Blood pressure loci identified with a gene-centric array.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

The value of ambulatory blood pressure in older adults: the Dublin outcome study.

BACKGROUND: ambulatory blood pressure (ABPM) appears to be a more accurate predictor of cardiovascular outcome than blood pressure (BP) measured in the clinic setting in younger adults. OBJECTIVES: the purpose of this study was to determine if ABPM predicted total and cardiovascular mortality independently of clinic BP and other cardiovascular risk factors in those aged 65 years and over. METHODS: one thousand one hundred and forty-four individuals aged 65 and over referred to a single BP clinic had 24-h ABP measurement and clinic measurement at baseline off treatment. There were 385 deaths (of which 246 were cardiovascular) during a mean follow-up period of 6.7 years. RESULTS: with adjustment for gender, age, risk indices and also for clinic BP, a higher mean value of ABPM was an independent predictor of cardiovascular mortality. The relative hazard ratio for each 10-mmHg rise in systolic blood pressure (SBP) was 1.10 (1.06-1.18, P < 0.001) for daytime and 1.18 (1.11-1.25, P < 0.001) for night-time SBP. The hazard ratios for each 5-mmHg rise in diastolic blood pressure (DBP) were 1.05 (1.00-1.10, P = NS) for daytime and 1.09 (1.04-1.14, P < 0.001) for night-time diastolic pressure. The hazard ratios for night-time ABPM remained significant after adjustment for daytime ABPM. CONCLUSIONS: ambulatory measurement of BP is superior to clinic measurement in predicting cardiovascular mortality in elderly subjects. Night-time BP is the strongest predictor of outcome in this age group.

OASIS-HT: design of a pharmacogenomic dose-finding study.

Experimental evidence and observations in humans strongly support an interactive role of mutated alpha-adducin, sodium (Na(+))/potassium (K(+))-adenosine triphosphatase (ATPase) activity and endogenous ouabain in Na(+) homeostasis and the pathogenesis of hypertension. The Ouabain and Adducin for Specific Intervention on Sodium in HyperTension (OASIS-HT) trial is an early Phase II dose-finding study, which will be conducted across 39 European centers. Following a run-in period of 4 weeks without treatment, eligible patients will be randomized to one of five oral doses of rostafuroxin consisting of 0.05, 0.15, 0.5, 1.5, or 5.0 mg/day. Each dose will be compared to a placebo in a double-blind crossover experiment with balanced randomization. Treatment will be initiated with the active drug and continued with placebo or vice versa. Each double-blind period will last 5 weeks. The primary end point is the reduction in systolic blood pressure defined as the average of three clinic readings with the patient in the sitting position. Secondary end points include the reduction in diastolic blood pressure on clinic measurement, the decrease in the 24-h blood pressure, and the incidence of end points related to safety. Secondary objectives are to investigate the dependence of the blood pressure-lowering activity on the plasma concentration of endogenous ouabain and the genetic variation of the enzymes involved in the metabolism of this hormone, and the adducin cytoskeleton proteins. Eligible patients will have Grade I or II systolic hypertension without associated conditions and no more than two additional risk factors. In conclusion, OASIS-HT is a combination of five concurrent crossover studies, one for each dose of rostafuroxin to be studied. To our knowledge, OASIS-HT is the first Phase II dose-finding study in which a genetic hypothesis is driving primary and secondary end points.

Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension.

