Racial Differences in XO (Xanthine Oxidase) and Mitochondrial DNA Damage-Associated Molecular Patterns in Resistant Hypertension.

BACKGROUND: We previously reported increased plasma XO (xanthine oxidase) activity in patients with resistant hypertension. Increased XO can cause mitochondrial DNA damage and promote release of fragments called mitochondrial DNA damage-associated molecular patterns (mtDNA DAMPs). Here, we report racial differences in XO activity and mtDNA DAMPs in Black and White adults with resistant hypertension. METHODS: This retrospective study includes 91 resistant hypertension patients (44% Black, 47% female) with blood pressure >140/90 mm Hg on ≥4 medications and 37 normotensive controls (30% Black, 54% female) with plasma XO activity, mtDNA DAMPs, and magnetic resonance imaging of left ventricular morphology and function. RESULTS: Black-resistant hypertension patients were younger (mean age 52±10 versus 59±10 years; P=0.001), with higher XO activity and left ventricular wall thickness, and worse diastolic dysfunction than White resistant hypertension patients. Urinary sodium excretion (mg/24 hour per kg) was positively related to left ventricular end-diastolic volume (r=0.527, P=0.001) and left ventricular mass (r=0.394, P=0.02) among Black but not White resistant hypertension patients. Patients with resistant hypertension had increased mtDNA DAMPs versus controls (P<0.001), with Black mtDNA DAMPS greater than Whites (P<0.001). Transmission electron microscopy of skeletal muscle biopsies in resistant hypertension patients demonstrates mitochondria cristae lysis, myofibrillar loss, large lipid droplets, and glycogen accumulation. CONCLUSIONS: These data warrant a large study to examine the role of XO and mitochondrial mtDNA DAMPs in cardiac remodeling and heart failure in Black adults with resistant hypertension.

Effect of Serum Urate Lowering With Allopurinol on Blood Pressure in Young Adults: A Randomized, Controlled, Crossover Trial.

OBJECTIVE: To determine whether serum urate reduction with allopurinol lowers blood pressure (BP) in young adults and the mechanisms mediating this hypothesized effect. METHODS: We conducted a single-center, randomized, double-blind, crossover clinical trial. Adults ages 18-40 years with baseline systolic BP ≥120 and <160 mm Hg or diastolic BP ≥80 and <100 mm Hg, and serum urate ≥5.0 mg/dl for men or ≥4.0 mg/dl for women were enrolled. Main exclusion criteria included chronic kidney disease, gout, or past use of urate-lowering therapies. Participants received oral allopurinol (300 mg daily) or placebo for 1 month followed by a 2-4 week washout and then were crossed over. Study outcome measures were change in systolic BP from baseline, endothelial function estimated as flow-mediated dilation (FMD), and high-sensitivity C-reactive protein (hsCRP) levels. Adverse events were assessed. RESULTS: Ninety-nine participants were randomized, and 82 completed all visits. The mean ± SD age was 28.0 ± 7.0 years, 62.6% were men, and 40.4% were African American. In the primary intent-to-treat analysis, systolic BP did not change during the allopurinol treatment phase (mean ± SEM -1.39 ± 1.16 mm Hg) or placebo treatment phase (-1.06 ± 1.08 mm Hg). FMD increased during allopurinol treatment periods compared to placebo treatment periods (mean ± SEM 2.5 ± 0.55% versus -0.1 ± 0.42%; P < 0.001). There were no changes in hsCRP level and no serious adverse events. CONCLUSION: Our findings indicate that urate-lowering therapy with allopurinol does not lower systolic BP or hsCRP level in young adults when compared with placebo, despite improvements in FMD. These findings do not support urate lowering as a treatment for hypertension in young adults.

Uric Acid Is Not Associated With Blood Pressure Phenotypes and Target Organ Damage According to Blood Pressure Phenotypes.

