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1.  African Caribbeans have greater subclinical cerebrovascular disease than Europeans: this is associated with both their elevated resting and ambulatory blood pressure and their hyperglycaemia 
Journal of hypertension  2013;31(12):2391-2399.
Stroke is elevated in people of black African descent, but evidence for excess subclinical cerebrovascular disease is conflicting, and the role of risk factors in determining any ethnic differences observed unexplored.
We compared prevalence of brain infarcts, and severe white matter hyperintensities (WMHs) on cerebral MRI, in a community-based sample of men and women aged 58–86 of African Caribbean (214) and European (605) descent, in London, UK. Resting, central and ambulatory blood pressure (BP) were measured; diabetes was assessed by blood testing and questionnaire.
Mean age was 70. Multiple (≥4) brain infarcts and severe WMH occurred more frequently in African Caribbeans (18/43%), than Europeans (7/33%, P = 0.05/0.008). Separately, clinic and night-time ambulatory BP were significantly associated with severe WMH in both ethnic groups; when both were entered into the model, the association for clinic SBP was attenuated and lost statistical significance [1.00 (0.98–1.02) P = 0.9 in Europeans, 1.00 (0.97–1.04) P = 0.9 in African Caribbeans], whereas the association for night-time SBP was retained [1.04 (1.02–1.07) P < 0.001 in Europeans, 1.08 (1.03–1.12), P = 0.001 in African Caribbeans]. The greater age-adjusted and sex-adjusted risk of severe WMH in African Caribbeans compared with Europeans [2.08 (1.15–3.76) P = 0.02], was attenuated to 1.45 [(0.74–2.83) P = 0.3] on adjustment for clinic and night-time systolic pressure, antihypertensive medication use and glycated haemoglobin.
African Caribbeans have a greater burden of subclinical cerebrovascular disease than Europeans. This excess is related to elevated clinic and ambulatory BP, and to hyperglycaemia.
PMCID: PMC4082237  PMID: 24029870
brain infarcts; diabetes; epidemiology; ethnicity; subclinical cerebrovascular disease; white matter hyperintensities
3.  Blood pressure and cognitive function: a prospective analysis among adolescents in the Seychelles 
Journal of hypertension  2013;31(6):10.1097/HJH.0b013e3283604176.
An inverse relationship between blood pressure and cognitive function has been found in adults, but limited data are available in adolescents and young adults. We examined the prospective relation between blood pressure and cognitive function in adolescence.
We examined the association between BP measured at the ages of 12–15 years in school surveys and cognitive endpoints measured in the Seychelles Child Development Study at ages 17 (n=407) and 19 (n=429) years, respectively. We evaluated multiple domains of cognition based on subtests of the Cambridge Neurological Test Automated Battery (CANTAB), the Woodcock Johnson Test of Scholastic Achievement (WJTA), the Finger Tapping test (FT) and the Kaufman Brief Intelligence Test (K-BIT). We used age-, sex- and height-specific z-scores of systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP).
Six out of the 21 cognitive endpoints tested were associated with BP. However, none of these associations were found to hold for both males and females or for different subtests within the same neurodevelopmental domain or for both SBP and DBP. Most of these associations disappeared when analyses were adjusted for selected potential confounding factors such as socio-economic status, birth weight, gestational age, body mass index, alcohol consumption, blood glucose, and total n-3 and n-6 polyunsaturated fats.
Our findings do not support a consistent association between BP and subsequent performance on tests assessing various cognitive domains in adolescents.
PMCID: PMC3874141  PMID: 23572201
blood pressure; cognitive function; adolescents; Seychelles and prospective
4.  Geometry-Independent Inclusion of Basal Myocardium Yields Improved Cardiac Magnetic Resonance Agreement with Echocardiography and Necropsy Quantified Left Ventricular Mass 
Journal of hypertension  2013;31(10):2069-2076.
LV mass (LVM) is widely used to guide clinical decision-making. Cardiac magnetic resonance (CMR) quantifies LVM by planimetry of contiguous short axis images, an approach dependent on reader-selection of images to be contoured. Established methods have applied different binary cutoffs using circumferential extent of LV myocardium to define the basal LV, omitting images containing lesser fractions of LV myocardium. This study tested impact of basal slice variability on LVM quantification.
CMR was performed in patients and laboratory animals. LVM was quantified with full inclusion of LV myocardium, and by established methods that use different cutoffs to define the LV basal-most slice: (1) 50% circumferential myocardium at end-diastole alone (ED50), (2) 50% circumferential myocardium throughout both end-diastole and end-systole (EDS50).
150 patients and 10 lab animals were studied. Among patients, fully inclusive LVM (172.6±42.3gm) was higher vs. ED50(167.2±41.8gm) and EDS50(150.6±41.1gm; both p<0.001). Methodological differences yielded discrepancies regarding proportion of patients meeting established criteria for LV hypertrophy and chamber dilation (p<0.05). Fully inclusive LVM yielded smaller differences with echocardiography (Δ=11.0±28.8gm) than did ED50 (Δ=16.4±29.1gm) and EDS50 (Δ=33.2±28.7gm, both p<0.001). Among lab animals, ex-vivo LV weight (69.8±13.2gm) was similar to LVM calculated using fully inclusive (70.1±13.5gm, p=0.67) and ED50 (69.4±13.9gm, p=0.70) methods, whereas EDS50 differed significantly (67.9±14.9gm, p=0.04).
