Measuring copeptin, a surrogate for vasopressin in patients with hypertension - Can it identify those who are volume Responsive?

BACKGROUND: Among hypertensive patients, plasma renin activity is lower and the response to diuretic monotherapy greater in volume responsive hypertensive patients. We hypothesized that hormones influencing extracellular volume such as vasopressin / antidiuretic hormone (ADH) might permit the development of a simple test to identify those with volume-related hypertension. Such a test might be of particular benefit to the Black population which is purported to have a higher incidence of volume-related and responsive hypertension. Thus, using copeptin, a surrogate marker for ADH, we studied if there were differences in this hormone between those with and without volume responsive hypertension. METHODS: Serum copeptin was measured in biobanked blood samples from the Genetic Epidemiology of Responses to Antihypertensives (GERA) I study and analyzed with other variables from the study dataset. RESULTS: There was no relationship between PRA and copeptin values nor could the response in blood pressure be predicted by the copeptin values. However, baseline copeptin levels were higher in Black than in White subjects (7.5 pmol/L vs 5.4 pmol/L, P < 0.001) while plasma sodium and calculated plasma osmolality were slightly lower in keeping with the concept that Black subjects have more volume-related hypertension. In addition, after hydrochlorothiazide (HCTZ), copeptin was significantly lower in Black (6.2 pmol/L, P = 0.004) but unchanged in White subjects (5.2 pmol/L, P = 0.901) and there were also changes in sodium. CONCLUSION: The current study suggests differences in ADH physiology between hypertensive Black and White patients. However, the use of copeptin to identify volume responsive patients could not be confirmed.

Sorting nexin 1 loss results in increased oxidative stress and hypertension.

Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D5 receptor (D5 R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1-/- mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT1 R), NADPH oxidase (NOX) subunits, D5 R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1-/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D5 R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D5 R agonist-induced increase in cAMP production and decrease in Na+ transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.

Plasma Renin Activity Is a Predictive Biomarker of Blood Pressure Response in European but not in African Americans With Uncomplicated Hypertension.

BACKGROUND: Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood. METHODS: Using systematic-phased approach, PRA's clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed. RESULTS: EAs with PRA < 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by -15.9 mm Hg, adjusted P < 0.0001), whereas those with PRA ≥ 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ≥ 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%. CONCLUSIONS: PRA at the previously established 0.60-0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs. TRIAL REGISTRATION: NCT01203852, NCT00246519, NCT00005520.

Associations of Nocturnal Blood Pressure With Cognition by Self-Identified Race in Middle-Aged and Older Adults: The GENOA (Genetic Epidemiology Network of Arteriopathy) Study.

BACKGROUND: Whether the association of blood pressure (BP) during sleep (nocturnal BP) with cognition differs by race is unknown. METHODS AND RESULTS: Participants in the GENOA (Genetic Epidemiology Network of Arteriopathy) Study underwent ambulatory BP measurements, brain magnetic resonance imaging, and cognitive function testing (the Rey Auditory Verbal Learning Test, the Digit Symbol Substitution Task, and the Trail Making Test Part B) between 2000 and 2007. We examined multivariable linear regression models of the nocturnal BP-cognition association. Among 755 participants (mean age, 63 years; 64% women; 42% self-identified black race; 76% taking antihypertensive medication), mean nocturnal systolic BP (SBP)/diastolic BP was 126/69 mm Hg, daytime SBP/diastolic BP level was 139/82 mm Hg, and mean reduction in SBP from day to night (dipping) was 9%. Among the entire sample, a race interaction was observed in Digit Symbol Substitution Task and Trail Making Test Part B (both P<0.15). Race-stratified analyses showed that a 1-SD increase in nocturnal SBP levels was associated with poorer Digit Symbol Substitution Task and log-transformed Trail Making Test Part B scores (unstandardized regression coefficient [95% confidence interval]: -1.98 [-3.28 to -0.69] and 0.06 [0.004-0.12]; both P<0.05) in black but not white individuals. Additional adjustments for white matter hyperintensity volumes or brain atrophy, measured via brain magnetic resonance imaging, did not change the results. Results were similar when nocturnal SBP dipping was assessed as the exposure, yet daytime SBP levels yielded no association with cognition. CONCLUSIONS: Nocturnal SBP measurements may be useful in assessing the potential risk for lower cognitive function in middle-aged and older adults, particularly in black individuals.

Blood pressure response to metoprolol and chlorthalidone in European and African Americans with hypertension.