BACKGROUND: Hypertensive patients with increased serum uric acid (SUA) are at increased cardiovascular (CV) risks. Both the European and American hypertension guidelines endorse the utilization of 24 h-ambulatory blood pressure monitoring (24 h-ABPM) for hypertensive patients with increased CV risk. While there is difference in identifying uric acid as a CV risk factor between the European and American guidelines. Therefore, it is unknown whether 24 h-ABPM should be used routinely in hypertensive patients with increased SUA. METHODS: To address this knowledge gap, we investigated (i) the correlation between SUA and 24 h-ABP; (ii) the association between SUA and blood pressure (BP) phenotypes (controlled hypertension [CH], white-coat uncontrolled hypertension [WCUH], masked uncontrolled hypertension [MUCH], and sustained uncontrolled hypertension [SUCH]); (iii) the association between SUA and target organ damage (TOD: microalbuminuria, left ventricular hypertrophy [LVH], and arterial stiffness) according to BP phenotypes. RESULTS: In 1,336 treated hypertensive patients (mean age 61.2 and female 55.4%), we found (i) there was no correlation between SUA and 24 h, daytime, and nighttime systolic blood pressure/diastolic blood pressure, respectively; (ii) in reference to CH, SUA increase was not associated WCUH (odds ratio [OR] 0.968, P = 0.609), MUCH (OR 1.026, P = 0.545), and SUCH (OR 1.003, P = 0.943); (iii) the overall prevalence of microalbuminuria, LVH, and arterial stiffness was 2.3%, 16.7%, and 23.2%, respectively. After adjustment for covariates, including age, sex, smoking, body mass index, diabetes mellitus, and estimated glomerular filtration rate, there was no association between SUA and TOD in all BP phenotypes. CONCLUSIONS: These preliminary findings did not support routine use of 24 h-ABPM in treated hypertensive patients with increased SUA.

Use of Aldosterone Antagonists for Treatment of Uncontrolled Resistant Hypertension.

BACKGROUND: Multiple studies indicate that primary aldosteronism (PA) is common in patients with resistant hypertension, with an estimated prevalence of approximately 20%. Additional studies suggest that beyond this 20% of patients with classical PA, there is a larger proportion of patients with lesser degrees of hyperaldosteronism which contributes even more broadly to antihypertensive treatment resistance. Given these observations, it is intuitive that use of aldosterone antagonists will provide antihypertensive benefit in patients with resistant hypertension and evidence of aldosterone excess. Intriguingly, however, are clinical findings demonstrating substantive benefit of aldosterone antagonists in patients with resistant hypertension, but without demonstrative evidence of hyperaldosteronism, that is, with seemingly normal or even low aldosterone levels. CONCLUSION: Spironolactone is clearly established as the most effective fourth agent for treatment of uncontrolled resistant hypertension. Emerging observations suggest a further role of spironolactone for counteracting the effects of diet high in sodium, particularly in obese, hypertensive patients.

The effects of urate lowering therapy on inflammation, endothelial function, and blood pressure (SURPHER) study design and rationale.

BACKGROUND: The association between hyperuricemia and hypertension is controversial. Animal models, epidemiological data, and small clinical trials have favored a causative role for hyperuricemia in hypertension but more studies are necessary to elucidate putative mechanisms, population susceptibility, and potential for urate-lowering therapies (ULT) to decrease blood pressure (BP). PURPOSE: To describe the background and design of the Serum Urate Reduction to Prevent Hypertension (SURPHER) study. METHODS: SURPHER is a single center, double-blinded, crossover trial in which participants are randomly assigned to allopurinol (300mg) or placebo. Enrollment focused on adults 18-40years old with baseline systolic blood pressure≥120 and <160mmHg or diastolic blood pressure≥80 and <100mmHg, and serum urate ≥5.0mg/dL or ≥4.0mg/dL for men or women, respectively. SURPHER recruitment targets participants without chronic kidney disease (estimated glomerular filtration rate>60mL/min/1.73m2), and without prior diagnosis of gout or use of ULT to treat gout. The primary outcome is change from baseline in blood pressure assessed by 24hour ambulatory blood pressure monitoring and mechanistic outcomes include changes in endothelial function as measured by flow-mediated dilation, as well as C-reactive protein levels. RESULTS: Since June 16, 2014 until present, SURPHER is recruiting participants in the city of Birmingham, Alabama. LIMITATIONS: The study aims to enroll otherwise healthy young adults for a pharmacological intervention study with multiple study-related procedures. Challenges related to recruitment are anticipated and multiple strategies for increasing recruitment and retention are planned if necessary.

