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1.  Nighttime Blood Pressure Variability is a Strong Predictor for Cardiovascular Events in Patients with Type 2 Diabetes 
American journal of hypertension  2008;22(1):10.1038/ajh.2008.294.
BACKGROUND
To test the hypothesis that short-term BP variability and abnormal patterns of diurnal BP variation, evaluated by ambulatory blood pressure (ABP), predicts risk of incident cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM).
METHODS
ABP monitoring was performed in 300 patients with uncomplicated T2DM without known CVD and without BP medications, who were followed for 54 ± 20 months. The relationships of different measures of BP variability, the presence of abnormal patterns of diurnal BP variation (non-dipper, riser, or morning BP surge) and the standard deviations (SD) of awake and asleep ABP, were determined. Cox proportional hazards models were used to estimate hazard ratios (HR) and their 95% CI, before and after controlling for various covariates.
RESULTS
The mean age was 67.8±9.6 years, 48% were male, 253 (84%) had a diagnosis of hypertension, and the mean of the SDs of awake SBP/DBP were 18±6/11±4 mmHg, and those of sleep SBP/DBP were 13±5/9±3 mmHg. During follow-up, there were 29 cardiovascular events. In multivariable analyses, the SDs of sleep SBP (HR=1.08; 95%CI, 1.01–1.16, p<0.05) and sleep DBP (HR=1.13; 1.04–1.23, p<0.01) were independently associated with incident CVD. Neither the non-dipper and riser patterns, nor the morning BP surge were associated with incident CVD events independently of clinic and 24-h BP levels
CONCLUSIONS
Abnormal diurnal BP variation was not a predictor of CVD in patients with T2DM. Nighttime BP variability was an independent predictor of future incidence of CVD, suggesting that this measure could reflect pathophysiology of T2DM.
doi:10.1038/ajh.2008.294
PMCID: PMC3881172  PMID: 18833198
Blood pressure variability; type 2 diabetes; ambulatory blood pressure; cardiovascular disease
2.  Ambulatory Blood Pressure is a Better Marker than Clinic Blood Pressure in Predicting Cardiovascular Events in Patients With/Without Type 2 Diabetes 
American journal of hypertension  2008;21(4):10.1038/ajh.2008.4.
Background
The prognostic significance of ambulatory blood pressure (ABP) has not been established in patients with type 2 diabetes (T2DM).
Methods
To clarify the impact of ABP on cardiovascular prognosis in patients with or without T2DM, we performed ABP monitoring (ABPM) in 1268 subjects recruited from nine sites in Japan, who were seen for the evaluation of hypertension. The mean age was 70.4±9.9 years, and 301 had diabetes; they were followed for 50±23 months. Incident cardiovascular disease (CVD) were related to different measures of ABP, including three categories of awake systolic BP (SBP <135, 135-150, and >150 mmHg), sleep SBP (<120, 120-135, and >135 mmHg), and nocturnal BP dipping (dippers, non-dippers, and risers). Cox regression models controlling for classic risk factors, were performed.
Results
Higher awake and sleep SBP predicted higher incidence of CVD in both diabetes and non-diabetes groups. In multivariable analyses, elevated awake and sleep SBP predicted increased risk of CVD more closely than clinic BP in both groups. The relationships between ABP level and CVD were similar in both groups. In Kaplan-Meier analyses, the incidence of CVD in non-dippers was similar to dippers, but risers experienced the highest risk of CVD in both groups (ps<0.01). The riser pattern was associated with approximately a 150% increase in risk of CVD, in both groups.
Conclusions
These findings suggest that ABPM improves the prediction of cardiovascular risk, over and above clinic BP, as much in patients with type 2 diabetes as it does in patients without diabetes.
doi:10.1038/ajh.2008.4
PMCID: PMC3881175  PMID: 18292756
type 2 diabetes; ambulatory blood pressure monitoring; non-dipper; riser; cardiovascular disease
3.  Change of Genetic Determinants of Left Ventricular Structure in Adolescence: Longitudinal Evidence from the Georgia Cardiovascular Twin Study 
American journal of hypertension  2008;21(7):10.1038/ajh.2008.178.
Objective
Genetic contribution to left ventricular (LV) structure is generally recognized, but whether and how this influence varies by ethnicity or with age is unknown.
Design and methods
Participants were 517 European American (EA) and African American (AA) twin pairs (mean age: 14.6 ± 3.0) at visit 1 and 422 EA and AA at follow-up 4.1 years later. Echocardiograms were obtained on both visits. Data were analyzed using structural equation modeling software Mx.
Results
Body mass index (BMI) was a strong predictor for all LV measures at both visit 1 and 2, accounting for 3.5-24.2% of the total variance. Hemodynamics explained up to 4.5% additional LV measures variance. After adjusting for BMI, LV measures showed substantial heritability (range: 21%-71%). Best-fitting longitudinal models revealed considerable novel genetic effects on the interventricular septum, posterior wall and relative wall thickness (but not LV inner diameter), accounting for 32-41% of the phenotypic variance at visit 2, with no significant gender and ethnic effects. There was a gender difference for LV mass index in AA (P < 0.01), with a significant influence of novel genetic effects in males (47%), but not in females. No gender difference was seen in EA, with 34% of the phenotypic variance at visit 2 attributable to novel genetic effects.
Conclusions
The heritability of cardiac structure and geometry was equally substantial in both AA and EA. Significant novel genetic influences were detected for all measures but LV inner diameter and LV mass index in AA females. Further developmental genetic studies are warranted to elucidate the nature of the emerging gene effects during the transition from adolescence into adulthood.
doi:10.1038/ajh.2008.178
PMCID: PMC3857089  PMID: 18443564
heritability; left ventricular mass; ethnicity
4.  Visit-to-visit and Ambulatory Blood Pressure Variability as Predictors of Incident Cardiovascular Events in Patients with Hypertension 
American journal of hypertension  2012;25(9):10.1038/ajh.2012.75.
