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Late-Breaking Clinical Trials

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  2. Late-Breaking Clinical Trials
  3. Late-Breaking Poster Session Cellular Mechanisms (Cell Biology; Cell Membrane Transport/Ion Channels; Coagulation/Thrombosis; Growth Factors; Ion Channels)
  4. Clinical Trials
  5. Blood Pressure Measurement/Monitoring

LB-OR-01

Evaluation of Cardiovascular Effects in three Double-blind, Placebo-controlled Clinical Trials with Controlled-release Phentermine/Topiramate (PHEN/TPM CR)

SuzanneOparil,1 Wesley Day,2 Charles Bowden2

1 University of Alabama, Birmingham, AL and 2Vivus, Mountain View, CA

Investigate the blood pressure (BP), heart rate (HR) and rate pressure product (RPP) effects of long-term administration of phentermine/topiramate CR (PHEN/TPM CR).

Methods:  Mean changes in systolic blood pressure (SBP), diastolic blood pressure (DBP) and HR from baseline (BL) to 56 weeks were evaluated. Categorical increases in BP (mm Hg) and HR (bpm) were defined as ≥2 consecutive measures above a given threshold. The RPP at BL to 56 weeks was calculated. Additional analyses included changes in BP and HR by BL risk category (high: known cardiovascular disease (CVD), medium: CVD risk factors and low: no CVD risk factors), changes in HR by baseline HR and BP.

Results:  Three thousand and seven subjects were included in this evaluation (1532 in placebo, 234 in PHEN/TPM CR [3.75 mg/23 mg], 488 in PHEN/TPM CR [7.5 mg/46 mg] and 1553 in PHEN/TPM CR [15 mg/92 mg]). Significant decreases in SBP and DBP were seen in the 7.5/46 and the 15/92 groups vs placebo (P<.01 for all comparisons). A significant increase in HR of 1.6 bpm was detected in the 15/92 (P<.0001) group but not in lower dose groups. No meaningful differences were observed amongst treatment groups in the percentages of subjects with consecutive increases in SBP or DBP, changes in BP by baseline risk category, nor changes in HR by baseline HR or BP. Greater dose-related reductions in SBP were observed in the patients with hypertension at baseline as compared to those without hypertension. Subjects with hypertension had smaller mean changes in HR than subjects without hypertension. Overall, mean reductions in RPP were observed in all treatment groups and no significant differences between treatment groups were detected at 56 weeks. Treatment with 15/92 decreased RPP compared to placebo in both subjects with (HR+) and without (HR−) HR elevations, and these results were significant (HR+ population, P=.0118; and HR− population, P=.0478).

Discussion:  PHEN/TPM CR use has demonstrated beneficial effects on several cardiovascular parameters in obese individuals. Although a small increase in HR of 1.6 bpm is seen with PHEN/TPM CR at 15/92, overall mean systolic and diastolic blood pressure reductions are associated with an overall improvement in RPP over 1 year suggesting no increased risk from the small HR change.

Keywords:  Cardiovascular safety; Hypertension; Pharmacotherapy; Obesity

LB-OR-02

Longterm (3–5 months) Spaceflight Promotes a Sustained Decrease in Blood Pressure and Systemic Vascular Resistance in Astronauts

PeterNorsk,1 Ali Asmar,1 Niels Juel Christensen2

1 University of Copenhagen, Copenhagen, DK and 2Herlev University Hospital, Herlev, DK

The effects of longterm (months) spaceflight on ambulatory brachial blood pressure and cardiac output are incompletely defined. We therefore monitored 24 hours ambulatory brachial blood pressure by portable equipment developed for spaceflight (ESA) in six astronauts on three occasions: (1) initially 2 months or more before flight, (2) once between 3 and 5 months into flight on the International Space Station and (3) finally 2 months or more following landing. Cardiac output (Freon-22, rebreathing technique) was measured at 3–5 hours intervals during the 24 hours, and on the ground when the astronauts were seated. One cubital venous sample was collected once in the morning after breakfast for plasma catecholamine determinations, and on the ground also when the astronauts were seated. Systolic/diastolic arterial pressure decreased during spaceflight from 128±3 (mean±SEM)/86±2 (preflight) to 121±2/77±2 mm Hg (P=.05/P 0.006) and mean arterial pressure from 103±3 to 93±1 (P=.014). Cardiac output increased by 29% from 6.5±0.4 to 8.4±0.4 L/min (P=.001) and systemic vascular resistance decreased by 32% from 16.4± 0.7 to 11.2± 0.6 mm Hg min/L (P<.001). Heart rate and plasma norepinephrine were unchanged, and all variables had returned to preflight levels after flight. The sustained blood pressure lowering and systemic vasodilatory effects of weightlessness indicate that gravitational stress on Earth modulate blood pressure in humans.

