high risk for cardiovascular events. These results strengthen the case for increasing the use of ACE inhibitor therapy. In accord with the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) guidelines, antihypertensive monotherapy for African Americans is based on the known ability of diuretics and calcium channel blockers to produce greater reductions in blood pressure in this population than those attainable with beta blockers and ACE inhibitors. The national guidelines also suggest ACE inhibitors for all hypertensive patients with left ventricular dysfunction or nephropathy, which implies that African Americans must cross a clinical threshold to become candidates for these agents. The rationale for delaying ACE inhibitor therapy is due in part to a perceived unique pathobiology in hypertensive African Americans: an excess prevalence of salt sensitivity, hypervolemia, and low plasma renin activity (PRA). At first glance, it would seem intuitive to avoid agents that further depress the renin-angiotensin system (RAS) and choose agents that reduce plasma volume. However, most hypertensive African Americans are not hypovolemic. Furthermore, dietary sodium restriction and diuretic therapy raise PRA and improve the response to ACE inhibitors. The overall aim of this article is to explain the rationale for expanded use of drugs that block the RAS in African Americans and low-renin populations.

Treating high-risk hypertensive patients.

Successful treatment of hypertension entails not only normalizing high blood pressure, but also addressing the associated risk factors that increase the likelihood of cardiovascular morbidity and mortality. Hypertension often occurs in a setting of insulin resistance, hyperinsulinemia, dyslipidemia, and a prothrombotic state. A number of epidemiologic studies have shown that the clustering of these abnormalities is associated with increased risk of cardiovascular morbidity and mortality. Therefore, it is rational to direct therapy at moderating these risk factors as well as at lowering blood pressure in hypertensive patients. This is particularly important in patients with comorbidities such as diabetes, cardiovascular disease, or renal insufficiency. Many physicians prescribe only diuretics and beta-blockers, agents that have demonstrated efficacy in long-term randomized controlled trials. However, this approach does not consider the potential benefits of newer agents for which long-term outcome data are not yet available. The ongoing Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, in which the angiotensin II subtype 1 receptor blocker valsartan is compared with the third-generation calcium channel blocker amlodipine, should provide important evidence on the long-term efficacy of these newer agents. A unique feature of VALUE is that it is specifically enrolling into the only current trial, now under way, hypertensive men and women at a relatively high risk for a cardiovascular event to determine the benefits of complete blockade of angiotensin II beyond those of the control of blood pressure.

Magnetic resonance evaluation of ventrolateral medullary compression in essential hypertension.

OBJECT: The authors designed a blinded prospective study comparing patients with essential hypertension to patients without hypertension in which magnetic resonance (MR) imaging was used to evaluate the role of lateral medullary compression by adjacent vascular structures as a cause of neurogenic hypertension. METHODS: Patients with documented essential hypertension were recruited to undergo thin-slice axial brainstem MR imaging evaluation. Nonhypertensive (control) patients scheduled to undergo MR imaging for other reasons also underwent thin-slice MR imaging to form a basis for comparison. Magnetic resonance images obtained in patients from the hypertensive (30 patients) and the control (45 patients) groups were then compared by four independent reviewers (two neuroradiologists and two neurosurgeons) who were blinded to the patients' diagnosis and hypertensive status. Images were reviewed with regard to left versus right vertebral artery (VA) dominance, compression of the medulla on the left and/or right side, and brainstem rotation. Medullary compression was graded as either vessel contact without associated brainstem deformity or vessel contact with associated brainstem deformity. CONCLUSIONS: There was a tendency toward left VA dominance in the hypertensive group compared with the control group, although a significant difference was shown by only one of the four reviewers. There were no differences in brainstem compression or rotation between the hypertensive and nonhypertensive groups. These results are contrary to those of recently published studies in which MR imaging and/or MR angiography revealed lateral brainstem vascular compression in hypertensive patients but not in nonhypertensive (control) patients. Reasons for this discrepancy are discussed. On the basis of their own experience and that of others, the authors believe that neurogenic hypertension does exist. However, thin-slice MR imaging may not be a reliable method for detecting neurovascularly induced essential hypertension and the prevalence of neurovascular compression as the source of hypertension may be overestimated when using current imaging techniques.

Home blood pressure as a predictor of future blood pressure stability in borderline hypertension. The Tecumseh Study.

