Alice Stanton

Differential Impact of Blood Pressure–Lowering Drugs on Central Aortic Pressure and Clinical Outcomes Principal Results of the Conduit Artery Function Evaluation (CAFE) Study

Background— Different blood pressure (BP)–lowering drugs could have different effects on central aortic pressures and thus cardiovascular outcome despite similar effects on brachial BP. The Conduit Artery Function Evaluation (CAFE) study, a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), examined the impact of 2 different BP lowering-regimens (atenolol±thiazide-based versus amlodipine±perindopril-based therapy) on derived central aortic pressures and hemodynamics. Methods and Results— The CAFE study recruited 2199 patients in 5 ASCOT centers. Radial artery applanation tonometry and pulse wave analysis were used to derive central aortic pressures and hemodynamic indexes on repeated visits for up to 4 years. Most patients received combination therapy throughout the study. Despite similar brachial systolic BPs between treatment groups (&Dgr;0.7 mm Hg; 95% CI, −0.4 to 1.7; P=0.2), there were substantial reductions in central aortic pressures with the amlodipine regimen (central aortic systolic BP, &Dgr;4.3 mm Hg; 95% CI, 3.3 to 5.4; P<0.0001; central aortic pulse pressure, &Dgr;3.0 mm Hg; 95% CI, 2.1 to 3.9; P<0.0001). Cox proportional-hazards modeling showed that central pulse pressure was significantly associated with a post hoc–defined composite outcome of total cardiovascular events/procedures and development of renal impairment in the CAFE cohort (unadjusted, P<0.0001; adjusted for baseline variables, P<0.05). Conclusions— BP-lowering drugs can have substantially different effects on central aortic pressures and hemodynamics despite a similar impact on brachial BP. Moreover, central aortic pulse pressure may be a determinant of clinical outcomes, and differences in central aortic pressures may be a potential mechanism to explain the different clinical outcomes between the 2 BP treatment arms in ASCOT.

Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study.

The purpose of this study was to determine if ambulatory blood pressure measurement predicted total and cardiovascular mortality over and beyond clinic blood pressure measurement and other cardiovascular risk factors; 5292 untreated hypertensive patients referred to a single blood pressure clinic who had clinic and ambulatory blood pressure measurement at baseline were followed up in a prospective study of mortality outcome. Multiple Cox regression was used to model time to total and cause-specific mortality for ambulatory blood pressure measurement while adjusting for clinic blood pressure measurement and other risk factors at baseline. There were 646 deaths (of which 389 were cardiovascular) during a median follow-up period of 8.4 years. With adjustment for gender, age, risk indices, and clinic blood pressure, higher mean values of ambulatory blood pressure were independent predictors for cardiovascular mortality. The relative hazard ratio for each 10-mm Hg increase in systolic blood pressure was 1.12 (1.06 to 1.18; P<0.001) for daytime and 1.21 (1.15 to 1.27; P<0.001) for nighttime systolic blood pressure. The hazard ratios for each 5-mm Hg increase in diastolic blood pressure were 1.02 (0.99 to 1.07; P=NS) for daytime and 1.09 (1.04 to 1.13; P<0.01) for nighttime diastolic pressures. The hazard ratios for nighttime ambulatory blood pressure remained significant after adjustment for daytime ambulatory blood pressure. These results have 2 important clinical messages: ambulatory measurement of blood pressure is superior to clinic measurement in predicting cardiovascular mortality, and nighttime blood pressure is the most potent predictor of outcome.

Structure-based design of aliskiren, a novel orally effective renin inhibitor

Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the Western world. Inhibitors of the renin-angiotensin system (RAS) have proven to be successful treatments for hypertension. As renin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition. Several peptide-like renin inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful. We employed a combination of molecular modelling and crystallographic structure analysis to design renin inhibitors lacking the extended peptide-like backbone of earlier inhibitors, for improved pharmacokinetic properties. This led to the discovery of aliskiren, a highly potent and selective inhibitor of human renin in vitro, and in vivo; once-daily oral doses of aliskiren inhibit renin and lower blood pressure in sodium-depleted marmosets and hypertensive human patients. Aliskiren represents the first in a novel class of renin inhibitors with the potential for treatment of hypertension and related cardiovascular diseases.

Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren

Abstract—Inhibition of the first and rate-limiting step of the renin-angiotensin system has long been an elusive therapeutic goal. Aliskiren, the first known representative of a new class of completely nonpeptide, orally active, renin inhibitors, has been shown to inhibit the production of angiotensin I and II in healthy volunteers and to reduce blood pressure (BP) in sodium-depleted marmosets. The aim of this randomized, double-blind, active comparator trial study was to assess the BP-lowering efficacy and safety of aliskiren. Two hundred twenty-six patients, 21 to 70 years of age, with mild to moderate hypertension, were randomly assigned to receive 37.5 mg, 75 mg, 150 mg, or 300 mg aliskiren or 100 mg losartan daily for 4 weeks. Dose-dependent reductions in daytime ambulatory systolic pressure (mean change, mm Hg [SD of change]; −0.4 [11.7], −5.3 [11.3], −8.0 [11.0], and −11.0 [11.0], P =0.0002) and in plasma renin activity (median change % [interquartile range]; −55 [−64, −11], −60 [−82, −46], −77 [−86, −72], and −83 [−92, −71], P =0.0008) were observed with 37.5, 75, 150, and 300 mg aliskiren. The change in daytime systolic pressure with 100 mg losartan (−10.9 [13.8]) was not significantly different from the changes seen with 75, 150, and 300 mg aliskiren. Aliskiren was well tolerated at all doses studied. This study demonstrates that aliskiren, through inhibition of renin, is an effective and safe orally active BP-lowering agent. Whether renin inhibition results in protection from heart attack, stroke, and nephropathy, similar to angiotensin-converting enzyme inhibition and angiotensin receptor blockade, needs to be researched.

Ambulatory Arterial Stiffness Index as a Predictor of Cardiovascular Mortality in the Dublin Outcome Study

We hypothesized that the dynamic relation between diastolic and systolic blood pressure over 24 hours provides a measure of arterial stiffness and might, therefore, predict cardiovascular mortality over and above pulse pressure. At baseline, while not on antihypertensive medication, 11 291 patients (mean age, 54.6 years; 5965 women) underwent ambulatory blood pressure monitoring. Using all of the blood pressure readings, we plotted diastolic against systolic blood pressure from each individual and calculated the regression slope. The ambulatory arterial stiffness index (AASI) was defined as 1 minus this regression slope. Over a median follow-up of 5.3 years, 566 cardiovascular deaths occurred, including 151 from stroke and 358 from cardiac disorders. Before and after adjustment for other cardiovascular risk factors, AASI and pulse pressure significantly predicted total cardiovascular mortality. AASI was a stronger predictor than pulse pressure for stroke (mutually adjusted relative hazard ratios for 1 SD increase, 1.21 versus 1.04; P=0.02 versus 0.66) with the opposite trend for cardiac mortality (relative hazard ratios, 1.03 versus 1.21; P=0.63 versus 0.002). In subjects with normal daytime ambulatory blood pressure (<135/<85 mm Hg), AASI was more predictive than pulse pressure of cardiovascular mortality (1.26 versus 0.96; P=0.04 versus 0.70) and of stroke mortality (1.81 versus 1.12; P=0.007 versus 0.58), whereas neither independently predicted cardiac mortality (1.11 versus 0.89; P=0.47 versus 0.40). AASI is a novel measure of arterial stiffness, which can be readily determined from ambulatory blood pressure recordings and which independently predicts cardiovascular mortality, even in normotensive subjects.