Keywords:  Spaceflight; Weightlessness; Blood pressure; Cardiac output

LB-OR-03

Azilsartan Medoxomil plus Chlorthalidone Reduces BP more Effectively than Olmesartan plus HCTZ in Stage 2 Systolic Hypertension

William C.Cushman,1 George Bakris,2 William B. White,3 Michael Weber,4 Domenic Sica,5 Andrew Roberts,6 Eric Lloyd,6 Stuart Kupfer6

1 University of TN College of Medicine; 2Uinversity of Chicago Pritzker School of Medicine; 3University of CT School of Medicine; 4New York, NY; 5VA Commonwealth U Health System and 6Takeda Global Research & Development

Background:  Azilsartan medoxomil (AZL-M) is a newly approved, highly effective, long-acting angiotensin II receptor blocker (ARB). Chlorthalidone (CLD) is a potent, long-acting thiazide-like diuretic.

Methods:  We compared fixed-dose combinations (FDCs) of AZL-M/CLD 20/12.5 mg QD force titrated to 40/25 mg or 40/12.5 mg QD force titrated to 80/25 mg with an FDC of the ARB olmesartan medoxomil (OLM) plus the thiazide diuretic hydrochlorothiazide (HCTZ) 20/12.5 mg QD force titrated to 40/25 mg (highest approved dose). The design was a randomized, double-blind, 12-week study of 1071 participants with mean clinic systolic BP (SBP) 160–190 mm Hg and diastolic BP ≤119 mm Hg. The primary endpoint was change from baseline to week 12 in trough seated clinic SBP; 24-hour ambulatory BP changes were secondary endpoints. Safety and tolerability were assessed.

Results:  At baseline, patients had a mean age of 57 years, 41% were women, and 22% were black, with an office BP of 165/96 mm Hg and 24-hour mean BP of 151/88 mm Hg. Changes in trough seated clinic SBP were significantly greater with both AZL-M/CLD doses than with olmesartan/HCTZ at 4, 8, and 12 weeks (Table). At 12 weeks, both AZL-M/CLD doses reduced 24-hour mean SBP more than OLM/HCTZ (−33.9 and −36.3 vs −27.5 mm Hg; both P<.001). Adverse events leading to permanent drug discontinuation occurred in 7.9%, 14.5%, and 7.1% of the groups given AZL-M/CLD 40/25 mg, AZL-M/CLD 80/25 mg, and OLM/HCTZ 40/25 mg, respectively.

Conclusions:  This first large, forced-titration study of an ARB-CLD combination demonstrated superior efficacy of AZL-M/CLD FDCs vs OLM/HCTZ. Tolerability was relatively similar for the lower dose of AZL-M/CLD, with a moderately higher adverse-event discontinuation rate for the higher dose.

Keywords:  Hypertension; Azilsartan medoxomil; Chlorthalidone; Fixed-dose combination

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LB-OR-04

Common Blood Pressure Genetic Variants and their Relations to Hypertension, Target-organ Damage, and Cardiovascular Disease Risk: The International Collaboration for Blood Pressure Genome-wide Association Studies (ICBP)

Georg Ehret,1 Patricia Munroe,2 Christopher Newton-Cheh,3 Kenneth Rice,4 Cornelia van Duin,5 Aravinda Chakravarti,1DanielLevy,6 Mark Caulfield,4 Toby Johnson4

1 Johns Hopkins, Baltimore, MD; 2London School of Medicine, London, GB; 3Broad Institute, Cambridge, MA; 4University of Washington, Seattle, WA; 5The Rotterdam Study, Rotterdam, NL and 6NHLBI, Framingham, MA