Despite the availability of many antihypertensive drug classes, half of patients with hypertension have uncontrolled blood pressure (BP). The authors sought to assess the effect of age on BP response in European American and African American patients with hypertension. Clinic BP from the PEAR2 (Pharmacogenomics Evaluation of Antihypertensive Responses 2) study was used to estimate BP responses from baseline following sequential treatment with metoprolol 100 mg twice daily and chlorthalidone 25 mg daily for 8 to 9 weeks each, with a minimum 4-week washout between treatments. BP responses to both drugs were compared in 159 European Americans and 119 African Americans by age with adjustment for baseline BP and sex. European Americans younger than 50 years responded better to metoprolol than chlorthalidone (diastolic BP: -9.6 ± 8.0 vs -5.9 ± 6.8 mm Hg, adjusted P = .003), whereas patients 50 years and older responded better to chlorthalidone than metoprolol (systolic BP: -18.7 ± 13.8 vs -13.6 ± 14.8 mm Hg, adjusted P = .008). African Americans younger than 50 years responded similarly to both drugs, whereas those 50 years and older responded better to chlorthalidone than metoprolol (-17.0 ± 13.2/-9.6 ± 7.5 vs -7.0 ± 18.6/-6.7 ± 9.3 mm Hg, adjusted P<.0001/.008). Therefore, age should be considered when selecting antihypertensive therapy in European and African American populations with hypertension.

Comparison of Blood Pressure Control Rates Among Recommended Drug Selection Strategies for Initial Therapy of Hypertension.

BACKGROUND: Several approaches to initiation of antihypertensive therapy have been suggested. These include thiazide diuretics (TDs) as the first drug in all patients, initial drug selection based on age and race criteria, or therapy selection based on measures of plasma renin activity (PRA). It is uncertain which of these strategies achieves the highest control rate with monotherapy in Stage-I hypertension. We sought to compare control rates among these strategies. METHODS: We used data from the Pharmacogenomic Evaluation of Antihypertensive Responses study (PEAR) to estimate control rates for each strategy: (i) TD for all, (ii) age- and race-based strategy: Hydrochlorothiazide (HCTZ) for all blacks and for whites ≥50 years and a renin-angiotensin system inhibitor (atenolol) for whites <50 years) or (iii) a PRA based strategy: HCTZ for suppressed PRA (<0.6ng/ml/h) and atenolol for non-suppressed PRA (≥0.6ng/ml/h) despite age or race. Hypertension was confirmed prior to treatment with HCTZ (148 blacks and 218 whites) or with atenolol (146 blacks and 221 whites). RESULTS: In the overall sample, using clinic blood pressure (BP) response, the renin-based strategy was associated with the greatest control rate (48.9% vs. 40.8% with the age and race-based strategy (P = 0.0004) and 31.7% with the TD for all strategy (P < 0.0001)). The findings were similar using home or by 24-hour ambulatory BP responses and within each racial subgroup. CONCLUSIONS: A strategy for selection of initial antihypertensive drug therapy based on PRA was associated with greater BP control rates compared to a thiazide-for-all or an age and race-based strategy.

Troponin T as a Predictor of End-Stage Renal Disease and All-Cause Death in African Americans and Whites From Hypertensive Families.

OBJECTIVE: To evaluate cardiac troponin T (cTnT) as a predictor of end-stage renal disease (ESRD) and death in a cohort of African American and white community-dwelling adults with hypertensive families. PATIENTS AND METHODS: A total of 3050 participants (whites from Rochester, Minnesota; African Americans from Jackson, Mississippi) of the Genetic Epidemiology Network of Arteriopathy study were followed from baseline examination (June 1, 1996, through August 31, 2000) through January 22, 2010. Cox proportional hazards regression models were used to examine the association of cTnT with ESRD and death after adjusting for traditional risk factors. RESULTS: Cohort demographic characteristics and measurements included 1395 whites (45.7%), 2174 hypertensive (71.3%), 992 estimated glomerular filtration rate of less than 60 mL/min per 1.73 m(2) (32.5%), 1574 high-sensitivity C-reactive protein level of greater than 3 mg/L (51.6%), and 66 abnormal cTnT level of 0.01 ng/mL or higher (2.2%). The estimated cumulative incidence of ESRD at 10 years was 27.4% among those with abnormal cTnT levels compared with 1.3% for those with normal levels. Similarly, the estimated cumulative incidence of death at 10 years was 47% among those with abnormal cTnT compared with 7.3% among those with normal cTnT. Abnormal cTnT levels were strongly associated with ESRD and death. This effect was attenuated but was still highly significant after adjustment for demographic characteristics, estimated glomerular filtration rate, and traditional risk factors for ESRD (unadjusted hazard ratio [HR], 23.91; 95% CI, 12.9-44.2; adjusted HR, 2.81; 95% CI, 1.3-5.9) and death (unadjusted HR, 8.43; 95% CI, 6.0-11.9; adjusted HR, 3.46; 95% CI, 2.3-5.1). CONCLUSION: Cardiac troponin T makes an independent contribution to the prediction of ESRD and all-cause death in community-dwelling individuals beyond traditional risk markers. Further studies may be needed to determine whether cTnT screening in individuals with hypertension or in a subset of hypertensive individuals would help identify those at risk of ESRD and all-cause death.