OBJECTIVE: To examine the association of clinic and ambulatory heart rate with total, cardiovascular, and noncardiovascular death in a cohort of elderly subjects with isolated systolic hypertension from the Systolic Hypertension in Europe Trial. METHODS: A total of 4682 patients participated, whose untreated blood pressure on conventional measurement at baseline was 160 to 219 mm Hg systolic and lower than 95 mm Hg diastolic. Clinic heart rate was the mean of 6 readings during 3 visits. Ambulatory heart rate was recorded with a portable intermittent technique in 807 subjects. RESULTS: Raised baseline clinic heart rate was positively associated with a worse prognosis for total, cardiovascular, and noncardiovascular mortality among the 2293 men and women taking placebo. Subjects with heart rates higher than 79 beats/min (bpm) (top quintile) had a 1.89 times greater risk of mortality than subjects with heart rate lower than or equal to 79 bpm (95% confidence interval, 1.33-2.68 bpm). In a Cox regression analysis, predictors of time to death were heart rate (P<.001), age (P<.001), serum creatinine level (P =.001), presence of diabetes (P =.002), previous cardiovascular disease (P =.01), triglyceride readings (P =.02), smoking (P =.04), and elevated systolic blood pressure (P =.05), while total cholesterol level was found to be nonsignificant in the model. In the ambulatory monitoring subgroup, clinic and ambulatory heart rates predicted noncardiovascular but not cardiovascular mortality. However, in a Cox regression analysis in which clinic and ambulatory heart rates were included, a significant association with noncardiovascular mortality was found only for clinic heart rate (P =.004). In the active treatment group, the weak predictive power of clinic heart rate for mortality disappeared after adjustment for confounders. CONCLUSIONS: In untreated older patients with isolated systolic hypertension, a clinic heart rate greater than 79 bpm was a significant predictor of all-cause, cardiovascular, and noncardiovascular mortality. Ambulatory heart rate did not add prognostic information to that provided by clinic heart rate.

Systolic blood pressure variability as a risk factor for stroke and cardiovascular mortality in the elderly hypertensive population.

OBJECTIVE: To investigate whether baseline systolic blood pressure variability was a risk factor for stroke, cardiovascular mortality or cardiac events during the Syst-Eur trial. DESIGN: The Syst-Eur study was a randomized, double-blind, placebo-controlled trial, powered to detect differences in stroke rate between participants on active antihypertensive treatment and placebo. Systolic blood pressure variability measurements were made on 744 participants at the start of the trial. Systolic blood pressure variability was calculated over three time frames: 24 h, daytime and night-time. The placebo and active treatment subgroups were analysed separately using an intention-to-treat principle, adjusting for confounding factors using a multiple Cox regression model. PARTICIPANTS: An elderly hypertensive European population. MAIN OUTCOME MEASURES: Stroke, cardiac events (fatal and non-fatal heart failure, fatal and non-fatal myocardial infarction and sudden death) and cardiovascular mortality (death attributed to stroke, heart failure, myocardial infarction, sudden death, pulmonary embolus, peripheral vascular disease and aortic dissection). RESULTS: The risk of stroke increased by 80% (95% confidence interval: 17-176%) for every 5 mmHg increase in night-time systolic blood pressure variability in the placebo group. Risk of cardiovascular mortality and cardiac events was not significantly altered. Daytime variability readings did not predict outcome. Antihypertensive treatment did not affect systolic blood pressure variability over the median 4.4-year follow-up. CONCLUSION: In the placebo group, but not the active treatment group, increased night-time systolic blood pressure variability on admission to the Syst-Eur trial was an independent risk factor for stroke during the trial.

Ambulatory pulse pressure as predictor of outcome in older patients with systolic hypertension.