Ambulatory Arterial Stiffness Index Derived From 24-Hour Ambulatory Blood Pressure Monitoring

We hypothesized that 1 minus the slope of diastolic on systolic pressure during 24-hour ambulatory monitoring (ambulatory arterial stiffness index [AASI]) might reflect arterial stiffness. We compared AASI with established measures of arterial stiffness and studied its distribution in Chinese and European populations. We used 90207 SpaceLabs monitors and the SphygmoCor device to measure AASI, central and peripheral pulse pressures, the central (CAIx) and peripheral (PAIx) systolic augmentation indexes, and aortic pulse wave velocity. In 166 volunteers, the correlation coefficient between AASI and pulse wave velocity was 0.51 (P<0.0001). In 348 randomly recruited Chinese subjects, AASI correlated (P<0.0001) with CAIx (r=0.48), PAIx (r=0.50), and central pulse pressure (r=0.50). AASI increased with age and mean arterial pressure but decreased with body height. Both before and after adjustment for arterial wave reflections by considering height and heart rate as covariates, AASI correlated more (P<0.0001) closely with CAIx and PAIx than 24-hour pulse pressure. Among normotensive subjects, the 95th percentile of AASI was 0.55 in Chinese and 0.57 in 1617 Europeans enrolled in the International Database on Ambulatory Blood Pressure Monitoring. The upper boundary of the 95% prediction interval of AASI in relation to age ranged from 0.53 at 20 years to 0.72 at 80 years. In conclusion, AASI is a new index of arterial stiffness that can be easily measured under ambulatory conditions. Pending additional validation in outcome studies, normal values of AASI are probably <0.50 and 0.70 in young and older subjects, respectively.

Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%–2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5′ region of Uromodulin (UMOD; rs13333226, combined P value of 3.6×10−11). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84–0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860–0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83–0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83–0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Effects of a Fixed-Dose Combination Strategy on Adherence and Risk Factors in Patients With or at High Risk of CVD: The UMPIRE Randomized Clinical Trial

IMPORTANCE Most patients with cardiovascular disease (CVD) do not take recommended medications long-term. The use of fixed-dose combinations (FDCs) improves adherence in several clinical areas. Previous trials of cardiovascular FDCs have assessed short-term effects compared with placebo or no treatment. OBJECTIVE To assess whether FDC delivery of aspirin, statin, and 2 blood pressure-lowering agents vs usual care improves long-term adherence to indicated therapy and 2 major CVD risk factors, systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C). DESIGN, SETTING, AND PARTICIPANTS The UMPIRE trial, a randomized, open-label, blinded-end-point trial among 2004 participants with established CVD or at risk of CVD enrolled July 2010-July 2011 in India and Europe. The trial follow-up concluded in July 2012. INTERVENTIONS Participants were randomly assigned (1:1) to an FDC-based strategy (n=1002) containing either (1) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 50 mg atenolol or (2) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 12.5 mg hydrochlorothiazide or to usual care (n=1002). MAIN OUTCOMES AND MEASURES Adherence to medication (defined as self-reported use of antiplatelet, statin, and ≥2 BP-lowering medications) and changes in SBP and LDL-C from baseline. RESULTS At baseline, mean BP was 137/78 mm Hg, LDL-C was 91.5 mg/dL, and 1233 (61.5%) of 2004 participants reported use of antiplatelet, statin, and 2 or more BP-lowering medications. Median follow-up was 15 months (interquartile range, 12-18 months). The FDC group had improved adherence vs usual care (86% vs 65%; relative risk [RR] of being adherent, 1.33; 95% CI, 1.26-1.41; P < .001) with concurrent reductions in SBP (-2.6 mm Hg; 95% CI, -4.0 to -1.1 mm Hg; P < .001) and LDL-C (-4.2 mg/dL; 95% CI, -6.6 to -1.9 mg/dL; P < .001) at the end of the study. Although there was consistency of effects across predefined subgroups, evidence existed of larger benefits in patients with lower adherence at baseline. In this subgroup of 727 participants (36%), adherence at the end of study was 77% vs 23% (RR, 3.35; 95% CI, 2.74-4.09; P < .001 for interaction), SBP was reduced by 4.9 mm Hg (95% CI 7.3-2.6 mm Hg; P = .01 for interaction), and LDL-C was reduced by 6.7 mg/dL (95% CI, 10.5-2.8 mg/dL; P = .11 for interaction). There were no significant differences in serious adverse events or cardiovascular events (50 [5%] in the FDC group and 35 [3.5%] in the usual care group; RR, 1.45; 95% CI, 0.94-2.24; P=.09) between the groups. CONCLUSIONS AND RELEVANCE Among patients with or at high risk of CVD, use of an FDC strategy for blood pressure, cholesterol, and platelet control vs usual care resulted in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01057537.