BACKGROUND
Visit-to-visit BP variability (BPV) has been shown to be a prognostic indicator in hypertensive patients. We designed this study to clarify the impacts of clinic and ambulatory BPV in predicting cardiovascular disease (CVD).
METHODS
We performed ambulatory BP monitoring in 457 hypertensive patients. Visit-to-visit BPV and ambulatory BPV were calculated as the standard deviations (SDs) of clinic BP, awake BP and sleep BP. The mean age of the subjects was 67.0±9.2 years, and they were followed for 67±26 months. Stroke, myocardial infarction, and sudden cardiac death were defined as Hard CVD events, and these plus angina, heart failure, and other CVDs were defined as All CVD events. Multivariable Cox hazard regression models predicting CVD events were used to estimate the adjusted hazard ratio (HR) and 95% confidence interval (CI) for different measures of BPV with adjustment for significant covariates.
RESULTS
In multivariable analyses, the BPV of clinic SBP was an independent predictor for All CVD events [Hazard ratio (HR), 2.20; 95% CI, 1.25-3.88; P<0.01], but not for Hard CVD events (P=0.20). On the other hand, the BPV of sleep SBP was an independent predictor for Hard CVD events (HR, 2.21; 95% CI, 1.08-4.53; P=0.03), but not for All CVD events (P=0.88). Diastolic BPV exhibited the same pattern.
CONCLUSIONS
These findings suggest that visit-to-visit BPV and ambulatory BPV are separately useful in predicting cardiovascular outcomes.
doi:10.1038/ajh.2012.75
PMCID: PMC3839090  PMID: 22739805
ambulatory blood pressure monitoring; clinic blood pressure variability; ambulatory blood pressure variability; cardiovascular disease
5.  Spousal Caregiving and Incident Hypertension 
American journal of hypertension  2011;25(4):10.1038/ajh.2011.232.
Background:
Caring for one’s spouse has been associated with poor health, including risk of cardiovascular disease onset and mortality. However, few studies have assessed the risk of incident hypertension associated with spousal caregiving. This paper investigates this association in a large, nationally representative sample of American older adults.
Methods:
Married, hypertension-free, Health and Retirement Study (HRS) respondents aged 50+ in 2000, (n=5,708) were followed up to 8 years (1,708 new self-reported hypertension diagnoses). Current caregiving exposure was defined as assisting a spouse with instrumental or basic activities of daily living (I/ADLs) 14+ hours/week; we define providing ≥14 hours/week of care at two consecutive biennial surveys as “long-term caregiving.” We used inverse probability weighted discrete-time hazard models with time-updated exposure and covariates to estimate effects of current and long-term caregiving on incident hypertension. We tested for effect modification by race, gender, and recipient memory illness. Sensitivity analyses restricted to respondents whose spouses had care needs.
Results:
After adjusting for demographic, socioeconomic and health factors, (including risk behaviors, comorbid conditions, and self-rated health), current caregiving significantly predicted hypertension incidence (RR=1.36, 95% CI: 1.01, 1.83). For long-term caregivers, there was significant evidence of risk of hypertension onset associated with caregiving (RR=2.29, 95% CI: 1.17, 4.49). The risk of hypertension onset associated with both current and long-term caregiving did not vary by race, gender, or recipient memory illness diagnosis. Sensitivity analyses supported the primary findings.
Conclusions:
Providing I/ADL care to a spouse significantly predicted hypertension onset in a nationally-representative sample of US adults.
doi:10.1038/ajh.2011.232
PMCID: PMC3836043  PMID: 22189941
spouse caregivers; caregiver; spouses; hypertension; longitudinal study; incidence
6.  Postmenopausal Hypertension 
American journal of hypertension  2011;24(7):10.1038/ajh.2011.71.
Cardiovascular disease is the leading cause of morbidity and mortality in postmenopausal women. Hypertension is a major risk factor for cardiovascular disease. The mechanisms responsible for postmenopausal hypertension have not been completely elucidated. However, various mechanisms have been implicated to play a role. For example, there is evidence that changes in estrogen/androgen ratios favoring increases in androgens, activation of the renin-angiotensin and endothelin systems, activation of the sympathetic nervous system, metabolic syndrome and obesity, inflammation, increased vasoconstrictor eicosanoids, and anxiety and depression may be important in the pathogenesis of postmenopausal hypertension. There is also evidence that hypertension is less well controlled in aging women than in aging men, but the reasons for this gender difference is not clear. Postmenopausal hypertension is likely multifactorial. Future studies will be necessary to determine the contribution of these systems listed above in mediating postmenopausal hypertension and to design treatment strategies that encompass these mechanisms to improve the quality of life of postmenopausal women as they age.
doi:10.1038/ajh.2011.71
PMCID: PMC3820162  PMID: 21509049
androgens; estrogens; angiotensinogen; endothelin; leptin; 20-HETE; sympathetic activity
7.  Paraoxonase 1 (PON1) C/T-108 Association With Longitudinal Mean Arterial Blood Pressure 
American journal of hypertension  2012;25(11):1188-1194.
Background
Blood pressure is a complex quantitative trait with a strong genetic component. In this study, we leveraged the Veterans Affairs electronic medical record system to explore the relationship between Paraoxonase 1 (PON1)-108 C/T (rs705379) and mean arterial blood pressure (MAP).
Methods
Outpatient blood pressure data over an approximate 8-year period was collected from the Veterans Affairs Hypertensive Cohort (N = 1,302). Association between genotype and longitudinal MAP was further explored using a random effects model controlling for age, ancestry, renal function, and other determinants of blood pressure. To control for population stratification, principal component groupings based on ancestry informative markers in this dataset were included as covariates (in addition to self-identified ancestry). Data from the African American Study of Kidney Disease and Hypertension (AASK, N = 857) was used to confirm significant findings in an independent cohort.