Established CMR methods that discordantly define the basal-most LV produce significant differences in calculated LVM. Fully inclusive quantification, rather than binary cutoffs that omit basal LV myocardium, yields smallest CMR discrepancy with echocardiography-measured LVM and non-significant differences with necropsy-measured LV weight.
PMCID: PMC4017912  PMID: 24107735
left ventricular mass; cardiovascular magnetic resonance; echocardiography
Journal of hypertension  2013;31(9):1806-1811.
Hypertension is believed to be an increasingly common driver of the epidemic of non-communicable diseases (NCDs) in sub-Saharan Africa, but prospective data are scarce. The objective of this prospective study was to determine the contribution of hypertension to deaths, admissions, and hospital days at a Tanzanian zonal hospital. Methods: Between 2009 and 2011, diagnoses were recorded for all medical admissions together with age, gender, length of hospitalization and in-hospital mortality.
Among 11,045 consecutive admissions, NCDs accounted for nearly half of all deaths, admissions, and hospital days. Among NCDs, hypertension-related diseases were the most common and accounted for 314 (33.9%) of the total NCD deaths, 1,611 (29.9%) of the NCD admissions, and 12,837 (27.8%) NCD hospital days. Stroke (167 deaths) was the leading cause of hypertension-related death. Hypertension was the leading cause of death in patients over the age of 50 years and 57% of hypertension-related deaths occurred in patients <65 years old.
NCDs account for half of all deaths, admissions and hospital days at our Tanzanian hospital and hypertension-related diseases were the most common NCD. Hypertension accounted for 34% of NCD deaths and 15% of all deaths. Hypertension was the second most common cause of death overall and the leading cause of death in patients >50 years old. More than half of hypertension-related deaths occurred before retirement age. These findings have important implications for public health and medical education in sub-Saharan Africa, where hypertension and related diseases have not traditionally been given a high priority.
PMCID: PMC4005815  PMID: 23777761
hypertension; non-communicable diseases; sub-Saharan Africa; hospital; mortality; admissions; hospital days; stroke
Journal of hypertension  2011;29(12):2359-2368.
Vascular dysfunction, including reduced endothelium-dependent dilation, is a major characteristic of hypertension. We previously investigated that TrxR inhibition impairs vasodilation via soluble guanylyl cyclase S-nitrosylation, but S-nitrosylation and TrxR function are not known in hypertension. We hypothesized that S-nitrosylation is associated with reduced vasodilation in hypertensive mice. Aortic rings from normotensive (sham) and angiotensin II (AngII)-induced hypertensive C57BL/6 mice were treated with a TrxR inhibitor, 1-chloro-2,4-dinitrobenzene (DNCB) for 30 min, and relaxation to acetylcholine (ACh) was measured in the rings following contraction with phenylephrine. DNCB reduced relaxation to ACh compared with vehicle in sham aorta but not in AngII (sham-vehicle Emax=77±2, sham-DNCB Emax=59±4, *p<0.05). DNCB shifted the concentration-response relaxation to sodium nitroprusside (SNP) to the right in both sham and AngII aortic rings (sham-vehicle pD2=8.8±0.1, sham-DNCB pD2=8.4±0.1, *p<0.05; AngII-vehicle pD2=8.5±0.1, AngII-DNCB pD2=8.3±0.1, *p<0.05). As downstream signaling of nitric oxide, cyclic GMP level was reduced by DNCB during activation with SNP. The effect of DNCB to increase S-nitrosylation was confirmed by the biotin-switch method and western blot analysis and total protein S-nitrosylation was increased in AngII aorta (1.5-fold) compared to sham. TrxR activity was inhibited in AngII aorta compared to sham. We conclude that increased S-nitrosylation contributes to impaired relaxation in aorta from AngII-induced hypertensive mice. AngII treatment resulted in inactivation of TrxR and increased S-nitrosylation, indicating that TrxR and S-nitrosylation may provide a critical mechanism in hypertension associated with abnormal vascular reactivity.
PMCID: PMC4004364  PMID: 22025239
S-Nitrosylation; Thioredoxin reductase; Vascular relaxation; Hypertension
7.  Angiotensin-II Induced Hypertension and Renovascular Remodeling in TIMP2 Knockout Mice 
Journal of hypertension  2013;31(11):2270-2281.
Sustained hypertension induces renovascular remodeling by altering extracellular matrix (ECM) components. Matrix metalloproteinases (MMPs) are Zn-dependent enzymes that regulate ECM turnover in concert with their inhibitors, tissue inhibitors of metalloproteinases, TIMPs. Increased MMP-2 & -9 have been implicated in hypertensive complications; however, the contribution of individual MMPs/TIMPs in renal remodeling has not been fully elucidated. The purpose of this study was to determine the effect of TIMP2 deficiency and thus MMP-2 on Ang-II induced renal remodeling. C57BL/6J (WT) and TIMP2 knockout mice were infused with Angiotensin-II (Ang-II) at 250 ng. kg-1. min-1 for 4 weeks. Blood pressure was measured weekly and end-point laser Doppler flowmetry was done to assess cortical blood flow. Immunohistochemical staining was performed for collagen and elastin analyses. The activity of MMP-9, and -2 was determined by Gelatin zymography. Ang-II induced similar elevation in mean blood pressure in TIMP2-/- and WT mice. In TIMP2-/- mice, Ang-II treatment was associated with a greater reduction in renal cortical blood flow and barium angiography demonstrated decreased vascular density compared to Ang-II treated WT mice. Peri-glomerular and vascular collagen deposition was increased and elastin content was decreased causing increased wall-to-lumen ratio in TIMP2-/- mice compared to WT mice receiving Ang-II. Ang-II increased the expression and activity of MMP-9 predominantly in TIMP2-/- mice than in WT mice. These results suggest that TIMP2 deficiency exacerbates renovascular remodeling in agonist induced hypertension by a mechanism which may, in part, be attributed to increased activity of MMP-9.
