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1.  Interactive roles of NPR1 gene-dosage and salt diets on cardiac angiotensin II, aldosterone and pro-inflammatory cytokines levels inmutantmice 
Journal of hypertension  2013;31(1):134-144.
Objective
The objective of the present study was to elucidate the interactive roles of guanylyl cyclase/natriuretic peptide receptor-A (NPRA) gene (Npr1) and salt diets on cardiac angiotensin II (ANG II), aldosterone and proinflammatory cytokines levels in Npr1 gene-targeted (1-copy, 2-copy, 3-copy, 4-copy) mice.
Methods
Npr1 genotypes included 1-copy gene-disrupted heterozygous (+/−), 2-copy wild-type (+/+), 3-copy gene-duplicated heterozygous (++/+) and 4-copy gene-duplicated homozygous (++/++) mice. Animals were fed low, normal and high-salt diets. Plasma and cardiac levels of ANG II, aldosterone and pro-inflammatory cytokines were determined.
Results
With a high-salt diet, cardiac ANG II levels were increased (+) in 1-copy mice (13.7 ± 2.8 fmol/mg protein, 111%) compared with 2-copy mice (6.5 ± 0.6), but decreased (−) in 4-copy (4.0 ± 0.5, 38%) mice. Cardiac aldosterone levels were increased (+) in 1-copy mice (80 ± 4 fmol/mg protein, 79%) compared with 2-copy mice (38 ± 3). Plasma tumour necrosis factor alpha was increased (+) in 1-copy mice (30.27 ± 2.32 pg/ml, 38%), compared with 2-copy mice (19.36 ± 2.49, 24%), but decreased (−) in 3-copy (11.59 ± 1.51, 12%) and 4-copy (7.13 ± 0.52, 22%) mice. Plasma interleukin (IL)-6 and IL-1α levels were also significantly increased (+) in 1-copy compared with 2-copy mice but decreased (−) in 3-copy and 4-copy mice.
Conclusion
These results demonstrate that a high-salt diet aggravates cardiac ANG II, aldosterone and proinflammatory cytokine levels in Npr1 gene-disrupted 1-copy mice, whereas, in Npr1 gene-duplicated (3-copy and 4-copy) mice, high salt did not render such elevation, suggesting the potential roles of Npr1 against salt loading.
doi:10.1097/HJH.0b013e32835ac15f
PMCID: PMC4312769  PMID: 23188418
aldosterone; angiotensin II; arterial pressure; atrial natriuretic peptide; gene duplication; gene knockout; pro-inflammatory cytokines; salt diet
2.  Retinal vascular caliber and the development of hypertension: a meta-analysis of individual participant data 
Journal of hypertension  2014;32(2):207-215.
Objective
Microvascular dysfunction has been suggested to be a major pathogenic factor for the development of hypertension. We examined the association between retinal vascular caliber, a marker of systemic microvascular dysfunction, and incident hypertension on a meta-analysis of individual participant data.
Methods
We performed a systematic review with relevant studies identified through a search of electronic databases, a review of reference lists, and correspondence with experts. Studies were included if participants were selected from a general population, retinal vascular caliber was measured from photographs using computer-assisted methods at baseline, and individuals were followed up to ascertain the incidence of hypertension. Prespecified individual recorded data from six population-based prospective cohort studies were included. Discrete time proportional odds models were constructed for each study with adjustment for hypertension risk factors. Log odds ratios (ORs) per 20-μm difference were pooled using random-effects meta-analysis.
Results
Among 10 229 participants without prevalent hypertension, diabetes, or cardiovascular disease, 2599 developed new-onset hypertension during median follow-up periods ranging from 2.9 to 10 years. Both narrower retinal arterioles [pooled multivariate-adjusted OR per 20-μm difference 1.29, 95% confidence interval (CI) 1.20–1.39] and wider venules (OR per 20-μm difference 1.14, 95% CI 1.06–1.23) were associated with an increased risk of hypertension. Each 20 μm narrower arterioles at baseline were associated with a 1.12 mmHg (95% CI 0.25–1.99) greater increase in SBP over 5 years.
Conclusions
Retinal arteriolar narrowing and venular widening were independently associated with an increased risk of hypertension. These findings underscore the importance of microvascular remodeling in the pathogenesis of hypertension.
doi:10.1097/HJH.0b013e32836586f4
PMCID: PMC4120649  PMID: 24322199
hypertension; meta-analysis; microvascular dysfunction
3.  Mitochondrial targeted peptides attenuate residual myocardial damage after reversal of experimental renovascular hypertension 
Journal of hypertension  2014;32(1):154-165.