Results
There was a significant interaction between PON1-108 C/T genotype and follow-up age group. At a younger age (<50 years), there was an estimated 2.53 mm Hg (95% confidence interval: 1.06, 4.00) increase in MAP with each additional C-allele. At the older age groups, there were no significant associations between PON1-108 C/T genotype and MAP. Using data from the AASK trial, the C-allele at PON1-108 C/T was significantly associated with a higher MAP (P = 0.005) but only among younger participants (<54 years).
Conclusions
The PON1-108 polymorphism may be associated with MAP in an age-dependent manner.
doi:10.1038/ajh.2012.106
PMCID: PMC3515680  PMID: 22854640
age; blood pressure; essential hypertension; hypertension; polymorphism; PON1; veterans
8.  Paraoxonase 1 (PON1) C/T-108 Association With Longitudinal Mean Arterial Blood Pressure 
American Journal of Hypertension  2012;25(11):1188-1194.
Background
Blood pressure is a complex quantitative trait with a strong genetic component. In this study, we leveraged the Veterans Affairs electronic medical record system to explore the relationship between Paraoxonase 1 (PON1)-108 C/T (rs705379) and mean arterial blood pressure (MAP).
Methods
Outpatient blood pressure data over an approximate 8-year period was collected from the Veterans Affairs Hypertensive Cohort (N = 1,302). Association between genotype and longitudinal MAP was further explored using a random effects model controlling for age, ancestry, renal function, and other determinants of blood pressure. To control for population stratification, principal component groupings based on ancestry informative markers in this dataset were included as covariates (in addition to self-identified ancestry). Data from the African American Study of Kidney Disease and Hypertension (AASK, N = 857) was used to confirm significant findings in an independent cohort.
Results
There was a significant interaction between PON1-108 C/T genotype and follow-up age group. At a younger age (<50 years), there was an estimated 2.53 mm Hg (95% confidence interval: 1.06, 4.00) increase in MAP with each additional C-allele. At the older age groups, there were no significant associations between PON1-108 C/T genotype and MAP. Using data from the AASK trial, the C-allele at PON1-108 C/T was significantly associated with a higher MAP (P = 0.005) but only among younger participants (<54 years).
Conclusions
The PON1-108 polymorphism may be associated with MAP in an age-dependent manner.
doi:10.1038/ajh.2012.106
PMCID: PMC3515680  PMID: 22854640
age; blood pressure; essential hypertension; hypertension; polymorphism; PON1; veterans
9.  Vitamin D3 supplementation for 16 weeks improves flow-mediated dilation in overweight African American adults 
American journal of hypertension  2011;24(5):10.1038/ajh.2011.12.
Background
A growing body of evidence has linked vitamin D deficiency to increased risk of cardiovascular disease. Vitamin D deficiency is also more common in African Americans for whom an increased cardiovascular disease risk exists. This study sought to test the hypothesis that 16 weeks of 60,000 IU monthly supplementation of oral vitamin D3 would improve flow-mediated dilation (FMD) in African Americans, whereas no change would be observed in the placebo group.
Methods
A randomized, double blind, placebo controlled clinical trial was conducted. Fifty-seven African American adults were randomly assigned to either the placebo group or vitamin D group.
Results
Following 16 weeks of placebo (n=23; mean age 31±2 years) or 60,000 IU monthly oral vitamin D3 (n=22; mean age 29±2 years), serum concentrations of 25 hydroxyvitamin D increased from 38.2±3.0 nmol/L to 48.7±3.2 nmol/L and 34.3±2.2 nmol/L to 100.9±6.6 nmol/L, respectively. No changes in serum parathyroid hormone, serum calcium, or urine calcium/creatinine were observed following either treatment. Following 16 weeks of treatment, significant improvements in FMD were only observed in the vitamin D group (1.8±1.3%), whereas the placebo group had no change (-1.3±0.6%). Similarly, the vitamin D group exhibited an increase in absolute change in diameter (0.005±0.004 cm) and FMD/shear (0.08±0.04 %/s-1, AUC × 103) following treatment, whereas no change (-0.005±0.002 cm and -0.02±0.02 %/s-1, AUC, respectively) was observed following placebo.
Conclusions
Supplementation of 60,000 IU monthly oral vitamin D3 (~2000 IU per day) for 16 weeks is effective at improving vascular endothelial function in African American adults.
doi:10.1038/ajh.2011.12
PMCID: PMC3812921  PMID: 21311504
Vitamin D; Endothelial Function; African American; Cardiovascular Disease
10.  PROSTASIN: A POSSIBLE CANDIDATE GENE FOR HUMAN HYPERTENSION 
American journal of hypertension  2008;21(9):10.1038/ajh.2008.224.
Background
Prostasin, a serine protease, is suggested to be a novel mechanism regulating the epithelial sodium channel expressed in the distal nephron. This study aimed to evaluate whether the human prostasin gene is a novel candidate gene underlying blood pressure (BP) elevation.
Methods
In a sample of healthy African American (AA) and European American (EA) twin subjects aged 17.6±3.3 years (n=920, 45% AAs), race-specific tagging single nucleotide polymorphisms (tSNPs) were identified to tag all the available SNPs ± 2Kb up- and downstream of the prostasin gene from HapMap at r2 of 0.8 – 1.0. Selection yielded four tSNPs in AAs and one in EAs, with one tSNP (rs12597511: C to T) present in both AAs and EAs.
Results
For rs12597511, CT and TT genotypes exhibited higher systolic BP than CC genotype (115.9±1.1 mmHg vs. 113.7±0.6 mmHg, p=0.025 [AAs]; and 110.7±0.5 mmHg vs. 109.6±0.6 mmHg, p=0.115 [EAs]). CT and TT genotypes compared to CC genotype showed a significant increase in diastolic BP in both racial groups (62.5±0.7 mmHg vs. 60.4±0.4 mmHg, p=0.003 [AAs]; and 58.2±0.3 mmHg vs. 56.7±0.4 mmHg, p=0.007 [EAs]). Furthermore, there was an increase in radial pulse wave velocity (PWV) in subjects with CT and TT genotype as compared to those with CC genotype (6.5±0.1 vs. 6.1±0.1 m/s, p<0.0001) [EAs]; and 6.7±0.1 vs. 6.6±0.1 m/s, p=0.354 [AAs]). Analyses combining AAs and EAs consistently demonstrated a statistical significance of rs1259751 on all the phenotypes including systolic/diastolic BP, and PWV.
