Vol 65, No 2 | Hypertension

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The burden of hypertension in Sub-Saharan Africa has been increasing over the past few decades. However, a large proportion of the population with hypertension remains undiagnosed, untreated, or inadequately treated, contributing to the rising burden of cardiovascular disease in the region. We conducted a systematic review and meta-analysis to assess the recent burden of hypertension in Sub-Saharan Africa, based on studies published between 2000 and 2013. We pooled data from 33 surveys involving over 110 414 participants of mean age 40 years. Hypertension prevalence varied widely across the studies (range 15%–70%), partly because of differences in participant mean ages (31–76 years). The predicted prevalence of hypertension at mean participant ages of 30, 40, 50, and 60 years were 16%, 26%, 35%, and 44%, respectively, with a pooled prevalence of 30% (95% confidence interval, 27%–34%). Of those with hypertension, only between 7% and 56% (pooled prevalence: 27%; 95% confidence interval, 23%–31%) were aware of their hypertensive status before the surveys. Overall, 18% (95% confidence interval, 14%–22%) of individuals with hypertension were receiving treatment across the studies, and only 7% (95% confidence interval, 5%–8%) had controlled blood pressure. This review found a high prevalence of hypertension, as well as low percentage of hypertension awareness, treatment, and control in Sub-Saharan Africa, highlighting the need for implementation of timely and appropriate strategies for diagnosis, control, and prevention.

Does Low Diastolic Blood Pressure Contribute to the Risk of Recurrent Hypertensive Cardiovascular Disease Events?

The Framingham Heart Study

Hypertension. 2015 | Volume 65, Issue 2: 299–305,

Published Online:November 24, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04581

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Whether low diastolic blood pressure (DBP) is a risk factor for recurrent cardiovascular disease (CVD) events in persons with isolated systolic hypertension is controversial. We studied 791 individuals (mean age 75 years, 47% female, mean follow-up time: 8±6 years) with DBP <70 (n=225) versus 70 to 89 mm Hg (n=566) after initial CVD events in the original and offspring cohorts of the Framingham Heart Study. Recurrent CVD events occurred in 153 (68%) participants with lower DBP and 271 (48%) with higher DBP (P<0.0001). Risk of recurrent CVD events in risk factor-adjusted Cox regression was higher in those with DBP <70 mm Hg versus DBP 70 to 89 mm Hg in both treated (hazard ratio, 5.1 [95% confidence interval: 3.8–6.9] P<0.0001) and untreated individuals (hazard ratio, 11.7 [95% confidence interval: 6.5–21.1] P<0.0001; treatment interaction: P=0.71). Individually, coronary heart disease, heart failure, and stroke recurrent events were more likely with DBP <70 mm Hg versus 70 to 89 mm Hg (P<0.0001). To examine for an effect of wide pulse pressure on excess risk associated with low DBP, we defined 4 binary groupings of pulse pressure (≥68 versus <68 mm Hg) and DBP (<70 versus 70–89 mm Hg). CVD incidence rates were higher only in the group with pulse pressure ≥68 and DBP <70 mm Hg (76% versus 46%–54%; P<0.001). Persons with isolated systolic hypertension and prior CVD events have increased risk for recurrent CVD events in the presence of DBP <70 mm Hg versus DBP 70 to 89 mm Hg, whether treated or untreated, supporting wide pulse pressure as an important risk modifier for the adverse effect of low DBP.

Glucagon-Like Peptide-1 and Blood Pressure in Young and Healthy Adults from the General Population

Hypertension. 2015 | Volume 65, Issue 2: 306–312,

Published Online:December 1, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04718

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Hypertension and diabetes mellitus are highly correlated, but the underlying mechanisms are only partly understood. Therefore, the aim of our study was to investigate the relationships between plasma levels of glucagon-like peptide-1, a key factor in the regulation of glucose homeostasis, and various blood pressure indices. Healthy adults aged 25 to 41 years were enrolled in a population-based study. Established cardiovascular disease, diabetes mellitus, or a body mass index >35 kg/m² were exclusion criteria. Fasting plasma glucagon-like peptide-1 levels as determined with a novel high-sensitive assay and ambulatory blood pressure data were available in 1479 participants not using antihypertensive treatment. Median age of our population was 38 years. Mean systolic and diastolic blood pressure across increasing glucagon-like peptide-1 quartiles were 120.6, 122.8, 123.2, and 124.9 mm Hg and 77.1, 78.7, 78.9, and 79.9 mm Hg, respectively. We found a linear relationship of glucagon-like peptide-1 with 24-hour ambulatory blood pressure after multivariable adjustment (β per 1 log-unit increase 2.01; 95% confidence interval, 1.02–3.00; P<0.0001 for systolic and 1.22; 0.47–1.97; P=0.002 for diastolic blood pressure). In separate analyses, glucagon-like peptide-1 was significantly related to both awake (β per 1 log-unit increase 2.05; 1.02–3.09; P=0.0001 for systolic and 1.15; 0.35–1.96; P=0.005 for diastolic blood pressure) and asleep blood pressure (β per 1 log-unit increase 1.34; 0.26–2.42; P=0.01 for systolic and 1.05; 0.26–1.84; P=0.009 for diastolic blood pressure). In conclusion, plasma levels of glucagon-like peptide-1 are significantly associated with both systolic and diastolic blood pressure levels.