PMCID: PMC4000563  PMID: 24077247
Hypertension; Angiotensin-II; renovascular remodeling; TIMP2-/-; matrix metalloproteinases
8.  Secular trends in blood pressure during early-to-middle adulthood: the Fels Longitudinal Study 
Journal of hypertension  2011;29(5):838-845.
Some studies have shown a decline in blood pressure (BP) over the second half of the twentieth century. However, the increasing prevalence of obesity may have opposite effects on recent cohorts.
Using serial BP data from the Fels Longitudinal Study, we examined secular trends in mean BP, the rate of change in BP with age (slopes), and the influence of obesity (i.e., BMI) and height on these trends during young-to-middle adulthood. The study sample consisted of 970 adults, aged 18–40 years, who were born between 1920 and 1979. Participants were grouped into birth decade cohorts and had up to 11 serial measurements of SBP, DBP, and BMI. Sex-stratified mixed longitudinal analyses were used to identify cohort effects on mean BP at ages 19, 29, and 39 years, and on the rate of change in BP with age.
For both sexes, mean SBP did not vary significantly by birth cohort, before and after adjusting for height and BMI. Mean DBP exhibited a U-shaped secular trend even after adjusting for BMI and height that was influenced by age-by-cohort effects. By age 39 years, those born most recently had the highest mean DBP.
There were cohort effects on the rate of change in DBP with age, but not on rate of SBP change. The most recent cohorts had higher rates of DBP change with age compared to the earlier cohorts. The secular trend was partially influenced by the trends in BMI.
PMCID: PMC3988666  PMID: 21430562
blood pressure; diastolic; longitudinal; secular trend; systolic; young adulthood
9.  Soluble ST2 predicts elevated SBP in the community 
Journal of hypertension  2013;31(7):1431-1436.
Soluble ST2 (sST2) is an emerging prognostic biomarker in patients with existing cardiovascular disease. ST2 and its ligand, interleukin-33 (IL-33), are expressed in endothelial cells, and may play an important role in the development of early atherosclerosis and vascular biology. We sought to investigate the association of sST2 and progression of blood pressure (BP), as well as the development of hypertension.
Circulating sST2 concentrations were measured in 1834 participants (mean age 56 years, 57% women) of the community-based Framingham Offspring study. Participants were free of hypertension at baseline. Multivariable linear and logistic regression models were used to evaluate the association of sST2 concentrations and subsequent BP outcomes.
Higher sST2 concentrations were associated with incident hypertension over 3 years of follow-up [multivariable-adjusted odds ratio per 1 standard deviation increase in sST2 1.22, 95% confidence interval 1.05–1.42, P =0.01]. Individuals in the upper sST2 quartile had a 2.6 mmHg greater increase in SBP compared with those in the lowest quartile (P for trend across quartiles 0.002) and a 1.8 mmHg greater increase in pulse pressure (P for trend 0.005). In contrast, sST2 concentrations were not associated with changes in DBP (P =0.27).
These findings suggest that sST2 concentrations predict changes in BP physiology typically seen with aging and progressive arterial stiffness. Further studies are needed to elucidate underlying mechanisms by which the ST2/IL-33 pathway may contribute to BP physiology.
PMCID: PMC3986262  PMID: 23615326
biological markers; blood pressure; epidemiology; hypertension; immune system; risk factors
10.  Apelin Protects Against Angiotensin II-Induced Cardiovascular Fibrosis and Decreases PAI-1 Production 
Journal of hypertension  2011;29(4):724-731.
To test the hypothesis that apelin protects against AngII-induced cardiovascular fibrosis and vascular remodeling.
Methods and Results
Wild type mice administered apelin or apelin plus Ang II exhibited less cardiovascular fibrosis and decreased PAI-1 gene expression than mice receiving Ang II, L-NAME, apelin plus L-NAME or apelin plus AngII plus L-NAME. In vitro analysis using a luciferase construct driven by 3.1Kb of the human PAI-1 promoter revealed that apelin blocks Ang II-mediated PAI-1 gene expression. Immunoblotting for phosphorylated myosin phosphatase subunit and myosin light chain revealed that apelin blocked Ang II activation of the Rho kinase pathway, which is associated with induction of PAI-1 gene expression by Ang II. In addition, treatment of human aortic smooth muscle cells with apelin reduced PAI-1 mRNA and protein production in the presence and absence of Ang II. Conversely, L-NAME treatment attenuated the down-regulation of PAI-1 by apelin in cells.
Apelin protects against cardiac fibrosis and vascular remodeling through direct regulation of PAI-1 gene expression. This protective effect is mediated through the synergistic inhibition of Ang II signaling and increased production of NO by apelin. Our data extend previous findings and provide new insight into the molecular mechanisms by which apelin elicits a cardio-protective effect.