Conclusion
Genetic variation of the prostasin gene may be implicated in the development of hypertension in youths.
doi:10.1038/ajh.2008.224
PMCID: PMC3812941  PMID: 18583984
Prostasin; ENaC; Polymorphisms; Blood Pressure; Arterial stiffness
11.  Inflammation and Hypertension: The Interplay of Interleukin-6, Dietary Sodium and the Renin-Angiotensin System in Humans 
American journal of hypertension  2011;24(10):10.1038/ajh.2011.113.
Background
Prior evidence suggests a link between inflammation and hypertension. Interleukin-6 (IL-6) has been implicated in animal studies to play an important role in angiotensin II (ANGII) mediated hypertension. The aim of this study was to examine the relationship of IL-6 and renin-angiotensin system (RAS) activity in human hypertension.
Methods
Data from 385 hypertensives and 196 normotensives are included in this report. Blood pressure and laboratory evaluation were performed on liberal and low sodium diets. IL-6 response to an ANGII infusion was evaluated to assess the effect of acute RAS activation.
Results
Hypertensives had higher baseline IL-6 and C-reactive protein (CRP) compared with normotensives on both diets. IL-6 increased in response to ANGII in hypertensives and normotensives (28% in hypertensives, 31% in normotensives, p = < 0.001 for change from baseline). In the setting of RAS activation by a low salt diet, multivariate regression analysis adjusted for age, BMI, gender, race and hypertension status demonstrated an independent positive association of PRA with CRP (beta = 0.199, p<0.0001). There was no significant difference in IL-6 or CRP levels between liberal and low sodium diets.
Conclusion
These findings confirm an association between hypertension and inflammation and provide human data supporting previous evidence from animal studies that IL-6 plays a role in ANGII mediated hypertension. Notably, compared to levels on a liberal sodium diet, neither IL-6 or CRP were higher with activation of the RAS by a low salt diet indicating that a low sodium diet is not inflammatory despite increased RAS activity.
doi:10.1038/ajh.2011.113
PMCID: PMC3807212  PMID: 21716327
hypertension; inflammation; sodium; angiotensin; CRP; IL-6
12.  Double Product Reflects the Predictive Power of Systolic Pressure in the General Population: Evidence from 9,937 Participants 
American journal of hypertension  2013;26(5):665-672.
BACKGROUND
The double product (DP), consisting of the systolic blood pressure (SBP) multiplied by the pulse rate (PR), is an index of myocardial oxygen consumption, but its prognostic value in the general population remains unknown.
METHODS
We recorded health outcomes in 9,937 subjects (median age, 53.2 years; 47.3% women) randomly recruited from 11 populations and enrolled in the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcomes (IDACO) study. We obtained the SBP, PR, and DP for these subjects as determined through 24-hour ambulatory monitoring.
RESULTS
Over a median period of 11.0 years, 1,388 of the 9,937 study subjects died, of whom 536 and 794, respectively, died of cardiovascular (CV) and non-CV causes, and a further 1,161, 658, 494, and 465 subjects, respectively, experienced a CV, cardiac, coronary, or cerebrovascular event. In multivariate-adjusted Cox models, not including SBP and PR, DP predicted total, CV, and non-CV mortality (standardized hazard ratio [HR], ≥ 1.10; P ≤ 0.02), and all CV, cardiac, coronary, and stroke events (HR, ≥ 1.21; P < 0.0001). For CV mortality (HR, 1.34 vs. 1.30; P = 0.71) and coronary events (1.28 vs. 1.21; P = 0.26), SBP and the DP were equally predictive. As compared with DP, SBP was a stronger predictor of all CV events (1.39 vs. 1.27; P = 0.002) and stroke (1.61 vs. 1.36; P < 0.0001), and a slightly stronger predictor of cardiac events (1.32 vs. 1.22; P = 0.06). In fully adjusted models, including both SBP and PR, the predictive value of DP disappeared for fatal endpoints (P ≥ 0.07), coronary events (P = 0.06), and stroke (P = 0.12), or DP was even inversely associated with the risk of all CV and cardiac events (both P ≤ 0.01).
CONCLUSION
In the general population, we did not observe DP to add to risk stratification over and beyond SBP and PR.
doi:10.1093/ajh/hps119
PMCID: PMC3792705  PMID: 23391621
blood pressure; double product; systolic blood pressure; cardiovascular risk; hypertension; general population
13.  Tetrahydrobiopterin Supplementation Enhances Carotid Artery Compliance in Healthy Older Men: A Pilot Study 
American Journal of Hypertension  2012;25(10):1050-1054.
Background
We performed a pilot study to test the hypothesis that acute oral ingestion of tetrahydrobiopterin (BH4), a key cofactor modulating vascular nitric oxide (NO) synthase activity, improves large elastic artery stiffness with aging in men.
Methods
Healthy older (63 ± 2 years; n = 8) and young (age 25 ± 1 years; n = 6) men were studied 3 h after ingestion of BH4 (10 mg·kg−1 body weight) or placebo on separate days in a randomized, placebo-controlled, double-blind study.
Results
Baseline carotid artery compliance was 37% lower (0.17 ± 0.02 vs. 0.22 ± 0.02 mm/mm Hg·10−1) and β-stiffness was 42% higher (7.3 ± 1.1 vs. 4.2 ± 0.5 AU) in the older men (both P < 0.05). BH4 ingestion markedly increased circulating BH4 concentrations in both groups (17–19-fold, P < 0.05), but increased compliance (+39% to 0.23 ± 0.02 mm/mm Hg.10−1, P < 0.01) and decreased β-stiffness index (–27% to 5.3 ± 0.7 AU, P < 0.01) only in the older men. BH4 also reduced carotid systolic blood pressure (SBP) in the older men (P < 0.05).