Background
Renovascular hypertension (RVHT) increases cardiovascular morbidity and mortality. Renal revascularization with percutaneous transluminal renal angioplasty and stenting (PTRS) may reverse RVHT but may not fully regress cardiac remodeling and damage, possibly due to persistent myocardial insults. Bendavia is a mitochondrial targeted peptide that reduces ischemic cardiomyopathy by improving mitochondrial function. However, its potential for attenuating residual myocardial damage after reversal of RVHT has not been explored. We hypothesized that treatment with Bendavia as an adjunct to PTRS would improve cardiac function and oxygenation, and decrease myocardial injury in swine RVHT.
Methods and results
After 6 weeks of RVHT (unilateral renal artery stenosis) or control, pigs underwent PTRS (or sham), with adjunct continuous infusion of Bendavia (0.05 mg/kg intravenously, 30 min before to 3.5 h after PTRS) or vehicle (n =7 each). Four weeks later, systolic and diastolic function were assessed by multidetector computed tomography, myocardial oxygenation by blood oxygen level-dependent MRI, and myocardial morphology, apoptosis, mitochondrial biogenesis, and fibrosis evaluated ex vivo. PTRS restored blood pressure in both groups, yet E/A ratio remained decreased. Myocardial oxygenation and mitochondrial biogenesis improved, and myocardial inflammation, oxidative stress, and fibrosis normalized in association with improvement in diastolic function in RVHT +PTRS +Bendavia animals.
Conclusion
Adjunct Bendavia during PTRS in swine RVHT improved diastolic function and oxygenation and reversed myocardial tissue damage. This approach may allow a novel strategy for preservation of cardiac function and structure in RVHT.
doi:10.1097/HJH.0b013e3283658a53
PMCID: PMC3976567  PMID: 24048008
mitochondria; myocardium; renal hypertension; revascularization
4.  Cardiovascular risk in Mozambique: who should be treated for hypertension? 
Journal of hypertension  2013;31(12):2348-2355.
Aim
To estimate the proportion of Mozambicans eligible for pharmacological treatment for hypertension, according to single risk factor and total cardiovascular risk approaches.
Methods
A representative sample of Mozambicans aged 40–64 years (n = 1116) was evaluated according to the WHO STEPwise Approach to Chronic Disease Risk Factor Surveillance (STEPS). We measured blood pressure (BP) and 12-h fasting blood glucose levels and collected data on sociodemographic characteristics, smoking, and use of antidiabetic and antihypertensive drugs. We estimated the 10-year risk of a fatal or nonfatal major cardiovascular event (WHO/lnternational Society of Hypertension risk prediction charts), and computed the proportion of untreated participants eligible for pharmacological treatment for hypertension, according to BP values alone and accounting also for the total cardiovascular risk (WHO guidelines for assessment and management of cardiovascular diseases).
Results
Among the Mozambicans aged 40–64 years and not taking antihypertensive drugs, less than 4% were classified as having cardiovascular risk at least 20% whereas the prevalence of SBP/DBP at least 140/90 mmHg was nearly 40%. A total of 19.8% of 40–64-year-olds would be eligible for pharmacological treatment of hypertension according to the WHO guidelines, all of whom had SBP/DBP at least 160/100 mmHg.
Conclusion
Among the Mozambicans aged 40–64 years not taking antihypertensive drugs and having SBP/DBP at least 140/90 mmHg, only half were eligible for pharmacological treatment according to the WHO guidelines. Taking the latter into account, when defining strategies to control hypertension at a population level, may allow a more efficient use of the scarce resources available in developing settings.
doi:10.1097/HJH.0b013e3283656a0a
PMCID: PMC4164281  PMID: 24220589
diabetes mellitus; hypertension; Mozambique; risk assessment; smoking
5.  Renal responses to three types of renin-angiotensin system blockers in patients with diabetes mellitus: a need for higher doses in diabetics? 
Journal of hypertension  2011;29(12):2454-2461.
Objective
Activation of the renal renin-angiotensin system in patients with diabetes mellitus appears to contribute to the risk of nephropathy. Recently it has been recognized than an elevation of prorenin in plasma also provides a strong indication of risk of nephropathy. This study was designed to examine renin-angiotensin system control mechanisms in the patient with diabetes mellitus.
Methods
We enrolled 43 subjects with Type 2 diabetes mellitus and, after an acute exposure to captopril (25 mg), randomized them to treatment with either irbesartan (300 mg) or aliskiren (300 mg) for two weeks.
Results
All agents acutely lowered blood pressure and plasma aldosterone, and increased renal plasma flow and glomerular filtration rate. Yet only captopril and Aliskiren acutely increased plasma renin and decreased plasma angiotensin II, while Irbesartan acutely affected neither renin nor angiotensin II. Plasma renin and angiotensin II subsequently did increase upon chronic irbesartan treatment. When given on day 14, irbesartan and aliskiren again induced the above hemodynamic, renal and adrenal effects, yet without significantly changing plasma renin. Irbesartan at that time did not affect plasma angiotensin II, while aliskiren lowered it to almost zero.