Predictors for glucose change in hypertensive participants following short-term treatment with atenolol or hydrochlorothiazide.

STUDY OBJECTIVE: To develop and validate a predictive model for glucose change and risk for new-onset impaired fasting glucose in hypertensive participants following treatment with atenolol or hydrochlorothiazide (HCTZ). DESIGN: Randomized multicenter clinical trial. PATIENTS: A total of 735 white or African-American men and women with uncomplicated hypertension. MEASUREMENTS AND MAIN RESULTS: Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) is a randomized clinical trial to assess the genetic and nongenetic predictors of blood pressure response and adverse metabolic effects following treatment with atenolol or HCTZ. To develop and validate predictive models for glucose change, PEAR participants were randomly divided into a derivation cohort of 367 and a validation cohort of 368. Linear and logistic regression modeling were used to build models of drug-associated glucose change and impaired fasting glucose (IFG), respectively, in the derivation cohorts. These models were then evaluated in the validation cohorts. For glucose change after atenolol or HCTZ treatment, baseline glucose was a significant (p<0.0001) predictor, explaining 13% of the variability in glucose change after atenolol and 12% of the variability in glucose change after HCTZ. Baseline glucose was also the strongest and most consistent predictor (p<0.0001) for development of IFG after atenolol or HCTZ monotherapy. The area under the receiver operating curve was 0.77 for IFG after atenolol and 0.71 after HCTZ treatment, respectively. CONCLUSION: Baseline glucose is the primary predictor of atenolol or HCTZ-associated glucose increase and development of IFG after treatment with either drug.

Renal denervation for hypertension.

Hypertension is the leading cause of mortality worldwide. Effective therapies are needed for resistant hypertension, a common condition characterized by inadequate blood pressure control despite 3 or more medications, which is associated with increased cardiovascular mortality. Percutaneous catheter-based renal denervation is a promising new treatment offering the potential to improve blood pressure control, reduce cardiovascular risk, and target end-organ damage in patients with resistant hypertension. Initial studies have demonstrated procedural safety and effectiveness in blood pressure reduction up to 2 years after procedure. Large randomized control trials are necessary and currently underway to define further the role of renal denervation and long-term consequences in the treatment of resistant hypertension.

Night blood pressure responses to atenolol and hydrochlorothiazide in black and white patients with essential hypertension.

BACKGROUND: Night blood pressure (BP) predicts patient outcomes. Variables associated with night BP response to antihypertensive agents have not been fully evaluated in essential hypertension. METHODS: We sought to measure night BP responses to hydrochlorothiazide (HCTZ), atenolol (ATEN), and combined therapy using ambulatory blood pressure (ABP) monitoring in 204 black and 281 white essential hypertensive patients. Initial therapy was randomized; HCTZ and ATEN once daily doses were doubled after 3 weeks and continued for 6 more weeks with the alternate medication added for combined therapy arms. ABP was measured at baseline and after completion of each drug. Night, day, and night/day BP ratio responses (treatment - baseline) were compared in race/sex subgroups. RESULTS: Baseline night systolic BP and diastolic BP, and night/day ratios were greater in blacks than whites (P < 0.01, all comparisons). Night BP responses to ATEN were absent and night/day ratios increased significantly in blacks (P < 0.05). At the end of combined therapy, women, blacks, and those starting with HCTZ as opposed to ATEN had significantly greater night BP responses (P < 0.01). Variables that significantly associated with ATEN response differed from those that associated with HCTZ response and those that associated with night BP response differed from those that associated with day BP response. CONCLUSIONS: In summary, after completion of HCTZ and ATEN therapy, women, blacks, and those who started with HCTZ had greater night BP responses. Reduced night BP response and increased night/day BP ratios occured with ATEN in blacks. Given the prognostic significance of night BP, strategies for optimizing night BP antihypertensive therapy should be considered. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00246519.