Conclusions
These preliminary results support the possibility that limited BH4 bioavailability contributes to impaired carotid artery compliance in healthy older men. Further studies are needed to determine if increasing BH4 bioavailability though oral BH4 supplementation may have therapeutic efficacy for improving large elastic artery compliance and reducing central SBP with aging.
American Journal of Hypertension, advance online publication 7 June 2012; doi:10.1038/ajh.2012.70
doi:10.1038/ajh.2012.70
PMCID: PMC3482981  PMID: 22673017
arterial stiffness; blood pressure; cardiovascular disease; central blood pressure; hypertension; nitric oxide
14.  Blood Pressure Indexes and End-Stage Renal Disease Risk in Adults With Chronic Kidney Disease 
American journal of hypertension  2012;25(7):789-796.
Background
Few studies have compared different blood pressure (BP) indexes for end-stage renal disease (ESRD) risk among individuals with chronic kidney disease.
Methods
We examined the relationship between systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP) and mean arterial pressure (MAP) and ESRD risk among 2,772 participants with an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 calculated using the Chronic Kidney Disease Epidemiology Collaboration equation in the REasons for the Geographic And Racial Differences in Stroke (REGARDS) study. BP was measured during a baseline study visit between January 2003 and October 2007 with ESRD incidence through August 2009 ascertained via linkage with the United States Renal Data System (n = 138 ESRD cases).
Results
The mean age was 72.1(standard deviation: 8.7) years. After multivariable adjustment for socio-demographic and clinical risk factors including antihypertensive medication use, the hazard ratio (HR) for ESRD associated with one standard deviation higher SBP (18 mm Hg) was 1.67, (95% confidence intervals (CI) 1.43–1.96), DBP (11 mm Hg) was 1.38, (95% CI 1.16–1.63), PP (15 mm Hg) was 1.50, (95% CI 1.27–1.78) and MAP (11 mm Hg) was 1.54, (95% CI 1.32–1.79). Higher levels of SBP remained associated with an increased HR for ESRD after additional adjustment for DBP (1.65, 95% CI: 1.35–2.01), PP (1.73, 95% CI: 1.32–2.26), and MAP (1.61, 95% CI: 1.16–2.23). After adjustment for SBP, the other BP indexes were not significantly associated with incident ESRD.
Conclusions
These data suggest that of several blood pressure indexes including DBP, PP and MAP, SBP may have the strongest association with ESRD incidence among individuals with reduced eGFR.
doi:10.1038/ajh.2012.48
PMCID: PMC3784349  PMID: 22573012
blood pressure; chronic kidney disease; end-stage renal disease; hypertension; pulse pressure; systolic blood pressure
15.  Activation of the Mineralocorticoid Receptor Increases Striatin Levels 
American journal of hypertension  2011;25(2):243-249.
BACKGROUND
Aldosterone (ALDO), a critical regulator of sodium homeostasis, mediates its effects via activation of the mineralocorticoid receptor (MR) through mechanisms that are not entirely clear. Striatin, a membrane associated protein, interacts with estrogen receptors in endothelial cells.
METHODS
We studied the effects of MR activation in vitro and in vivo on striatin levels in vascular tissue.
RESULTS
We observed that dietary sodium restriction was associated with increased striatin levels in mouse heart and aorta and that striatin and MR are present in the human endothelial cell line, (EA.hy926), and in mouse aortic endothelial cells (MAEC). Further, we show that MR co-precipitates with striatin in vascular tissue. Incubation of EA.hy926 cells with ALDO (10−8 mol/l for 5–24 h) increases striatin protein and mRNA expression, an effect that was inhibited by canrenoic acid, an MR antagonist. Consistent with these observations, incubation of MAEC with ALDO increased striatin levels that were likewise blocked by canrenoic acid. To test the in vivo relevance of these findings, we studied two previously described mouse models of increased ALDO levels. Intraperitoneal ALDO administration augmented the abundance of striatin protein in mouse heart. We also observed that in a murine model of chronic ALDO-mediated cardiovascular damage following treatment with NG-nitro-L-arginine methyl ester plus angiotensin II an increased abundance of striatin protein in heart and kidney tissue.
CONCLUSION
Our results provide evidence that increased striatin levels is a component of MR activation in the vasculature and suggest that regulation of striatin by ALDO may modulate estrogen’s nongenomic effects.
doi:10.1038/ajh.2011.197
PMCID: PMC3773217  PMID: 22089104
aldosterone; angiotensin; animal physiology; antagonists; blood pressure; endothelial cells; heart tissue; hypertension; inflammation; L-NAME; mineralocorticoid receptor; RAAS
16.  Associations of Non-Invasive Measures of Arterial Compliance and Ankle-Brachial Index: The Multi-Ethnic Study of Atherosclerosis (MESA) 
American journal of hypertension  2012;25(5):535-541.
Background
The association between measures of arterial compliance and peripheral arterial disease (PAD) is unclear. Early changes in arterial wall compliance could be a useful marker of patients at high risk for developing lower extremity atherosclerosis.
Methods
We used linear and logistic regression models on baseline data from 2803 female and 2558 male participants in the Multi-Ethnic Study of Atherosclerosis (MESA) to study associations between tonometry-derived baseline measures of arterial compliance (large artery compliance [C1] and small artery compliance [C2]) and the baseline ankle-brachial index (ABI), as well as change in the ABI over approximately 3 years of follow up.
Results
In cross-sectional analyses, lower C1 and C2 values, indicating poorer arterial compliance, were associated with lower ABI. There were significant linear trends across strata of ABI, especially in C2 which ranged from 3.7ml/mmHg × 100 (95% confidence interval (CI) 3.3 to 4.2) in women with an ABI < 0.90 to 4.2ml/mmHg × 100 (95% CI 4.1 to 4.3 p<0.001) in women with ABI 1.10 - <1.40. Similar significant trends (p<0.001) were seen in men. In prospective analyses, those with the lowest tertile of C2 values at baseline had a greater multivariable-adjusted odds for decline in ABI of ≥ 0.15 over 3 years compared to those with the highest C2 values at baseline (OR 1.80 95% CI 1.23–2.64).