Exposure to Bisphenol A From Drinking Canned Beverages Increases Blood Pressure

Randomized Crossover Trial

Sanghyuk Bae and
Yun-Chul Hong

Hypertension. 2015 | Volume 65, Issue 2: 313–319,

Published Online:December 8, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04261

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Bisphenol A (BPA) is a chemical used in plastic bottles and inner coating of beverage cans, and its exposure is almost ubiquitous. BPA has been associated with hypertension and decreased heart rate variability in the previous studies. The aim of the present study was to determine whether increased BPA exposure from consumption of canned beverage actually affects blood pressure and heart rate variability. We conducted a randomized crossover trial with noninstitutionalized adults, who were aged ≥60 years and recruited from a local community center. A total of 60 participants visited the study site 3 times, and they were provided the same beverage in 2 glass bottles, 2 cans, or 1 can and 1 glass bottle at a time. The sequence of the beverage was randomized. We then measured urinary BPA concentration, blood pressure, and heart rate variability 2 hours after the consumption of each beverage. The paired t test and mixed model were used to compare the differences. The urinary BPA concentration increased after consuming canned beverages by >1600% compared with that after consuming glass bottled beverages. Systolic blood pressure adjusted for daily variance increased by ≈4.5 mm Hg after consuming 2 canned beverages compared with that after consuming 2 glass bottled beverages, and the difference was statistically significant. The parameters of the heart rate variability did not show statistically significant differences.The present study demonstrated that consuming canned beverage and consequent increase of BPA exposure increase blood pressure acutely.

Dietary Nitrate Provides Sustained Blood Pressure Lowering in Hypertensive Patients

A Randomized, Phase 2, Double-Blind, Placebo-Controlled Study

Hypertension. 2015 | Volume 65, Issue 2: 320–327,

Published Online:November 24, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04675

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Abstract—
Single dose administration of dietary inorganic nitrate acutely reduces blood pressure (BP) in normotensive healthy volunteers, via bioconversion to the vasodilator nitric oxide. We assessed whether dietary nitrate might provide sustained BP lowering in patients with hypertension. We randomly assigned 68 patients with hypertension in a double-blind, placebo-controlled clinical trial to receive daily dietary supplementation for 4 weeks with either dietary nitrate (250 mL daily, as beetroot juice) or a placebo (250 mL daily, as nitrate-free beetroot juice) after a 2-week run-in period and followed by a 2-week washout. We performed stratified randomization of drug-naive (n=34) and treated (n=34) patients with hypertension aged 18 to 85 years. The primary end point was change in clinic, ambulatory, and home BP compared with placebo. Daily supplementation with dietary nitrate was associated with reduction in BP measured by 3 different methods. Mean (95% confidence interval) reduction in clinic BP was 7.7/2.4 mm Hg (3.6–11.8/0.0–4.9, P<0.001 and P=0.050). Twenty-four-hour ambulatory BP was reduced by 7.7/5.2 mm Hg (4.1–11.2/2.7–7.7, P<0.001 for both). Home BP was reduced by 8.1/3.8 mm Hg (3.8–12.4/0.7–6.9, P<0.001 and P<0.01) with no evidence of tachyphylaxis over the 4-week intervention period. Endothelial function improved by ≈20% (P<0.001), and arterial stiffness was reduced by 0.59 m/s (0.24–0.93; P<0.01) after dietary nitrate consumption with no change after placebo. The intervention was well tolerated. This is the first evidence of durable BP reduction with dietary nitrate supplementation in a relevant patient group. These findings suggest a role for dietary nitrate as an affordable, readily-available, adjunctive treatment in the management of patients with hypertension (funded by The British Heart Foundation).
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01405898.

Estrogen Inhibits Mast Cell Chymase Release to Prevent Pressure Overload-Induced Adverse Cardiac Remodeling

Hypertension. 2015 | Volume 65, Issue 2: 328–334,

Published Online:November 17, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04238

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Estrogen regulation of myocardial chymase and chymase effects on cardiac remodeling are unknown. To test the hypothesis that estrogen prevents pressure overload–induced adverse cardiac remodeling by inhibiting mast cell (MC) chymase release, transverse aortic constriction or sham surgery was performed in 7-week-old intact and ovariectomized (OVX) rats. Three days before creating the constriction, additional groups of OVX rats began receiving 17β-estradiol, a chymase inhibitor, or a MC stabilizer. Left ventricular function, cardiomyocyte size, collagen volume fraction, MC density and degranulation, and myocardial and plasma chymase levels were assessed 18 days postsurgery. Aortic constriction resulted in ventricular hypertrophy in intact and OVX groups, whereas collagen volume fraction was increased only in OVX rats. Chymase protein content was increased by aortic constriction in the intact and OVX groups, with the magnitude of the increase being greater in OVX rats. MC density and degranulation, plasma chymase levels, and myocardial active transforming growth factor-β1 levels were increased by aortic constriction only in OVX rats. Estrogen replacement markedly attenuated the constriction-increased myocardial chymase, MC density and degranulation, plasma chymase, and myocardial active transforming growth factor-β1, as well as prevented ventricular hypertrophy and increased collagen volume fraction. Chymostatin attenuated the aortic constriction–induced ventricular hypertrophy and collagen volume fraction in the OVX rats similar to that achieved by estrogen replacement. Nedocromil yielded similar effects, except for the reduction of chymase content. We conclude that the estrogen-inhibited release of MC chymase is responsible for the cardioprotection against transverse aortic constriction-induced adverse cardiac remodeling.

Calcium/Calmodulin-Dependent Protein Kinase II Couples Wnt Signaling With Histone Deacetylase 4 and Mediates Dishevelled-Induced Cardiomyopathy

Hypertension. 2015 | Volume 65, Issue 2: 335–344,

Published Online:December 8, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04467

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Activation of Wnt signaling results in maladaptive cardiac remodeling and cardiomyopathy. Recently, calcium/calmodulin-dependent protein kinase II (CaMKII) was reported to be a pivotal participant in myocardial remodeling. Because CaMKII was suggested as a downstream target of noncanonical Wnt signaling, we aimed to elucidate the role of CaMKII in dishevelled-1–induced cardiomyopathy and the mechanisms underlying its function. Dishevelled-1–induced cardiomyopathy was reversed by deletion of neither CaMKIIδ nor CaMKIIγ. Therefore, dishevelled-1–transgenic mice were crossed with CaMKIIδγ double-knockout mice. These mice displayed a normal cardiac phenotype without cardiac hypertrophy, fibrosis, apoptosis, or left ventricular dysfunction. Further mechanistic analyses unveiled that CaMKIIδγ couples noncanonical Wnt signaling to histone deacetylase 4 and myosin enhancer factor 2. Therefore, our findings indicate that the axis, consisting of dishevelled-1, CaMKII, histone deacetylase 4, and myosin enhancer factor 2, is an attractive therapeutic target for prevention of cardiac remodeling and its progression to left ventricular dysfunction.