We enrolled 808 older patients with isolated systolic hypertension (160 to 219/71 <95 mm Hg) to investigate whether ambulatory measurement of pulse pressure and mean pressure can refine risk stratification. The patients (> or =60 years) were randomized to nitrendipine (10 to 40 mg/day) with the possible addition of enalapril (5 to 20 mg/day) or hydrochlorothiazide (12.5 to 25 mg/day) or to matching placebos. At baseline, pulse pressure and mean pressure were determined from six conventional blood pressure (BP) readings and from 24-h ambulatory recordings. With adjustment for significant covariables, we computed mutually adjusted relative hazard rates associated with 10 mm Hg increases in pulse pressure or mean pressure. In the placebo group, the 24-h and nighttime pulse pressures consistently predicted total and cardiovascular mortality, all cardiovascular events, stroke, and cardiac events. Daytime pulse pressure predicted cardiovascular mortality, all cardiovascular end points, and stroke. The hazard rates for 10 mm Hg increases in pulse pressure ranged from 1.25 to 1.68. Conventionally measured pulse pressure predicted only cardiovascular mortality with a hazard rate of 1.35. In the active treatment group compared with the placebo patients, the relation between outcome and ambulatory pulse pressure was attenuated to a nonsignificant level. Mean pressure determined from ambulatory or conventional BP measurements was not associated with poorer prognosis. In conclusion, in older patients with isolated systolic hypertension higher pulse pressure estimated by 24-h ambulatory monitoring was a better predictor of adverse outcomes than conventional pulse pressure, whereas conventional and ambulatory mean pressures were not correlated with a worse outcome.

Antihypertensive treatment based on home or office blood pressure--the THOP trial.

OBJECTIVE AND METHODS: In this randomized clinical trial, conducted in 400 hypertensive patients [sitting diastolic blood pressure (DBP) >95 mmHg], blood pressure-lowering therapy was adjusted in a stepwise manner, either on the basis of the self-measured DBP at home or on the basis of conventional DBP measured at the doctor's office. RESULTS: Therapy guided by home blood pressure instead of office blood pressure led to less intensive drug treatment and marginally lower costs, but also to less blood pressure control with no differences in left ventricular mass. Self-measurement helped to identify patients with white-coat hypertension. CONCLUSIONS: The present findings support a stepwise strategy for the evaluation of blood pressure, in which self-measurement and ambulatory monitoring are complementary to conventional office blood pressure measurement.

Antihypertensive treatment based on blood pressure measurement at home or in the physician's office: a randomized controlled trial.

CONTEXT: Self-measurement of blood pressure is increasingly used in clinical practice, but how it affects the treatment of hypertension requires further study. OBJECTIVE: To compare use of blood pressure (BP) measurements taken in physicians' offices and at home in the treatment of patients with hypertension. DESIGN, SETTING, AND PARTICIPANTS: Blinded randomized controlled trial conducted from March 1997 to April 2002 at 56 primary care practices and 3 hospital-based outpatient clinics in Belgium and 1 specialized hypertension clinic in Dublin, Ireland. Four hundred participants with a diastolic BP (DBP) of 95 mm Hg or more as measured at physicians' offices were enrolled and followed up for 1 year. INTERVENTIONS: Antihypertensive drug treatment was adjusted in a stepwise fashion based on either the self-measured DBP at home (average of 6 measurements per day during 1 week; n = 203) or the average of 3 sitting DBP readings at the physician's office (n = 197). If the DBP guiding treatment was above (>89 mm Hg), at (80-89 mm Hg), or below (<80 mm Hg) target, a physician blinded to randomization intensified antihypertensive treatment, left it unchanged, or reduced it, respectively. MEAN OUTCOME MEASURES: Office and home BP levels, 24-hour ambulatory BP, intensity of drug treatment, electrocardiographic and echocardiographic left ventricular mass, symptoms reported by questionnaire, and costs of treatment. RESULTS: At the end of the study (median follow-up, 350 days; interquartile range, 326-409 days), more home BP than office BP patients had stopped antihypertensive drug treatment (25.6% vs 11.3%; P<.001) with no significant difference in the proportions of patients progressing to multiple-drug treatment (38.7% vs 45.1%; P =.14). The final office, home, and 24-hour ambulatory BP measurements were higher (P<.001) in the home BP group than in the office BP group. The mean baseline-adjusted systolic/diastolic differences between the home and office BP groups averaged 6.8/3.5 mm Hg, 4.9/2.9 mm Hg, and 4.9/2.9 mm Hg, respectively. Left ventricular mass and reported symptoms were similar in the 2 groups. Costs per 100 patients followed up for 1 month were only slightly lower in the home BP group (3875 vs 3522 [4921 dollars vs 4473 dollars]; P =.04). CONCLUSIONS: Adjustment of antihypertensive treatment based on home BP instead of office BP led to less intensive drug treatment and marginally lower costs but also to less BP control, with no differences in general well-being or left ventricular mass. Self-measurement allowed identification of patients with white-coat hypertension. Our findings support a stepwise strategy for the evaluation of BP in which self-measurement and ambulatory monitoring are complementary to conventional office measurement and highlight the need for prospective outcome studies to establish the normal range of home-measured BP.