Effects of the once-weekly glucagon-like peptide-1 receptor agonist dulaglutide on ambulatory blood pressure and heart rate in patients with type 2 diabetes mellitus.

Glucagon-like peptide-1 receptor agonists, used to treat type 2 diabetes mellitus, are associated with small reductions in systolic blood pressure (SBP) and increases in heart rate. However, findings based on clinic measurements do not adequately assess a drug's 24-hour pharmacodynamic profile. The effects of dulaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, on BP and heart rate were investigated using ambulatory BP monitoring. Patients (n=755; 56±10 years; 81% white; 48% women), with type 2 diabetes mellitus, taking ≥1 oral antihyperglycemic medication, with a clinic BP between 90/60 and 140/90 mm Hg were randomized to dulaglutide (1.5 or 0.75 mg) or placebo subcutaneously for 26 weeks. Ambulatory BP monitoring was performed at baseline and at 4, 16, and 26 weeks. The primary end point was change from baseline to week 16 in mean 24-hour SBP, a tree gatekeeping strategy compared the effects of dulaglutide to placebo. Both doses of dulaglutide were noninferior to placebo for changes in 24-hour SBP and diastolic blood pressure, and dulaglutide 1.5 mg significantly reduced SBP (least squares mean difference [95% confidence interval]), -2.8 mm Hg [-4.6, -1.0]; P≤0.001). Dulaglutide 0.75 mg was noninferior to placebo (1.6 bpm; [0.3, 2.9]; P≤0.02) for 24-hour heart rate (least squares mean difference [95% confidence interval]), but dulaglutide 1.5 mg was not (2.8 bpm [1.5, 4.2]). Dulaglutide 1.5 mg was associated with a reduction in 24-hour SBP and an increase in 24-hour heart rate. The mechanisms responsible for the observed effects remain to be clarified.

Characterizing workers participating in a worksite wellness health screening program using blood pressure control, self-monitoring, medication adherence, depression, and exercise.

Blood pressure control remains a serious public health issue because hypertension is the most common risk factor for cardiovascular disease. Effective management of hypertension often requires lifestyle modification and medication adherence. The objective of this study was to identify the prevalence of blood pressure control, medication adherence, self-monitoring of blood pressure, depression, and exercise among workers with access to health resources. Faculty and staff (N = 484) from a university and health care institution in the southeastern United States participated in biometric and questionnaire screening. The researchers used initial screening data from this worksite wellness program to describe baseline blood pressure control (< 140/90 mm Hg), self-monitoring of blood pressure, medication adherence, depression, and exercise. Overall, 63% of the workers' blood pressure was controlled; however, 23% of the sample had been prescribed antihypertensive medication to control their blood pressure. Thirty percent of the sample reported practicing blood pressure self-monitoring, 72.2% reported that they exercised, and 22% reported feeling down and depressed. More than half (64.9%) who used prescribed antihypertensive medication reported adherence to these medications.

Healthy lifestyle factors and risk of cardiovascular events and mortality in treatment-resistant hypertension: the Reasons for Geographic and Racial Differences in Stroke study.