PMCID: PMC3982221  PMID: 21358420
fibrosis; apelin; angiotensin II; plasminogen activator inhibitor type-1 (PAI-1)
11.  Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in hypertensive patients treated with thiazide diuretics 
Journal of hypertension  2013;31(4):698-704.
Single-nucleotide polymorphisms (SNPs) in NEDD4L may influence the ability of the NEDD4L protein to reduce epithelial sodium channel expression. A variant in NEDD4L, rs4149601, was associated with antihypertensive response and cardiovascular outcomes during treatment with thiazide diuretics and β-blockers in a Swedish population. We sought to further evaluate associations between NEDD4L polymorphisms, blood pressure response and cardiovascular outcomes with thiazide diuretics and β-blockers.
Four SNPs, rs4149601, rs292449, rs1008899 and rs75982813, were genotyped in 767 patients from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) clinical trial and association was assessed with blood pressure response to hydrochlorothiazide and atenolol. One SNP, rs4149601, was also genotyped in 1345 patients from the International Verapmil SR Trandolapril Study (INVEST), and association was examined with adverse cardiovascular outcomes relative to hydrochlorothiazide treatment.
Significant associations or trends were found between rs4149601, rs292449, rs75982813 and rs1008899 and decreases in blood pressure in whites on hydrochlorothiazide, and a significant association was observed with increasing copies of the GC rs4149601-rs292449 haplotype and greater blood pressure response to hydrochlorothiazide in whites (P = 0.0006 and 0.006, SBP and DBP, respectively). Significant associations were also seen with rs4149601 and an increased risk for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide [P = 0.022, odds ratio (95% confidence interval) = 10.65 (1.18–96.25)].
NEDD4L rs4149601, rs292449 and rs75982813 may be predictors for blood pressure response to hydrochlorothiazide in whites, and NEDD4L rs4149601 may be a predictor for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide.
PMCID: PMC3756535  PMID: 23353631
epithelial sodium channel; hypertension; International Verapamil SR Trandolapril Study; neural precursor cell expressed developmentally down-regulated 4 like; Pharmacogenomic Evaluation of Antihypertensive Responses; pharmacogenetics
12.  Fenofibrate lowers blood pressure in salt-sensitive but not salt-resistant hypertension 
Journal of hypertension  2013;31(4):820-829.
Peroxisome proliferator-activated receptor α agonists reduce blood pressure in rodents, but clinical trials provide conflicting data regarding their effects in humans. We tested the hypothesis that the effect of fenofibrate on blood pressure depends on salt sensitivity.
Thirty-one hypertensive volunteers (17 salt-resistant, 14 salt-sensitive) completed a randomized, crossover, double-blind protocol with three dietary phases: low salt diet (10 mmol/day) followed by two consecutive high salt diets (200 mmol/day), each for 6 days. During high salt, volunteers were randomized to fenofibrate 160 mg/day or placebo. Hemodynamic and metabolic parameters were measured on the last morning of each treatment arm.
Fenofibrate reduced triglycerides similarly in salt-sensitive and salt-resistant volunteers. Fenofibrate did not affect blood pressure in salt-resistant volunteers. In salt-sensitive volunteers, fenofibrate significantly decreased diastolic (P =0.02 versus placebo) and mean arterial (P = 0.04 versus placebo) blood pressure during high salt. In all volunteers, the decrease in systolic pressure during fenofibrate correlated inversely with the salt sensitivity of mean arterial pressure as a continuous variable. Fenofibrate significantly decreased heart rate, plasma renin activity, and renal vascular resistance during high salt in salt-sensitive volunteers, but not salt-resistant volunteers. Fenofibrate did not affect sodium excretion or weight gain during high salt. The effect of salt intake and fenofibrate on plasma and urine epoxyeicosatrienoic acid concentrations differed in salt-resistant and salt-sensitive volunteers.
Fenofibrate reduces blood pressure, heart rate and renal vasoconstriction in salt-sensitive volunteers, but not in salt-resistant volunteers. These findings have implications for the treatment of hyperlipidemia in hypertensive individuals.
PMCID: PMC3800119  PMID: 23385647
blood pressure; fenofibrate; hypertension; peroxisome proliferator-activated receptor α; salt
13.  Predictors of lowering SBP to assigned targets at 12 months in the Secondary Prevention of Small Subcortical Strokes study 
Journal of hypertension  2012;30(6):1233-1240.
Lowering blood pressure for secondary stroke prevention remains a challenge. These analyses were conducted to identify factors predicting achievement of SBP targets in the Secondary Prevention of Small Subcortical Strokes (SPS3) study.
SPS3 is a randomized trial assigning patients with lacunar stroke to two targets of SBP control (130–149 mmHg or <130 mmHg). Logistic regression models were used to identify patient and SPS3 site characteristics predictive of lowering SBP to target at the 12-month study visit.
Of those above target at baseline (n = 1041), 69% were within their assigned target at 12 months. In the model with baseline characteristics only, those receiving treatment for hypertension at baseline were 68% less likely to achieve target [odds ratio (OR) = 0.32; 95% confidence interval (CI) = 0.17–0.60], whereas those of Hispanic ethnicity were 1.49 times more likely (95% CI = 1.09–2.03) to achieve SBP target. When clinical site characteristics were added to the model, only treated hypertension at baseline remained significant. In addition, management at a larger site (OR = 1.51; 95% CI = 1.03–2.20), SBP in target at 6 months (OR = 2.39; 95% CI = 1.79–3.19), and medication adherence (OR = 2.73; 95% CI = 1.51–4.95) were positively associated with achieving target SBP. Missed appointments (OR = 0.55; 95% CI = 0.41–0.73) were negatively associated with lowering SBP to target at 12 months.
