Vol 61, No 6 | Hypertension

Abstract Export Citations PDF/EPUB
The predictive value of blood pressure (BP) for cardiovascular morbidity and mortality diminishes in the elderly, which may be confounded and compensated by the BP differences across the 4 limbs, markers of peripheral arterial disease. In a prospective elderly (≥60 years) Chinese study, we performed simultaneous 4-limb BP measurement using an oscillometric device in the supine position, and calculated BP differences between the 4 limbs. At baseline, the mean age of the 3133 participants (1383 men) was 69 years. During 4 years (median) of follow-up, all-cause and cardiovascular deaths occurred in 203 and 93 subjects, respectively. In multiple regression analyses, arm BPs on the higher arm side of systolic BP did not predict mortality (P≥0.06) except for a negative association between mean arterial pressure and total mortality (P=0.04). However, in adjusted analyses, the hazard ratios associated with a 1-SD decrease in ankle-brachial BP index or increase in interarm or interankle BP difference were 1.15 to 1.23 for total mortality (P≤0.01) and 1.17 to 1.24 for cardiovascular mortality (P≤0.04). In categorical analyses, similar results were observed for a decreased ankle-brachial index (≤0.90, ≤0.95, or ≤1.00) or increased interarm or interankle difference (≥15 mm Hg or ≥10 mm Hg). In conclusion, in the elderly, above and beyond arm BP level and together with ankle-brachial index, the interarm and interankle BP differences improve prediction of mortality. Simultaneous 4-limb BP measurement has become feasible with current technology and might be useful in cardiovascular prevention.

Urinary Magnesium Excretion and Risk of Hypertension

The Prevention of Renal and Vascular End-Stage Disease Study

Hypertension. 2013 | Volume 61, Issue 6: 1161–1167,

Published Online:April 22, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01333

Abstract Export Citations PDF/EPUB
Observational studies on dietary or circulating magnesium and risk of hypertension have reported weak-to-modest inverse associations, but have lacked measures of actual dietary uptake. Urinary magnesium excretion, an indicator of intestinal magnesium absorption, may provide a better insight in this association. We examined 5511 participants aged 28 to 75 years free of hypertension in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, a prospective population–based cohort study. Circulating magnesium was measured in plasma and urinary magnesium in two 24-hour urine collections, both at baseline. Incident hypertension was defined as blood pressure ≥140 mm Hg systolic or ≥90 mm Hg diastolic, or initiation of antihypertensive medication. During a median follow-up of 7.6 years (interquartile range, 5.0–9.3 years), 1172 participants developed hypertension. The median urinary magnesium excretion was 3.8 mmol/24 hour (interquartile range, 2.9–4.8 mmol/24 hour). Urinary magnesium excretion was associated with risk of hypertension in an inverse log-linear fashion, and this association remained after adjustment for age, sex, body mass index, smoking status, alcohol intake, parental history of hypertension, and urinary excretion of sodium, potassium, and calcium. Each 1-unit increment in ln-transformed urinary magnesium excretion was associated with a 21% lower risk of hypertension after multivariable adjustment (adjusted hazard ratio, 0.79; 95% confidence interval, 0.71–0.88). No associations were observed between circulating magnesium and risk of hypertension. In conclusion, in this cohort of men and women, urinary magnesium excretion was inversely associated with risk of hypertension across the entire range of habitual dietary intake.

Novel Description of the 24-Hour Circadian Rhythms of Brachial Versus Central Aortic Blood Pressure and the Impact of Blood Pressure Treatment in a Randomized Controlled Clinical Trial

The Ambulatory Central Aortic Pressure (AmCAP) Study

Hypertension. 2013 | Volume 61, Issue 6: 1168–1176,

Published Online:April 29, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00763

Abstract Export Citations PDF/EPUB
Elevated brachial blood pressure (BP) is associated with increased cardiovascular risk and predicts morbidity and mortality in humans. Recently, 24-hour ambulatory BP monitoring and assessment of central aortic BP have been introduced to improve BP phenotyping. The Ambulatory Central Aortic Pressure (AmCAP) study combines these approaches and describes, for the first time, the diurnal patterns of simultaneously measured 24-hour ambulatory brachial and central pressures in a prespecified substudy embedded within a clinical trial of BP lowering in patients with hypertension. Twenty-four–hour ambulatory brachial and central pressure measurements were acquired using a tonometer mounted into the articulating strap of a wristwatch-like device (BPro) in 171 participants with hypertension recruited into the ASSERTIVE (AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients) trial. Participants were randomly assigned to BP lowering with either aliskiren 300 mg QD or telmisartan 80 mg QD for 12 weeks. Ambulatory brachial and central BP was measured in all participants both at baseline and at study end. Brachial and central BP both demonstrated typical diurnal patterns with lower pressures at night. However, night time was associated with smaller reductions in central relative to brachial pressure and decreased pulse pressure amplification (P<0.0001 for both). These effects were not modulated after BP lowering and were maintained after adjustment for day and night-time BP and heart rate (P=0.02). This study demonstrates that brachial and central pressure show different diurnal patterns, which are not modulated by BP-lowering therapy, with relatively higher night-time central pressures. These novel data indicate that night-time central BP may provide prognostic importance and warrants further investigation.
Clinical Trial Registration–
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865020.

Dapper-1 Induces Myocardial Remodeling Through Activation of Canonical Wnt Signaling in Cardiomyocytes

Hypertension. 2013 | Volume 61, Issue 6: 1177–1183,

Published Online:March 18, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00391

Abstract Export Citations PDF/EPUB
Heart failure has an increasing contribution to cardiovascular disease burden and is governed by the myocardial remodeling process. The contribution of Wnt signaling to cardiac remodeling has recently drawn significant attention. Here, we report that upregulation of Dapper-1 in a transgenic mouse model activates the canonical/β-catenin–dependent Wnt pathway through dishevelled-2. These mice exhibited increased heart weight/tibia length ratio, myocyte cross-sectional area, and upregulation of hypertrophic marker genes compared with wild-type mice. Furthermore, impairment of left ventricular systolic and diastolic function was observed in all indicating features of myocardial remodeling. Depletion of Dapper-1 and dishevelled-2 in cardiomyocytes demonstrated that Dapper-1 functions upstream of dishevelled-2 and that activity of both Dapper-1 and dishevelled-2 is essential for activating canonical Wnt signaling. Moreover, Dapper-1 depletion alleviated Wnt3a- and phenylephrine-induced cardiomyocyte hypertrophy. These observations provide evidence that Dapper-1–mediated activation of canonical Wnt signaling is necessary and sufficient to induce cardiomyocyte hypertrophy. Inhibition of this pathway may thus serve as a novel therapeutic strategy for alleviating cardiac hypertrophy.

Cathepsin K Knockout Alleviates Pressure Overload–Induced Cardiac Hypertrophy

Hypertension. 2013 | Volume 61, Issue 6: 1184–1192,

Published Online:March 25, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00947

Abstract Export Citations PDF/EPUB
Evidence from human and animal studies has documented elevated levels of lysosomal cysteine protease cathepsin K in failing hearts. Here, we hypothesized that ablation of cathepsin K mitigates pressure overload–induced cardiac hypertrophy. Cathepsin K knockout mice and their wild-type littermates were subjected to abdominal aortic constriction, resulting in cardiac remodeling (heart weight, cardiomyocyte size, left ventricular wall thickness, and end diastolic and end systolic dimensions) and decreased fractional shortening, the effects of which were significantly attenuated or ablated by cathepsin K knockout. Pressure overload dampened cardiomyocyte contractile function along with decreased resting Ca²⁺ levels and delayed Ca²⁺ clearance, which were partly resolved by cathepsin K knockout. Cardiac mammalian target of rapamycin and extracellular signal-regulated kinases (ERK) signaling cascades were upregulated by pressure overload, the effects of which were attenuated by cathepsin K knockout. In cultured H9c2 myoblast cells, silencing of cathepsin K blunted, whereas cathepsin K transfection mimicked phenylephrine–induced hypertrophic response, along with elevated phosphorylation of mammalian target of rapamycin and ERK. In addition, cathepsin K protein levels were markedly elevated in human hearts of end-stage dilated cardiomyopathy. Collectively, our data suggest that cathepsin K ablation mitigates pressure overload–induced hypertrophy, possibly via inhibition of the mammalian target of rapamycin and ERK pathways.

