Shawna D. Nesbitt

Baseline characteristics in the Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial: A hypertensive population at high cardiovascular risk

ACCOMPLISH is the first trial designed to compare the effects on major fatal and non‐fatal cardiovascular endpoints of two forms of antihypertensive combination therapy: benazepril plus hydrochlorothiazide and amlodipine plus benazepril in hypertensive patients at high cardiovascular risk. Enrollment for this trial is now complete and this report describes the clinical characteristics of the study cohort. Patients with hypertension and a previous history of cardiovascular events, strokes or diabetes mellitus were randomized to double‐blind treatment with either of the two combination regimens. The data in this report detail the clinical history and demographic characteristics in patients immediately prior to randomization to study drugs. A total of 11,454 patients were randomized. Mean age (±SD) was 68.4±6.9 years, 60% were men, and 1360 (12%) were African American. Mean body mass index (BMI) was 31.0±6.3 kg/m2. At study entry, 46% of patients had a history of acute coronary syndromes, coronary artery bypass grafts or percutaneous coronary interventions; 13% had a history of stroke. A history of diabetes mellitus was reported in 6928 (60%) of patients. Mean blood pressure at baseline (on prior hypertension therapy) was 145.4/80.0 mmHg; only 38% of patients had a BP less than 140/90mmHg. Overall, 97% of patients had received previous antihypertensive treatment (74% on at least two drugs); 53% were on oral diabetes therapy or insulin, 68% on anti‐lipid therapy and 63% on anti‐platelet agents. In summary, the ACCOMPLISH trial has recruited hypertensive patients at high risk of cardiovascular morbidity and mortality. It is noteworthy that the mean BMI of 31 in this cohort is clearly above the accepted diagnostic criterion of obesity and that 60% of patients are diabetic, possibly reflecting secular trends in clinical disease.

A Titrate‐to‐Goal Study of Switching Patients Uncontrolled on Antihypertensive Monotherapy to Fixed‐Dose Combinations of Amlodipine and Olmesartan Medoxomil ± Hydrochlorothiazide

In the prospective, open‐label, titrate‐to‐goal Blood Pressure Control in All Subgroups With Hypertension (BP‐CRUSH) study, 999 patients with hypertension uncontrolled on monotherapy (mean age, 55.6±11.4 years; baseline blood pressure [BP], 153.7±9.2/91.9±8.6 mm Hg) were switched to fixed‐dose amlodipine/olmesartan medoxomil (AML/OM) 5/20 mg. Patients were uptitrated every 4 weeks to AML/OM 5/40 mg and 10/40 mg to achieve BP <120/70 mm Hg. Patients were subsequently uptitrated every 4 weeks to AML/OM+hydrochlorothiazide (HCTZ) 10/40+12.5 mg and 10/40+25 mg to achieve BP <125/75 mm Hg. The primary end point, the cumulative percentage of patients achieving seated systolic BP <140 mm Hg (<130 mm Hg for patients with diabetes) by week 12, was 75.8%. The mean (±standard error) BP changes from baseline during the titration periods ranged from −14.2±0.4 mm Hg/−7.7±0.3 mm Hg for AML/OM 5/20 mg to −25.1±0.7 mm Hg/−13.7±0.4 mm Hg for AML/OM+HCTZ 10/40+25 mg. By week 20, the cumulative BP threshold of <140/90 mm Hg was achieved by 90.3% of patients. An ambulatory BP monitoring substudy (n=243) showed that 24‐hour efficacy was maintained. Treatment‐emergent adverse events (TEAEs), mostly mild to moderate in severity, occurred in 529 patients (53.0%). Drug‐related TEAEs occurred in 255 patients (25.5%). This well‐tolerated, treat‐to‐goal algorithm enabled a large proportion of patients with uncontrolled hypertension on monotherapy to safely achieve BP control on single‐pill AML/OM combination therapy or triple therapy with the addition of HCTZ. J Clin Hypertens (Greenwich). 2011;13:404–412. ©2011 Wiley Periodicals, Inc.

Angiotensin Receptor Blockers: Pharmacology, Efficacy, and Safety

J Clin Hypertens (Greenwich). 2011;13:677–686. ©2011 Wiley Periodicals, Inc.

Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy.