Conclusions
The relative resistance of the renal renin response to acute (irbesartan) and chronic (irbesartan and aliskiren) renin-angiotensin system blockade supports the concept of an activated renal renin-angiotensin system in diabetes, particularly at the level of the juxtaglomerular cell, and implies that diabetics require higher doses of renin-angiotensin system blockers to fully suppress the renal renin-angiotensin system.
doi:10.1097/HJH.0b013e32834c627a
PMCID: PMC4220417  PMID: 22002336
chronic kidney disease; renin-angiotensin system; prorenin; juxtaglomerular cell
6.  Hypertension in pregnancy is associated with elevated C-reactive protein levels later in life 
Journal of hypertension  2013;31(11):2213-2219.
Objectives
We assessed if hypertension in pregnancy is associated with elevated CRP levels in later life, possibly reflecting an increased risk of CVD.
Background
Elevated C-reactive protein (CRP) levels have been associated with hypertension in pregnancy and with cardiovascular disease (CVD).
Methods
We studied 2463 women from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Subjects were categorized as nulliparous women (n=219), women with a history of normotensive pregnancies (n=1839), or women with a history of a hypertensive pregnancy (n=405). Using multiple linear regression models we compared mean CRP levels among the groups after adjusting for age, race, education, smoking, hypertension, personal history of CHD or stroke, diabetes, dyslipidemia, statins, hormone replacement therapy, and family history of CHD or stroke. As CRP levels may be influenced by body mass index (BMI), the model was fit both with and without adjusting for BMI.
Results
There was no significant difference in CRP levels between nulliparous women and those with a history of normotensive pregnancies, either with (p=0.82) or without (p=0.46) adjusting for BMI. In contrast, women with hypertensive pregnancies, compared to those with normotensive pregnancies, had higher CRP levels, both with (p=0.009) and without (p<0.001) adjusting for BMI.
Conclusions
A history of hypertension in pregnancy is associated with elevated CRP levels later in life, independent of traditional CVD risk factors and BMI. An elevated CRP may reflect an inflammatory state in women with a history of hypertensive pregnancy disorders who are at increased risk for CVD.
doi:10.1097/HJH.0b013e3283642f6c
PMCID: PMC3925682  PMID: 24029867
hypertension; pregnancy; CRP; cardiovascular disease
7.  Effects of sex and hypertension subtype on haemodynamics and left ventricular diastolic function in older patients with stage 1 hypertension 
Journal of hypertension  2013;31(11):10.1097/HJH.0b013e3283649730.
Background
Hypertension is associated with cardiovascular stiffening and left ventricular diastolic dysfunction, leading to comorbidities such as heart failure with preserved ejection fraction (HFpEF). It is unknown whether sex and hypertension subtype affect haemodynamics and left ventricular function in older individuals.
Methods
Ninety-five older patients with Stage 1 hypertension (ambulatory awake SBP135–159 mmHg) and 56 normotensive controls were enrolled. Patients were stratified prospectively into isolated systolic hypertension (ISH, DBP <85 mmHg) or systolic-diastolic hypertension (SDH, DBP ≥85 mmHg). Haemodynamics and Doppler variables including early filling (E) and averaged mitral annular (E′mean) velocities were measured during supine rest.
Results
Ambulatory awake blood pressures (BPs) were the highest in SDH, whereas supine SBP was similar in both hypertensive groups. No sex difference was observed in supine or ambulatory awake BPs in all groups. Stroke volume was similar among groups within the same sex, but smaller in women. Women exhibited faster E, slower E′mean and greater E/E′mean, whereas no group difference was observed in E within the same sex. In women, E′mean was significantly slower in SDH (5.9 ± 1.6 vs. 7.4 ± 1.1 cm/s, P < 0.01) and ISH (6.6 ± 1.6 cm/s, P = 0.07) than controls, resulting in the highest E/E′mean in SDH. In men, E′mean and E/E′mean were similar among the three groups.
Conclusion
These results suggest that elderly hypertensive women may have left ventricular early diastolic dysfunction and higher estimated filling pressure, consistent with their susceptibility to HFpEF. Women with SDH seemed to have more left ventricular diastolic dysfunction, which might be explained by the greater cumulative afterload when ambulatory.
doi:10.1097/HJH.0b013e3283649730
PMCID: PMC3864621  PMID: 24077248
haemodynamics; left ventricular diastolic function; sex difference; stage 1 hypertension
8.  Role of arterial telomere dysfunction in hypertension: relative contributions of telomere shortening and telomere uncapping 
Journal of hypertension  2014;32(6):1293-1299.
Objective
Telomere shortening in arteries could lead to telomere uncapping and cellular senescence, which in turn could promote the development of hypertension.