Role of Interferon Regulatory Factor 4 in the Regulation of Pathological Cardiac Hypertrophy

Hypertension. 2013 | Volume 61, Issue 6: 1193–1202,

Published Online:April 15, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00614

Abstract Export Citations PDF/EPUB
IRF4, a member of the interferon regulatory factor (IRF) family, was previously shown to be restricted in the immune system and involved in the differentiation of immune cells. However, we interestingly observed that IRF4 was also highly expressed in both human and animal hearts. Given that several transcription factors have been shown to regulate the pathological cardiac hypertrophy, we then ask whether IRF4, as a new transcription factor, plays a critical role in pressure overload–elicited cardiac remodeling. A transgenic mouse model with cardiac-specific overexpression of IRF4 was generated and subjected to an aortic banding for 4 to 8 weeks. Our results demonstrated that overexpression of IRF4 aggravated pressure overload–triggered cardiac hypertrophy, fibrosis, and dysfunction. Conversely, IRF4 knockout mice showed an attenuated hypertrophic response to chronic pressure overload. Mechanistically, we discovered that the expression and activation of cAMP response element–binding protein (CREB) were significantly increased in IRF4-overexpressing hearts, while being greatly reduced in IRF4-KO hearts on aortic banding, compared with control hearts, respectively. Similar results were observed in ex vivo cultured neonatal rat cardiomyocytes on the treatment with angiotensin II. Inactivation of CREB by dominant-negative mutation (dnCREB) offset the IRF4-mediated hypertrophic response in angiotensin II–treated myocytes. Furthermore, we identified that the promoter region of CREB contains 3 IRF4 binding sites. Altogether, these data indicate that IRF4 functions as a necessary modulator of hypertrophic response by activating the transcription of CREB in hearts. Thus, our study suggests that IRF4 might be a novel target for the treatment of pathological cardiac hypertrophy and failure.

Enhanced Angiotensin Receptor-Associated Protein in Renal Tubule Suppresses Angiotensin-Dependent Hypertension

Hypertension. 2013 | Volume 61, Issue 6: 1203–1210,

Published Online:March 25, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00572

Abstract Export Citations PDF/EPUB
We have previously shown that angiotensin II type 1 receptor-associated protein (ATRAP/Agtrap) interacts with the angiotensin II type 1 receptor and promotes constitutive internalization of the receptor so as to inhibit the pathological activation of its downstream signaling but preserve baseline physiological signaling activity. The present study was designed to investigate the role of renal ATRAP in angiotensin II–dependent hypertension. We generated transgenic mice dominantly expressing ATRAP in the renal tubules, including renal distal tubules. The renal ATRAP transgenic mice exhibited no significant change in blood pressure at baseline on normal salt diet. However, in the renal ATRAP transgenic mice compared with wild-type mice, the following took place: (1) the development of high blood pressure in response to angiotensin II infusion was significantly suppressed based on radiotelemetry, (2) the extent of daily positive sodium balance was significantly reduced during angiotensin II infusion in metabolic cage analysis, and (3) the renal Na⁺-Cl⁻ cotransporter activation and α-subunit of the epithelial sodium channel induction by angiotensin II infusion were inhibited. Furthermore, adenoviral overexpression of ATRAP suppressed the angiotensin II–mediated increase in the expression of α-subunit of the epithelial sodium channel in mouse distal convoluted tubule cells. These results indicate that renal tubule–dominant ATRAP activation provokes no evident effects on blood pressure at baseline but exerts an inhibitory effect on the pathological elevation of blood pressure in response to angiotensin II stimulation, thereby suggesting that ATRAP is a potential target of interest in blood pressure modulation under pathological conditions.

Angiotensin II Stimulates Basolateral 10-pS Cl Channels in the Thick Ascending Limb

Hypertension. 2013 | Volume 61, Issue 6: 1211–1217,

Published Online:April 8, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.01069

Abstract Export Citations PDF/EPUB
Chloride channels in the basolateral membrane play a key role in Cl absorption in the thick ascending limb (TAL). The patch-clamp experiments were performed to test whether angiotensin II (AngII) increases Cl absorption in the TAL by stimulating the basolateral 10-pS Cl channels. AngII (1–100 nmol/L) stimulated the 10-pS Cl channel in the TAL, an effect that was blocked by losartan (angiotension AT1 receptor [AT₁R] antagonist) but not by PD123319 (angiotension AT2 receptor [AT₂R] antagonist). Inhibition of phospholipase C or protein kinase C also abolished the stimulatory effect of AngII on Cl channels. Moreover, stimulation of protein kinase C with phorbol-12-myristate-13-acetate mimicked the effect of AngII and increased Cl channel activity. However, the stimulatory effect of AngII on Cl channels was absent in the TAL pretreated with diphenyleneiodonium sulfate, an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Moreover, treatment of the TAL with diphenyleneiodonium sulfate also blocked the effect of phorbol-12-myristate-13-acetate on the 10-pS Cl channel. Western blotting demonstrated that incubation of isolated TAL with AngII increased phosphorylation of p47^phox at Ser³⁰⁴, suggesting that AngII stimulates the basolateral Cl channels by increasing NADPH oxidase–dependent superoxide generation. This notion was also supported by the observation that H₂O₂ significantly increased 10-pS Cl channel activity in the TAL. We conclude that stimulation of AT₁R increased the basolateral Cl channels by activating the protein kinase C–dependent NADPH oxidase pathway. The stimulatory effect of AngII on the basolateral Cl channel may contribute to AngII-induced increases in NaCl reabsorption in the TAL and AngII-infuse–induced hypertension.

Proximal Tubule Angiotensin AT₂ Receptors Mediate an Anti-Inflammatory Response via Interleukin-10

Role in Renoprotection in Obese Rats

Hypertension. 2013 | Volume 61, Issue 6: 1218–1226,

Published Online:April 1, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00422

Abstract Export Citations PDF/EPUB
The angiotensin type 2 receptor (AT₂R) has been shown to lower inflammation in the kidney. However, the role of the anti-inflammatory cytokine interleukin (IL)-10 in AT₂R-mediated attenuation of inflammation has not been elucidated. We hypothesized that AT₂R activation is renoprotective by directly increasing the levels of anti-inflammatory cytokine IL-10 in the kidney via nitric oxide (NO) signaling. For in vitro studies, the human proximal tubule epithelial cell-line (human kidney-2 [HK-2]) was activated with lipopolysaccharide (10 μg/mL) and AT₂R agonist C21 (1 μmol/L) for 24 hours, and media cytokine levels were assessed. Lipopolysaccharide modestly downregulated AT₂R expression. Treatment with C21 lowered lipopolysaccharide-induced levels of both tumor necrosis factor-α and IL-6, but increased IL-10 levels. Treatment with neutralizing IL-10 antibody (1 μg/mL) or NO synthase inhibitor L-NAME (1 mmol/L) abolished this effect. For in vivo studies, prehypertensive obese Zucker rats and age-matched lean Zucker rats were treated for 2 weeks with C21 (300 μg/kg per day, IP) and AT₂R antagonist (PD123319; 50 μg/kg per minute, SC infusion). Compared with lean Zucker rats, obese Zucker rats had higher levels of renal AT₂R expression, tumor necrosis factor-α, and IL-6. C21 treatment decreased levels of tumor necrosis factor-α by 75% and IL-6 by 60%. Conversely, PD treatment lowered the renal IL-10 levels in obese Zucker rats by ≈60%. Renal morphometry revealed increased mesangial matrix expansion and glomerular macrophage infiltration, which was improved by C21 treatment in obese Zucker rats. Our findings suggest that proximal tubule AT₂R activation is anti-inflammatory by increasing IL-10 production, which is largely NO dependent and thus offers renoprotection by preventing early inflammation–induced renal injury in obesity.