Conclusions
We observed that less compliant arteries were significantly associated with low ABI in cross-sectional analysis and with greater decline in ABI over time.
doi:10.1038/ajh.2012.13
PMCID: PMC3748962  PMID: 22357412
Ankle-Brachial Index; Arterial Compliance; Peripheral Arterial Disease
17.  A Practice-based Trial of Motivational Interviewing and Adherence in Hypertensive 065African Americans1 
American journal of hypertension  2008;21(10):1137-1143.
BACKGROUND
Poor medication adherence is a significant problem in hypertensive African Americans. Although motivational interviewing (MINT) is effective for adoption and maintenance of health behaviors in patients with chronic diseases, its effect on medication adherence remains untested in this population.
METHODS
This randomized controlled trial tested the effect of a practice-based MINT counseling versus usual care (UC) on medication adherence and blood pressure (BP) in 190 hypertensive African Americans (88% women; mean age 54 years). Patients were recruited from two community-based primary care practices in New York City. The primary outcome was adherence measured by electronic pill monitors; the secondary outcome was within-patient change in office BP from baseline to 12 months.
RESULTS
Baseline adherence was similar in both groups (56.2% and 56.6% for MINT and UC respectively, p = 0.94). Based on intent-to-treat analysis using mixed effects regression, a significant time X group interaction with model-predicted post-treatment adherence rates of 43% and 57% were found in the UC and MINT groups, respectively (p = 0.027), with a between-group difference of 14% (95% CI, −0.2% to −27%). The between-group difference in systolic and diastolic BP was −6.1 mm Hg (p = .065) and −1.4 mm Hg (p = .465), respectively, in favor of the MINT group.
CONCLUSIONS
A practice-based MINT counseling led to steady maintenance of medication adherence over time, compared to significant decline in adherence for UC patients. This effect was associated with a clinically meaningful net reduction in systolic BP in favor of the MINT group.
doi:10.1038/ajh.2008.240
PMCID: PMC3747638  PMID: 18654123
Motivational Interviewing; Medication Adherence; African American; Hypertension
18.  High Tail-Cuff Blood Pressure in Mice 1 Week After Shipping: The Need For Longer Acclimation 
American journal of hypertension  2011;24(5):534-536.
Background
For vendor-derived mice, an acclimation period of 1 week is usually recommended before blood pressure measurements are started. However, we observed hypertension in wild-type vendor-derived mice 1 week after shipping.
Methods
The index group (n = 12, BALB/c, age 3 months, weight 26-28 g) was shipped overnight (by truck, duration 13 h). Tail-cuff systolic blood pressures (SBPs) of the index group were compared to two control groups (n = 6/group), one acclimated for 3 weeks after shipping, and one derived from an in-house colony.
Results
One week after shipping, SBP in the index group was 141 ± 3 mm Hg. Because this was much higher than reported previously for this strain, acclimation was prolonged. Six weeks after shipping, SBP had fallen to 124 ± 3 mm Hg (P < 0.005). During this time, heart rate also fell from 721 ± 15 to 665 ± 13 bpm (P < 0.01). SBP in the two control groups was also lower than in the index group 1 week after shipping, including the group acclimated for 3 weeks (129 ± 3 vs. 141 ± 3 mm Hg, P < 0.05) and the in-house mice (124 ± 3 vs. 141 ± 3 mm Hg, P < 0.005).
Conclusions
Vendor-derived mice are hypertensive 1 week after shipping, become normotensive after 3 weeks, but do not return to levels of in-house mice until after 6 weeks. Acclimation periods of at least 3 weeks are required when measuring blood pressure in mice.
doi:10.1038/ajh.2011.7
PMCID: PMC3740725  PMID: 21293389
19.  Inhibition of Angiotensin-Converting Enzyme 2 Exacerbates Cardiac Hypertrophy and Fibrosis in Ren-2 Hypertensive Rats 
American journal of hypertension  2010;23(6):687-693.
Background
Emerging evidence suggests that cardiac angiotensin-converting enzyme 2 (ACE2) may contribute to the regulation of heart function and hypertension-induced cardiac remodeling. We tested the hypothesis that inhibition of ACE2 in the hearts of (mRen2)27 hypertensive rats may accelerate progression of cardiac hypertrophy and fibrosis by preventing conversion of angiotensin II (Ang II) into the antifibrotic peptide, angiotensin-(1–7) (Ang-(1–7)).
Methods
Fourteen male (mRen2)27 transgenic hypertensive rats (12 weeks old, 401 ± 7 g) were administered either vehicle (0.9% saline) or the ACE2 inhibitor, MLN-4760 (30 mg/kg/day), subcutaneously via mini-osmotic pumps for 28 days.
Results
Although ACE2 inhibition had no effect on average 24-h blood pressures, left ventricular (LV) Ang II content increased 24% in rats chronically treated with the ACE2 inhibitor (P < 0.05). Chronic ACE2 inhibition had no effect on plasma Ang II or Ang-(1–7) levels. Increased cardiac Ang II levels were associated with significant increases in both LV anterior, posterior, and relative wall thicknesses, as well as interstitial collagen fraction area and cardiomyocyte hypertrophy in the transgenic animals chronically treated with the ACE2 inhibitor. Cardiac remodeling was not accompanied by any further alterations in LV function.
Conclusions
These studies demonstrate that chronic inhibition of ACE2 causes an accumulation of cardiac Ang II, which exacerbates cardiac hypertrophy and fibrosis without having any further impact on blood pressure or cardiac function.
doi:10.1038/ajh.2010.51
PMCID: PMC3739444  PMID: 20300067
angiotensin-converting enzyme 2; angiotensin II; angiotensin-(1-7); blood pressure; cardiac hypertrophy; hypertension
20.  Predictors of Large and Small Artery Elasticity in Healthly Subjects 9 to 89 Years Old 
American journal of hypertension  2011;24(5):599-605.