Few data exist on whether healthy lifestyle factors are associated with better prognosis among individuals with apparent treatment-resistant hypertension, a high-risk phenotype of hypertension. The purpose of this study was to assess the association of healthy lifestyle factors with cardiovascular events, all-cause mortality, and cardiovascular mortality among individuals with apparent treatment-resistant hypertension. We studied participants (n=2043) from the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) study with apparent treatment-resistant hypertension (blood pressure ≥140/90 mm Hg despite the use of 3 antihypertensive medication classes or the use of ≥4 classes of antihypertensive medication regardless of blood pressure control). Six healthy lifestyle factors adapted from guidelines for the management of hypertension (normal waist circumference, physical activity ≥4 times/week, nonsmoking, moderate alcohol consumption, high Dietary Approaches to Stop Hypertension diet score, and low sodium-to-potassium intake ratio) were examined. A greater number of healthy lifestyle factors were associated with lower risk for cardiovascular events (n=360) during a mean follow-up of 4.5 years. Multivariable-adjusted hazard ratios [HR (95% confidence interval)] for cardiovascular events comparing individuals with 2, 3, and 4 to 6 versus 0 to 1 healthy lifestyle factors were 0.91 (0.68-1.21), 0.80 (0.57-1.14), and 0.63 (0.41-0.95), respectively (P-trend=0.020). Physical activity and nonsmoking were individual healthy lifestyle factors significantly associated with lower risk for cardiovascular events. Similar associations were observed between healthy lifestyle factors and risk for all-cause and cardiovascular mortality. In conclusion, healthy lifestyle factors, particularly physical activity and nonsmoking, are associated with a lower risk for cardiovascular events and mortality among individuals with apparent treatment-resistant hypertension.

Effects of demographics on the antihypertensive efficacy of triple therapy with amlodipine, valsartan, and hydrochlorothiazide for moderate to severe hypertension.

OBJECTIVE: To compare the antihypertensive efficacy and safety of once-daily triple therapy with amlodipine (Aml) 10 mg, valsartan (Val) 320 mg, and hydrochlorothiazide (HCTZ) 25 mg versus dual-therapy combinations of these components in patients with moderate to severe hypertension. RESEARCH DESIGN: Subgroup analysis of a multinational, randomized, double-blind, parallel-group, active-controlled trial. METHODS: After antihypertensive washout and a placebo run-in of up to 4 weeks, 2271 patients were randomly allocated in a 1:1:1:1 ratio to receive Aml/Val/HCTZ triple therapy or dual therapy with Val/HCTZ, Aml/Val, or Aml/HCTZ for 8 weeks. Forced titration to the full dose was done over the first 2 weeks of treatment. Efficacy and safety parameters were determined by age group (<65 vs. ≥65 years), gender, race (White vs. Black), ethnicity (Hispanic/Latino vs. non-Hispanic/Latino), and body mass index (BMI, <30 vs. ≥30 kg/m²). MAIN OUTCOME MEASURES: Change from baseline to endpoint in mean sitting systolic blood pressure (MSSBP) and mean sitting diastolic blood pressure (MSDBP); blood pressure (BP) control rate <140/90 mmHg. RESULTS: Triple therapy was numerically superior and, for the majority of comparisons, statistically superior to each dual therapy in reducing MSSBP and MSDBP and in improving BP control rates in all subgroups. Across subgroups, triple therapy reduced MSSBP by 5.7-10.7 mmHg more than Val/HCTZ, 3.4-8.3 mmHg more than Aml/Val, and 4.4-9.4 mmHg more than Aml/HCTZ. Triple therapy was well tolerated across all subgroups. Limitations of our analysis included the lack of stratification of patients by subgroup at randomization and the small sample size of some subgroups (e.g., Blacks, elderly). CONCLUSIONS: Triple therapy with Aml/Val/HCTZ is effective and well tolerated in patients with moderate to severe hypertension regardless of age, gender, race, ethnicity, or BMI. TRIAL REGISTRATION NUMBER: NCT00327587.

The contributions of unhealthy lifestyle factors to apparent resistant hypertension: findings from the Reasons for Geographic And Racial Differences in Stroke (REGARDS) study.