Association of Smoking With Phenotype at Diagnosis and Vascular Interventions in Patients With Renal Artery Fibromuscular Dysplasia

Hypertension. 2013 | Volume 61, Issue 6: 1227–1232,

Published Online:April 22, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00838

Abstract Export Citations PDF/EPUB
The pathogenesis of fibromuscular dysplasia (FMD) remains unclear, but tobacco use is thought to be involved. This retrospective cross-sectional study aimed to evaluate smoking first as a risk factor for renal artery FMD diagnosis and second as a modifier of the clinical and radiological phenotype of this disease. We retrieved 337 adult patients diagnosed with FMD in a referral center for hypertension management, who were first individually matched to controls with essential hypertension for sex, age, systolic blood pressure, number of antihypertensive drugs, and year of visit. Smoking status and other relevant data were collected at first visit. The proportion of current smokers was higher for patients with FMD than for the controls (30% and 18%, respectively, P<0.001; odds ratio, 2.5 [95% confidence interval, 1.6–3.9]). Second, characteristics of FMD were compared between current smokers and other patients. Among patients with multifocal FMD, current smokers experienced an earlier diagnosis of hypertension (36 versus 42 years, respectively; P<0.001) and FMD (43 versus 51 years; P<0.001) than other patients, and a greater likelihood of renal artery interventions (57% versus 31%; P<0.001) and of kidney asymmetry (21% versus 4%; P=0.001). In conclusion, current smoking is associated with a higher likelihood of renal artery FMD diagnosis. Rather than a higher incidence of FMD, this may reflect a more aggressive course in smokers, who have earlier hypertension leading to increased and earlier recognition of the disease. Smoking cessation should be strongly encouraged in patients with FMD.

Angiotensin-Converting Enzyme 2 Activation Improves Endothelial Function

Hypertension. 2013 | Volume 61, Issue 6: 1233–1238,

Published Online:April 22, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00627

Abstract Export Citations PDF/EPUB
Diminished release and function of endothelium-derived nitric oxide coupled with increases in reactive oxygen species production is critical in endothelial dysfunction. Recent evidences have shown that activation of the protective axis of the renin–angiotensin system composed by angiotensin-converting enzyme 2, angiotensin-(1–7), and Mas receptor promotes many beneficial vascular effects. This has led us to postulate that activation of intrinsic angiotensin-converting enzyme 2 would improve endothelial function by decreasing the reactive oxygen species production. In the present study, we tested 1-[[2-(dimetilamino)etil]amino]-4-(hidroximetil)-7-[[(4-metilfenil)sulfonil]oxi]-9H-xantona-9 (XNT), a small molecule angiotensin-converting enzyme 2 activator, on endothelial function to validate this hypothesis. In vivo treatment with XNT (1 mg/kg per day for 4 weeks) improved the endothelial function of spontaneously hypertensive rats and of streptozotocin-induced diabetic rats when evaluated through the vasorelaxant responses to acetylcholine/sodium nitroprusside. Acute in vitro incubation with XNT caused endothelial-dependent vasorelaxation in aortic rings of rats. This vasorelaxation effect was attenuated by the Mas antagonist D-pro7-Ang-(1–7), and it was reduced in Mas knockout mice. These effects were associated with reduction in reactive oxygen species production. In addition, Ang II–induced reactive oxygen species production in human aortic endothelial cells was attenuated by preincubation with XNT. These results showed that chronic XNT administration improves the endothelial function of hypertensive and diabetic rat vessels by attenuation of the oxidative stress. Moreover, XNT elicits an endothelial-dependent vasorelaxation response, which was mediated by Mas. Thus, this study indicated that angiotensin-converting enzyme 2 activation promotes beneficial effects on the endothelial function and it is a potential target for treating cardiovascular disease.

Effect of Contrasted Sodium Diets on the Pharmacokinetics and Pharmacodynamic Effects of Renin–Angiotensin System Blockers

Hypertension. 2013 | Volume 61, Issue 6: 1239–1245,

Published Online:April 22, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01196

Abstract Export Citations PDF/EPUB
Dietary sodium, the main determinant of the pharmacodynamic response to renin–angiotensin system blockade, influences the pharmacokinetics of various cardiovascular drugs. We compared the effect of contrasted sodium diets on the pharmacokinetics of single oral doses of 8 mg candesartan cilexetil, 160 mg valsartan, 10 mg ramipril, and 50 mg atenolol administered to 64 (16 per group) normotensive male subjects randomly assigned to sodium depletion (SD) or sodium repletion (SR) in a crossover study. Pharmacodynamic response was assessed as the increase in plasma renin concentration for renin–angiotensin system blockers and electrocardiographic changes in PR interval duration for atenolol. The area under the curve (AUC) for plasma candesartan and atenolol concentrations was significantly lower for SR than for SD (respective ratios of AUC_0–∞: 0.74; [90% CI, 0.66–0.82] and 0.69 [90% CI, 0.54–0.88], respectively), indicating a lack of bioequivalence between SR and SD. SR did not affect the pharmacokinetics of valsartan or ramipril. The increase in plasma renin concentration with the 3 renin–angiotensin system blockers was 10 times lower during the SR than the SD period. In the multiple regression analysis, the AUC_0–24 of plasma drug concentration explained <1% and 21% of the variance of the AUC_0–24 of delta plasma renin concentration for candesartan (P=0.8882/P=0.0368) during the SR and SD periods, respectively. The atenolol-induced lengthening of PR interval was fully reversed by SR. Thus, sodium balance modulates the pharmacokinetics of candesartan cilexetil and atenolol, with measurable effects on the selected pharmacodynamic end points.

Estrogen Normalizes Perinatal Nicotine–Induced Hypertensive Responses in Adult Female Rat Offspring

Hypertension. 2013 | Volume 61, Issue 6: 1246–1254,

Published Online:March 25, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01152

Abstract Export Citations PDF/EPUB
Perinatal nicotine exposure caused a sex-dependent heightened vascular response to angiotensin II (Ang II) and increased blood pressure in adult male but not in female rat offspring. The present study tested the hypothesis that estrogen normalizes perinatal nicotine–induced hypertensive response to Ang II in female offspring. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps from day 4 of gestation to day 10 after birth. Ovariectomy and 17β-estradiol replacement were performed on 8-week-old female offspring. At 5 months of age, Ang II–induced blood pressure responses were not changed by nicotine treatment in the sham groups. In contrast, nicotine significantly enhanced Ang II–induced blood pressure responses as compared with saline control in the ovariectomy groups, which was associated with increased Ang II–induced vascular contractions. These heightened responses were abrogated by 17β-estradiol replacement. In addition, nicotine enhanced Ang II receptor type I, NADPH (nicotinamide adenine dinucleotide phosphate) oxidase type 2 protein expressions, and reactive oxygen species production of aortas as compared with saline control in the ovariectomy groups. Antioxidative agents, both apocynin and tempol, inhibited Ang II–induced vascular contraction and eliminated the differences of contractions between nicotine-treated and control ovariectomy rats. These findings support a key role of estrogen in the sex difference of perinatal nicotine–induced programming of vascular dysfunction, and suggest that estrogen may counteract heightened reactive oxygen species production, leading to protection of females from development programming of hypertensive phenotype in adulthood.