Aliskiren monotherapy results in the greatest and the least blood pressure lowering in patients with high- and low-baseline PRA levels, respectively.

Hypertensive patients with low-baseline plasma renin activity (PRA) are known to respond best to natriuretic drugs, and those with high PRA respond best to renin-angiotensin system (RAS) blockade. However, there has been recent speculation that blood pressure (BP)-lowering responses to the renin inhibitor, aliskiren, might also be blunted in some patients with medium-to-high baseline PRA. It has been suggested that treatment resistance in these patients may result from excessive reactive increases in renin secretion, such that aliskiren's blockade of PRA is overwhelmed. In order to test for evidence in support of this hypothesis, we conducted a reanalysis of original data from three published clinical trials of aliskiren. When aliskiren was administered as a monotherapy, or in combination with other blockers of the RAS, changes in PRA were closely correlated with baseline PRA. Patients with low-baseline PRA demonstrated small reductions or rises in PRA, rather than patients with medium-to-high baseline PRA. We confirmed that ambulatory BP-lowering responses to full dose aliskiren monotherapy were greatest and least among patients with high- and low-baseline PRA, respectively. However no such association was demonstrated during aliskiren combination therapy. With either monotherapy or combination therapy, no patient with a baseline PRA >0.65 ng/ml/h was observed to have a rise in both PRA and BP. We conclude, therefore, that there is only evidence for one type of resistance to aliskiren--as with all blockers of the RAS, lesser BP-lowering responses to aliskiren occur in those with the least renin to block.

The Anglo-Scandinavian Cardiac Outcomes Trial lipid lowering arm: extended observations 2 years after trial closure.

AIMS: To determine the cardiovascular benefits in those originally assigned atorvastatin in the Anglo-Scandinavian Cardiac Outcomes Trial-2.2 years after closure of the lipid-lowering arm of the trial (ASCOT-LLA). METHODS AND RESULTS: The Blood Pressure Lowering Arm of the ASCOT trial (ASCOT-BPLA) compared two different antihypertensive treatment strategies on cardiovascular outcomes. ASCOT-LLA was a double-blind placebo-controlled trial of atorvastatin in those enrolled into ASCOT-BPLA with total cholesterol concentrations at baseline of < or =6.5 mmol/L. A total of 19 342 hypertensive patients were enrolled in ASCOT-BPLA and 10 305 were further assigned either atorvastatin, 10 mg, or placebo. ASCOT-LLA was stopped prematurely after a median 3.3 years follow-up because of substantial cardiovascular benefits in those assigned atorvastatin. Trial physicians were invited to offer atorvastatin to all ASCOT-LLA patients until the end of ASCOT-BPLA. The primary outcome of ASCOT-LLA was combined fatal coronary heart disease (CHD) or non-fatal myocardial infarction. Secondary outcomes included all coronary events, all cardiovascular events and procedures, fatal and non-fatal stroke, cardiovascular mortality, all cause mortality, development of chronic stable angina, heart failure, and peripheral arterial disease. By the end of ASCOT-LLA, there was a 36% relative risk reduction in primary events (n = 254) in favour of atorvastatin [hazard ratio (HR) 0.64, 95% CI: 0.50-0.83, P = 0.0005]. At the end of ASCOT-BPLA, 2.2 years later, despite extensive crossovers from and to statin usage, the relative risk reduction in primary events (n = 412) among those originally assigned atorvastatin remained at 36% (HR 0.64, 95% CI: 0.53-0.78, P = 0.0001). For almost all other endpoints, risk reductions also remained essentially unchanged and in the case of all cause mortality, the risk reduction of 15% now achieved borderline statistical significance (P = 0.02). CONCLUSION: Carry-over benefits from those originally assigned atorvastatin but no longer taking the drug may account for unchanged relative risk reductions in most cardiovascular endpoints observed 2 years after ASCOT-LLA closed.