These results demonstrate that it is feasible to achieve targets of SBP control in this multiethnic stroke cohort across multiple sites and countries. The results highlight the important variables reflecting clinical site management.
PMCID: PMC3970550  PMID: 22499292
blood pressure control; hypertension; lacunar stroke; predictors; Secondary Prevention of Small Subcortical Strokes Study; stroke
14.  CD4+CD25+Foxp3 regulatory T cells and vascular dysfunction in hypertension 
Journal of hypertension  2013;31(10):1939-1943.
Endothelial dysfunction plays a key role in the development and progression of cardiovascular disease. In patients with hypertension, endothelial dysfunction is characterized by a decrease of vasodilator factors release. Recent evidence highlights the involvement of regulatory T cell in the cardiovascular physiology and pathology. An increasing body of data suggest that an imbalance in the immune system triggers inflammation and compromises the cardiovascular homeostasis. In this mini-review, we will highlight the role of immune regulatory T cells in hypertension-induced vascular dysfunction.
PMCID: PMC3915504  PMID: 23881298
hypertension; regulatory T cell; vascular dysfunction
15.  Gender Differences in Cardiovascular Outcomes in Patients with Incident Hypertension 
Journal of hypertension  2013;31(2):271-277.
The time of initial hypertension diagnosis represents an opportunity to assess subsequent risk of adverse cardiovascular outcomes. The extent to which women and men with newly identified hypertension are at similar risk for adverse cardiovascular events, including chronic kidney disease, is not well known.
Among women and men with incident hypertension from 2001–2006 enrolled in the Cardiovascular Research Network (CVRN) Hypertension Registry, we compared incident events including all-cause death; hospitalization for myocardial infarction (MI), heart failure (HF), or stroke; and the development of chronic kidney disease (CKD). Multivariable models adjusted for patient demographic and clinical characteristics.
Among 177,521 patients with incident hypertension, 55% were women. Compared to men, women were older, more likely white and had more kidney disease at baseline. Over median 3.2 years (IQR 1.6–4.8) of follow-up, after adjustment, women were equally likely to be hospitalized for HF (HR 0.90, 95% CI 0.76–1.07) and were significantly less likely to die of any cause (HR 0.85, 95% CI 0.80–0.90) or be hospitalized for MI (HR 0.44, 95% CI 0.39–0.50) or stroke (HR 0.68, 95% CI 0.60–0.77) compared to men. Women were significantly more likely to develop chronic kidney disease (9.60% vs. 7.15%; adjusted HR 1.17, 95% CI 1.12–1.22) than men.
In this cohort with incident hypertension, women were more likely to develop chronic kidney disease and less likely to develop other cardiovascular outcomes compared to men. Future studies should investigate the potential reasons for these gender differences.
PMCID: PMC3686286  PMID: 23303353
16.  Antihypertensive and renoprotective actions of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME 
Journal of hypertension  2013;31(2):321-332.
The present study was performed to investigate in a model of malignant hypertension if the antihypertensive actions of soluble epoxide hydrolase (sEH) inhibition are nitric oxide (NO)-dependent.
ANG II-dependent malignant hypertension was induced through dietary administration for 3 days of the natural xenobiotic indole-3-carbinol (I3C) in Cyp1a1-Ren-2 transgenic rats. Blood pressure (BP) was monitored by radiotelemetry and treatment with the sEH inhibitor [cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyl-oxy]-benzoic acid (c-AUCB)] was started 48h before administration of the diet containing I3C. In separate groups of rats, combined administration of the sEH inhibitor and the nonspecific NO synthase inhibitor [Nω-nitro-l-arginine methyl ester (L-NAME)] on the course of BP in I3C-induced and noninduced rats were evaluated. In addition, combined blockade of renin–angiotensin system (RAS) was superimposed on L-NAME administration in separate groups of rats. After 3 days of experimental protocols, the rats were prepared for renal functional studies and renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolites dihydroxyeicosatrienoic acids (DHETEs) were measured.
Treatment with c-AUCB increased the renal EETs/DHETEs ratio, attenuated the increases in BP, and prevented the decreases in renal function and the development of renal damage in I3C-induced Cyp1a1-Ren-2 rats. The BP lowering and renoprotective actions of the treatment with the sEH inhibitor c-AUCB were completely abolished by concomitant administration of L-NAME and not fully rescued by double RAS blockade without altering the increased EETs/DHETEs ratio.
Our current findings indicate that the antihypertensive actions of sEH inhibition in this ANG II-dependent malignant form of hypertension are dependent on the interactions of endogenous bioavailability of EETs and NO.
PMCID: PMC3773167  PMID: 23307303
cytochrome P-450 metabolites; epoxyeicosatrienoic acids; malignant hypertension; nitric oxide; nitric oxide synthase; renin–angiotensin system; soluble epoxide hydrolase
17.  Insulin Increases the Functional Activity of the Renal NaCl cotransporter 
Journal of hypertension  2013;31(2):303-311.