Estrogen Receptor-β in the Paraventricular Nucleus and Rostroventrolateral Medulla Plays an Essential Protective Role in Aldosterone/Salt-Induced Hypertension in Female Rats

Hypertension. 2013 | Volume 61, Issue 6: 1255–1262,

Published Online:April 22, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00903

Abstract Export Citations PDF/EPUB
The identification of the specific estrogen receptor (ER) subtypes that are involved in estrogen protection from hypertension and their specific locations in the central nervous system is critical to our understanding and design of effective estrogen replacement therapies in women. Using selective ER agonists and recombinant adeno-associated virus (AAV) carrying small interference (si) RNA to silence either ERα (AAV-siRNA-ERα) or ERβ (AAV-siRNA-ERβ), the present study investigated regional specificity of different ER subtypes in the protective actions of estrogen in aldosterone (Aldo)-induced hypertension. Intracerebroventricular infusions of either diarylpropionitrile, a selective ERβ agonist, or propyl-pyrazole-triol, a selective ERα agonist, attenuated Aldo/NaCl-induced hypertension in ovariectomized rats. In contrast, intracerebroventricular injections of siRNA-ERα or siRNA-ERβ augmented Aldo-induced hypertension in intact females. Site-specific paraventricular nucleus (PVN) or rostroventrolateral medulla (RVLM) injections of siRNA-ERβ augmented Aldo-induced hypertension. However, rats with PVN or RVLM injections of siRNA-ERα did not significantly increase blood pressure induced by Aldo. Real-time polymerase chain reaction analyses of the PVN and RVLM of siRNA-injected rat confirmed a marked reduction in the expression of ERα and ERβ. In cultured PVN neurons, silencing either ERα or ERβ by culturing PVN neurons with siRNA-ERα or siRNA-ERβ enhanced Aldo-induced reactive oxygen species production. Ganglionic blockade after Aldo infusion showed an increase in sympathetic activity in ERβ knockdown rats. These results indicate that both PVN and RVLM ERβ, but not ERα in these nuclei, contribute to the protective effects of estrogen against Aldo-induced hypertension. The brain regions responsible for the protective effects of estrogen interaction with ERα in Aldo-induced hypertension still need to be determined.

Differential Effects of Nebivolol Versus Metoprolol on Functional Sympatholysis in Hypertensive Humans

Hypertension. 2013 | Volume 61, Issue 6: 1263–1269,

Published Online:April 1, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01302

Abstract Export Citations PDF/EPUB
In young healthy humans, sympathetic vasoconstriction is markedly blunted during exercise to optimize blood flow to the metabolically active muscle. This phenomenon known as functional sympatholysis is impaired in hypertensive humans and rats by angiotensin II–dependent mechanisms, involving oxidative stress and inactivation of nitric oxide (NO). Nebivolol is a β1-adrenergic receptor blocker that has NO-dependent vasodilatory and antioxidant properties. We therefore asked whether nebivolol would restore functional sympatholysis in hypertensive humans. In 21 subjects with stage 1 hypertension, we measured muscle oxygenation and forearm blood flow responses to reflex increases in sympathetic nerve activity evoked by lower body negative pressure at rest, and during rhythmic handgrip exercise at baseline, after 12 weeks of nebivolol (5–20 mg/d) or metoprolol (100–300 mg/d), using a double-blind crossover design. We found that nebivolol had no effect on lower body negative pressure–induced decreases in oxygenation and forearm blood flow in resting forearm (from −29±5% to −30±5% and from −29±3% to −29±3%, respectively; P=NS). However, nebivolol attenuated the lower body negative pressure–induced reduction in oxygenation and forearm blood flow in exercising forearm (from −14±4% to −1±5% and from −15±2% to −6±2%, respectively; both P<0.05). This effect of nebivolol on oxygenation and forearm blood flow in exercising forearm was not observed with metoprolol in the same subjects, despite a similar reduction in blood pressure. Nebivolol had no effect on sympathetic nerve activity at rest or during handgrip, suggesting a direct effect on vascular function. Thus, our data demonstrate that nebivolol restored functional sympatholysis in hypertensive humans by a mechanism that does not involve β1-adrenergic receptors.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01502787.

Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats

Hypertension. 2013 | Volume 61, Issue 6: 1270–1280,

Published Online:April 22, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00469

Abstract Export Citations PDF/EPUB
Perturbations of proper functions of the endoplasmic reticulum (ER) cause accumulation of misfolded or unfolded proteins in the cell, creating a condition known as ER stress. Prolonged ER stress has been implicated in hypertension. Oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons for the maintenance of vasomotor tone reside, plays a pivotal role in neurogenic hypertension. This study aimed to evaluate the contribution of ER stress in RVLM to oxidative stress–associated hypertension and delineate the underlying molecular mechanisms. The expression of glucose-regulated protein 78 kDa and the phosphorylation of protein kinase RNA-like ER kinase–translation initiation factor α, 2 major protein markers of ER stress, were augmented in RVLM and preceded the development of hypertensive phenotype in spontaneously hypertensive rats. In RVLM of spontaneously hypertensive rats, stabilizing ER stress by salubrinal promoted antihypertension, and scavenging the reactive oxygen species by tempol reduced the augmented ER stress. Furthermore, induction of oxidative stress by angiotensin II induced ER stress in RVLM, and induction of ER stress by tunicamycin in RVLM induced pressor response in normotensive Wistar-Kyoto rats. Autophagy, as reflected by the expression of lysosome-associated membrane protein-2 and microtubule-associated protein 1 light chain 3-II (LC3-II), was significantly increased in RVLM of spontaneously hypertensive rats and was abrogated by salubrinal. In addition, inhibition of autophagy or silencing LC3-II gene in RVLM resulted in antihypertension in spontaneously hypertensive rats. These results suggest that redox-sensitive induction of ER stress and activation of autophagy in RVLM contribute to oxidative stress–associated neurogenic hypertension.

Integrated Proteomics Pipeline Yields Novel Biomarkers for Predicting Preeclampsia

Hypertension. 2013 | Volume 61, Issue 6: 1281–1288,

Published Online:April 1, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01168

Abstract Export Citations PDF/EPUB
Preeclampsia, a hypertensive pregnancy complication, is largely unpredictable in healthy nulliparous pregnant women. Accurate preeclampsia prediction in this population would transform antenatal care. To identify novel protein markers relevant to the prediction of preeclampsia, a 3-step mass spectrometric work flow was applied. On selection of candidate biomarkers, mostly from an unbiased discovery experiment (19 women), targeted quantitation was used to verify and validate candidate biomarkers in 2 independent cohorts from the SCOPE (SCreening fOr Pregnancy Endpoints) study. Candidate proteins were measured in plasma specimens collected at 19 to 21 weeks’ gestation from 100 women who later developed preeclampsia and 200 women without preeclampsia recruited from Australia and New Zealand. Protein levels (n=25), age, and blood pressure were then analyzed using logistic regression to identify multimarker models (maximum 6 markers) that met predefined criteria: sensitivity ≥50% at 20% positive predictive value. These 44 algorithms were then tested in an independent European cohort (n=300) yielding 8 validated models. These 8 models detected 50% to 56% of preeclampsia cases in the training and validation sets; the detection rate for preterm preeclampsia cases was 80%. Validated models combine insulin-like growth factor acid labile subunit and soluble endoglin, supplemented with maximally 4 markers of placental growth factor, serine peptidase inhibitor Kunitz type 1, melanoma cell adhesion molecule, selenoprotein P, and blood pressure. Predictive performances were maintained when exchanging mass spectrometry measurements with ELISA measurements for insulin-like growth factor acid labile subunit. In conclusion, we demonstrated that biomarker combinations centered on insulin-like growth factor acid labile subunit have the potential to predict preeclampsia in healthy nulliparous women.