Genetic Interference With Peroxisome Proliferator–Activated Receptor γ in Smooth Muscle Enhances Myogenic Tone in the Cerebrovasculature via A Rho Kinase–Dependent Mechanism

Hypertension. 2015 | Volume 65, Issue 2: 345–351,

Published Online:November 10, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04541

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Myogenic responses by resistance vessels are a key component of autoregulation in brain, thus playing a crucial role in regulating cerebral blood flow and protecting the blood–brain barrier against potentially detrimental elevations in blood pressure. Although cerebrovascular disease is often accompanied by alterations in myogenic responses, mechanisms that control these changes are poorly understood. Peroxisome proliferator–activated receptor γ has emerged as a regulator of vascular tone. We hypothesized that interference with peroxisome proliferator–activated receptor γ in smooth muscle would augment myogenic responses in cerebral arteries. We studied transgenic mice expressing a dominant-negative mutation in peroxisome proliferator–activated receptor γ selectively in smooth muscle (S-P467L) and nontransgenic littermates. Myogenic tone in middle cerebral arteries from S-P467L was elevated 3-fold when compared with nontransgenic littermates. Rho kinase is thought to play a major role in cerebrovascular disease. The Rho kinase inhibitor, Y-27632, abolished augmented myogenic tone in middle cerebral arteries from S-P467L mice. CN-03, which modifies RhoA making it constitutively active, elevated myogenic tone to ≈60% in both strains, via a Y-27632–dependent mechanism. Large conductance Ca²⁺-activated K⁺ channels (BK_Ca) modulate myogenic tone. Inhibitors of BK_Ca caused greater constriction in middle cerebral arteries from nontransgenic littermates when compared with S-P467L. Expression of RhoA or Rho kinase-I/II protein was similar in cerebral arteries from S-P467L mice. Overall, the data suggest that peroxisome proliferator–activated receptor γ in smooth muscle normally inhibits Rho kinase and promotes BK_Ca function, thus influencing myogenic tone in resistance arteries in brain. These findings have implications for mechanisms that underlie large- and small-vessel disease in brain, as well as regulation of cerebral blood flow.

Intracerebroventricular Infusion of the (Pro)renin Receptor Antagonist PRO20 Attenuates Deoxycorticosterone Acetate-Salt–Induced Hypertension

Hypertension. 2015 | Volume 65, Issue 2: 352–361,

Published Online:November 24, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04458

This article corrects the following:
- Correction to: Intracerebroventricular Infusion of the (Pro)renin Receptor Antagonist PRO20 Attenuates Deoxycorticosterone Acetate-Salt–Induced Hypertension
  - Volume 70Issue 4Hypertension
  - 1 October 2017

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We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT₁ receptor–dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension.

Altered Dependence of Aortic Pulse Wave Velocity on Transmural Pressure in Hypertension Revealing Structural Change in the Aortic Wall

Hypertension. 2015 | Volume 65, Issue 2: 362–369,

Published Online:November 17, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04370

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Aortic pulse wave velocity (aPWV), a major prognostic indicator of cardiovascular events, may be augmented in hypertension as a result of the aorta being stretched by a higher distending blood pressure or by a structural change. We used a novel technique to modulate intrathoracic pressure and thus aortic transmural pressure (TMP) to examine the variation of intrathoracic aPWV with TMP in hypertensive (n=20; mean±SD age, 52.1±15.3 years; blood pressure, 159.6±21.2/92.0±15.9 mm Hg) and normotensive (n=20; age, 55.5±11.1 years; blood pressure, 124.5±11.9/72.6±9.1 mm Hg) subjects. aPWV was measured using dual Doppler probes to insonate the right brachiocephalic artery and aorta at the level of the diaphragm. Resting aPWV was greater in hypertensive compared with normotensive subjects (897±50 cm/s versus 784±43 cm/s; P<0.05). aPWV was equal in hypertensive and normotensive subjects when measured at a TMP of 96 mm Hg. However, dependence of aPWV on TMP in normotensive subjects was greater than that in hypertensive subjects (9.6±1.6 versus 3.8±0.7 cm/s per mm Hg increase in TMP, respectively, means±SEM; P<0.01). This experimental behavior was best explained by a theoretical model incorporating strain-induced recruitment of stiffer fibers in normotensive subjects and fully recruited stiffer fibers in hypertensive subjects. These results explain previous contradictory findings with respect to isobaric aPWV in hypertensive compared with normotensive subjects. They suggest that hypertension is associated with a profound change in aortic wall mechanical properties possibly because of destruction of elastin leading to less strain-induced stiffening and predisposition to aortic dissection.