Retinal vascular tree morphology: a semi-automatic quantification

A semi-automatic method to measure and quantify geometrical and topological properties of continuous vascular trees in clinical fundus images is described. Measurements are made from binary images obtained with a previously described segmentation process. The skeletons of the segmented trees are produced by thinning, ff branch and crossing points are identified and segments of the trees are labeled and stored as a chain code. The operator selects a tree to be measured and decides if it is an arterial or venous tree. An automatic process then measures the lengths, areas and angles of the individual segments of the tree. Geometrical data and the connectivity information between branches from continuous retinal vessel trees are tabulated. A number of geometrical properties and topological indexes are derived. Vessel diameters and branching angles are validated against manual measurements and several derived geometrical and topological properties are extracted from red-free fundus images of ten normotensive and ten age- and sex-matched hypertensive subjects and compared with previously reported results.

Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an Angiotensin-Converting Enzyme Inhibitor, or an Angiotensin Receptor Blocker

Thiazide diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers all cause reactive rises in plasma renin activity. We hypothesized that renin inhibition with aliskiren would prevent this reactive rise and also enhance blood pressure lowering. In 3 open-label studies in which blood pressure was assessed with ambulatory measurement, aliskiren was administered to patients with mild-to-moderate hypertension in combination with hydrochlorothiazide (n=23), ramipril (n=21), or irbesartan (n=23). In the diuretic combination study, the addition of 25 mg of hydrochlorothiazide to 150 mg of aliskiren daily for 3 weeks significantly lowered daytime pressure, compared with aliskiren monotherapy (systolic/diastolic mean change from baseline [SEM]: daytime: −18.4 [2.1]/ −10.6 [1.7] versus −10.4 [1.8]/−5.8 [1.4]; nighttime: −15.6 [2.7]/−8.1 [1.8] versus −8.8 [2.9]/−5.0 [2.2]). In the angiotensin-converting enzyme inhibitor combination study, the addition of 75 or 150 mg of aliskiren to 5 mg of ramipril alone for 3 weeks further lowered both daytime and nighttime pressures compared with ramipril monotherapy (daytime: −10.5 [2.9]/−8.1 [2.1] and −14 [3.7]/−8.7 [2.3] versus −6.1 [2.4]/−5.9 [1.5]; nighttime: −8.1 [2.6]/−5.3 [2.4] and −9.6 [3.4]/−5.3 [2.4] versus −2 [2.3]/−0.7 [2.2]). In the angiotensin receptor blocker combination study, the addition of 75 or 150 mg of aliskiren to 150 mg of irbesartan alone, for 3 weeks, resulted in significantly lower nighttime pressures compared with irbesartan monotherapy (daytime: −14.8 [2]/−8.2 [1.3] and −13.3 [1.6]/−6.8 [0.9] versus −11.4 [1.6]/−6.5 [1.1]; nighttime: −16.1 [2.4]/−8.6 [1.7] and −13.2 [2.7]/−7.2 [1.9] versus −9.0 [2.5]/−4.7 [1.9]). Aliskiren (150 mg) alone significantly inhibited plasma renin activity by 65% (P<0.0001). Ramipril and irbesartan monotherapy caused 90% and 175% increases in plasma renin activity, respectively. By contrast, when aliskiren was coadministered with hydrochlorothiazide, ramipril, or irbesartan, plasma renin activity did not increase but remained similar to baseline levels or was decreased (combination therapy versus untreated; median [interquartile range]; aliskiren and hydrochlorothiazide: 0.4 [0.2 to 1.1] versus 0.7 [0.5 to 1.3]; ramipril and aliskiren: 0.5 [0.3 to 0.9] versus 0.6 [0.5 to 0.8]; irbesartan and aliskiren: 0.4 [0.2 to 0.9] versus 0.6 [0.4 to 0.9]). These results suggest that renin inhibition with aliskiren in these combinations increases renin-angiotensin system suppression, improves 24-hour blood pressure control, and may ultimately provide better end-organ protection in patients with hypertension.