Insulin is recognized to increase renal salt reabsorption in the distal nephron and hyperinsulinemic states have been shown to be associated with increased expression of the renal NaCl cotransporter, NCC. However, the effect of insulin on NCC functional activity has not been reported.
Using a heterologous expression system of Xenopus laevis oocytes, a mouse distal convoluted cell line, mDCT15 cells, endogenously expressing NCC, and an ex vivo kidney perfusion technique, we assessed the effect of insulin on the activity and phosphorylation of NCC. The signaling pathway involved was analyzed.
In Xenopus oocytes insulin increases the activity of NCC together with its phosphorylation at threonine residue 58. Activation of NCC by insulin was also observed in mDCT15 cells. Additionally, insulin increased the NCC phosphorylation in kidney under the ex vivo perfusion technique. In oocytes and mDCT15 cells, insulin effect on NCC was prevented with inhibitors of PI3K, mTORC2, and AKT1 kinases, but not by inhibitors of MAP or mTORC1 kinases, suggesting that PI3K-mTORC2-AKT1 is the intracellular pathway required. Additionally, activation of NCC by insulin was not affected by wild type or mutant versions of WNK1, WNK4, or SGK1, but it was no longer observed in the presence of wild type or the dominant negative, catalytically inactive WNK3, implicating this kinase in the process.
Insulin induces activation and phosphorylation of NCC. This effect could play an important role in arterial hypertension associated with hyperinsulinemic states, such as obesity, metabolic syndrome, or type 2 diabetes mellitus.
PMCID: PMC3781588  PMID: 23303355
Thiazide; distal convoluted tubule; obesity; salt transport; hypertension; WNK3
18.  The Nigerian Anti-Hypertensive Adherence Trial (NA-HAT): A Community-Based Randomized Trial 
Journal of hypertension  2013;31(1):201-207.
Research in industrialized countries has demonstrated that a key factor limiting the control of hypertension is poor patient adherence and that the most successful interventions for long-term adherence employ multiple strategies. Very little data exist on this question in low-income countries, where medication-taking behavior may be less well developed. We conducted a treatment adherence trial of 544 subjects (mean age ~63 years, mean BP ~168/92 mmHg) with previously untreated hypertension in urban and rural Nigeria. Eligible participants were randomized to one of two arms: clinic management only, or clinic management + home visits. Both interventions included three elements: a community based, nurse-led treatment program with physician backup; facilitation of clinic visits and health education; and the use of diuretics plus a beta blocker as needed. After initial diagnosis, the management protocol was implemented by a nurse with physician backup. Participants were evaluated monthly for 6 months. Medication adherence was assessed with pill count and urine testing. Dropout rates, by treatment group, ranged from 12% to 28%. Among participants who completed the 6 month trial, overall adherence was high (~77% of participants took > 98% of prescribed pills). Adherence did not differ by treatment arm, but was better at the rural than the urban site and among those with higher baseline BP. Hypertension control (BP < 140/90 mmHg) was achieved in ~66% of participants at 6 months. This community-based intervention confirms relatively modest default rates compared to industrialized societies, and suggests that medication adherence can be high in developing world settings in clinic attenders.
PMCID: PMC3530610  PMID: 23137954
anti-hypertensive; adherence; compliance trial
19.  Heredity and cardiometabolic risk: naturally occurring polymorphisms in the human neuropeptide Y2 receptor promoter disrupt multiple transcriptional response motifs 
Journal of hypertension  2013;31(1):123-133.
The neuropeptide Y2 G-protein-coupled receptor (NPY2R) relays signals from PYY or neuropeptide Y toward satiety and control of body mass. Targeted ablation of the NPY2R locus in mice yields obesity, and studies of NPY2R promoter genetic variation in more than 10 000 human participants indicate its involvement in control of obesity and BMI. Here we searched for genetic variation across the human NPY2R locus and probed its functional effects, especially in the proximal promoter.
Methods and results
Twin pair studies indicated substantial heritability for multiple cardiometabolic traits, including BMI, SBP, DBP, and PYY, an endogenous agonist at NPY2R. Systematic polymorphism discovery by resequencing across NPY2R uncovered 21 genetic variants, 10 of which were common [minor allele frequency (MAF) >5%], creating one to two linkage disequilibrium blocks in multiple biogeographic ancestries. In vivo, NPY2R haplotypes were associated with both BMI (P =3.75E–04) and PYY (P =4.01E–06). Computational approaches revealed that proximal promoter variants G-1606A, C-599T, and A-224G disrupt predicted IRF1 (A>G), FOXI1 (T>C), and SNAI1 (A>G) response elements. In neuroendocrine cells transfected with NPY2R promoter/luciferase reporter plasmids, all three variants and their resulting haplotypes influenced transcription (G-1606A, P <2.97E–06; C-599T, P <1.17E–06; A-224G, P <2.04E–06), and transcription was differentially augmented or impaired by coexpression of either the cognate full-length transcription factors or their specific siRNAs at each site. Endogenous expression of transcripts for NPY2R, IRF1, and SNAI1 was documented in neuroendocrine cells, and the NPY2R mRNA was differentially expressed in two neuroendocrine tissues (adrenal gland, brainstem) of a rodent model of hypertension and the metabolic syndrome, the spontaneously hypertensive rat.