Augmented Vascular Smooth Muscle Cell Stiffness and Adhesion When Hypertension Is Superimposed on Aging

Hypertension. 2015 | Volume 65, Issue 2: 370–377,

Published Online:December 1, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04456

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Hypertension and aging are both recognized to increase aortic stiffness, but their interactions are not completely understood. Most previous studies have attributed increased aortic stiffness to changes in extracellular matrix proteins that alter the mechanical properties of the vascular wall. Alternatively, we hypothesized that a significant component of increased vascular stiffness in hypertension is due to changes in the mechanical and adhesive properties of vascular smooth muscle cells, and that aging would augment the contribution from vascular smooth muscle cells when compared with the extracellular matrix. Accordingly, we studied aortic stiffness in young (16-week-old) and old (64-week-old) spontaneously hypertensive rats and Wistar–Kyoto wild-type controls. Systolic and pulse pressures were significantly increased in young spontaneously hypertensive rats when compared with young Wistar–Kyoto rats, and these continued to rise in old spontaneously hypertensive rats when compared with age-matched controls. Excised aortic ring segments exhibited significantly greater elastic moduli in both young and old spontaneously hypertensive rats versus Wistar–Kyoto rats. were isolated from the thoracic aorta, and stiffness and adhesion to fibronectin were measured by atomic force microscopy. Hypertension increased both vascular smooth muscle cell stiffness and vascular smooth muscle cell adhesion, and these increases were both augmented with aging. By contrast, hypertension did not affect histological measures of aortic collagen and elastin, which were predominantly changed by aging. These findings support the concept that stiffness and adhesive properties of vascular smooth muscle cells are novel mechanisms contributing to the increased aortic stiffness occurring with hypertension superimposed on aging.

Aortic-Brachial Stiffness Mismatch and Mortality in Dialysis Population

Hypertension. 2015 | Volume 65, Issue 2: 378–384,

Published Online:December 1, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04587

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We hypothesized that increased aortic stiffness (central elastic artery) combined with a decrease in brachial stiffness (peripheral muscular artery) leads to the reversal of the physiological stiffness gradient (ie, mismatch), promoting end-organ damages through increased forward pressure wave transmission into the microcirculation. We, therefore, examined the effect of aortic-brachial stiffness mismatch on mortality in patients in need of dialysis. In a prospective observational study, aortic-brachial arterial stiffness mismatch (pulse wave velocity ratio) was assessed using carotid-femoral pulse wave velocity divided by carotid-radial pulse wave velocity in 310 adult patients on dialysis. After a median follow-up of 29 months, 146 (47%) deaths occurred. The hazard ratio (HR) for mortality related to PWV ratio in a Cox regression analysis was 1.43 (95% confidence interval [CI], 1.24–1.64; P<0.001 per 1 SD) and was still significant after adjustments for confounding factors, such as age, dialysis vintage, sex, cardiovascular disease, diabetes mellitus, smoking status, and weight (HR, 1.23; 95% CI: 1.02–1.49). The HRs for changes in 1 SD of augmentation index (HR, 1.35; 95% CI, 1.12–1.63), carotid-femoral pulse wave velocity (HR, 1.29; 95% CI, 1.11–1.50), and carotid-radial pulse wave velocity (HR, 0.80; 95% CI, 0.67–0.95) were statistically significant in univariate analysis, but were no longer statistically significant after adjustment for age. In conclusion, aortic-brachial arterial stiffness mismatch was strongly and independently associated with increased mortality in this dialysis population. Further studies are required to confirm these finding in lower-risk groups.

Soluble Guanylate Cyclase Is Required for Systemic Vasodilation But Not Positive Inotropy Induced by Nitroxyl in the Mouse

Hypertension. 2015 | Volume 65, Issue 2: 385–392,

Published Online:December 1, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04285

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Nitroxyl (HNO), the reduced and protonated form of nitric oxide (NO·), confers unique physiological effects including vasorelaxation and enhanced cardiac contractility. These features have spawned current pharmaceutical development of HNO donors as heart failure therapeutics. HNO interacts with selective redox sensitive cysteines to effect signaling but is also proposed to activate soluble guanylate cyclase (sGC) in vitro to induce vasodilation and potentially enhance contractility. Here, we tested whether sGC stimulation is required for these HNO effects in vivo and if HNO also modifies a redox-sensitive cysteine (C42) in protein kinase G-1α to control vasorelaxation. Intact mice and isolated arteries lacking the sGC-β subunit (sGCKO, results in full sGC deficiency) or expressing solely a redox-dead C42S mutant protein kinase G-1α were exposed to the pure HNO donor, CXL-1020. CXL-1020 induced dose-dependent systemic vasodilation while increasing contractility in controls; however, vasodilator effects were absent in sGCKO mice whereas contractility response remained. The CXL-1020 dose reversing 50% of preconstricted force in aortic rings was ≈400-fold greater in sGCKO than controls. Cyclic-GMP and cAMP levels were unaltered in myocardium exposed to CXL-1020, despite its inotropic-vasodilator activity. In protein kinase G-1α^C42S mice, CXL-1020 induced identical vasorelaxation in vivo and in isolated aortic and mesenteric vessels as in littermate controls. In both groups, dilation was near fully blocked by pharmacologically inhibiting sGC. Thus, sGC and cGMP-dependent signaling are necessary and sufficient for HNO-induced vasodilation in vivo but are not required for positive inotropic action. Redox modulation of protein kinase G-1α is not a mechanism for HNO-mediated vasodilation.

