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1.  Socioeconomic Position Is Positively Associated With Blood Pressure Dipping Among African-American Adults: The Jackson Heart Study 
American journal of hypertension  2011;24(9):1015-1021.
BACKGROUND
Blunted nocturnal blood pressure (NBP) dipping is a significant predictor of cardiovascular events. Lower socioeconomic position (SEP) may be an important predictor of NBP dipping, especially in African Americans (AA). However, the determinants of NBP dipping are not fully understood.
METHODS
The cross-sectional associations of individual and neighborhood SEP with NBP dipping, assessed by 24-h ambulatory BP monitoring, were examined among 837 AA adults (Mean age: 59.2 ± 10.7 years; 69.2% women), after adjustment for age, sex, hypertension status, body mass index (BMI), health behaviors, office, and 24-h systolic BP (SBP).
RESULTS
The mean hourly SBP was consistently lower among participants in the highest category of individual income compared to those in the lowest category, and these differences were most pronounced during sleeping hours. The odds of NBP dipping (defined as >10% decline in the mean asleep SBP compared to the mean awake SBP) increased by 31% (95% confidence interval: 13–53%) and 18% (95% confidence interval: 0–39%) for each s.d. increase in income and years of education, respectively, after multivariable adjustment.
CONCLUSIONS
NBP dipping is patterned by income and education in AA adults even after accounting for known risk factors. These results suggest that low SEP is a risk factor for insufficient NBP dipping in AA.
doi:10.1038/ajh.2011.98
PMCID: PMC4206938  PMID: 21654853
ambulatory blood pressure monitoring; blood pressure; hypertension; Jackson Heart Study; nocturnal dipping; socioeconomic position; systole
2.  Ethnic Differences in the Effects of the DASH Diet on Nocturnal Blood Pressure Dipping in Individuals with High Blood Pressure 
American journal of hypertension  2011;24(12):1338-1344.
BACKGROUND
Ethnic differences in nocturnal blood pressure (BP) dipping may contribute to the increased risk for adverse cardiovascular events noted in African Americans (AAs). The DASH (Dietary Approaches to Stop Hypertension) diet has been shown to be efficacious in lowering clinic and ambulatory BP; however, the effect of the DASH diet on BP dipping is unclear.
METHODS
One hundred and eighteen men and women with high clinic BP (systolic BP (SBP) 130–159; diastolic BP 85–99) and above ideal body weight were randomized to a DASH diet intervention or to a usual diet control (UC) condition. Measures of 24-h ambulatory BP were obtained at baseline and at the end of the 4-month intervention period.
RESULTS
At baseline, AAs (n = 43) displayed blunted nocturnal SBP dipping compared to Caucasians (CAs; n = 75) and were more likely to be categorized as nondippers (<10% nocturnal decline in SBP, AAs: 51% vs. CAs: 27%). AAs randomized to the DASH diet intervention showed a significant improvement in SBP dipping postintervention compared to AAs in the UC condition (P = 0.04), whereas there was no appreciable change in SBP dipping in CAs (P = 0.72). Following the intervention, ethnic differences in SBP dipping were no longer statistically significant (nondipper status: AAs: 44% vs. CAs: 32%; P = 0.19).
CONCLUSIONS
Our study provides preliminary evidence suggesting that in overweight men and women with high BP, AAs may be especially likely to benefit from augmented SBP dipping associated with consumption of the DASH diet.
doi:10.1038/ajh.2011.152
PMCID: PMC4180759  PMID: 21866183
blood pressure; DASH diet; ethnicity; hypertension; nocturnal blood pressure
3.  Overexpression of Mouse Angiotensinogen in Renal Proximal Tubule Causes Salt-Sensitive Hypertension in Mice 
American journal of hypertension  2012;25(6):684-689.
BACKGROUND
The role of proximal tubule (PT) angiotensinogen (AGT) in modulating blood pressure has previously been examined using mice expressing PT human AGT and human renin, or rat AGT. These animals are hypertensive; however, the question remains whether alterations in mouse PT AGT alone affects arterial pressure.
METHODS
Mouse AGT cDNA was knocked-in to the endogenous kidney androgen protein (KAP) gene using an internal ribosomal entry site (IRES)-based strategy.