Renin gene polymorphisms and haplotypes, blood pressure, and responses to renin-angiotensin system inhibition.

Renin catalyzes the rate-limiting step of the renin-angiotensin system. A T allele variant at position -5312 within a distal enhancer region has been reported to increase in vitro renin gene transcription. Among 387 White bank employees, ambulatory blood pressures were higher in 133 -5312T allele carriers than in 254 CC homozygotes-mean differences [99% confidence interval] between carriers and homozygotes for daytime and night-time systolic/diastolic pressure were 2.5[0.4,4.6]/1.7[0.2,3.2] and 2.4[0.5,4.4]/1.5[0.1,2.9] respectively. Ambulatory pressure estimates for the only common renin haplotype including the -5312T variant (-5312T, 5090C, 5912A, 9479A, 10194G), were statistically significantly higher than estimates for all other haplotypes. Among 259 White hypertensive participants in a randomized double-blind clinical trial comparing a renin antagonist, aliskiren, with an angiotensin receptor blocker, losartan, plasma renin activity did not differ with renin -5312C/T genotype. Nocturnal blood pressure reductions with losartan 100 mg daily were significantly greater in -5312T allele carriers than in CC homozygotes (mean[standard error]; -12.9[3.7]/-7.9[2.4] versus -7.1[2.5]/-4.2[1.6]) whereas with aliskiren 150 and 300 mg daily, lesser reductions were observed in -5312T allele carriers than in CC homozygotes (-5.4[2.0]/-4.1[1.3] versus -10.1[1.4]/-6.5[1.1]; P<0.03 for treatmentxgenotype interaction for night-time systolic and diastolic pressures). Hence, the -5312 renin C/T enhancer polymorphism does contribute to blood pressure variation in Whites and also appears to predict responses to inhibition of the renin-angiotensin system. These findings suggest that genotyping at this locus may aid in the identification of susceptibility to hypertension and in the selection of optimal therapy for individual hypertensive patients.

Cardiovascular risk in white-coat and sustained hypertensive patients.

We compared cardiovascular outcome between patients with white-coat and sustained hypertension who had previously participated in the Ambulatory Blood Pressure Monitoring and Treatment of Hypertension (APTH) trial. Baseline characteristics, including office and ambulatory blood pressure (BP), were measured during the 2-month run-in period of the APTH trial. During follow-up, information on the occurrence of major cardiovascular events (death, myocardial infarction, stroke and heart failure), achieved office BP and treatment status was obtained. At entry, 326 patients had sustained hypertension (daytime ambulatory BP > or = 140 mmHg systolic and/or > or = 90 mmHg diastolic) and 93 had daytime ambulatory BP below these limits and were classified as white-coat hypertensives. During 2088 patient-years of follow-up (median follow-up 5.3 years), all major cardiovascular events (n = 22) occurred in the patients with sustained hypertension (rate 12.7 per 1000 patient-years, p = 0.02 for between-group difference). Furthermore, multiple Cox regression confirmed that after adjustment for important covariables, daytime ambulatory BP--but not office BP at entry--significantly and independently predicted cardiovascular outcome. After additional adjustment for office BP, daytime ambulatory BP still predicted the occurrence of major cardiovascular events. Although white-coat hypertension was less frequently associated with antihypertensive drug treatment during follow-up, it carried a significantly better prognosis than sustained hypertension.