Reinnervation of Renal Afferent and Efferent Nerves at 5.5 and 11 Months After Catheter-Based Radiofrequency Renal Denervation In Sheep

Hypertension. 2015 | Volume 65, Issue 2: 393–400,

Published Online:November 17, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04176

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Previous studies indicate that catheter-based renal denervation reduces blood pressure and renal norepinephrine spillover in human resistant hypertension. The effects of this procedure on afferent sensory and efferent sympathetic renal nerves, and the subsequent degree of reinnervation, have not been investigated. We therefore examined the level of functional and anatomic reinnervation at 5.5 and 11 months after renal denervation using the Symplicity Flex catheter. In normotensive anesthetized sheep (n=6), electric stimulation of intact renal nerves increased arterial pressure from 99±3 to 107±3 mm Hg (afferent response) and reduced renal blood flow from 198±16 to 85±20 mL/min (efferent response). In a further group (n=6), immediately after denervation, renal sympathetic nerve activity was absent and the responses to electric stimulation were abolished. At 11 months after denervation (n=5), renal sympathetic nerve activity and the responses to electric stimulation were at normal levels. Immunohistochemical staining for renal efferent (tyrosine hydroxylase) and renal afferent nerves (calcitonin gene–related peptide), as well as renal norepinephrine levels, was normal 11 months after denervation. Findings at 5.5 months after denervation were similar (n=5). In summary, catheter-based renal denervation effectively ablated the renal afferent and efferent nerves in normotensive sheep. By 11 months after denervation the functional afferent and efferent responses to electric stimulation were normal. Reinnervation at 11 months after denervation was supported by normal anatomic distribution of afferent and efferent renal nerves. In view of this evidence, the mechanisms underlying the prolonged hypotensive effect of catheter-based renal denervation in human resistant hypertension need to be reassessed.

Magnitude of Blood Pressure Reduction in the Placebo Arms of Modern Hypertension Trials

Implications for Trials of Renal Denervation

Hypertension. 2015 | Volume 65, Issue 2: 401–406,

Published Online:November 17, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04640

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Early phase studies of novel interventions for hypertension, such as renal sympathetic denervation, are sometimes single-armed (uncontrolled). We explored the wisdom of this by quantifying the blood pressure fall in the placebo arms of contemporary trials of hypertension. We searched Medline up to June 2014 and identified blinded, randomized trials of hypertension therapy in which the control arm received placebo medication or a sham (placebo) procedure. For nonresistant hypertension, we have identified all such trials of drugs licensed by the US Food and Drug Administration since 2000 (5 drugs). This US Food and Drug Administration–related restriction was not applied to resistant hypertension trials. This produced 7451 patients, who were allocated to a blinded control from 52 trials of nonresistant hypertension and 694 patients from 8 trials of resistant hypertension (3 drugs and 2 interventions). Systolic blood pressure fell by 5.92 mm Hg (95% confidence interval, 5.14–6.71; P<0.0001) in the nonresistant cohort and by 8.76 mm Hg (95% confidence interval, 4.83–12.70; P<0.0001) in the resistant cohort. Using metaregression, the falls were larger in trials that did not use ambulatory blood pressure monitoring as an inclusion criterion (z=2.84; P=0.0045), in those with higher baseline blood pressures (z=−0.3; P=0.0001), and in those where the patients were prescribed a continuous background of antihypertensives (z=−2.72; P=0.0065). The nontrivial magnitude of these apparent blood pressure reductions with perfectly ineffective intervention (placebo) illustrates that efficacy explorations of novel therapies for hypertension, once safety is established, should be performed with a randomized, appropriately controlled, and blinded design.

Randomized Comparison of Renal Denervation Versus Intensified Pharmacotherapy Including Spironolactone in True-Resistant Hypertension

Six-Month Results From the Prague-15 Study

Hypertension. 2015 | Volume 65, Issue 2: 407–413,

Published Online:November 24, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04019

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This prospective, randomized, open-label multicenter trial evaluated the efficacy of catheter-based renal denervation (Symplicity, Medtronic) versus intensified pharmacological treatment including spironolactone (if tolerated) in patients with true-resistant hypertension. This was confirmed by 24-hour ambulatory blood pressure monitoring after excluding secondary hypertension and confirmation of adherence to therapy by measurement of plasma antihypertensive drug levels before enrollment. One-hundred six patients were randomized to renal denervation (n=52), or intensified pharmacological treatment (n=54) with baseline systolic blood pressure of 159±17 and 155±17 mm Hg and average number of drugs 5.1 and 5.4, respectively. A significant reduction in 24-hour average systolic blood pressure after 6 months (−8.6 [95% cofidence interval: −11.8, −5.3] mm Hg; P<0.001 in renal denervation versus −8.1 [95% cofidence interval: −12.7, −3.4] mm Hg; P=0.001 in pharmacological group) was observed, which was comparable in both groups. Similarly, a significant reduction in systolic office blood pressure (−12.4 [95% cofidence interval: −17.0, −7.8] mm Hg; P<0.001 in renal denervation versus −14.3 [95% cofidence interval: −19.7, −8.9] mm Hg; P<0.001 in pharmacological group) was present. Between-group differences in change were not significant. The average number of antihypertensive drugs used after 6 months was significantly higher in the pharmacological group (+0.3 drugs; P<0.001). A significant increase in serum creatinine and a parallel decrease of creatinine clearance were observed in the pharmacological group; between-group difference were borderline significant. The 6-month results of this study confirmed the safety of renal denervation. In conclusion, renal denervation achieved reduction of blood pressure comparable with intensified pharmacotherapy.

miR-29a-3p Attenuates Hypoxic Pulmonary Hypertension by Inhibiting Pulmonary Adventitial Fibroblast Activation

Hypertension. 2015 | Volume 65, Issue 2: 414–420,

Published Online:November 24, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04600

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Activation of pulmonary adventitial fibroblasts plays a key role in the pulmonary vascular remodeling in hypoxic pulmonary hypertension. Previous studies showed that miRNAs participated in the regulation of fibroblast activation. This study explored the role of miR-29 in the activation of pulmonary adventitial fibroblasts and the therapeutic potential in hypoxic pulmonary hypertension. We found that hypoxia-induced pulmonary adventitial fibroblasts activation was accompanied with a drastic decrease of miR-29a-3p expression. Knockdown of hypoxia-inducible factor-1 α or Smad3 reversed the hypoxia-induced decrease of miR-29-3p in cultured pulmonary adventitial fibroblasts. In vitro, miR-29a-3p mimic inhibited the hypoxia-induced proliferation, migration, and secretion of pulmonary adventitial fibroblasts, suppressed the hypoxia-induced expression of α-smooth muscle actin and extracellular matrix collagen in pulmonary adventitial fibroblasts; however, miR-29a-3p inhibitor mimicked the effect of hypoxia on the activation of pulmonary adventitial fibroblasts. Further studies revealed that preventative or therapeutic administration of miR-29a-3p significantly decreased pulmonary artery pressure and right ventricle hypertrophy index and ameliorated pulmonary vascular remodeling in hypoxic pulmonary hypertension rats. These findings suggest that miR-29a-3p regulates the activation and phenotype of pulmonary adventitial fibroblasts in hypoxia and has preventative and therapeutic potential in hypoxic pulmonary hypertension.