Podocyturia Predates Proteinuria and Clinical Features of Preeclampsia

Longitudinal Prospective Study

Hypertension. 2013 | Volume 61, Issue 6: 1289–1296,

Published Online:March 25, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01115

Abstract Export Citations PDF/EPUB
Podocyturia, the shedding of live podocytes, is present at delivery in women with preeclampsia. The aim of this study was to test whether podocyturia is present earlier in pregnancy and predicts for preeclampsia. We also aimed to compare test characteristics of podocyturia with those of angiogenic factors previously implicated in the pathogenesis of this disorder. We prospectively enrolled 315 women who provided blood and urine samples at the end of the second trimesters of their pregnancies (median, 27 gestational weeks) and within 24 hours of their deliveries (median, 39.5 gestational weeks). Blood samples were analyzed for angiogenic markers, including placental growth factor, the soluble receptor fms-like tyrosine kinase receptor-1 for vascular endothelial growth factor, and endoglin. The urine sediments were analyzed for podocytes, identified by staining for podocin after culturing the urinary sediments for 24 hours. This analysis included all women who developed preeclampsia (n=15), gestational hypertension (n=15), and a subsample of women who remained normotensive throughout pregnancy (n=44), matched for maternal age and number of previous pregnancies to those who developed preeclampsia. At the second trimester collection, all women who developed preeclampsia had podocyturia, compared with none of those who remained normotensive or were diagnosed with gestational hypertension. Podocyturia in the second trimester had a significantly greater sensitivity and specificity for the subsequent diagnosis of preeclampsia than any single angiogenic marker or a combination thereof. Screening for podocyturia at the end of the second trimester may allow for accurate identification of pregnant women at risk for preeclampsia.

Maternal Cardiovascular Risk Profile After Placental Abruption

Hypertension. 2013 | Volume 61, Issue 6: 1297–1301,

Published Online:March 25, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00930

Abstract Export Citations PDF/EPUB
The prevalence of premature cardiovascular diseases (CVD) is increased in women with a history of maternal placental syndromes, including pregnancy-associated hypertensive disorders (eg, preeclampsia), fetal growth restriction, and placental abruption. Whereas previous studies have shown a high prevalence of CVD risk factors after pregnancies complicated by preeclampsia, this has not been studied for women with a history of placental abruption. To explore the association of placental abruption with CVD risk factors after delivery, we compared 75 women with a history of placental abruption with a control group of 79 women with uneventful pregnancies at 6 to 9 months postpartum for the presence of common CVD risk factors. In a subanalysis, data were stratified according to the presence or absence of concomitant hypertensive disease and further adjusted for potential confounders. Women with previous placental abruption had significantly higher mean systolic blood pressure, body-mass index, fasting blood glucose, C-reactive protein, total cholesterol, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol as compared with controls with only uneventful pregnancies. In the subanalysis, all differences remained significant for women with a history of placental abruption only (ie, without concomitant gestational hypertension), except for the associations with low-density lipoprotein-cholesterol and diastolic and systolic blood pressure. Most likely, the identified CVD risk factors predispose to placental abruption and development of premature CVD later in life.

Blood Pressure in Treated Hypertensive Individuals With the MTHFR 677TT Genotype Is Responsive to Intervention With Riboflavin

Findings of a Targeted Randomized Trial

Hypertension. 2013 | Volume 61, Issue 6: 1302–1308,

Published Online:April 22, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.01047

Abstract Export Citations PDF/EPUB
Intervention with riboflavin was recently shown to produce genotype-specific lowering of blood pressure (BP) in patients with premature cardiovascular disease homozygous for the 677C→T polymorphism (TT genotype) in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR). Whether this effect is confined to patients with high-risk cardiovascular disease is unknown. The aim of this randomized trial, therefore, was to investigate the responsiveness of BP to riboflavin supplementation in hypertensive individuals with the TT genotype but without overt cardiovascular disease. From an available sample of 1427 patients with hypertension, we identified 157 with the MTHFR 677TT genotype, 91 of whom agreed to participate in the trial. Participants were stratified by systolic BP and randomized to receive placebo or riboflavin (1.6 mg/d) for 16 weeks. At baseline, despite being prescribed multiple classes of antihypertensive drugs, >60% of participants with this genotype had failed to reach goal BP (≤140/90 mm Hg). A significant improvement in the biomarker status of riboflavin was observed in response to intervention (P<0.001). Correspondingly, an overall treatment effect of 5.6±2.6 mm Hg (P=0.033) in systolic BP was observed, with pre- and postintervention values of 141.8±2.9 and 137.1±3.0 mm Hg (treatment group) and 143.5±3.0 and 144.3±3.1 mm Hg (placebo group), whereas the treatment effect in diastolic BP was not significant (P=0.291). In conclusion, these results show that riboflavin supplementation targeted at hypertensive individuals with the MTHFR 677TT genotype can decrease BP more effectively than treatment with current antihypertensive drugs only and indicate the potential for a personalized approach to the management of hypertension in this genetically at-risk group.
Clinical Trial Registration—
URL: http://www.clinicaltrials.gov. Unique identifier: ISRCTN23620802.

Intensive Blood Pressure Lowering Increases Cerebral Blood Flow in Older Subjects With Hypertension

Hypertension. 2013 | Volume 61, Issue 6: 1309–1315,

Published Online:March 25, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.112.200972

Abstract Export Citations PDF/EPUB
Hypertension is associated with reduced cerebral blood flow (CBF). Intensive (<130/80 mm Hg) blood pressure (BP) lowering in older people might give greater reduction in cardiovascular risk, but there are concerns that this might produce hypoperfusion which may precipitate falls and possibly stroke. We determined the effect of intensive compared with usual BP lowering on CBF in hypertensive older subjects. Individuals aged >70 years with a history of systolic hypertension on 1 or no BP lowering drugs were recruited from primary care (n=37; age, 75±4 years; systolic BP, >150 mm Hg) and randomized to receive intensive (target BP, <130/80 mm Hg) or usual (target BP, <140/85 mm Hg) BP lowering for 12 weeks, with reviews every 2 weeks. CBF, determined using 3T arterial spin labeling MRI, and 24-hour ambulatory BP were performed at baseline and after 12 weeks of treatment. Baseline BP (ambulatory or in clinic) and baseline gray matter CBF were not significantly different between the groups. After treatment, BP was reduced significantly in both groups but fell more in the intensive group (26/17 versus 15/5 mm Hg; P<0.01). Over the same period, gray matter CBF increased significantly in the intensive group (7±11 mL/min per 100 g; P=0.013) but was unchanged in the usual BP target group (−3±9 mL/min per 100 g; P=0.23); P<0.01 for comparison. Intensive BP lowering in older people with hypertension increases CBF, compared with BP lowering to usual target. These findings suggest hypertension in older people shifts the autoregulatory CBF curve rightward and downward and is reversible with BP lowering.