OBJECTIVES: Unhealthy lifestyle factors may contribute to apparent treatment resistant hypertension (aTRH). We examined associations of unhealthy lifestyle factors with aTRH in individuals taking antihypertensive medications from three or more classes. METHODS: Participants (n = 2602) taking three or more antihypertensive medication classes were identified from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study. aTRH was defined as having SBP/DBP at least 140/90 mmHg despite the use of three or more antihypertensive medication classes or the use of four or more classes to achieve blood pressure control. Lifestyle factors included obesity, physical inactivity, current smoking, heavy alcohol consumption, a low Dietary Approaches to Stop Hypertension (DASH) diet score and high sodium-to-potassium (Na/K) intake. RESULTS: Among participants taking three or more antihypertensive medication classes, 1293 (49.7%) participants had aTRH. The prevalence of unhealthy lifestyle factors in participants with and without aTRH was 55.2 and 51.7%, respectively, for obesity, 42.2 and 40.5% for physical inactivity, 11.3 and 11.5% for current smoking, 3.1 and 4.0% for heavy alcohol consumption, 23.1 and 21.5% for low-DASH diet score, and 25.4 and 24.4% for high Na/K intake. After adjustment for age, sex, race, and geographic region of residence, none of the unhealthy lifestyle factors were associated with aTRH. The associations between each unhealthy lifestyle factor and aTRH remained nonsignificant after additional adjustment for education, income, depressive symptoms, total calorie intake, and comorbidities. CONCLUSIONS: Unhealthy lifestyle factors did not have independent associations with aTRH among individuals taking three or more antihypertensive medication classes.

Moderate waist circumference and hypertension prevalence: the REGARDS Study.

BACKGROUND: High waist circumference (WC) (women: >88 cm; men: >102 cm) increases cardiovascular risk. Less is known about moderate WC (women: 80-88 cm; men: 94-102 cm). Therefore, we examined the association between moderate WC and hypertension prevalence, independent of body mass index (BMI). METHODS: Among 24,247 eligible adults 45-84 years old, when recruited from January 2003 to October 2007 in the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort, we examined hypertension prevalence (systolic blood pressure (BP) ≥140 mm Hg, or diastolic BP ≥90 mm Hg, or self-reported antihypertensive medication use) by WC before and after stratification by BMI (normal: 18.5-24.9; overweight: 25-29.9; obese class I: 30-34.9). Logistic regression adjusted associations between WC, BMI, and hypertension prevalence for age, race, sex, region, income, education, cigarette smoking, glomerular filtration rate, alcohol use, and physical activity. RESULTS: Overall, hypertension prevalence was 44% among those with low WC (n = 8,068), 55% with moderate WC (n = 6,488), and 66% with high WC (n = 9,691). After full adjustment, moderate WC was independently associated with hypertension prevalence among persons with normal BMI, (adjusted odds ratio (aOR), 1.49; 95% confidence interval (CI), 1.31-1.70), overweight BMI (aOR, 1.80; 95% CI, 1.64-1.98), and obese class I BMI (aOR, 2.28; 95%CI, 1.96-2.65) (referent: low WC-normal BMI). The moderate WC-hypertension association was observed in blacks and whites and in men and women. CONCLUSION: Moderate WC is associated with hypertension prevalence independent of BMI and several hypertension risk factors in middle-aged and older adults.

Geographic and demographic variability in 20-year hypertension incidence: the CARDIA study.

Although the variability of cardiovascular disease mortality by geography, race, and sex is well known, less is known about risk factor variation. We assessed 20-year incidence of hypertension, a cardiovascular disease risk factor, across 4 US urban areas and by race-sex. Among 3436 eligible adults 18 to 30 years of age when recruited in 1985 to 1986 in the community-based Coronary Artery Risk Development in Young Adults (CARDIA) cohort, we examined 20-year cumulative incidence of hypertension (systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg or antihypertensive medication use at any examination) by site and race-sex, adjusting for baseline and time-dependent covariates with Cox regression. Twenty-year incidence, when the mean age was ≈ 45 years, was 34.5% in black men (n = 617), 37.6% in black women (n = 965), 21.4% in white men (n = 856), and 12.3% in white women (n = 998; P<0.001). Incidence was 33.6% in Birmingham, Ala, 23.4% in Chicago, Ill, 19% in Minneapolis, Minn, and 27.4% in Oakland, Calif (P<0.001). After adjustment for age, race, sex, heart rate, body mass index, smoking, family history, education, uric acid, alcohol use, physical activity, and baseline systolic blood pressure, hazard ratios (95% CI) compared with Birmingham were 0.72 (0.59 to 0.87) for Chicago, 0.60 (0.50 to 0.74) for Minneapolis, and 0.73 (0.61 to 0.87) for Oakland. Race-sex differences persisted after adjustment for site, especially for black women. From young adulthood to middle age, hypertension incidence varies significantly across urban areas. Independent of geography, blacks, especially women, are at markedly higher risk of hypertension. Hypertension incidence may contribute to geographic and racial differences in cardiovascular disease mortality, including stroke.