Bioinformatics Approach Reveals Evidence for Impaired Endometrial Maturation Before and During Early Pregnancy in Women Who Developed Preeclampsia

Hypertension. 2015 | Volume 65, Issue 2: 421–429,

Published Online:November 24, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04481

This article corrects the following:
- Correction
  - Volume 65Issue 6Hypertension
  - 1 June 2015

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Impaired uterine invasion by extravillous trophoblast in early gestation is implicated in the genesis of preeclampsia, a potentially lethal malady of human pregnancy. However, reasons for extravillous trophoblast dysfunction remain unclear because of virtual inaccessibility of early placental and uterine tissues from women who develop preeclampsia, and the absence of animal models in which the disease spontaneously occurs. Consequently, the possibility that deficient or defective maturation of the endometrium (decidualization) may compromise extravillous trophoblast invasion in preeclampsia remains unexplored. Using a bioinformatics approach, we tested this hypothesis identifying 396 differentially expressed genes (DEG) in chorionic villous samples from women at ≈11.5 gestational weeks who developed severe preeclampsia symptoms 6 months later compared with chorionic villous samples from normal pregnancies. A large number, 154 or 40%, overlapped with DEG associated with various stages of normal endometrial maturation before and after implantation as identified by other microarray data sets (P=4.7×10⁻¹⁴). One-hundred and sixteen of the 154 DEG or 75% overlapped with DEG associated with normal decidualization in the absence of extravillous trophoblast, ie, late-secretory endometrium (LSE) and endometrium from tubal ectopic pregnancy (EP; P=4.2×10⁻⁹). Finally, 112 of these 154 DEG or 73% changed in the opposite direction in microarray data sets related to normal endometrial maturation (P=0.01), including 16 DEG upregulated in decidual (relative to peripheral blood) natural killer cells that were downregulated in chorionic villous samples from women who developed preeclampsia (P<0.0001). Taken together, these results suggest that insufficient or defective maturation of endometrium and decidual natural killer cells during the secretory phase and early pregnancy preceded the development of preeclampsia.

Neurokinin 3 Receptor and Phosphocholine Transferase

Missing Factors for Pathogenesis of C-Reactive Protein in Preeclampsia

Hypertension. 2015 | Volume 65, Issue 2: 430–439,

Published Online:December 1, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04439

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C-reactive protein (CRP), an innate immune mediator, is elevated in the circulation before symptoms in patients with preeclampsia, a severe hypertensive pregnancy disorder with high mortality and morbidity. However, the specific sources underlying increased CRP and the role of elevated CRP in preeclampsia are undefined. Here, we report that circulating CRP levels are significantly increased in a large cohort of normotensive pregnant individuals when compared with nulligravid women and is further increased in patients with preeclampsia. These findings led us to discover further that placental syncytiotrophoblasts are previously unrecognized cellular sources of CRP and underlie elevated CRP in normotensive pregnant women and the additional increase in patients with preeclampsia. Next, we demonstrated that injection of CRP induces preeclampsia features, including hypertension (157 mm Hg CRP treated versus 119 mm Hg control), proteinuria (35.0 mg/μg CRP treated versus 14.1 mg/μg control), kidney, and placental damage and increased levels of sFlt-1 in pregnant mice but not in nonpregnant mice. Our study implicates that phosphocholine transferase, a placental-specific enzyme post-translationally modifying neurokinin B, is essential for the pathogenic role of CRP in preeclampsia through activation of the neurokinin 3 receptor. Overall, our studies have provided significant new insight on the pathogenic role of CRP in preeclampsia and highlighted innovative therapeutic strategies.

Effectiveness of a Tailored Behavioral Intervention to Improve Hypertension Control

Primary Outcomes of a Randomized Controlled Trial

Hypertension. 2015 | Volume 65, Issue 2: 440–446,

Published Online:November 17, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.03483

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Blood pressure (BP) control rates are suboptimal. We evaluated the effectiveness of 2 behavioral interventions to improve BP control via a 3-arm, randomized controlled trial of 533 adults with repeated uncontrolled BP, despite antihypertensive drug treatment for ≥6 months. The interventions were a tailored stage-matched intervention (SMI) or a nontailored health education intervention (HEI) of 6 monthly calls targeting diet, exercise, and medication. Control was usual care (UC). There were no baseline group differences. Baseline BP control was 42.6%, 40.6%, and 44.6% in SMI, HEI, and UC (P=0.74), respectively; systolic BP (with SEs) was 136 (0.89), 137 (1.33), and 137 (0.96) mm Hg. Six-month control was 64.6% (SMI), 54.3% (HEI), and 45.8% (UC) (P values for pairwise comparisons versus UC, 0.001 [SMI] and 0.108 [HEI]). At 6 months, systolic BP (SE) was 131.2 (1.05), 131.8 (0.99), and 134.7 (1.02) for SMI, HEI, and UC, respectively (P values for pairwise comparisons versus UC, 0.009 for SMI and 0.047 for HEI). SMI led to lower systolic BP and better BP control than UC. SMI constitutes a new, potent approach to assist patients with uncontrolled hypertension to reach BP goals.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00286754.