Objective Hypertension and insulin resistance might be associated through peripheral vascular hypertrophy/rarefaction which compromises skeletal muscle blood flow and decreases glucose uptake, inducing insulin resistance. We hypothesized that treatment with losartan as compared to atenolol would improve insulin sensitivity through regression of peripheral vascular hypertrophy/rarefaction. Methods In 70 hypertensive patients with electrocardiographic left ventricular hypertrophy, we measured minimal forearm vascular resistance (MFVR) by plethysmography and insulin sensitivity (M/IG) by a 2-h isoglycemic hyperinsulinemic clamp at baseline and after 1, 2 and 3 years of blinded treatment with atenolol- or losartan-based regimens. Results Blood pressures were reduced similarly in the two treatment groups. After 3 years, MFVR was increased (3.7 versus 3.2 mmHg × min × 100, P < 0.05) and M/IG decreased (8.6 versus 12.1 l2/kg × mmol × min, P < 0.05) in patients treated with atenolol, whereas MFVR and M/IG were unchanged (3.5 versus 3.5 mmHg × min × 100 and 12.6 versus 11.1 l2/kg × mmol × min, both P = NS) in patients treated with losartan. As compared to atenolol, losartan treatment was associated with less increase in MFVR (4.3 versus 27%, P < 0.05) and less decrease in M/IG (24 versus −14%, P < 0.01). The relative change in M/IG was inversely associated with the relative change in MFVR (r = −0.16, P < 0.05) independently of the relative change in body mass index (r = −0.29, P < 0.001). Conclusions As compared to atenolol, losartan treatment was associated with less peripheral vascular hypertrophy/rarefaction and higher insulin sensitivity. The relative change in MFVR and M/IG were inversely related, supporting the hypothesis that peripheral vascular changes in hypertension may induce insulin resistance. The ability of losartan to preserve insulin sensitivity may explain the lower incidence of new onset diabetes in patients treated with losartan in the LIFE study.

Reversible sympathetic overactivity in hypertensive patients with primary aldosteronism

CONTEXT Aldosterone has been shown to exert a central sympathoexcitatory action in multiple animal models, but evidence in humans is still lacking. OBJECTIVES Our objective was to determine whether hyperaldosteronism causes reversible sympathetic activation in humans. METHODS We performed a cross-sectional comparison of muscle sympathetic nerve activity (SNA, intraneural microelectrodes) in 14 hypertensive patients with biochemically proven primary aldosteronism (PA) with 20 patients with essential hypertension (EH) and 18 age-matched normotensive (NT) controls. Seven patients with aldosterone-producing adenoma (APA) were restudied 1 month after unilateral adrenalectomy. RESULTS Mean blood pressure values in patients with PA and EH and NT controls was 145 ± 4/88 ± 2, 150 ± 4/90 ± 2, and 119 ± 2/76 ± 2 mm Hg, respectively. The major new findings are 2-fold: 1) baseline SNA was significantly higher in the PA than the NT group (40 ± 3 vs. 30 ± 2 bursts/min, P = 0.014) but similar to the EH group (41 ± 3 bursts/min) and 2) after unilateral adrenalectomy for APA, SNA decreased significantly from 38 ± 5 to 27 ± 4 bursts/min (P = 0.01), plasma aldosterone levels fell from 72.4 ± 20.3 to 11.4 ± 2.3 ng/dl (P < 0.01), and blood pressure decreased from 155 ± 8/94 ± 3 to 117 ± 4/77 ± 2 mm Hg (P < 0.01). CONCLUSION These data provide the first evidence in humans that APA is accompanied by reversible sympathetic overactivity, which may contribute to the accelerated hypertensive target organ disease in this condition.

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.

Relative influence of insulin resistance versus blood pressure on vascular changes in longstanding hypertension. ICARUS, a LIFE sub study

Background Insulin resistance is associated with hypertension. The relative influences of hyperinsulinaemia and high blood pressure on vascular hypertrophy and carotid distensibility is unclear in patients with longstanding hypertension. Methods In 88 unmedicated patients with stage II–III hypertension and left ventricular hypertrophy on electrocardiogram we measured blood pressure, minimal forearm vascular resistance (MFVR) using plethysmography, intima–media thickness (IMT) and the wall distensibility of the common carotid arteries using ultrasound, and insulin sensitivity using a 2-h isoglycaemic hyperinsulinaemic clamp. Results IMT was positively correlated to systolic blood pressure (r = 0.26, P < 0.05), whole body glucose uptake index (M/IG; r = 0.22, P < 0.05), age (r = 0.24, P < 0.05) and negatively correlated to body mass index (r = −0.24, P < 0.05); IMT did not correlate to fasting serum insulin (r = −0.14, NS). In men (n = 64) MFVR was positively correlated to systolic blood pressure (r = 0.30, P < 0.05), but was unrelated to M/G and serum insulin. The distensibility of the common carotid arteries was negatively correlated to systolic blood pressure (r = −0.40, P < 0.001) and in untreated patients (n = 22) positively correlated to M/IG (r = 0.47, P < 0.05). Conclusions High systolic blood pressure was related to vascular hypertrophy, whereas hyperinsulinaemia and insulin resistance were not, suggesting that longstanding high blood pressure is a far more important determinant for structural vascular changes than insulin resistance at this stage of the hypertensive disease. However, hyperinsulinaemia and insulin resistance were associated with low distensibility of the common carotid arteries in the subgroup of never treated hypertensive patients.