Methods and results
To assess the novel role of arterial telomere dysfunction in hypertension, we compared mean telomere length (qPCR), telomere uncapping (serine 139 phosphorylated histone γ-H2A.X (γ-H2) localized to telomeres: ChIP), and tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence (P53 bound to P21 gene promoter: ChIP) in arteries from 55 age-matched hypertensive and nonhypertensive individuals. Arterial mean telomere length was not different in hypertensive patients compared with nonhypertensive individuals (P = 0.29). Arterial telomere uncapping and P53/P21- induced senescence were two-fold greater in hypertensive patients compared with nonhypertensive individuals (P = 0.04 and P = 0.02, respectively). Arterial mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence (r=– 0.02, P = 0.44 and r = 0.01, P = 0.50, respectively), but telomere uncapping was a highly influential covariate for the hypertension group difference in P53/P21-induced senescence (r = 0.62, P < 0.001, ηp2 = 0.35). Finally, telomere uncapping was a significant predictor of hypertension status (P = 0.03), whereas mean telomere length was not (P = 0.68).
Conclusion
Collectively, these findings demonstrate that arterial telomere uncapping and P53/P21-induced senescence are linked to hypertension independently of mean telomere length, and telomere uncapping influences hypertension status more than mean telomere length.
doi:10.1097/HJH.0000000000000157
PMCID: PMC4198301  PMID: 24686009
arteries; cellular senescence; hypertension; telomere
9.  Are personality traits associated with white coat and masked hypertension? 
Journal of hypertension  2014;32(10):1987-1992.
Objectives
Anxiety and other psychological dispositions are thought to be associated with blood pressure. This study tests whether personality traits have long-term associations with masked and white coat effects.
Methods
A community-based sample of 2,838 adults from Sardinia (Italy) completed the Revised NEO Personality Inventory and seven years later blood pressure was assessed in the clinic and with ambulatory monitoring. Logistic regressions were used to test whether anxiety, neuroticism, extraversion, openness, agreeableness, and conscientiousness predicted the white coat and masked hypertension phenomena. Age, sex, and antihypertensive medication use were tested as moderators.
Results
Significant interactions were found between personality traits and antihypertensive medications in predicting masked and white coat effects. Only among those taking antihypertensive medication, higher anxiety was associated with a higher risk of pseudo-resistant hypertension due to white coat effect (OR = 1.39, 95%CI = 1.01–1.91) and higher conscientiousness was associated with a lower risk of masked uncontrolled hypertension (OR = 0.70, 95%CI = 0.49–0.99). There were no significant interactions with age or sex.
Conclusions
Among those on antihypertensive medications, anxious individuals were more likely to have pseudo-resistant hypertension due to white coat effect and less conscientious individuals were at increased risk of masked uncontrolled hypertension. Particularly among anxious and less conscientious individuals, ambulatory monitoring may improve the tailoring of pharmacological treatments.
doi:10.1097/HJH.0000000000000289
PMCID: PMC4196211  PMID: 25186529
Personality; Anxiety; Conscientiousness; Antagonism; Ambulatory Blood Pressure Monitoring; White coat hypertension; Pseudo-resistant hypertension due to white coat effect; Masked hypertension; Masked uncontrolled hypertension; Antihypertensive medications
10.  HYPERTENSIVE RENAL DISEASE: SUSCEPTIBILITY AND RESISTANCE IN INBRED HYPERTENSIVE RAT LINES 
Journal of hypertension  2013;31(10):2050-2059.
SHR lines differ in their susceptibility to hypertensive end-organ disease and may provide an informative model of genetic risk of disease. Lines derived from the original SHR-B and SHR-C clades are highly resistant to hypertensive end-organ disease, while lines derived from the SHR-A clade were selected for stroke susceptibility and experience hypertensive renal disease. Here we characterize the temporal development of progressive renal injury in SHR-A3 animals consuming 0.3% sodium in the diet and drinking water. SHR-A3 rats demonstrate albuminuria, glomerular damage, tubulo-interstitial injury and renal fibrosis that emerge at 18 weeks of age and progress. Mortality of SHR-A3 animals was 50% at 40 weeks of age, and animals surviving to this age had reduced renal function. In contrast SHR-B2, which are 87% genetically identical to SHR-A3, are substantially protected from renal injury and demonstrate only moderate changes in albuminuria and renal histological injury over this time period. At 40 weeks of age, electron microscopy of the renal glomerulus revealed severe podocyte effacement in SHR-A3, but slit diaphragm architecture in SHR-B2 at this age was well preserved. Renal injury traits in the F1 and F2 progeny of an intercross between SHR-A3 and SHR-B2 were measured to determine heritability of renal injury in this model. Heritability of albuminuria, glomerular injury and tubulo-interstitial injury were estimated at 48.9, 66.5 and 58.6% respectively. We assessed the relationship between blood pressure and renal injury measures in the F2 animals and found some correlation between these variables that explain up to 26% of the trait variation. Quantitative trait locus (QTL) mapping was performed using over 200 SNP markers distributed across the 13% of the genome that differs between these two closely related lines. Mapping of albuminuria, tubulo-interstitial injury and renal fibrosis failed to identify loci linked with disease susceptibility, suggesting a complex inheritance of disease risk. We detected a single QTL conferring susceptibility to glomerular injury that was confined to a small haplotype block at chromosome 14:70–76Mb.
doi:10.1097/HJH.0b013e328362f9a5
PMCID: PMC4130350  PMID: 24107734
11.  Pulsatile Hemodynamics of Hypertension: Systematic Review of Aortic Input Impedance 
Journal of hypertension  2012;30(8):1493-1499.