Maternal Diet During Gestation and Lactation Modifies the Severity of Salt-Induced Hypertension and Renal Injury in Dahl Salt-Sensitive Rats

Hypertension. 2015 | Volume 65, Issue 2: 447–455,

Published Online:December 1, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04179

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Environmental exposure of parents or early in life may affect disease development in adults. We found that hypertension and renal injury induced by a high-salt diet were substantially attenuated in Dahl SS/JrHsdMcwiCrl (SS/Crl) rats that had been maintained for many generations on the grain-based 5L2F diet compared with SS/JrHsdMcwi rats (SS/Mcw) maintained on the casein-based AIN-76A diet (mean arterial pressure, 116±9 versus 154±25 mm Hg; urinary albumin excretion, 23±12 versus 170±80 mg/d). RNAseq analysis of the renal outer medulla identified 129 and 82 genes responding to a high-salt diet uniquely in SS/Mcw and SS/Crl rats, respectively, along with minor genetic differences between the SS substrains. The 129 genes responding to salt in the SS/Mcw strain included numerous genes with homologs associated with hypertension, cardiovascular disease, or renal disease in human. To narrow the critical window of exposure, we performed embryo-transfer experiments in which single-cell embryos from 1 colony (SS/Mcw or SS/Crl) were transferred to surrogate mothers from the other colony, with parents and surrogate mothers maintained on their respective original diet. All offspring were fed the AIN-76A diet after weaning. Salt-induced hypertension and renal injury were substantially exacerbated in rats developed from SS/Crl embryos transferred to SS/Mcw surrogate mothers. Conversely, salt-induced hypertension and renal injury were significantly attenuated in rats developed from SS/Mcw embryos transferred to SS/Crl surrogate mothers. Together, the data suggest that maternal diet during the gestational–lactational period has substantial effects on the development of salt-induced hypertension and renal injury in adult SS rats.

IgG Receptor FcγRIIB Plays a Key Role in Obesity-Induced Hypertension

Hypertension. 2015 | Volume 65, Issue 2: 456–462,

Published Online:November 3, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04670

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There is a well-recognized association between obesity, inflammation, and hypertension. Why obesity causes hypertension is poorly understood. We previously demonstrated using a C-reactive protein (CRP) transgenic mouse that CRP induces hypertension that is related to NO deficiency. Our prior work in cultured endothelial cells identified the Fcγ receptor IIB (FcγRIIB) as the receptor for CRP whereby it antagonizes endothelial NO synthase. Recognizing known associations between CRP and obesity and hypertension in humans, in the present study we tested the hypothesis that FcγRIIB plays a role in obesity-induced hypertension in mice. Using radiotelemetry, we first demonstrated that the hypertension observed in transgenic mouse-CRP is mediated by the receptor, indicating that FcγRIIB is capable of modifying blood pressure. We then discovered in a model of diet-induced obesity yielding equal adiposity in all study groups that whereas FcγRIIB^+/+ mice developed obesity-induced hypertension, FcγRIIB^−/− mice were fully protected. Levels of CRP, the related pentraxin serum amyloid P component which is the CRP-equivalent in mice, and total IgG were unaltered by diet-induced obesity; FcγRIIB expression in endothelium was also unchanged. However, whereas IgG isolated from chow-fed mice had no effect, IgG from high-fat diet–fed mice inhibited endothelial NO synthase in cultured endothelial cells, and this was an FcγRIIB-dependent process. Thus, we have identified a novel role for FcγRIIB in the pathogenesis of obesity-induced hypertension, independent of processes regulating adiposity, and it may entail an IgG-induced attenuation of endothelial NO synthase function. Approaches targeting FcγRIIB may potentially offer new means to treat hypertension in obese individuals.

Inactive Matrix Gla Protein Is Causally Related to Adverse Health Outcomes

A Mendelian Randomization Study in a Flemish Population

Hypertension. 2015 | Volume 65, Issue 2: 463–470,

Published Online:November 24, 2014,

https://doi.org/10.1161/HYPERTENSIONAHA.114.04494

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Matrix Gla-protein is a vitamin K–dependent protein that strongly inhibits arterial calcification. Vitamin K deficiency leads to production of inactive nonphosphorylated and uncarboxylated matrix Gla protein (dp–ucMGP). The risk associated with dp–ucMGP in the population is unknown. In a Flemish population study, we measured circulating dp–ucMGP at baseline (1996–2011), genotyped MGP, recorded adverse health outcomes until December 31, 2012, and assessed the multivariable-adjusted associations of adverse health outcomes with dp–ucMGP. We applied a Mendelian randomization analysis using MGP genotypes as instrumental variables. Among 2318 participants, baseline dp–ucMGP averaged 3.61 μg/L. Over 14.1 years (median), 197 deaths occurred, 58 from cancer and 70 from cardiovascular disease; 85 participants experienced a coronary event. The risk of death and non-cancer mortality curvilinearly increased (P≤0.008) by 15.0% (95% confidence interval, 6.9–25.3) and by 21.5% (11.1–32.9) for a doubling of the nadir (1.43 and 0.97 μg/L, respectively). With higher dp–ucMGP, cardiovascular mortality log-linearly increased (hazard ratio for dp–ucMGP doubling, 1.14 [1.01–1.28]; P=0.027), but coronary events log-linearly decreased (0.93 [0.88–0.99]; P=0.021). dp–ucMGP levels were associated (P≤0.001) with MGP variants rs2098435, rs4236, and rs2430692. For non-cancer mortality and coronary events (P≤0.022), but not for total and cardiovascular mortality (P≥0.13), the Mendelian randomization analysis suggested causality. Higher dp–ucMGP predicts total, non-cancer and cardiovascular mortality, but lower coronary risk. For non-cancer mortality and coronary events, these associations are likely causal.