RESULTS
The KAP-mAGT animals showed kidney-specific KAP-AGT mRNA expression; renal in situ hybridization detected KAP-AGT mRNA only in PT. Urinary AGT was markedly increased in KAP-mAGT mice. On a high Na diet, radiotelemetric arterial pressure showed a systolic pressure elevation; no significant difference in arterial pressure was observed on a normal diet. Plasma renin concentration (PRC) was reduced in KAP-mAGT animals given a high Na diet, but was not different between mouse lines during normal Na intake. Plasma AGT concentration was not altered by overexpression of PT mouse AGT.
CONCLUSIONS
In summary, PT overexpression of mouse AGT leads to salt-sensitive hypertension without recruitment of the systemic renin–angiotensin system.
doi:10.1038/ajh.2012.16
PMCID: PMC4164431  PMID: 22378037
angiotensinogen; blood pressure; hypertension; kidney; proximal tubule; renin; transgene
4.  Effect of Luminal Angiotensin II Receptor Antagonists on Proximal Tubule Transport 
American journal of hypertension  1999;12(5):499-503.
The proximal tubule can endogenously synthesize and secrete luminal angiotensin II at a concentration approximately 100- to 1000-fold higher than that in the systemic circulation. We have recently shown that this endogenously produced and luminally secreted angiotensin II regulates proximal tubule volume reabsorption, which is a reflection of sodium transport within this segment. In this study, we use in vivo microperfusion of angiotensin II receptor antagonists into the lumen of the proximal tubule to examine the role of the luminal AT1 and AT2 receptor in the regulation of volume reabsorption. Systemically administered (intravenous) AT1 and AT2 receptor antagonists, acting through basolateral angiotensin II receptors, have previously been shown to inhibit proximal tubule transport. Luminal perfusion of 10−6 mol/L Dup 753 (AT1 antagonist) and 10−6 mol/L PD 123319 (AT2 antagonist) decreased proximal tubule volume reabsorption from 2.94 ± 0.18 to 1.65 ± 0.18 and 1.64 ± 0.19 nL/mm · min, respectively, P < .01. Luminal perfusion of 10−4 mol/L CGP 42112A, another AT2 antagonist, similarly decreased volume reabsorption to 1.32 ± 0.36 nL/nm · min, P < .01. The inhibition of transport with AT1 and AT2 antagonist was additive, as luminal perfusion of 10−6 mol/L Dup 753 plus 10−6 mol/L 123319 resulted in a decrease in volume reabsorption to 0.41 ± 0.31 nL/mm · min, P < .001 v control, P < .05 v Dup 753, and P < .01 v PD 123319. These results show that endogenously produced angiotensin II regulates proximal tubule volume transport via both luminal AT1 and AT2 receptors.
PMCID: PMC4132668  PMID: 10342788
Renin-angiotensin system; in vivo microperfusion; DUP-753; PD-123319; CGP 42112A
5.  Effect of Prenatal Dexamethasone on Postnatal Serum and Urinary Angiotensin II Levels 
American journal of hypertension  2010;23(4):420-424.
BACKGROUND
Prenatal programming of hypertension has been described in humans and in animal models that receive a prenatal insult, but the mechanism for the increase in blood pressure remains elusive.
METHODS
In male rats whose mothers received dexamethasone between days 15 and 18 of gestation systemic and urinary levels of angiotensin II were measured to determine whether angiotensin II was a potential factor for the generation (4 weeks of age) or maintenance (8 weeks of age) of hypertension.
RESULTS
A group 4- and 8-week-old male rats that were the product of a pregnancy where the mother received prenatal dexamethasone between days 15 and 18 of gestation had comparable plasma renin and angiotensin II levels to the offspring of vehicle-treated controls. Renal angiotensin II levels were not different at 4 and 8 weeks of age between the controls and the prenatal dexamethasone group. Urine angiotensin II/Creatinine levels, a reflection of filtered and renally generated and secreted angiotensin II, were higher at both 4 and 8 weeks of age in male rats that received prenatal dexamethasone compared to controls.