Resistant hypertension, secondary hypertension, and hypertensive crises: diagnostic evaluation and treatment.

Hypertension is a very common modifiable risk factor for cardiovascular morbidity and mortality. Patients with hypertension represent a diverse group. In addition to those with primary hypertension, there are patients whose hypertension is attributable to secondary causes, those with resistant hypertension, and patients who present with a hypertensive crisis. Secondary causes of hypertension account for less than 10% of cases of elevated blood pressure (BP), and screening for these causes is warranted if clinically indicated. Patients with resistant hypertension, whose BP remains uncontrolled in spite of use of 3 or more antihypertensive agents, are at increased cardiovascular risk compared with the general hypertensive population. After potentially correctible causes of uncontrolled BP (pseudoresistance, secondary causes, and intake of interfering substances) are eliminated, patients with true resistant hypertension are managed by encouraging therapeutic lifestyle changes and optimizing the antihypertensive regimen, whereby the clinician ensures that the medications are prescribed at optimal doses using drugs with complementary mechanisms of action, while adding an appropriate diuretic if there are no contraindications. Mineralocorticoid receptor antagonists are formidable add-on agents to the antihypertensive regimen, usually as a fourth drug, and are effective in reducing BP even in patients without biochemical evidence of aldosterone excess. In the setting of a hypertensive crisis, the BP has to be reduced within hours in the case of a hypertensive emergency (elevated BP with evidence of target organ damage) using parenteral agents, and within a few days if there is hypertensive urgency, using oral antihypertensive agents.

Amlodipine/valsartan/hydrochlorothiazide triple combination therapy in moderate/severe hypertension: Secondary analyses evaluating efficacy and safety.

INTRODUCTION: An 8-week trial of amlodipine/valsartan/hydrochlorothiazide (Aml/Val/HCTZ) for moderate or severe hypertension demonstrated more-pronounced blood pressure (BP)-lowering effects compared with dual-component therapies. To elucidate the effects of time and baseline BP on the observed responses, exploratory analyses were performed. METHODS: Patients aged 18-85 years with mean sitting systolic BP (MSSBP) 145 to <200 mmHg and mean sitting diastolic BP (MSDBP) 100 to <120 mmHg were randomized to Aml 10 mg/Val 320 mg/HCTZ 25 mg; Val 320 mg/HCTZ 25 mg; Aml 10 mg/Val 320 mg; or Aml 10 mg/HCTZ 25 mg. During the first 2 weeks, regimens were force-titrated in two stages. RESULTS: All least-square mean reductions in MSSBP and MSDBP (baseline to Week 3 and end of study) were significantly greater with triple therapy than with each dual therapy in the overall population and the severe systolic subgroup (baseline MSSBP > or =180 mmHg; except vs. Aml 10 mg/Val 320 mg at Week 3). At Week 3, more patients on triple therapy achieved MSSBP reductions of > or =-60, > or =-50, > or =-40, > or =-30, and > or =-20 mmHg (2.5%, 9.7%, 23.2%, 46.9% and 74.5%, respectively) than those on dual therapy (1.1%-2%, 5.6%-5.9%, 14.5%-16.7%, 33.5%-39.1%, and 58.8%-65.5%, respectively); this was also true at study endpoint. End-of-study MSSBP reductions were greater in triple-therapy recipients who had higher (vs. lower) baseline MSSBPs. LSM reductions ranged from -27.2 mmHg for baseline MSSBP 145 to <150 mmHg, to > or =49.6 mmHg for baseline MSSBP > or =180 mmHg. All treatments were well tolerated regardless of baseline MSSBP. CONCLUSION: Aml 10 mg/Val 320 mg/HCTZ 25 mg triple therapy is highly effective in reducing BP compared with dual components early in therapy, and systolic BP-lowering effects were proportionate to hypertension severity.