Background
We identified demographic variables, cardiovascular risk factors, and ambulatory activity measures that predict large and small artery elasticity in apparently healthy subjects between 9 and 89 years of age.
Methods
480 subjects were assessed on large artery elasticity index (LAEI), small artery elasticity index (SAEI), demographic measures, cardiovascular risk factors, and daily ambulation during seven consecutive days. All possible regression and Mallow's Cp were used to select multivariate models for prediction of LAEI and SAEI.
Results
In subjects 20 years of age and younger, LAEI model (R2 = 0.25, p < 0.001) included age, average ambulatory cadence, and obesity. SAEI model (R2 = 0.39, p < 0.001) contained body mass index (BMI), maximum daily ambulatory cadence for 30 continuous minutes, age, and total ambulatory strides. In subjects between 21 and 50 years, LAEI model (R2 = 0.41, p < 0.001) included systolic blood pressure (SBP), gender, race, and diastolic blood pressure (DBP). SAEI model (R2 = 0.42, p < 0.001) contained gender, BMI, DBP, race, dyslipidemia, and SBP. In subjects older than 50 years, LAEI model (R2 = 0.54, p < 0.001) included SBP, gender, age, and BMI. SAEI model (R2 = 0.45, p < 0.001) contained gender, age, BMI, DBP, current smoking, and SBP.
Conclusions
Daily ambulatory activity, particularly cadence of 30 continuous minutes of ambulation, is positively associated with arterial elasticity in children and adolescents. In contrast, the predominant factors related to the decline in arterial elasticity in adults are blood pressure and age.
doi:10.1038/ajh.2011.5
PMCID: PMC3732160  PMID: 21293385
Arterial Elasticity; Age; Ambulation; Physical Activity
21.  Decreased NKCC1 Activity in Erythrocytes From African Americans With Hypertension and Dyslipidemia 
American journal of hypertension  2009;23(3):321-326.
Background
Recent studies demonstrated a key role of ubiquitous isoform of Na+,K+,2Cl− co-transport (NKCC 1) in regulation of myogenic tone and peripheral resistance. We examined the impact of race, gender, and plasma lipid on NKCC 1 activity in French Canadians and African Americans with hypertension and dyslipidemia.
Methods
NKCC and passive erythrocyte membrane permeability to K+, measured as ouabain-resistant, bumetanide-sensitive, and (ouabain+bumetanide)-resistant 86Rb influx, respectively, were compared in 111 French-Canadian men, 107 French-Canadian women, 26 African-American men, and 45 African-American women with essential hypertension and dyslipidemia.
Results
The African-American men and women were 7 years younger and presented twofold decreased plasma triglycerides compared to their French-Canadian counterparts (P < 0.01) whereas body mass index (BMI), total cholesterol, low-density lipoprotein, and high-density lipoprotein (HDL) were not different. NKCC was respectively 50 and 38% lower in the African-American men and women than in the French Canadians (P < 0.005) without any differences in passive erythrocyte membrane permeability for K+. We did not observe any impact of age on NKCC in all groups under investigation, whereas plasma triglycerides correlated positively with the activity of this carrier in the French-Canadian men only.
Conclusions
NKCC 1 activity is lower in erythrocytes of African Americans with essential hypertension and dyslipidemia than in Caucasian counterparts. We suggest that decreased NKCC 1 may contribute to the feature of the pathogenesis of salt-sensitive hypertension seen in A frican Americans.
doi:10.1038/ajh.2009.249
PMCID: PMC3727424  PMID: 20044742
African Americans; blood pressure; hypertension; Na+,K+,Cl− co-transport; plasma lipids; renal complications; salt retention
22.  Inhibitory Effect of the D3 Dopamine Receptor on Insulin Receptor Expression and Function in Vascular Smooth Muscle Cells 
American journal of hypertension  2011;24(6):654-660.
BACKGROUND
Vascular smooth muscle cell (VSMC) proliferation is regulated by numerous hormones and humoral factors. Our previous study found that stimulation of D1-like dopamine receptors inhibited insulin receptor expression and function in VSMCs. We hypothesize that there is also an interaction between D3 dopamine and insulin receptors, i.e., stimulation of the D3 receptor inhibits insulin receptor expression and function.
METHODS
Receptor expression was determined by immunoblotting, immunohistochemisty, and reverse transcriptase-PCR; VSMC proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-diphenyl-tetrazolium bromide (MTT) assay and cell number.
RESULTS
Insulin receptor protein is increased in the aorta of D3 receptor deficient mice. Stimulation of the D3 receptor inhibited insulin receptor mRNA and protein expression and insulin-mediated VSMC proliferation, and increased protein kinase A (PKA) activity, insulin receptor phosphorylation, and degradation in immortalized aortic VSMCs (A10 cells). These effects were blocked by a PKA inhibitor, indicating that the D3 receptor-mediated decrease in insulin receptor expression was related to a decrease in transcription/post-transcription and increased degradation, involving PKA signaling.
CONCLUSIONS
D3 receptor stimulation may be a target to reduce the adverse effect of insulin in hypertension by inhibition of insulin receptor expression and function in arterial VSMCs.
doi:10.1038/ajh.2011.41
PMCID: PMC3722590  PMID: 21415841
blood pressure; dopamine receptor; hypertension; insulin receptor; proliferation; vascular smooth muscle cells
23.  LYSINE-SPECIFIC DEMETHYLASE 1: AN EPIGENETIC REGULATOR OF SALT-SENSITIVE HYPERTENSION 
American journal of hypertension  2012;25(7):812-817.