CONCLUSIONS
The high-urine angiotensin II levels in prehypertensive and hypertensive rats that were the product of mothers that received dexamethasone compared to vehicle suggest that luminal angiotensin II may play a role in the generation and maintenance of hypertension in this model of prenatal programming.
doi:10.1038/ajh.2009.274
PMCID: PMC4130337  PMID: 20075846
blood pressure; hypertension; intrarenal renin–angiotensin system (RAS); prenatal programming
6.  A Genetic Risk Variant for Myocardial Infarction on Chromosome 6p24 Is Associated With Impaired Central Hemodynamic Indexes 
American journal of hypertension  2012;25(7):797-803.
Background
Genome-wide association studies (GWAS) have identified novel variants associated with myocardial infarction (MI) in Caucasians. We hypothesized that those variants whose mechanism of risk is currently unknown, confer risk via pathways mediating arterial wave reflections which is an increasingly recognized risk factor for cardiovascular disease.
Methods
Single-nucleotide polymorphisms (SNPs) at eight MI risk loci were genotyped and correlated with noninvasively determined pulse wave analysis (PWA)-derived central hemodynamic indexes (augmentation index (AIx); augmented pressure (AP); time to reflected wave (TrW) and central systolic blood pressure (SBP) and diastolic BP (DBP)) in two independent Caucasian populations including (i) those free of measured cardiovascular risk factors (n = 133) and (ii) a community-based population (n = 270).
Results
Of the eight SNPs examined in the healthy group, the variants at loci 6p24 (AIx and AP both P < 0.001, TrW P = 0.02) and 21q22 (AIx P = 0.002, TrW P = 0.037) were significantly associated with PWA indexes. In the replication group, only the 6p24 variant correlated with these phenotypes (AIx P = 0.005, AP P = 0.049, TrW P = 0.013). In the pooled population (n = 403), no new associations were identified but the association with 6p24 and AIx remained significant even after Bonferroni correction and adjustment for covariates including age, mean arterial pressure, height, gender, glucose, cholesterol, body mass index (BMI), and smoking (AIx (P = 0.03)). Each copy of the risk allele C increased the AIx by 3.5%.
Conclusions
The GWAS discovered MI risk variant at 6p24 in the protein phosphatase 1 regulator gene (PHACTR1) is associated with adverse arterial wave reflection indexes and may mediate MI risk through this pathway.
doi:10.1038/ajh.2012.41
PMCID: PMC4127881  PMID: 22513829
6p24; augmentation index; blood pressure; elasticity; genetic; genomic; GWAS; hypertension; myocardial infarction; SNP; stiffness
7.  β-AR Polymorphisms and Glycemic and Lipid Parameters in Hypertensive Individuals Receiving Carvedilol or Metoprolol 
American journal of hypertension  2012;25(8):920-926.
Background
β-blocker therapy and β-adrenergic receptor (β-AR) polymorphisms are associated with increases in glucose and lipid levels. We investigated associations of common β1 and β2- AR single nucleotide polymorphisms (SNPs) with metabolic and lipid variables, and examined interactions with β-blocker treatment assignment to affect these parameters.
Methods
This was a Post hoc analysis of a double-blinded clinical trial of non-diabetic, hypertensive individuals that were randomized to receive carvedilol or metoprolol succinate. Fasting glucose, insulin, and lipid levels were measured at baseline, 3, and after 6 months. Genotypes for β1-AR SNPs Ser49Gly & Gly389Arg and β2-AR Arg16Gly & Gln27Glu were determined. Multivariable mixed models were used to examine associations between β-AR polymorphisms, metabolic parameters, and SNP interactions with β-blocker therapy (pinteraction).
Results
The 322 subjects were mean (standard deviation) 51.5 (11.2) years old. After 6 months, insulin levels increased by 35.6% on metoprolol but decreased by 9.9% on carvedilol (p=0.015). In univariate models, the Gln27Gln genotype had higher overall insulin levels with β-blockade compared to the Glu27Glu genotype (p=0.006). Both Arg16Gly (p=0.012) and Gln27Glu (p=0.037) SNPs were associated with triglycerides levels. An interaction between the Arg16Gly SNP and treatment was identified (pint=0.048).
Conclusions
These data suggest that insulin and triglycerides may be influenced by β2-AR polymorphisms in patients taking β–blockers.
doi:10.1038/ajh.2012.54
PMCID: PMC4126246  PMID: 22647787
beta blocker; beta adrenergic receptor gene polymorphism; triglycerides
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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