Characterization and treatment of resistant hypertension.

Resistant hypertension is a common medical problem. It carries a significantly increased risk of end-organ damage and cardiovascular events compared with more easily controlled hypertension. Resistant hypertension is most often related to isolated systolic hypertension and is characterized by aldosterone excess and increased intravascular volume. Its diagnosis requires the exclusion of pseudoresistance. The etiology of resistant hypertension is almost always multifactorial. Common reversible contributing factors need to be identified and addressed. Secondary causes of hypertension, such as primary aldosteronism, parenchymal and vascular kidney disease, and obstructive sleep apnea, require investigation and effective treatment if present. Therapy for resistant hypertension should be based on use of rational drug class combinations at optimal doses, with particular attention to adequate diuretic use. The addition of an aldosterone antagonist may further improve blood pressure control.

Triple antihypertensive therapy with amlodipine, valsartan, and hydrochlorothiazide: a randomized clinical trial.

Many patients with hypertension require > or =3 agents to achieve target blood pressure (BP). The efficacy/safety of the dual combinations of valsartan (Val)/hydrochlorothiazide (HCTZ) and amlodipine (Aml)/Val in hypertension are well established. This randomized, double-blind study evaluated the efficacy/safety of triple therapy with Aml/Val/HCTZ for moderate or severe hypertension (mean sitting systolic BP: > or =145 mm Hg; mean sitting diastolic BP: > or =100 mm Hg). The study included a single-blind, placebo run-in period, followed by double-blind treatment for 8 weeks; patients were randomly assigned to 1 of 4 groups titrated to Aml/Val/HCTZ 10/320/25 mg, Val/HCTZ 320/25 mg, Aml/Val 10/320 mg, or Aml/HCTZ 10/25 mg once daily. Dual-therapy recipients received half of the target doses of both agents for the first 2 weeks, titrating to target doses during week 3. Those on triple therapy received Val/HCTZ 160.0/12.5 mg during week 1, Aml/Val/HCTZ 5.0/160.0/12.5 mg during week 2, and target doses of all 3 of the agents during week 3. Of the 4285 patients enrolled, 2271 were randomly assigned to treatment, and 2060 completed the study. Triple therapy was significantly superior to all of the dual therapies in reducing mean sitting systolic BP and mean sitting diastolic BP from baseline to end point (all P<0.0001). Significantly more patients on triple therapy achieved overall BP control (<140/90 mm Hg; P<0.0001) and systolic and diastolic control (P< or =0.0002) compared with each dual therapy. Aml/Val/HCTZ was well tolerated. The benefits of triple therapy over dual therapy were observed regardless of age, sex, race, ethnicity, or baseline mean sitting systolic BP. In conclusion, this study demonstrates the efficacy/safety of treating moderate and severe hypertension with Aml/Val/HCTZ 10/320/25 mg.

Sleep apnea, aldosterone, and resistant hypertension.

Obstructive sleep apnea, aldosterone excess, and resistant hypertension are common comorbidities in obese patients. The mechanisms that link these conditions are not fully elucidated, but sympathetic nervous system activation, sodium retention, renin-angiotensin-aldosterone system stimulation, endothelial dysfunction, and increased production of reactive oxidative species may be contributing factors. Patients diagnosed with this triad should be treated with low-salt diet, weight-loss counseling, and continuous positive airway pressure, as well as aggressive antihypertensive therapy, usually with multiple agents, including a mineralocorticoid receptor antagonist. Patients with aldosterone-producing adenoma may require adrenalectomy.