Objective
Input impedance is the frequency-dependent afterload to pulsatile blood flow. Studies of input impedance have been performed as early as the 1960s and have been applied to hypertension (HTN). However, to date, these studies have not been systematically evaluated. This systematic review aims to summarize the literature, interpret existing data from the perspective of impedance theory, and to discuss their potential for generating physiological insights into HTN.
Methods
We identified 11 studies where computed impedance moduli from both HTN and control (CNT) groups were reported. In addition, we performed bivariate analyses of raw data from 3 of these studies.
Results
Major findings include (1) HTN groups had consistently elevated impedance moduli at 0Hz (Z0) and at heart rate frequency (Z1), an increased frequency where impedance phase first crosses 0 (f0), but no consistent pattern in characteristic impedance (Zc), when compared to CNT groups; (2) systolic (SBP) and diastolic (DBP) blood pressure are highly correlated with Z0 and Z1, moderately correlated with f0, less correlated with Zc; and (3) the measurement and calculation methods for Zc are varied and inconsistent, and (4) a not insignificant proportion of hypertensive subjects have “normal” Z0, Z1 and Zc values. These findings are limited by the heterogeneous study populations and small sample sizes.
Conclusions
These findings suggest that Z0, Z1 and f0 are significantly associated with hypertension, while the role of Zc is less clear. Additional studies are needed to evaluate these input impedance variables in order to generate substantial implications in clinic settings.
doi:10.1097/HJH.0b013e328354e81d
PMCID: PMC4179285  PMID: 22635138
input impedance; characteristic impedance; hypertension; wave reflection
12.  High Dietary Sodium Intake Impairs Endothelium-Dependent Dilation in Healthy Salt-Resistant Humans 
Journal of hypertension  2013;31(3):530-536.
Excess dietary sodium has been linked to the development of hypertension and other cardiovascular diseases. In humans, the effects of sodium consumption on endothelial function have not been separated from the effects on blood pressure. The present study was designed to determine if dietary sodium intake affected endothelium-dependent dilation (EDD) independently of changes in blood pressure. Fourteen healthy salt resistant adults were studied (9M, 5F; age 33 ± 2.4 years) in a controlled feeding study. After a baseline run-in diet, participants were randomized to a 7 day high sodium (HS) (300-350 mmol/day) and 7 day low sodium (LS) (20 mmol/day) diet. Salt resistance, defined as a ≤ 5 mm Hg change in a 24-hour mean arterial pressure, was individually assessed while on the low sodium and high sodium diets and confirmed in the subjects undergoing study (LS: 85±1 mm Hg; HS: 85±2 mmHg). EDD was determined in each subject via brachial artery flow-mediated dilation on the last day of each diet. Sodium excretion increased during the high sodium diet (p < 0.01). EDD was reduced on the high sodium diet (Low: 10.3±0.9%, High: 7.3±0.7%, p < 0.05). The HS diet significantly suppressed plasma renin activity (PRA), plasma angiotensin II, and aldosterone (p < 0.05). These data demonstrate that excess salt intake in humans impairs endothelium-dependent dilation independently of changes in blood pressure.
doi:10.1097/HJH.0b013e32835c6ca8
PMCID: PMC4176919  PMID: 23263240
dietary sodium; endothelium-dependent dilation; blood pressure; salt-resistance
13.  Age and the Effectiveness of Anti-Hypertensive Therapy on Improvement in Diastolic Function 
Journal of hypertension  2014;32(1):174-180.
Objective
Diastolic dysfunction is associated with adverse outcomes and is highly prevalent among older adults with hypertension. Lowering systolic blood pressure (SBP) with anti-hypertensive therapy has been shown to improve diastolic function, but whether or not age influences this effect is unknown.
Methods
In the Exforge Intensive Control of Hypertension to Evaluate Efficacy in Diastolic Dysfunction trial, 189 patients (age range, 45 to 93 years) with hypertension and diastolic dysfunction underwent echocardiography before and after 24 weeks of intensive versus standard anti-hypertensive therapy titrated to a goal SBP <135 versus <140 mmHg. We performed linear regression analyses to examine the association between age and improvement in diastolic function achieved with SBP reduction.