We evaluated time-related blood pressure trends in the Tecumseh study participants, none of whom received antihypertensive treatment. At baseline the blood pressures were measured in the field clinic and by self measurement at home (twice daily for 7 days). After a mean of 3.2 +/- 0.42 years, the clinic and home pressure readings were repeated. Nine hundred forty-six subjects had clinic and home blood pressure readings at baseline. Of these 735 (380 men, 355 women; average age, 32 years) also completed the second examination. Blood pressure, morphometric data, and biochemical measures at the first examination were used as predictors of future clinic blood pressures. Five hundred ninety-six subjects were normotensive on both examinations (81%). Of 79 subjects (10.7%) with clinic hypertension (> 140 mg Hg systolic or 90 mm Hg diastolic) at baseline, 38 remained hypertensive ("sustained hypertension") and 41 became normotensive ("transient hypertension") after 3 years. Another 60 normotensives at baseline (10.4%) became hypertensive on second examination ("de novo hypertensives"; incidence; 8.1%). The home blood pressure readings on both examinations were reproducible. The three hypertensive groups had elevated home blood pressure, were overweight, had dyslipidemia, and higher insulin values. Only the home blood pressure proved predictive of subsequent blood pressure trends. A home blood pressure of 128 and 83 mm Hg or higher detected "sustained" hypertension with a 48% sensitivity and 93% specificity. Readings of 120 and 80 mm Hg or lower predicted future normotension with a 45% sensitivity and a 91% specificity. We conclude that self determination of the blood pressure at home is useful in the management of borderline hypertension. An algorithm for the management of these patients is proposed.

Angiotensin mediates forearm glucose uptake by hemodynamic rather than direct effects.

Insulin sensitivity may be improved with the angiotensin-converting enzyme inhibitor captopril, suggesting that inhibition of angiotensin II (Ang II) improves insulin resistance. However, the administration of systemic Ang II has also been associated with an improvement in rather than worsening of glucose utilization. Since both stimulating and antagonizing the renin-angiotensin system improve glucose uptake and both angiotensin-converting enzyme inhibitors and intravenous Ang II elicit skeletal muscle vasodilation, it is conceivable that hemodynamic factors rather than a direct effect of either Ang II or angiotensin-converting enzyme inhibitors on skeletal muscle metabolism modulate the increase in glucose utilization. The direct effects of Ang II on glucose extraction in intact human skeletal muscle have not been previously described. We investigated the effects of local infusion of Ang II on glucose uptake in the forearm of 20 healthy subjects. With the use of the isolated insulin-perfused forearm model, local plasma insulin values were raised to 100 mU/mL over fasting values and maintained there for a 90-minute infusion period. After the first 60 minutes of insulin alone, Ang II was infused into the brachial artery for the last 30 minutes. Intra-arterial Ang II infusion caused a 38% decrease in forearm blood flow (P <.05) and 59% increase in the arteriovenous glucose gradients (P <.05) to maintain a steady glucose utilization (a decrease of 4%, P=NS). Thus, local Ang II infusion does not impair insulin-stimulated glucose utilization. Furthermore, glucose extraction increases to compensate for the decrease in forearm blood flow (as the Fick principle would predict for freely diffusible substances). We conclude that the described increase in glucose utilization from systemic infusion of Ang II and during angiotensin-converting enzyme inhibitor treatment is mediated by hemodynamic factors rather than a direct effect of Ang II on skeletal muscle metabolism.

Vasoconstriction with norepinephrine causes less forearm insulin resistance than a reflex sympathetic vasoconstriction.

We used the insulin-perfused human forearm model to assess the effects of vasoconstriction induced with norepinephrine on the extraction of glucose in the forearm in two groups of healthy young volunteers. The norepinephrine findings were compared with a previously studied group in which vasoconstriction has been caused by reflex activation of the sympathetic nervous system. The aim of the study was to determine the relative importance of hemodynamic and receptor-mediated mechanisms of insulin resistance. Plasma insulin, arterial and venous glucose samples, and forearm blood flow were measured at 10-minute intervals during a 30-minute baseline, a 60-minute intra-arterial insulin infusion, and during 30 minutes of insulin infusion plus vasoconstriction. Group 1 (n = 14) had physiological vasoconstriction induced by inflation of bilateral thigh cuffs to 40 mm Hg to cause pooling of blood in the lower extremities and reflex vasoconstriction in the forearm; group 2 (n = 8) had intra-arterial infusion of norepinephrine to achieve the same degree of vasoconstriction as seen with inflation of thigh cuffs in group 1. Subjects in group 3 (n = 7) had infusion of intra-arterial norepinephrine to achieve a twofold increase in physiological vasoconstriction. With a physiological decrease in forearm blood flow (group 1), there was a 19% decrease in forearm blood flow resulting in a 23% reduction in glucose uptake in the forearm (P < .03). The same degree of reduction in forearm blood flow with a predominantly alpha-adrenergic agonist, norepinephrine (group 2), causes much less insulin resistance (a decrease in utilization of 13%) (P < .04).(ABSTRACT TRUNCATED AT 250 WORDS)

Prevalence of complications and response to different treatments of hypertension in African Americans and white Americans in the U.S..