We conclude that common genetic variation in the proximal NPY2R promoter influences transcription factor binding so as to alter gene expression in neuroendocrine cells, and consequently cardiometabolic traits in humans. These results unveil a novel control point, whereby cis-acting genetic variation contributes to control of complex cardiometabolic traits, and point to new transcriptional strategies for intervention into neuropeptide actions and their cardiometabolic consequences.
PMCID: PMC3615981  PMID: 23149563
autonomic; genetics; hypertension; nervous system; obesity
20.  Prevalence, awareness and risk factors of hypertension in a large cohort of Iranian adult population 
Journal of hypertension  2013;31(7):1364-1371.
There is considerable variation in hypertension prevalence and awareness, and their correlates, across different geographic locations and ethnic groups. We performed this cross-sectional analysis on data from the Golestan Cohort Study (GCS).
Enrollment in this study occurred in 2004–2008, and included 50,045 healthy subjects from Golestan Province in northeastern Iran. Hypertension was defined as a systolic blood pressure (SBP) ≥140, a diastolic blood pressure (DBP) ≥90, a prior diagnosis of hypertension, or the use of antihypertensive drugs. Potential correlates of hypertension and its awareness were analyzed by logistic regression adjusted for sex, age, BMI, place of residence, literacy, ethnicity, physical activity, smoking, black and green tea consumption and wealth score.
Of the total cohort participants, 21,350 (42.7%) were hypertensive. Age-standardized prevalence of hypertension, using the 2001 WHO standard world population, was 41.8% (95%CI: 38.3%–45.2%). Hypertension was directly associated with female sex, increased BMI, Turkmen ethnicity, and lack of physical activity, and inversely associated with drinking black tea and wealth score. Among hypertensive subjects, 46.2% were aware of their disease, 17.6% were receiving antihypertensive medication, and 32.1% of the treated subjects had controlled hypertension. Hypertension awareness was greater among women, the elderly, overweight and obese subjects, and those with a higher wealth score.
Hypertension is highly prevalent in rural Iran, many of the affected individuals are unaware of their disease, and the rate of control by antihypertensive medications is low. Increasing hypertension awareness and access to health services, especially among less privileged residents are recommended.
PMCID: PMC3766446  PMID: 23673348
hypertension; awareness; obesity; smoking; socioeconomic status
21.  Association of ATP1B1, RGS5 and SELE polymorphisms with hypertension and blood pressure in African–Americans 
Journal of hypertension  2011;29(10):10.1097/HJH.0b013e32834b000d.
Although an increasing number of hypertension-associated genetic variants is being reported, replication of these findings in independent studies has been challenging. Several genes in a human chromosome 1q linkage region have been reported to be associated with hypertension. We examined polymorphisms in three of these genes (ATP1B1, RGS5 and SELE) in relation to hypertension and blood pressure in a cohort of African–Americans.
We genotyped 87 single nucleotide polymorphisms (SNPs) from the ATP1B1, RGS5 and SELE genes in a well characterized cohort of 968 African–Americans and performed a case–control study to identify susceptibility alleles for hypertension and blood pressure regulation. Single SNP and haplotype association testing was done under an additive genetic model with adjustment for age, sex, BMI and ancestry-by-genotype (principal components).
A total of 12 SNPs showed nominal association with hypertension and/or blood pressure. The strongest signal for hypertension was for rs2815272 in the RGS5 gene (P = 9.3 × 10–3). For SBP, rs3917420 in the SELE gene (P = 9.0 × 10–4) and rs4657251 in the RGS5 gene (P = 9.7 × 10–3) were the top hits. Effect size for each of these variants was approximately 2–3 mmHg. A five-SNP haplotype in the SELE gene also showed significant association with SBP after correction for multiple testing (P < 0.01).
These findings provide additional support for the genetic role of ATP1B1, RGS5 and SELE in hypertension and blood pressure regulation.
PMCID: PMC3862027  PMID: 21881522
African–Americans; candidate gene; haplotype; hypertension; single nucleotide polymorphism
22.  Genetic and environmental influences on blood pressure variability: a study in twins 
Journal of hypertension  2013;31(4):10.1097/HJH.0b013e32835e2a4a.
Blood pressure variability (BPV) and its reduction in response to antihypertensive treatment are predictors of clinical outcomes; however, little is known about its heritability. In this study, we examined the relative influence of genetic and environmental sources of variance of BPV and the extent to which it may depend on race or sex in young twins.
Twins were enrolled from two studies. One study included 703 white twins (308 pairs and 87 singletons) aged 18–34 years, whereas another study included 242 white twins (108 pairs and 26 singletons) and 188 black twins (79 pairs and 30 singletons) aged 12–30 years. BPV was calculated from 24-h ambulatory blood pressure recording.
Twin modeling showed similar results in the separate analysis in both twin studies and in the meta-analysis. Familial aggregation was identified for SBP variability (SBPV) and DBP variability (DBPV) with genetic factors and common environmental factors together accounting for 18–40% and 23–31% of the total variance of SBPV and DBPV, respectively. Unique environmental factors were the largest contributor explaining up to 82–77% of the total variance of SBPV and DBPV. No sex or race difference in BPV variance components was observed. The results remained the same after adjustment for 24-h blood pressure levels.
The variance in BPV is predominantly determined by unique environment in youth and young adults, although familial aggregation due to additive genetic and/or common environment influences was also identified explaining about 25% of the variance in BPV.