The ICBP conducted a genome-wide association study of systolic and diastolic BP using a staged design in up to 200,000 individuals of European descent. We identified 29 genome-wide significant SNPs at 28 loci; 16 were novel and 12 were previously reported. We developed a genetic risk score that incorporated the 29 risk alleles, weighted for their effect sizes on BP, and tested the risk score for association with BP, hypertension, hypertensive target-organ damage, and hypertension-related cardiovascular disease events. In an independent sample of 23,294 women, the genetic risk score was highly associated with SBP (P=7 × 10–63) and DBP (P=8 × 10–57). Individuals in the top quintile of the risk score had higher BP (4.6/3.0 mm Hg), and 1.8 fold increased odds of hypertension (P=3 × 10–33). The genetic risk score was also positively associated with left ventricular wall thickness (P=6 × 10–6), an important indicator of hypertensive target-organ damage. Finally, we found strong association of the risk score with stroke (P=.0002) and coronary disease (P=8 × 10–29), which are two of the most common causes of hypertension-related morbidity and mortality worldwide.[Figure 1]Our findings provide new insights into the genetic basis of hypertension and its sequelae, highlight approaches to the identification of high risk individuals, and offer a glimpse into potential therapeutic targets for cardiovascular disease prevention.

Keywords:  Genetics; Target-organ damage; Risk prediction; Blood pressure

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LB-OR-05

Sixteen Novel Loci Influence Blood Pressure in Diverse Populations

Georg B. Ehret,1 Patricia B. Munroe,2 Kenneth M. Rice,3 Murielle Bochud,4 Andrew D. Johnson,5 Daniel I. Chasman,6 Albert V. Smith,7 Bruce M. Pstay,3 Goncalo R. Abecasis,8 Aravinda Chakravarti,1 Paul Elliott,9 Cornelia M. van Duijn,10 Christopher Newton Cheh,11 Daniel Levy,5Mark J.Caulfield,2 Toby Johnson2

1 Johns Hopkins University School of Medicine; 2Queen Mary University of London, GB; 3University of Washington, Seattle; 4University of Lausanne, CH; 5National Heart Lung, and Blood Institute, Bethesda; 6Brigham and Women's Hospital, Boston; 7University of Iceland, Reykajvik, IS; 8University of Michigan School of Public Health, Ann Arbor; 9Imperial College, GB; 10Erasmus Medical Center, NL and 11Massachusetts General Hospital

Blood pressure (BP) is a heritable determinant of cardiovascular disease. We conducted a genome-wide association study testing 2.5 million single nucleotide polymorphisms (SNPs) for association with systolic and diastolic BP in ~70,000 people of European ancestry with validation in ~130,000 people of European ancestry. This identified 29 significant SNPs at 28 loci at P<5 × 10−9 in meta-analysis, an order of magnitude beyond the standard genome-wide significance level. Sixteen of these 29 loci are novel and lie in, or near, MOV10, SLC4A7, MECOM, SLC39A8, GUCY1A3-GUCY1B3, NPR3-C5orf23, EBF1, HFE, BAT2-BAT5, PLCE1, ADM, FLJ32810-TMEM133, FES, GOSR2, JAG1, and GNAS-EDN3. Each variant exhibits small effects on BP (<1 mm Hg for SBP and <0.5 mm Hg DBP per risk allele) and mostly the effects were concordant across analyses of SBP, DBP, and hypertension. A few of the loci contain plausible candidate genes that might affect BP, including NPR3, GUCY1A3,GUCY1B3, ADM, GNAS and EDN3, but many do not contain clear candidates for BP. In addition, we evaluated the association of these 29 BP variants in East Asians (N=20,720), South Asians (N=26,679), and Africans (N=14,213) using a genetic risk score that combined the 29 novel and previously described BP variants. In each non-European ancestry group, we found an association with SBP (P=7.86 × 10−30 in East Asians, P=2.64 × 10−9 in South Asians, P=9.83 × 10−4 in Africans) and DBP (P=7.86 × 10−35, P=6.30 × 10−10 and P=5.30 × 10−5). Our findings provide new insight into the genetic architecture of BP regulation, and suggest therapeutic targets for hypertension.

Keywords:  Genetics; Blood pressure

Late-Breaking Poster Session Cellular Mechanisms (Cell Biology; Cell Membrane Transport/Ion Channels; Coagulation/Thrombosis; Growth Factors; Ion Channels)

  1. Top of page
  2. Late-Breaking Clinical Trials
  3. Late-Breaking Poster Session Cellular Mechanisms (Cell Biology; Cell Membrane Transport/Ion Channels; Coagulation/Thrombosis; Growth Factors; Ion Channels)
  4. Clinical Trials
  5. Blood Pressure Measurement/Monitoring

LB-PO-01

ANP-cGMP-PKG ACTIVATION INHIBITS TGFβ-INDUCED SMAD3 NUCLEAR TRANSLOCATION BY INCREASING SMAD3 BINDING TO CYTOSOLIC β2-TUBULIN IN RAT PULMONARY ARTERIAL SMOOTH MUSCLE CELLS