Correction

Hypertension. 2015 | Volume 65, Issue 2: e7,

Published Online:February 1, 2015,

https://doi.org/10.1161/HYP.0000000000000019

Correction(s) for this article
- Addition of Spironolactone in Patients With Resistant Arterial Hypertension (ASPIRANT)
  - Jan Václavík
  - Richard Sedlák
  - Martin Plachý
  - Karel Navrátil
  - Jiří Plášek
  - Jiří Jarkovský
  - Tomáš Václavík
  - Roman Husár
  - Eva Kociánová
  - Miloš Táborský
  - Volume 57Issue 6Hypertension
  - 2 May 2011

Table of Contents

Clinical Implications

Clinical Implications

Recent Advances in Hypertension

Aging, Arterial Stiffness, and Hypertension

Brief Reviews

Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases

Mitochondria

A Pathogenic Paradigm in Hypertensive Renal Disease

Editorial Commentaries

Estrogens and Myocardial Chymase

New Insights Into Pathological Hypertrophy and Remodeling

Effectiveness of a Tailored Behavioral Intervention to Improve Hypertension Control

What Underlies the Prolonged Hypotensive Effect of Catheter-Based Renal Denervation in Humans?

(Pro)renin Receptor as a Therapeutic Target for the Treatment of Hypertension?

Aldosterone Antagonists and Renal Denervation

Friends or Foes?

Salt-Sensitive Hypertension

Food for Thought

C-Reactive Protein and Its Role in Preeclampsia

Wnt-1 Dishevelled Signaling Functionally Links Calcium-Calmodulin–Dependent Protein Kinase II and Cardiac Dysfunction

Pulse Wave Velocity Ratio

The New “Gold Standard” for Measuring Arterial Stiffness

Original Articles

Epidemiology/Population

Burden of Undiagnosed Hypertension in Sub-Saharan Africa

A Systematic Review and Meta-Analysis

Does Low Diastolic Blood Pressure Contribute to the Risk of Recurrent Hypertensive Cardiovascular Disease Events?

The Framingham Heart Study

Glucagon-Like Peptide-1 and Blood Pressure in Young and Healthy Adults from the General Population

Canned Beverages and Blood Pressure

Exposure to Bisphenol A From Drinking Canned Beverages Increases Blood Pressure

Randomized Crossover Trial

Dietary Nitrate and Hypertension

Dietary Nitrate Provides Sustained Blood Pressure Lowering in Hypertensive Patients

A Randomized, Phase 2, Double-Blind, Placebo-Controlled Study

Abstract—

Clinical Trial Registration—

Heart

Estrogen Inhibits Mast Cell Chymase Release to Prevent Pressure Overload-Induced Adverse Cardiac Remodeling

Calcium/Calmodulin-Dependent Protein Kinase II Couples Wnt Signaling With Histone Deacetylase 4 and Mediates Dishevelled-Induced Cardiomyopathy

Nervous System

Genetic Interference With Peroxisome Proliferator–Activated Receptor γ in Smooth Muscle Enhances Myogenic Tone in the Cerebrovasculature via A Rho Kinase–Dependent Mechanism

Intracerebroventricular Infusion of the (Pro)renin Receptor Antagonist PRO20 Attenuates Deoxycorticosterone Acetate-Salt–Induced Hypertension

Correction to: Intracerebroventricular Infusion of the (Pro)renin Receptor Antagonist PRO20 Attenuates Deoxycorticosterone Acetate-Salt–Induced Hypertension

Vessels

Altered Dependence of Aortic Pulse Wave Velocity on Transmural Pressure in Hypertension Revealing Structural Change in the Aortic Wall

Augmented Vascular Smooth Muscle Cell Stiffness and Adhesion When Hypertension Is Superimposed on Aging

Aortic-Brachial Stiffness Mismatch and Mortality in Dialysis Population

Soluble Guanylate Cyclase Is Required for Systemic Vasodilation But Not Positive Inotropy Induced by Nitroxyl in the Mouse

Renal Denervation

Reinnervation of Renal Afferent and Efferent Nerves at 5.5 and 11 Months After Catheter-Based Radiofrequency Renal Denervation In Sheep

Magnitude of Blood Pressure Reduction in the Placebo Arms of Modern Hypertension Trials

Implications for Trials of Renal Denervation

Randomized Comparison of Renal Denervation Versus Intensified Pharmacotherapy Including Spironolactone in True-Resistant Hypertension

Six-Month Results From the Prague-15 Study

miRNA and Pulmonary Hypertension

miR-29a-3p Attenuates Hypoxic Pulmonary Hypertension by Inhibiting Pulmonary Adventitial Fibroblast Activation

Preeclampsia

Bioinformatics Approach Reveals Evidence for Impaired Endometrial Maturation Before and During Early Pregnancy in Women Who Developed Preeclampsia

Correction

Neurokinin 3 Receptor and Phosphocholine Transferase

Missing Factors for Pathogenesis of C-Reactive Protein in Preeclampsia

Tailored Behavioral Intervention

Effectiveness of a Tailored Behavioral Intervention to Improve Hypertension Control

Primary Outcomes of a Randomized Controlled Trial

Clinical Trial Registration—

Maternal Diet and Salt Sensitivity

Maternal Diet During Gestation and Lactation Modifies the Severity of Salt-Induced Hypertension and Renal Injury in Dahl Salt-Sensitive Rats

Obesity and Hypertension

IgG Receptor FcγRIIB Plays a Key Role in Obesity-Induced Hypertension

Mendelian Randomization

Inactive Matrix Gla Protein Is Causally Related to Adverse Health Outcomes

A Mendelian Randomization Study in a Flemish Population

Correction

Correction

Addition of Spironolactone in Patients With Resistant Arterial Hypertension (ASPIRANT)

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