Results
Anti-hypertensive therapy reduced SBP by 28±19 mmHg overall, and this was not significantly different across age strata. However, percent improvement in diastolic relaxation velocity (lateral E’ peak velocity) for every 10 mmHg reduction in SBP was lower in older compared to younger patients. In analyses adjusting for age stratum, sex, treatment arm, baseline relaxation velocity, and baseline blood pressure, older age was associated with reduced improvement in diastolic relaxation velocity per 10 mmHg of SBP reduction (β −1.64; P=0.009). In contrast, the degree of change in left ventricular mass index per 10 mmHg reduction in SBP was not influenced by age (P=0.89).
Conclusions
In our sample of individuals with hypertension and diastolic dysfunction, older compared to younger adults experienced less improvement in diastolic function in response to similar reductions in SBP.
doi:10.1097/HJH.0b013e32836586da
PMCID: PMC4172399  PMID: 24309488
aging; blood pressure; hypertension; diastolic dysfunction; antihypertensive agents
14.  Essential Hypertension: Perspectives and future directions 
Journal of hypertension  2012;30(1):42-45.
doi:10.1097/HJH.0b013e32834ee23c
PMCID: PMC4152852  PMID: 22157586
15.  Chronic Aldosterone Administration Causes NOX2-Mediated Increases In Reactive Oxygen Species Production and Endothelial Dysfunction in the Cerebral Circulation 
Journal of hypertension  2014;32(9):1815-1821.
Objective
An elevated plasma aldosterone level is an independent cardiovascular risk factor. Although excess aldosterone promotes cardiovascular disease, no studies have examined the effect of increased plasma aldosterone on the cerebral circulation. A major source of vascular reactive oxygen species (ROS) during cardiovascular disease is the NADPH oxidases. Because NOX2-containing NADPH oxidase (NOX2 oxidase) is highly expressed in cerebral endothelium, we postulated that it might contribute to ROS generation and vascular dysfunction in response to aldosterone. Here we examined the effect of aldosterone and NOX2 oxidase on ROS production and endothelial dysfunction in the cerebral circulation, and whether the effects of aldosterone are exacerbated in aged mice.
Methods and Results
In adult (average age ~24–25 wk) wild-type (WT) and Nox2-deficient (Nox2−/y) mice, neither vehicle nor aldosterone (0.28 mg/kg/day for 14 days) affected blood pressure (measured using tail-cuff). By contrast, aldosterone treatment reduced dilation of the basilar artery (measured using myography) to the endothelium-dependent agonist acetylcholine in WT mice (P<0.05), but had no such effect in NOX2−/y mice (P>0.05). Aldosterone increased basal and phorbol-dibutyrate stimulated superoxide production (measured using L-012-enhanced chemiluminesence) in cerebral arteries from WT but not Nox2−/y mice. In aged WT mice (average age ~70 wk), aldosterone treatment increased blood pressure, but had a similar effect on cerebral artery superoxide levels as in adult WT mice.
Conclusions
These data indicate that NOX2 oxidase mediates aldosterone-induced increases in ROS production and endothelial dysfunction in cerebral arteries from adult mice independently of blood pressure changes. Aldosterone-induced hypertension is augmented during aging.
doi:10.1097/HJH.0000000000000259
PMCID: PMC4151299  PMID: 24991871
cerebral artery; cerebrovascular disease; endothelium; NOX2; aging
16.  Sex differences in obesity-related changes in left ventricular morphology: the Strong Heart Study 
Journal of hypertension  2011;29(7):1431-1438.
Objectives
It is unclear whether there are sex differences in the relations of left ventricular mass to body composition and fat distribution in nonobese or obese hypertensive and nonhypertensive individuals and whether the obesity-related increase in left ventricular mass is similar in men and women.
Methods
We examined sex differences in the relations between left ventricular mass and both body composition and fat distribution, in the presence or absence of obesity in 1068 men and 1851 women (65%) of the Strong Heart Study cohort, without prevalent cardiovascular disease or severe chronic kidney disease. Fat-free mass (FFM) and adipose mass were estimated by bioelectric impedance analysis and fat distribution by waist-to-hip ratio (WHR).
Results
Adipose mass was significantly higher in women than in men for any weight category (P < 0.0001). After adjusting for age, hypertension, systolic blood pressure (BP) and diabetes, both left ventricular mass/height2.7 (LVMi) and left ventricular mass (LVM)/FFM were greater in obese women than obese men (P < 0.0001). Relative wall thickness was also greater in women than in men (P < 0.0001). LVM was independently related to Doppler-stroke volume, FFM and systolic BP in both sexes, with WHR and adipose mass contributing to variance of LVM in women but not in men (both P < 0.03).