KaizhengGong,1,2 Dongqi Xing,1 Peng Li,1 Namasivayam Ambalavanan,3 Suzanne Oparil,1 Yiu-Fai Chen1

1 University of Alabama at Birmingham, Birmingham, AL; 2The Second Medical School of Yangzhou University, Yangzhou, CN and 3University of Alabama at Birmingham, Birmingham, AL

We have demonstrated that atrial natriuretic peptide(ANP) and transforming growth factor-β (TGF-β) play important conterregulatory roles in pulmonary vascular adaptation to chronic hypoxia. ANP-cGMP-PKG signaling exerts its anti-fibrogenic effect on the pro-fibrogenic TGF-β signaling pathway by blocking TGF-β-induced nuclear translocation of Smad3 in pulmonary artery smooth muscle cells (PASMCs). The current study examined the mechanism of this interaction by testing the novel hypothesis that activation of the cGMP-PKG pathway limits TGF-β-induced nuclear translocation of Smad3 by enhancing Smad3 binding to cytosolic proteins in isolated PASMCs. PASMCs were pretreated with vehicle or cGMP (0.5 mM, 1 hour), followed by TGF-β (2 ng/mL) treatment for 1 hour. Cytosolic fractions were isolated and immunoprecipitated with a specific anti-Smad3 antibody. Differential proteomic study demonstrated that the cytoskeleton protein β2-tubulin was bound to Smad3 in a TGF-β, cGMP-dependent manner. Using co-immunoprecipitation analysis, we further demonstrated that TGF-β decreased, and cGMP increased Smad3 binding to β2-tubulin.[Figure 1]We observed that disruption of β2-tubulin with nocodazole promoted Smad3 dissociation from β2-tubulin, increased TGF-β-induced Smad3 nuclear translocation and the target gene plasminogen activator inhibitor-1 mRNA expression, and abolished the inhibitory effects of cGMP on these processes. The findings provide direct evidence that increasing Smad3 binding to β2-tubulin in cytosol is a key mechanism by which ANP-cGMP-PKG signaling interferes with downstream signaling from TGF-β and thus protects against pulmonary arterial remodeling/fibrosis in response to hypoxia stress.

Keywords:  ANP; TGF-beta; Smad3; beta-tubulin

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Clinical Trials

  1. Top of page
  2. Late-Breaking Clinical Trials
  3. Late-Breaking Poster Session Cellular Mechanisms (Cell Biology; Cell Membrane Transport/Ion Channels; Coagulation/Thrombosis; Growth Factors; Ion Channels)
  4. Clinical Trials
  5. Blood Pressure Measurement/Monitoring

LB-PO-02

Effect of Carvedilol CR, Lisinopril and their Combination on Markers of Early Cardiovascular Disease in Subjects with High-normal Blood Pressure: The Detect Study

Sara M.Saul,1 Daniel A. Duprez,1 Wei Zhong,2 Gregory A. Grandits,2 Jay N. Cohn1

1 University of Minnesota Medical School, Minneapolis, MN and 2University of Minnesota School of Public Health, Minneapolis, MN

The DETECT study examined the combined and individual effects of carvedilol CR and lisinopril on cardiovascular disease score and its components in asymptomatic individuals with high-normal to borderline blood pressures and at least one additional cardiovascular risk factor. Although these medications are commonly used to treat hypertension, their benefit in patients with blood pressure below the usual treatment threshold has not been demonstrated. In addition, β-blockers have been questioned as first-line therapy for hypertension because of less favorable vascular effects when compared to other drug classes.

Participants with blood pressures ≥130 mm Hg systolic or ≥85 mm Hg diastolic were enrolled. Cardiovascular risk was determined by a Disease Score (DS) which combines the following tests of cardiovascular function and structure: resting blood pressure (BP), large and small artery elasticity, blood pressure response to exercise, retinal vasculature analysis, ECG, carotid intima-medial thickness, left ventricular mass, microalbuminuria, and NT-proBNP. DS was assessed at baseline and after 3 and 9 months of double blind treatment with: (1) 40 mg carvedilol CR+20 mg lisinopril; n=23, (2) 40 mg carvedilol CR; n=24, (3) 20 mg lisinopril; n=21, or (4) placebo; n=23.

After 9 months of treatment all groups receiving active medication showed improvement in BP averaging below 120/80 mm Hg (P<.005) along with increased small artery elasticity (P=.036). Improvements in DS, left ventricle mass, and large artery elasticity were also observed but remained above the significance threshold (P=.057–.070).