Background
Hypertension represents a complex heritable disease in which environmental factors may directly affect gene function via epigenetic mechanisms. The aim of this study was to test the hypothesis that dietary salt influences the activity of a histone modifying enzyme, lysine-specific demethylase 1 (LSD-1), which in turn is associated with salt-sensitivity of blood pressure (BP).
Methods
Animal and human studies were performed. Salt-sensitivity of LSD-1 expression was assessed in wild-type and LSD-1 heterozygote knockout (LSD-1+/−) mice. Clinical relevance was tested by multivariate associations between single nuclear polymorphisms (SNPs) in the LSD-1 gene and salt-sensitivity of BP, with control of dietary sodium, in a primary African-American hypertensive cohort and two replication hypertensive cohorts (Caucasian and Mexican-American).
Results
LSD1 expression was modified by dietary salt in wild-type mice with lower levels associated with liberal salt intake. LSD-1+/− mice expressed lower LSD-1 protein levels than wild-type mice in kidney tissue. Similar to LSD-1+/− mice, African-American minor allele carriers of two LSD-1 SNPs displayed greater change in systolic BP in response to change from low to liberal salt diet (rs671357, p=0.01; rs587168, p=0.005). This association was replicated in the Hispanic (rs587168, p=0.04) but not the Caucasian cohort. Exploratory analyses demonstrated decreased serum aldosterone concentrations in African-American minor allele carriers similar to findings in the LSD-1+/− mice, decreased alpha-EnaC expression in LSD-1+/− mice, and impaired renovascular responsiveness to salt loading in minor allele carriers.
Conclusion
The results of this translational research study support a role for LSD1 in the pathogenesis of salt-sensitive hypertension.
doi:10.1038/ajh.2012.43
PMCID: PMC3721725  PMID: 22534796
Hypertension; Salt-sensitivity; LSD1; Genetics; Epigenetic
24.  TELMISARATAN PROVIDES BETTER RENAL PROTECTION THAN VALSARTAN IN A RAT MODEL OF METABOLIC SYNDROME 
American journal of hypertension  2011;24(7):816-821.
BACKGROUND
Angiotension receptor blockers (ARB), telmisartan and valsartan were compared for renal protection in spontaneously hypertensive rats (SHR) fed high fat diet. We hypothesized that in cardiometabolic syndrome, telmisartan an ARB with PPAR-γ activity will offer better renal protection.
METHODS
SHR were fed either normal (SHR-NF, 7% fat) or high fat (SHR-HF, 36% fat) diet and treated with an ARB for 10 weeks.
RESULTS
Blood pressure was similar between SHR-NF (190±3 mmHg) and SHR-HF (192±4 mmHg) at the end of the 10 week period. Telmisartan and valsartan decreased blood pressure to similar extents in SHR-NF and SHR-HF groups. Body weight was significantly higher in SHR-HF (368±5g) compared to SHR-NF (328±7g). Telmisartan but not valsartan significantly reduced the body weight gain in SHR-HF. Telmisartan was also more effective than valsartan in improving glycemic and lipid status in SHR-HF. Monocyte chemoattractant protein-1 (MCP-1), an inflammatory marker, was higher in SHR-HF (24±2 ng/d) compared to SHR-NF (14±5 ng/d). Telmisartan reduced MCP-1 excretion in both SHR-HF and SHR-NF to a greater extent than valsartan. An indicator of renal injury, urinary albumin excretion increased to 85±8 mg/d in SHR-HF compared to 54±9 mg/d in SHR-NF. Telmisartan (23±5 mg/d) was more effective than valsartan (45±3 mg/d) in lowering urinary albumin excretion in SHR-HF. Moreover, telmisartan reduced glomerular damage to a greater extent than valsartan in the SHR-HF.
CONCLUSIONS
Collectively, our data demonstrate that telmisartan was more effective than valsartan in reducing body weight gain, renal inflammation, and renal injury in a rat model of cardiometabolic syndrome.
doi:10.1038/ajh.2011.34
PMCID: PMC3721747  PMID: 21415842
cardiometabolic syndrome; renin-angiotensin system; high fat diet; hypertension; inflammation; renal injury
25.  Moderate Waist Circumference and Hypertension Prevalence: The REGARDS Study 
American journal of hypertension  2011;24(4):482-488.
Background
High waist circumference (WC) (women: >88 cm; men: >102 cm) increases cardiovascular risk. Less is known about moderate WC (women: 80–88 cm; men: 94–102 cm). Therefore, we examined the association between moderate WC and hypertension prevalence, independent of body mass index (BMI).
Methods
Among 24,247 eligible adults 45–84 years old, when recruited from January 2003 to October 2007 in the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort, we examined hypertension prevalence (systolic blood pressure (BP) ≥140 mm Hg, or diastolic BP ≥90 mm Hg, or self-reported antihypertensive medication use) by WC before and after stratification by BMI (normal: 18.5–24.9; overweight: 25–29.9; obese class I: 30–34.9). Logistic regression adjusted associations between WC, BMI, and hypertension prevalence for age, race, sex, region, income, education, cigarette smoking, glomerular filtration rate, alcohol use, and physical activity.
RESULTS
Overall, hypertension prevalence was 44% among those with low WC (n = 8,068), 55% with moderate WC (n = 6,488), and 66% with high WC (n = 9,691). After full adjustment, moderate WC was independently associated with hypertension prevalence among persons with normal BMI, (adjusted odds ratio (aOR), 1.49; 95% confidence interval (CI), 1.31–1.70), overweight BMI (aOR, 1.80; 95% CI, 1.64–1.98), and obese class I BMI (aOR, 2.28; 95%CI, 1.96–2.65) (referent: low WC-normal BMI). The moderate WC–hypertension association was observed in blacks and whites and in men and women.
CONCLUSION
Moderate WC is associated with hypertension prevalence independent of BMI and several hypertension risk factors in middle-aged and older adults.
doi:10.1038/ajh.2010.258
PMCID: PMC3717383  PMID: 21233800
blood pressure; clinical epidemiology; hypertension; obesity; race; waist circumference

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