Role of T Regulatory Lymphocytes in the Pathogenesis of High-Fructose Diet–Induced Metabolic Syndrome

Hypertension. 2013 | Volume 61, Issue 6: 1316–1321,

Published Online:March 25, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.203521

Abstract Export Citations PDF/EPUB
We recently showed that T regulatory lymphocytes (Treg), which are immune suppressors of inflammatory responses, play a role blunting the development of hypertension-induced injury. Treg are unchanged or decreased in children with metabolic syndrome, and therefore, their role in metabolic syndrome remains unclear. We hypothesized that Treg number or function would be depressed in a high-fructose diet–induced metabolic syndrome-like model in rats. Sprague-Dawley rats were fed normal chow or a high-fructose diet for 5 weeks. The high-fructose diet–induced a 3.8-fold increase in plasma triglycerides and a 14% reduction in high-density lipoprotein cholesterol (P<0.001). The high-fructose diet increased reactive oxygen species in aorta and periaortic adipose tissue 2.8-fold (P<0.05), and reduced nicotinamide adenine dinucleotide phosphate oxidase activity 1.9-fold in aorta, and 2.5-fold in the heart (P<0.05). It also increased plasma nitric oxide metabolite levels 6.4-fold (P<0.001). Western blots showed that the high-fructose diet increased ≥2.3-fold vascular and in platelet endothelial cell adhesion molecule 1 in aorta (P<0.01). It did not affect monocyte/macrophage aortic infiltration but caused a 2.4-fold increase in collagen deposition in the aortic media (P<0.01). No change in plasma interleukin-10 was detected. The percentage of spleen CD4⁺CD25⁻ and Treg (CD4⁺CD25^high) cells was unaltered by the high-fructose diet. However, cultured Treg from high-fructose diet–fed rats secreted 62% less interleukin-10 than control cells (P<0.05), suggesting a decreased Treg function, which could play a role in the development of cardiovascular complications of the metabolic syndrome.

Body Fat Is Associated With Reduced Aortic Stiffness Until Middle Age

Hypertension. 2013 | Volume 61, Issue 6: 1322–1327,

Published Online:April 22, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01177

Abstract Export Citations PDF/EPUB
Obesity is a major risk factor for cardiometabolic disease, but the effect of body composition on vascular aging and arterial stiffness remains uncertain. We investigated relationships among body composition, blood pressure, age, and aortic pulse wave velocity in healthy individuals. Pulse wave velocity in the thoracic aorta, an indicator of central arterial stiffness, was measured in 221 volunteers (range, 18–72 years; mean, 40.3±13 years) who had no history of cardiovascular disease using cardiovascular MRI. In univariate analyses, age (r=0.78; P<0.001) and blood pressure (r=0.41; P<0.001) showed a strong positive association with pulse wave velocity. In multivariate analysis, after adjustment for age, sex, and mean arterial blood pressure, elevated body fat% was associated with reduced aortic stiffness until the age of 50 years, thereafter adiposity had an increasingly positive association with aortic stiffness (β=0.16; P<0.001). Body fat% was positively associated with cardiac output when age, sex, height, and absolute lean mass were adjusted for (β=0.23; P=0.002). These findings suggest that the cardiovascular system of young adults may be capable of adapting to the state of obesity and that an adverse association between body fat and aortic stiffness is only apparent in later life.

Chronic Knockdown of the Nucleus of the Solitary Tract AT₁ Receptors Increases Blood Inflammatory-Endothelial Progenitor Cell Ratio and Exacerbates Hypertension in the Spontaneously Hypertensive Rat

Hypertension. 2013 | Volume 61, Issue 6: 1328–1333,

Published Online:April 1, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00156

Abstract Export Citations PDF/EPUB
AT₁ receptor subtype a (AT₁Ra) expression is increased in the nucleus of the solitary tract (NTS) in spontaneously hypertensive rat (SHR) compared with Wistar Kyoto controls. However, the chronic role of AT₁Ra in the NTS for cardiovascular control is not well understood. In this study, we investigated the hypothesis that the NTS AT₁Ra is involved in the neural regulation of the peripheral inflammatory status and linked with hypertension. Transduction of brain neuronal cultures with recombinant adeno-associated virus type 2 (AAV2)-AT₁R-small hairpin RNA (shRNA) resulted in a 72% decrease in AT₁Ra mRNA and attenuated angiotensin II–induced increase in extracellular signal–regulated kinase 1/2 phosphorylation and neuronal firing. Specific NTS microinjection of AAV2-AT₁R-shRNA vector in the SHR resulted in a ≈30 mm Hg increase in the mean arterial pressure compared with control vector–injected animals (Sc-shRNA: 154±4 mm Hg; AT₁R-shRNA: 183±10 mm Hg) and induced a resetting of the baroreflex control of heart rate to higher mean arterial pressure. In addition, AAV2-AT₁R-shRNA–treated SHRs exhibited a 74% decrease in circulating endothelial progenitor cells (CD90⁺, CD4⁻/CD5⁻/CD8⁻) and a 300% increase in the circulating inflammatory cells, including CD4⁺⁺CD8⁺, CD45⁺/3⁺ T lymphocytes, and macrophages (CD68⁺). As a result, the endothelial progenitor cell/inflammatory cells ratio was decreased by 8- to 15-fold in the AT₁R-shRNA–treated SHR. However, identical injection of AAV2-AT₁R-shRNA into the NTS of Wistar Kyoto rats had no effect on mean arterial pressure and inflammatory cells. These observations suggest that increased expression of the AT₁Ra in SHR NTS may present a counterhypertensive mechanism involving inflammatory/angiogenic cells.

Renal Responses to Long-Term Carotid Baroreflex Activation Therapy in Patients With Drug-Resistant Hypertension

Teba Alnima,
Peter W. de Leeuw,
Frans E.S. Tan,
Abraham A. Kroon and
for the Rheos Pivotal Trial Investigators

Hypertension. 2013 | Volume 61, Issue 6: 1334–1339,

Published Online:April 15, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01159

Abstract Export Citations PDF/EPUB
Carotid baroreflex activation has been demonstrated to provide enduring reductions in arterial blood pressure. The aim of this study was to investigate the effect of long-term therapy on renal function. A total of 322 patients were enrolled in the Rheos Pivotal Trial. Group 1 consisted of 236 patients who started baroreflex activation therapy 1 month after device implantation, whereas in the 86 patients from group 2 the device was activated 6 months later. Serum creatinine and urine albumin/creatinine ratio were collected at screening (before device activation), and at months 6 and 12. Multilevel statistical analyses were adjusted for various covariables. Serum creatinine increased from 78 to 84 μmol/L, and glomerular filtration rate decreased from 92 to 87 mL/min per 1.73 m² in group 1 at month 6 (P<0.05). These values did not change any further after 12 months of therapy. Patients with highest glomerular filtration rate showed the greatest decrease in glomerular filtration. Group 2 showed the same trends as group 1 even before device activation at month 6. Systolic blood pressure reduction seemed to be significantly related to the change in glomerular filtration rate in both groups. Albumin/creatinine ratio did not change in both groups during follow-up. In conclusion, baroreflex activation therapy in hypertensive patients is associated with an initial mild decrease in glomerular filtration rate, which may be considered as a normal hemodynamic response to the drop in blood pressure. Long-term treatment does not result in further decrease in renal function, indicating baroreflex activation as a safe and effective therapy.