Short-term treatment with carvedilol CR and lisinopril, both separately and in combination, favorably modified early indicators of cardiovascular abnormalities and reduced cardiovascular disease risk in subjects with high-normal to borderline blood pressure. Similar improvements in vascular function were found following carvedilol CR and lisinopril treatment suggesting that objections to β-blocker therapy may not be valid for vasodilating drugs such as carvedilol.

Keywords:  Beta-blocker; ACE inhibitor; Prehypertension; Early cardiovascular disease markers

Blood Pressure Measurement/Monitoring

  1. Top of page
  2. Late-Breaking Clinical Trials
  3. Late-Breaking Poster Session Cellular Mechanisms (Cell Biology; Cell Membrane Transport/Ion Channels; Coagulation/Thrombosis; Growth Factors; Ion Channels)
  4. Clinical Trials
  5. Blood Pressure Measurement/Monitoring

LB-PO-03

Consistency of Masked Hypertension in African Americans during Repeat Office Visits

PraveenVeerabhadrappa, Keith M. Diaz, Sheara M. Williamson, Jan Kretzschmar, Deboarh L. Feairheller, Kathleen M. Sturgeon, Shannon B. Watkins, Michael D. Brown

Temple University, Philadephia, PA

Objective:  The prevalence of masked hypertension (MH) in African Americans (~70%) has been reported to be far greater than that reported in the general population (~10%). However, previous studies reporting on MH in African Americans were based on blood pressure (BP) measurements from a single office visit. Therefore, it is not clear whether this high prevalence is truly a systematic BP pattern or whether it is confounded by the limitations of a BP measurement during a single office visit due to inherent variability of BP within an individual. The aim of our study was to examine the reproducibility of MH based on BP recordings on three separate office visits in apparently healthy African Americans.

Methods:  We recruited 32 African Americans (33F, 5M; 51±4 years) with a BMI of 30.1±0.8 kg/m2, who were sedentary, non-diabetic, non-smoking, devoid of cardiovascular (CV) disease and not on antihypertensive medication. We performed office BP measurements (three readings/visit,at three visits) in accordance with JNC-7 guidelines. ABPM was performed using Spacelabs 902019 recorders on a day of typical activity with BP recordings obtained at 30-minutes intervals during the day (6:00AM–10:00PM) and 60-minutes intervals at night (10:00PM–6:00AM).

Results:  The mean BP during each of the office visits were; 1st visit: 124/79 mm Hg, 2nd visit: 126/80 mm Hg and 3rd visit: 128/79 mm Hg. For ABPM, mean daytime BP was 128/80 mm Hg and mean night BP was 116/68 mm Hg. Prevalence of MH during a single office visit; 1st visit: 59%, 2nd visit: 40%, 3rd visit: 38% and the average for all three visits: 46%. The concordance for classifying MH between 1st and 2nd visits: 50%, between 2nd and 3rd visits: 44% and across all three visits: 44%. Using Cohen's kappa coefficient as an indicator of consistency for MH categorization, mean κ=0.745 (95% CI 0.54–0.94; P<.001).

Conclusions:  MH was prevalent in ~45% of subjects on any single office visit and during repeated visits, and showed high reproducibility. Our preliminary findings provide further evidence that African Americans have a high prevalence of MH that is not confounded by office BP measurements obtained from a single visit. These findings suggest that office BP measurements by itself may be sub-optimal in estimating the precise BP of an individual and warrants out-of-office BP monitoring to reveal MH.

Keywords:  Masked hypertension; ABPM; African Americans; Reproducibility

Financial Disclosure Index The following authors provided disclosures.

C

Caulfield, Mark J.,

Nothing to disclose LB-OR-05

Cushman, William C.,

Grant/Research Support: Merck, GSK, Novartis; Consultant: Takeda, Novartis, Daiichi-Sankyo LB-OR-03

G

Gong, Kaizheng,

Nothing to disclose LB-PO-01

L

Levy, Daniel,

Nothing to disclose LB-OR-04

N

Norsk, Peter,

Nothing to disclose LB-OR-02

O

Oparil, Suzanne,

Consultant: Vivus advisory board member; Other Financial or Material Support: Drs. Day and Bowden are employees of Vivus LB-OR-01

S

Saul, Sara M.,

Nothing to disclose LB-PO-02

V

Veerabhadrappa, Praveen,

Nothing to disclose LB-PO-03