PMCID: PMC3848497  PMID: 23470779
blacks; blood pressure variability; heritability; meta-analysis; twin study
23.  CLCNKB-T481S and Essential Hypertension in a Ghanaian Population 
Journal of hypertension  2009;27(2):298-304.
Prior to the discovery of CLCNKB-T481S there were no variants or clinical disorders associated with gain-of-function defects in thick ascending limb (TAL) of the kidney channels or transporters. CLCNKB-T481S is a novel gain-of-function variant that has been associated with essential hypertension. This finding has not been replicated until our current study. In this study we re-examine CLCNKB-T481S using a large homogenous population from Ghana, and coupled genetic analyses with the functional characterization of this polymorphism using a mammalian expression system.
We genotyped CLCNKB-T481S in four ethnically-defined control populations and a homogenous cohort of normotensive and hypertensive Ghanaians. Functional analysis was performed by whole-cell patch-clamp recording of tsA201 cells (a cell line derived from the human renal cell line, HEK-293) transiently transfected with ClC-Kb and barttin.
CLCNKB-T481S was found more commonly in the African and Caucasian-Americans when compared to the Asian and Hispanic American populations having minor allele frequencies of 0.20, 0.15 and 0.06 and 0.01 respectively. Additionally, CLCNKB-T481S was significantly associated with hypertension in Ghanaian males. In stratified logistic regression analysis with Ghanaian males we observed a significant odds ratio of 3.29 (1.17 - 9.20 95% CI, p=0.024) in the recessive model (TT v AT&TT). Unlike previous results obtained in Xenopus oocytes, co-expression of CLCNKB-T481S with the obligatory accessory subunit barttin in tsA201 cells did not generate larger currents than co-expression of the wild type allele.
We conclude that CLCNKB-T481S is associated with essential hypertension in males within the Ghanaian population; however further studies are needed to understand its gender and ethnic segregation as well as to identify cellular factors that account for the divergent functional expression of ClC-Kb-T481S plus barttin in Xenopus oocytes and mammalian cells.
PMCID: PMC3845205  PMID: 19226700
24.  Interactive Relations of Blood Pressure and Age to Subclinical Cerebrovascular Disease 
Journal of hypertension  2012;30(12):2352-2356.
Examine interactive relations of blood pressure (BP) and age to magnetic resonance imaging (MRI) indices of subclinical cerebrovascular disease in middle-aged to older adults.
One hundred thirteen stroke- and dementia-free, community-dwelling adults (ages 54–81; 65% male; 91% White) engaged in a) clinical assessment of resting systolic and diastolic BP; b) magnetic resonance imaging (MRI) rated for periventricular and deep white matter hyperintensities (PWMH & DWMH), silent brain infarction (SBI), and brain atrophy [i.e., ventricular enlargement (VE) and sulcal widening (SW)]. Principal components analysis of the MRI ratings yielded a two component solution – (1) PWMH, DWMH, SBI; and (2) VE, SW.
Relations of systolic BP, diastolic BP, and pulse pressure (PP) (and their interactions with age) to each MRI component were examine in multiple regression analyses adjusted for age, sex, fasting plasma glucose and cholesterol, and antihypertensives. For component one, results indicated significant interactions of systolic BP and PP with age (p’s < .05); higher levels of systolic BP and PP were associated with greater white matter disease and brain infarction at younger ages (
Higher BP and PP are associated with greater subclinical cerebrovascular disease most prominently in the “young old.” Appropriate management of hypertension and arterial stiffening may be critical to the preservation of brain structure with aging.
PMCID: PMC3742068  PMID: 23107913
blood pressure; hypertension; pulse pressure; subclinical cerebrovascular disease; silent cerebrovascular disease; white matter disease; brain atrophy; magnetic resonance imaging
Journal of hypertension  2013;31(2):10.1097/HJH.0b013e32835b6be7.
Unhealthy lifestyle factors may contribute to apparent treatment resistant hypertension (aTRH). We examined associations of unhealthy lifestyle factors with aTRH in individuals taking antihypertensive medications from three or more classes.
Participants (n=2,602) taking three or more antihypertensive medication classes were identified from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study. aTRH was defined as having systolic/diastolic blood pressure ≥140/90 mmHg despite the use of three or more antihypertensive medication classes or the use of four or more classes to achieve blood pressure control. Lifestyle factors included obesity, physical inactivity, current smoking, heavy alcohol consumption, a low DASH diet score and high sodium-to-potassium (Na/K) intake.
Among participants taking three or more antihypertensive medication classes, 1,293 (49.7%) participants had aTRH. The prevalence of unhealthy lifestyle factors in participants with and without aTRH was 55.2% and 51.7% respectively for obesity, 42.2% and 40.5% for physical inactivity, 11.3% and 11.5% for current smoking, 3.1% and 4.0% for heavy alcohol consumption, 23.1% and 21.5% for low DASH diet score, and 25.4% and 24.4% for high Na/K intake. After adjustment for age, sex, race, and geographic region of residence, none of the unhealthy lifestyle factors was associated with aTRH. The associations between each unhealthy lifestyle factor and aTRH remained non-significant after additional adjustment for education, income, depressive symptoms, total calorie intake, and co-morbidities.
Unhealthy lifestyle factors did not have independent associations with aTRH among individuals taking three or more antihypertensive medication classes.
PMCID: PMC3838894  PMID: 23303356
Hypertension; blood pressure; antihypertensive agents; epidemiology

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