The treatment of hypertension during pregnancy: when should blood pressure medications be started?

Hypertensive pregnancy disorders (HPD) are important causes of maternal and fetal morbidity and mortality worldwide. In addition, a history of HPD has been associated with an increased risk for maternal cardiovascular disease later in life, possibly because of irreversible vascular and metabolic changes that persist beyond the affected pregnancies. Therefore, treatment of HPD may not only improve immediate pregnancy outcomes, but also maternal long-term cardiovascular health. Unlike the recommendations for hypertension treatment in the general population, treatment recommendations for HPD have not changed substantially for more than 2 decades. This is particularly true for mild to moderate hypertension in pregnancy, defined as a blood pressure of 140-159/90-109 mm Hg. This review focuses on the goals of therapy, treatment strategies, and new developments in the field of HPD that should be taken into account when considering blood pressure targets and pharmacologic options for treatment of hypertension in pregnant women.

Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide.

To identify novel genes influencing blood pressure response to thiazide diuretic therapy for hypertension, we conducted genome-wide association meta-analyses of ≈1.1 million single-nucleotide polymorphisms in a combined sample of 424 European Americans with primary hypertension treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses study (n=228) and the Genetic Epidemiology of Responses to Antihypertensive study (n=196). Polymorphisms associated with blood pressure response at P<10(-5) were tested for replication of the associations in independent samples of hydrochlorothiazide-treated European hypertensives. The rs16960228 polymorphism in protein kinase C, α replicated for same-direction association with diastolic blood pressure response in the Nordic Diltiazem study (n=420) and the Genetics of Drug Responsiveness in Essential Hypertension study (n=206), and the combined 4-study meta-analysis P value achieved genome-wide significance (P=3.3 × 10(-8)). Systolic or diastolic blood pressure responses were consistently greater in carriers of the rs16960228 A allele than in GG homozygotes (>4/4 mm Hg) across study samples. The rs2273359 polymorphism in the GNAS-EDN3 region also replicated for same-direction association with systolic blood pressure response in the Nordic Diltiazem study, and the combined 3-study meta-analysis P value approached genome-wide significance (P=5.5 × 10(-8)). The findings document clinically important effects of genetic variation at novel loci on blood pressure response to a thiazide diuretic, which may be a basis for individualization of antihypertensive drug therapy and identification of new drug targets.

The role of plasma renin activity, age, and race in selecting effective initial drug therapy for hypertension.

BACKGROUND: Strategies for initial drug therapy of hypertension are a thiazide diuretic for all or drug selection based on age/race criteria or on plasma renin activity (PRA). It is uncertain which of these strategies will achieve the highest control rate among patients with stage 1 essential hypertension. We sought to compare control rates among 3 drug selection strategies: (i) thiazide diuretic for all, (ii) thiazide diuretic for all black subjects and white subjects aged ≥50 years and a renin-angiotensin system blocker for white subjects aged <50 years, or (iii) thiazide diuretic for PRA < 0.6ng/ml/h (suppressed PRA) and a renin-angiotensin system blocker for PRA ≥ 0.6ng/ml/h (nonsuppressed PRA). METHODS: Blood pressure responses from the Genetic Epidemiology of Responses to Antihypertensives (GERA) study were used to determine control rates for each of the 3 strategies. In GERA, hypertensive adults were treated with hydrochlorothiazide (n = 286 black subjects and 284 white subjects) or with candesartan (n = 248 black subjects and 278 white subjects). RESULTS: In the overall sample, the PRA strategy was associated with the highest control rate of 69.4% vs. 61.3% with the age/race strategy (P < 0.001) and 53.8% with the thiazide for all strategy (P < 0.001). This was also true in each racial subgroup (in black subjects: 62.1% vs. 55.2% for the other 2 strategies, P = 0.02; in white subjects: 76.3% vs. 67.1% with the age/race strategy (P < 0.001) and 52.4% with the thiazide for all strategy (P < 0.001)). CONCLUSIONS: This exploratory analysis suggests that choice of initial therapy for hypertension using a PRA strategy may be associated with higher control rates than alternative strategies recommended in current guidelines.