Smoking is associated with higher cardiovascular risk in young women than in men: The Tecumseh Blood Pressure Study

Background Tobacco smoking is associated with a higher prevalence of atherosclerosis and respiratory disease. Objective To investigate differences between hemodynamic and biochemical findings in smokers and nonsmokers in the two sexes separately in the Tecumseh population. Methods We studied 851 subjects. They were divided according to smoking habits into group 1, nonsmokers (258 men and 234 women); and group 2, smokers (185 men and 174 women). Results Unpaired Students t-tests and nonparametric tests were performed to determine the between-group P-values. Only hematocrit differed significantly between smokers and nonsmokers in both sexes (43.9 ± 0.2 and 44.6 ± 9.3%, P < 0.05 in men; 39.2 ± 0.3 and 40.3 ± 0.3%, P = 0.007 in women, respectively in nonsmokers and smokers). Triglycerides (80.6 ± 3.8 and 99.6 ± 4.3 mg/dl, P < 0.001), left ventricular mass index (95.4 ± 1.9 and 100.0 ± 1.2 g/m2, P = 0.008), and posterior wall thickness (9.5 ± 0.1 and 9.71 ± 0.01 mm, P = 0.044) were elevated and high-density lipoproteins were decreased (48.7 ± 0.8 and 44.5 ± 0.9 mg/dl, P < 0.01) only in women smokers. After adjustment for home systolic blood pressure and body mass index the differences in women remained significant except for posterior wall thickness. Conclusion Tobacco smoking is deleterious to both sexes but it appears to be particularly harmful to women. Our data can, in part, explain why the relative risk of myocardial infarction is higher in women than it is in men.

TROPHY study: Outcomes based on the Seventh Report of the Joint National Committee on Hypertension definition of hypertension

Trial of Preventing Hypertension (TROPHY) investigated whether pharmacological treatment of prehypertension prevents or postpones stage 1 hypertension. Hypertension was originally defined when a participant had blood pressure (BP) >/=140 and/or >/=90 mm Hg at any three clinic visits over 4 years. Contemporary guidelines define hypertension if the BP is >/=140 and/or >/=90 at two consecutive visits. TROPHY results were recalculated based on the current definition. Participants with repeated BP of 130 - 139 and/or 85 - 89 mm Hg were randomly assigned to 2 years of candesartan or placebo, followed by 2 years of placebo for all. All participants received lifestyle counseling at every visit. When participants reached hypertension, antihypertensive treatment was initiated. The 4-year incidence of hypertension was significantly (P < .001) lower than previously reported in the placebo (-11.3%) and candesartan (-11.0%) groups. During the first 2 years, hypertension developed in 162 placebo and 53 candesartan participants (relative risk reduction [RRR], 68%; P < .001; original report 66%; P < .001). After 4 years, hypertension occurred in 197 placebo and 165 candesartan participants (RRR, 18%; P < .009; original report 16%; P < .007). The new definition resulted in a lower incidence of hypertension, but the outcomes were remarkably similar with both definitions and confirmed our original findings.

Parental Hyperdynamic Circulation Predicts Insulin Resistance in Offspring The Tecumseh Offspring Study

Controversy surrounds the pathogenetic mechanisms of the relationship between hyperdynamic circulation and insulin resistance. Two hundred eight children and young adults (mean age, 17.2+/-3.0 years; range, 11 to 26 years) from the Tecumseh Offspring Study whose parents had been assessed with Doppler echocardiography at the age of 34 years during the previous Tecumseh Blood Pressure Study were considered for this analysis. Offspring data were stratified according to tertiles of parental cardiac index. Parents in the top cardiac index tertile had increased heart rate (P=0.001), stroke volume (P=0.0001), left ventricular fractional shortening (P=0.02), and plasma epinephrine (P=0.02) compared with parents in the other tertiles. Body mass index (BMI) and blood pressure were similar in all groups. Offspring of parents with a high cardiac index had greater BMI (P=0.001), skinfold thickness (P=0.008), and waist/hip ratio (P=0.02), higher diastolic blood pressure (P=0.02) and plasma insulin level (P=0.001), and higher heart rate during Stroops color test (P=0.02) than offspring of parents with a lower cardiac index. In a multivariate regression analysis, offspring BMI was predicted by parental BMI and cardiac index (P=0.0001 and 0.003, respectively). The mother-child relationship explained most of the cardiac index-BMI association. In summary, parental hyperdynamic circulation was an important predictor of overweight, abnormal fat distribution, increased blood pressure, and hyperinsulinemia in offspring. Our results illustrate the complexity of interaction between a genetic tendency and its phenotypic expression. We speculate that the degree of beta-adrenergic responsiveness may be a major determinant of the phenotypic differences between the parents and offspring found in this study.