Central Pulse Pressure Is an Independent Determinant of Vascular Remodeling in the Retinal Circulation

Hypertension. 2013 | Volume 61, Issue 6: 1340–1345,

Published Online:April 8, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00617

Abstract Export Citations PDF/EPUB
Pulse pressure has been recognized as a risk factor for stroke. Moreover, it was shown that central pulse pressure relates more strongly to vascular disease and outcome than (peripheral) brachial pulse pressure. Because vascular remodeling in the retinal circulation mirrors the 1 in the cerebral circulation and represents an easy, noninvasive possibility to assess microvascular changes in humans, we analyzed the impact of central pulse pressure on retinal vascular structure in humans. The study cohort comprised 135 nondiabetic patients across a wide range of blood pressure values. Parameter of retinal arteriolar remodeling (wall-to-lumen ratio) was assessed noninvasively and in vivo by scanning laser Doppler flowmetry. Central pulse pressure and augmentation index normalized to a heart rate of 75 beats per minute were assessed by pulse wave analysis. Central pulse pressure correlated with wall-to-lumen ratio (r=0.302; P<0.001), central augmentation index normalized to a heart rate of 75 beats per minute correlated with wall-to-lumen ratio (r=0.190; P=0.028), and in accordance pulse pressure amplification (peripheral pulse pressure/central pulse pressure) was negatively correlated with wall-to-lumen ratio (r=−0.223; P=0.009). In contrast, central mean arterial pressure was not correlated with wall-to-lumen ratio (r=0.110; P=0.203). Multiple regression analysis revealed an independent relationship between wall-to-lumen ratio and central pulse pressure (β=0.277; P=0.009), but not with other classical cardiovascular risk factors. Thus, central pulse pressure, indicative of changes in large conduit arteries is an independent determinant of vascular remodeling in small retinal arterioles. Such a relationship indicates a coupling and crosstalk between the microvascular and macrovascular changes attributable to hypertension.

White Coat Hypertension Is More Risky Than Prehypertension

Important Role of Arterial Wave Reflections

Hypertension. 2013 | Volume 61, Issue 6: 1346–1353,

Published Online:April 22, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00569

Abstract Export Citations PDF/EPUB
Arterial aging may link cardiovascular risk to white coat hypertension (WCH). The aims of the present study were to investigate the role of arterial aging in the white coat effect, defined as the difference between office and 24-hour ambulatory systolic blood pressures, and to compare WCH with prehypertension (PH) with respect to target organ damage and long-term cardiovascular mortality. A total of 1257 never-been-treated volunteer subjects from a community-based survey were studied. WCH and PH were defined by office and 24-hour ambulatory blood pressures. Left ventricular mass index, carotid intima-media thickness, estimated glomerular filtration rate, carotid-femoral pulse wave velocity, carotid augmentation index, amplitude of the reflection pressure wave, and 15-year cardiovascular mortality were determined. Subjects with WCH were significantly older and had greater body mass index, blood pressure values, intima-media thickness, carotid-femoral pulse wave velocity, augmentation index, amplitude of the backward pressure wave, and a lower estimated glomerular filtration rate than PH. Amplitude of the backward pressure wave was the most important independent correlate of the white coat effect in multivariate analysis (model r²=0.451; partial r²/model r²=90.5%). WCH had significantly greater cardiovascular mortality than PH (hazard ratio, 2.94; 95% confidence interval, 1.09–7.91), after accounting for age, sex, body mass index, smoking, fasting plasma glucose, and total cholesterol/high-density lipoprotein-cholesterol ratio. Further adjustment of the model for amplitude of the backward pressure wave eliminated the statistical significance of the WCH effect. In conclusion, the white coat effect is mainly caused by arterial aging. WCH carries higher risk for cardiovascular mortality than PH, probably via enhanced wave reflections that accompany arterial aging.

High Blood Pressure and Cerebral White Matter Lesion Progression in the General Population

Hypertension. 2013 | Volume 61, Issue 6: 1354–1359,

Published Online:March 25, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.111.00430

Abstract Export Citations PDF/EPUB
High blood pressure is considered an important risk factor for cerebral white matter lesions (WMLs) in the aging population. In a longitudinal population-based study of 665 nondemented persons, we investigated the longitudinal relationship of systolic blood pressure, diastolic blood pressure, and pulse pressure with annual progression of WMLs. Means of blood pressure were calculated over a 5-year period before longitudinal MRI scanning. WML progression was subsequently measured on 2 scans 3.5 years apart. We performed analyses with linear regression models and evaluated adjustments for age, sex, cardiovascular risk factors, and baseline WML volume. In addition, we evaluated whether treatment of hypertension is related to less WML progression. Both systolic and diastolic blood pressures were significantly associated with annual WML progression (regression coefficient [95% confidence interval], 0.08 [0.03; 0.14] mL/y and 0.09 [0.03; 0.15] mL/y per SD increase in systolic and diastolic blood pressure, respectively). Pulse pressure was also significantly associated with WML progression, but not independent from hypertension. After adjustment for baseline WML volume, only systolic blood pressure remained significantly associated: 0.05 (0.00; 0.09) mL/y per SD increase. People with uncontrolled untreated hypertension had significantly more WML progression than people with uncontrolled treated hypertension (difference [95% confidence interval], 0.12 [0.00; 0.23] mL/y). The present study further establishes high blood pressure to precede WMLs and implies that hypertension treatment could reduce WML progression in the general population.

Beyond Medications and Diet: Alternative Approaches to Lowering Blood Pressure

A Scientific Statement From the American Heart Association

Robert D. Brook,
Lawrence J. Appel,
Melvyn Rubenfire,
Gbenga Ogedegbe,
John D. Bisognano,
William J. Elliott,
Flavio D. Fuchs,
Joel W. Hughes,
Daniel T. Lackland,
Beth A. Staffileno,
Raymond R. Townsend,
Sanjay Rajagopalan and
on behalf of the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research, Council on Cardiovascular and Stroke Nursing, Council on Epidemiology and Prevention, and Council on Nutrition, Physical Activity and Metabolism

Hypertension. 2013 | Volume 61, Issue 6: 1360–1383,

Published Online:April 22, 2013,

https://doi.org/10.1161/HYP.0b013e318293645f

Abstract Export Citations PDF/EPUB
Many antihypertensive medications and lifestyle changes are proven to reduce blood pressure. Over the past few decades, numerous additional modalities have been evaluated in regard to their potential blood pressure–lowering abilities. However, these nondietary, nondrug treatments, collectively called alternative approaches, have generally undergone fewer and less rigorous trials. This American Heart Association scientific statement aims to summarize the blood pressure–lowering efficacy of several alternative approaches and to provide a class of recommendation for their implementation in clinical practice based on the available level of evidence from the published literature. Among behavioral therapies, Transcendental Meditation (Class IIB, Level of Evidence B), other meditation techniques (Class III, Level of Evidence C), yoga (Class III, Level of Evidence C), other relaxation therapies (Class III, Level of Evidence B), and biofeedback approaches (Class IIB, Level of Evidence B) generally had modest, mixed, or no consistent evidence demonstrating their efficacy. Between the noninvasive procedures and devices evaluated, device-guided breathing (Class IIA, Level of Evidence B) had greater support than acupuncture (Class III, Level of Evidence B). Exercise-based regimens, including aerobic (Class I, Level of Evidence A), dynamic resistance (Class IIA, Level of Evidence B), and isometric handgrip (Class IIB, Level of Evidence C) modalities, had relatively stronger supporting evidence. It is the consensus of the writing group that it is reasonable for all individuals with blood pressure levels >120/80 mm Hg to consider trials of alternative approaches as adjuvant methods to help lower blood pressure when clinically appropriate. A suggested management algorithm is provided, along with recommendations for prioritizing the use of the individual approaches in clinical practice based on their level of evidence for blood pressure lowering, risk-to-benefit ratio, potential ancillary health benefits, and practicality in a real-world setting. Finally, recommendations for future research priorities are outlined.