Conclusion
Obesity influences left ventricular geometry substantially more in women than in men, possibly due to biological factors specifically associated with female adiposity.
doi:10.1097/HJH.0b013e328347a093
PMCID: PMC4139509  PMID: 21558955
adipose mass; blood pressure; body composition; hypertension; hypertrophy; risk factors; stroke volume
17.  Angiotensin receptor blockers: are they related to lung cancer? 
Journal of hypertension  2013;31(8):10.1097/HJH.0b013e3283621ea3.
Introduction
Angiotensin receptor blockers (ARBs) are commonly used antihypertensive medication with several other additional proven benefits. Recent controversy on association of lung cancer and other solid malignancy with the use of ARBs is concerning, although the follow-up studies have shown no such association.
Methods
We used data from the Department of Veterans Affairs electronic medical record system and registries to conduct a retrospective cohort study that compared first-time ARB users with nonusers in 1:15 ratio, after balancing for many baseline differences using inverse probability of treatment weights. We conducted time-to-event survival analyses on the weighted cohort.
Results
Of the 1 229 902 patients in the analytic cohort, 346 (0.44%) of the 78 075 treated individuals had a newly incident lung cancer and 6577 (0.57%) of 1 151 826 nontreated individuals were diagnosed with lung cancer. On double robust regression, the weighted hazard ratio was 0.74 (0.67–0.83, P<0.0001), suggesting a lung cancer reduction effect with ARB use. There was no difference in rates by ARB subtype.
Conclusion
In this large nationwide cohort of United States Veterans, we found no evidence to support any concern of increased risk of lung cancer among new users of ARBs compared with nonusers. Our findings were consistent with a protective effect of ARBs.
doi:10.1097/HJH.0b013e3283621ea3
PMCID: PMC3879726  PMID: 23822929
angiotensin receptor blockers; cancer registry; Department of Veterans Affairs; drug safety; inverse probability of treatment weight; lung cancer; propensity score; survival analysis
18.  Relationship of dietary monounsaturated fatty acids to blood pressure: the international study of macro/micronutrients and blood pressure 
Journal of hypertension  2013;31(6):1144-1150.
Objective
In short-term feeding trials, replacement of other macronutrients with monounsaturated fatty acid reduces blood pressure. However, observational studies have not clearly demonstrated a relationship between monounsaturated fatty acid intake and blood pressure. We report associations of monounsaturated fatty acid intake of individuals with blood pressure in a cross-sectional study.
Methods
The International Study of Macro/Micronutrients and Blood Pressure is a cross-sectional epidemiologic study of 4680 men and women ages 40–59 years from 17 population samples in China, Japan, UK and USA. Nutrient intake data were based on four in-depth multipass 24-h dietary recalls/person and two-timed 24-h urine collections/person. Blood pressure was measured eight times at four visits.
Results
Mean monounsaturated fatty acid intake ranged from 8.1%kcal (China) to 12.2%kcal (USA). With sequential models to control for possible confounders (dietary, other), linear regression analyses showed significant inverse relationship of total monounsaturated fatty acid intake with DBP for all participants; for 2238 ‘nonintervened’ individuals, the relationship was stronger. Estimated DBP differences with 2-SD higher monounsaturated fatty acids (5.35%kcal) were −0.82mmHg (P<0.05) for all participants and −1.70mmHg (P<0.01) for nonintervened individuals. Inverse associations of dietary total oleic acid (main monounsaturated) with blood pressure in nonintervened individuals were not significant, but those of oleic acid from vegetable sources were stronger and significant (P<0.05).
Conclusion
Dietary monounsaturated fatty acid intake, especially oleic acid from vegetable sources, may contribute to prevention and control of adverse blood pressure levels in general populations.
doi:10.1097/HJH.0b013e3283604016
PMCID: PMC4109685  PMID: 23572200
blood pressure; monounsaturated fatty acids; nutrition; oleic acid; population study
19.  Regulation of mouse-renin gene by apurinic/apyrimidinic-endonuclease1 (APE1/Ref-1) via recruitment of histone deacetylase1corepressor complex 
Journal of hypertension  2012;30(5):917-925.
Objectives
Apurinic/apyrimidinic-endonuclease 1 (APE1) heterozygous mice have chronically elevated blood pressure. Renin of the renin–angiotensin (ANG) system for blood pressure maintenance regulates production of ANG II, a vasoactive hormone. Renin expression and secretion from kidney juxtaglomerular cells are regulated by intracellular calcium. Our objective in this study is to investigate APE1’s regulatory role in renin expression.
Methods
Effect of APE1 on calcium-mediated modulation of renin expression was examined by real-time reverse transcriptase-PCR, Western analysis and renin promoter-dependent luciferase activity in APE1-knockdown, APE1-overexpressing or control mouse kidney As4.1 cells. Furthermore, coimmunoprecipitation and chromatin immunoprecipitation assays were utilized to examine the association of APE1 with histone deacetylase (HDAC)1 corepressor complex and their recruitment to renin enhancer. Finally, kidney renin mRNA level and plasma– renin activity were measured in wild-type and APE1-heterozygous mice.