The aim of this review is to compare the prevalence of complications and response to different treatment for hypertension in African and European Americans. African Americans when compared to European Americans respond less favorably to beta-blockers (BB's) and angiotensin converting enzyme inhibitors (ACEI's). Nevertheless the observed response of African Americans to ACEI's and BB's is significant and these agents are very effective in this subgroup. African American race is not a clinically significant predictor of poor response to any class of antihypertensive therapy and there is little justification to use racial profiling as a criterion for choice of medication. Evidence to restrict or defer usage of BB's and ACEI's in African Americans is lacking. The mortality from hypertensive heart disease, stroke, and the incidence of hypertensive renal disease is higher in African Americans which leads some investigators to postulate that hypertension in African Americans is intrinsically different from whites. They therefore search for a separate etiology and suggest specific approaches to treatment. Awareness of racial differences in hypertension outcomes evolved in the U.S. in an historical context that does not fully appreciate that race is often a surrogate for many social and economic factors that influence health status and health care delivery in the U.S. Poor outcomes in African Americans occur in many diseases including hypertension.

Reflex sympathetic activation induces acute insulin resistance in the human forearm.

Inferences about the association between sympathetic overactivity and insulin resistance have been drawn from the infusion of sympathomimetic amines in supraphysiological doses. We used the isolated perfused human forearm to investigate the effect of reflex-induced sympathetic nervous system activation on the peripheral utilization of glucose in the skeletal muscles of 14 healthy men. Local hyperinsulinemia in the forearm (132 +/- 25 microunits/mL for 90 minutes) induced a significant increase in the utilization of glucose from baseline (16.4 +/- 3.1 mg.dL-1.min-1 per 100 mL forearm volume) to a plateau (85.7 +/- 15.1 mg.dL-1.min-1 per 100 mL forearm volume) between 40 and 60 minutes of insulin infusion but did not alter the utilization of oxygen. Reflex sympathetic nervous system activation was elicited by unloading of cardiopulmonary receptors with bilateral thigh cuff inflation to 40 mm Hg between 60 and 90 minutes of insulin infusion. Blood flow in the forearm was significantly decreased with inflation of thigh cuffs (average decrease of 19%, p < 0.0001). As a result of thigh cuff inflation, there was a reduction in the utilization of glucose (a decrease of 23%, p < 0.02), whereas oxygen utilization was unchanged. We find that an increase in sympathetic nervous system activation (within the normal range of physiological responses) can cause acute insulin resistance in the forearm of healthy volunteers. The reflex caused no change in oxygen utilization, but the same stimulus elicited a decrease in the utilization of glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of home blood pressure and gender on estimates of the familial aggregation of blood pressure. The Tecumseh Blood Pressure Study.

Blood pressure (BP) readings from a single clinic visit are often used in population studies investigating the genetic basis of BP. We examined first-degree relatives in the Tecumseh Blood Pressure study to compare heritability estimates of BP readings obtained in the clinic-office setting (the average of two seated readings) with self-reported home BP readings (the average of 14 readings) taken over a 1-week period. The hypothesis tested was that repeated BP readings obtained in the home over the 1-week period would have fewer artifacts (i.e., environmentally induced variability in BP) and thus would better estimate the true "basal" BP that, in turn, would improve heritability estimates. We and others assume that the true basal BP level is heritable. We therefore expected that this "true" BP, by reducing BP variability of offspring, would show a stronger between-sibling correlation and that it would correlate better to parental BP as measured in a clinic setting. Correlation coefficients were calculated between siblings in the present Tecumseh study using self-reported home BP and clinic BP readings. Among 380 siblings (average age, 31.4 years), correlation coefficients for the home readings were of the same magnitude as for office readings (home, r = 0.23, p less than 0.01; office, r = 0.24, p less than 0.01). When offspring clinic BP readings were compared with archived BP data on parents, the correlation between offspring clinic and parental clinic BP readings was stronger (r = 0.24, p less than 0.05) than the correlation of offspring home BP readings to parental clinic BP readings (r = 0.17, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)