Effect of Fenofibrate on Vascular Endothelial Function: Statistical Appraisal and its Validity

Tomoyuki Kawada

Hypertension. 2013 | Volume 61, Issue 6: e55,

Published Online:April 15, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01227

Response to Effect of Fenofibrate on Vascular Endothelial Function: Statistical Appraisal and its Validity

Hypertension. 2013 | Volume 61, Issue 6: e56,

Published Online:April 15, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01310

Role of the Carotid Body in Obesity-Related Sympathoactivation

Hypertension. 2013 | Volume 61, Issue 6: e57,

Published Online:May 6, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01248

Response to Role of the Carotid Body in Obesity-Related Sympathoactivation

Hypertension. 2013 | Volume 61, Issue 6: e58,

Published Online:May 6, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01301

Mortality Benefits From US Population-Wide Reduction in Sodium Consumption: Projections From 3 Modeling Approaches

Hypertension. 2013 | Volume 61, Issue 6: e59,

Published Online:April 15, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01307

Response to Mortality Benefits From US Population-Wide Reduction in Sodium Consumption: Projections From 3 Modeling Approaches

Hypertension. 2013 | Volume 61, Issue 6: e60,

Published Online:April 15, 2013,

https://doi.org/10.1161/HYPERTENSIONAHA.113.01317

Correction

Hypertension. 2013 | Volume 61, Issue 6: e61,

Published Online:June 1, 2013,

https://doi.org/10.1161/HYP.0b013e3182949149

Correction(s) for this article
- Angiotensin Receptor Agonistic Autoantibody-Mediated Soluble Fms-Like Tyrosine Kinase-1 Induction Contributes to Impaired Adrenal Vasculature and Decreased Aldosterone Production in Preeclampsia
  - Athar H. Siddiqui
  - Roxanna A. Irani
  - Weiru Zhang
  - Wei Wang
  - Sean C. Blackwell
  - Rodney E. Kellems
  - Yang Xia
  - Volume 61Issue 2Hypertension
  - 2 January 2013

Table of Contents

Clinical Implications

Clinical Implications

Recent Advances in Hypertension

Endothelin, Kidney Disease, and Hypertension

Editorial Commentaries

Four-Limb Blood Pressure Measurement

A Research Tool Looking for Clinical Use

Ambulatory Central Blood Pressure

A New Opportunity for Mechanistic and Clinical Cardiovascular Research

Angiotensin II Type 1 Receptor–associated Protein

A Novel Modulator of Angiotensin II Actions in the Nephron

Is β the α Dog in Estrogen Receptor–Mediated Protection From Hypertension?

Original Articles

Epidemiology/Population Science

Four-Limb Blood Pressure as Predictors of Mortality in Elderly Chinese

Urinary Magnesium Excretion and Risk of Hypertension

The Prevention of Renal and Vascular End-Stage Disease Study

Clinical Trial - The AmCAP Study

Novel Description of the 24-Hour Circadian Rhythms of Brachial Versus Central Aortic Blood Pressure and the Impact of Blood Pressure Treatment in a Randomized Controlled Clinical Trial

The Ambulatory Central Aortic Pressure (AmCAP) Study

Clinical Trial Registration–

Heart

Dapper-1 Induces Myocardial Remodeling Through Activation of Canonical Wnt Signaling in Cardiomyocytes

Cathepsin K Knockout Alleviates Pressure Overload–Induced Cardiac Hypertrophy

Role of Interferon Regulatory Factor 4 in the Regulation of Pathological Cardiac Hypertrophy

Kidney

Enhanced Angiotensin Receptor-Associated Protein in Renal Tubule Suppresses Angiotensin-Dependent Hypertension

Angiotensin II Stimulates Basolateral 10-pS Cl Channels in the Thick Ascending Limb

Proximal Tubule Angiotensin AT2 Receptors Mediate an Anti-Inflammatory Response via Interleukin-10

Role in Renoprotection in Obese Rats

Association of Smoking With Phenotype at Diagnosis and Vascular Interventions in Patients With Renal Artery Fibromuscular Dysplasia

Renin-Angiotensin System

Angiotensin-Converting Enzyme 2 Activation Improves Endothelial Function

Effect of Contrasted Sodium Diets on the Pharmacokinetics and Pharmacodynamic Effects of Renin–Angiotensin System Blockers

Estrogen

Estrogen Normalizes Perinatal Nicotine–Induced Hypertensive Responses in Adult Female Rat Offspring

Estrogen Receptor-β in the Paraventricular Nucleus and Rostroventrolateral Medulla Plays an Essential Protective Role in Aldosterone/Salt-Induced Hypertension in Female Rats

Sympathetic Nervous System

Differential Effects of Nebivolol Versus Metoprolol on Functional Sympatholysis in Hypertensive Humans

Clinical Trial Registration—

Redox-Sensitive Endoplasmic Reticulum Stress and Autophagy at Rostral Ventrolateral Medulla Contribute to Hypertension in Spontaneously Hypertensive Rats

Preeclampsia

Integrated Proteomics Pipeline Yields Novel Biomarkers for Predicting Preeclampsia

Podocyturia Predates Proteinuria and Clinical Features of Preeclampsia

Longitudinal Prospective Study

Pregnancy

Maternal Cardiovascular Risk Profile After Placental Abruption

Stratified Treatment of Hypertension

Blood Pressure in Treated Hypertensive Individuals With the MTHFR 677TT Genotype Is Responsive to Intervention With Riboflavin

Findings of a Targeted Randomized Trial

Clinical Trial Registration—

Blood Pressure Lowering and Cerebral Blood Flow

Intensive Blood Pressure Lowering Increases Cerebral Blood Flow in Older Subjects With Hypertension

Metabolic Syndrome

Role of T Regulatory Lymphocytes in the Pathogenesis of High-Fructose Diet–Induced Metabolic Syndrome

Obesity

Body Fat Is Associated With Reduced Aortic Stiffness Until Middle Age

Inflammation and Hypertension

Chronic Knockdown of the Nucleus of the Solitary Tract AT1 Receptors Increases Blood Inflammatory-Endothelial Progenitor Cell Ratio and Exacerbates Hypertension in the Spontaneously Hypertensive Rat

Renal Response to Baroreflex Activation Therapy

Renal Responses to Long-Term Carotid Baroreflex Activation Therapy in Patients With Drug-Resistant Hypertension

Retinal Vessels

Central Pulse Pressure Is an Independent Determinant of Vascular Remodeling in the Retinal Circulation

White Coat Hypertension

White Coat Hypertension Is More Risky Than Prehypertension

Important Role of Arterial Wave Reflections

White Matter Lesions

High Blood Pressure and Cerebral White Matter Lesion Progression in the General Population

AHA Scientific Statement

Beyond Medications and Diet: Alternative Approaches to Lowering Blood Pressure

A Scientific Statement From the American Heart Association

Letters to the Editor

Effect of Fenofibrate on Vascular Endothelial Function: Statistical Appraisal and its Validity

Response to Effect of Fenofibrate on Vascular Endothelial Function: Statistical Appraisal and its Validity

Role of the Carotid Body in Obesity-Related Sympathoactivation

Response to Role of the Carotid Body in Obesity-Related Sympathoactivation

Mortality Benefits From US Population-Wide Reduction in Sodium Consumption: Projections From 3 Modeling Approaches

Response to Mortality Benefits From US Population-Wide Reduction in Sodium Consumption: Projections From 3 Modeling Approaches

Correction

Proximal Tubule Angiotensin AT₂ Receptors Mediate an Anti-Inflammatory Response via Interleukin-10

Chronic Knockdown of the Nucleus of the Solitary Tract AT₁ Receptors Increases Blood Inflammatory-Endothelial Progenitor Cell Ratio and Exacerbates Hypertension in the Spontaneously Hypertensive Rat