Results
Here we show that APE1 is involved in calcium mediated repression of renin gene. Our results further indicate that APE1 is a component of HDAC1 corepressor complex bound to renin-enhancer region. Increase in intracellular calcium ion concentration enhances the association of APE1 with HDAC1 corepressor complex and their recruitment to the enhancer region. Furthermore, APE1’s N-terminal region is critical for formation and recruitment of the enhancer-bound corepressor complex. Increased renin expression in kidneys and higher plasma–renin activity in APE1 heterozygous mice further supports APE1’s corepressor role in vivo.
Conclusion
This study uncovers APE1’s function as a novel negative regulator of renin expression, and thereby in blood pressure maintenance.
doi:10.1097/HJH.0b013e3283525124
PMCID: PMC4108083  PMID: 22441348
apurinic/apyrimidinic-endonuclease 1 (APE1/Ref-1); calcium; hypertension; renin; transcriptional repression
20.  Obstructive sleep apnea and diurnal nondipping hemodynamic indices in patients at increased cardiovascular risk 
Journal of hypertension  2014;32(2):267-275.
Rationale
We hypothesized increasing obstructive sleep apnea (OSA) severity would be associated with nondipping blood pressure (BP) in increased cardiovascular disease (CVD) risk.
Methods
Baseline data from 298 cardiology patients recruited for a multicenter randomized controlled trial were examined. Dipping was defined as a sleep-related BP or heart rate (HR) reduction of at least 10%. Logistic regression models were fit, adjusting for age, sex, race, BMI, CVD risk factors, CVD, and study site.
Results
There was a statistically significant 4% increase in the odds of nondipping SBP per 1-unit increase in both Apnea Hypopnea Index (AHI) and Oxygen Desaturation Index (ODI). There was no significant relationship between AHI and nondipping mean arterial pressure (MAP); however, a 3% increase in the odds of nondipping MAP per 1-unit increase in ODI was observed (odds ratio, OR =1.03; 95% confidence interval, CI 1.00–1.05). At severe OSA levels, a 10 and 4% increase in odds of nondipping DBP per 1-unit increase in AHI and ODI were observed, respectively. A 6% [OR =1.06; 95% CI (1.01–1.10)] increase in nondipping HR odds was observed with each increase in ODI until the upper quartile of ODI.
Conclusion
In patients at cardiovascular risk and moderate-to-severe OSA, increasing AHI and/or ODI were associated with increased odds of nondipping SBP and nondipping MAP. More severe levels of AHI and ODI also were associated with nondipping DBP. These results support progressive BP burden associated with increased OSA severity even in patients managed by cardiology specialty care.
doi:10.1097/HJH.0000000000000011
PMCID: PMC4096765  PMID: 24351803
cardiovascular disease; hypertension; hypoxia; sleep apnea
21.  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.
Objectives
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1097/HJH.0b013e328364f5bc
PMCID: PMC4082237  PMID: 24029870
brain infarcts; diabetes; epidemiology; ethnicity; subclinical cerebrovascular disease; white matter hyperintensities
22.  Sexual Activity and Function among Middle-Aged and Older Men and Women with Hypertension 
Journal of hypertension  2013;31(6):10.1097/HJH.0b013e32835fdefa.
doi:10.1097/HJH.0b013e32835fdefa
PMCID: PMC3837567  PMID: 23640604
23.  Blood pressure and cognitive function: a prospective analysis among adolescents in the Seychelles 
Journal of hypertension  2013;31(6):10.1097/HJH.0b013e3283604176.
Objective
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.
Methods
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).
Results
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.
Conclusions
Our findings do not support a consistent association between BP and subsequent performance on tests assessing various cognitive domains in adolescents.
doi:10.1097/HJH.0b013e3283604176
PMCID: PMC3874141  PMID: 23572201
blood pressure; cognitive function; adolescents; Seychelles and prospective
24.  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.
Objectives
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.
Methods
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).
Results
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).
Conclusions
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.
doi:10.1097/HJH.0b013e328362d935
PMCID: PMC4017912  PMID: 24107735
left ventricular mass; cardiovascular magnetic resonance; echocardiography
25.  HYPERTENSION-RELATED DISEASES AS A COMMON CAUSE OF HOSPITAL MORTALITY IN TANZANIA: A 3-YEAR PROSPECTIVE STUDY 
Journal of hypertension  2013;31(9):1806-1811.
Objective
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.
Results
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.
Conclusion
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.
doi:10.1097/HJH.0b013e328362bad7
PMCID: PMC4005815  PMID: 23777761
hypertension; non-communicable diseases; sub-Saharan Africa; hospital; mortality; admissions; hospital days; stroke

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