BACKGROUND

Hypertension is highly prevalent and contributes to cardiovascular morbidity and mortality. Appropriate identification of hypertension is fundamental for its management. The rates of appropriate hypertension diagnosis in outpatient settings using an electronic health record (EHR) have not been well studied. We sought to identify prevalent and incident hypertension cases in a large outpatient healthcare system, examine the diagnosis rates of prevalent and incident hypertension, and identify clinical and demographic factors associated with appropriate hypertension diagnosis.

METHODS

We analyzed a three-year, cross-sectional sample of 251,590 patients aged ≥18 years using patient EHRs. Underlying hypertension was defined as two or more abnormal blood pressure (ABP) readings ≥140/90 mmHg and/or pharmaceutical treatment. Appropriate hypertension diagnosis was defined by the reporting of ICD-9 codes (401.0 – 401.9). Factors associated with hypertension diagnosis were assessed through multivariate analyses of patient clinical and demographic characteristics.

RESULTS

The prevalence of hypertension was 28.7%, and the diagnosis rate was 62.9%. The incidence of hypertension was 13.3%, with a diagnosis rate of 19.9%. Predictors of diagnosis for prevalent hypertension included older age, Asian, African American, higher BMI, and increased number of ABP readings. Predictors for incident hypertension diagnosis were similar. Patients with underlying hypertension were more likely to be treated when they had a hypertension diagnosis in the EHR (92.6%) than if they did not (15.8%, p < 0.0001).

CONCLUSIONS

Outpatient EHR diagnosis rates are suboptimal, yet EHR diagnosis of hypertension is strongly associated with treatment. Targeted efforts to improve diagnosis should be a priority.

BACKGROUND

Thiazides and β-blockers cause adverse metabolic effects (AMEs), but whether these effects share predictors with blood pressure (BP) response is unknown. We aimed to determine whether AMEs are correlated with BP response in uncomplicated hypertensives.

METHODS

In a multicenter, open-label, parallel-group trial, we enrolled 569 persons, aged 17–65, with random assignment to 9 weeks of daily hydrochlorothiazide (HCTZ) or atenolol monotherapy, followed by 9 weeks of add-on therapy with the alternate agent. Measurements included home BP, averaged over 1 week, weight and fasting levels of serum glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, and uric acid (UA) before and after monotherapy and after add-on therapy.

RESULTS

Increases in UA correlated with reductions in systolic BP (SBP) (r = −0.18; P = 0.003) and diastolic BP (DBP) (r = −0.20; P = 0.001) following HCTZ monotherapy and add-on therapy (r = −0.27 and r = −0.21, respectively; both P < 0.001). After adjustment for age, race, gender, and baseline body mass index (BMI), only the correlation between UA and DBP response became nonsignificant. Reductions in HDL correlated with systolic response following atenolol monotherapy (r = 0.18; P = 0.002) and with systolic and diastolic response following add-on therapy (r = 0.30 and r = 0.24, respectively; both P < 0.0001). These correlations remained significant after covariate adjustment. BP responses were not correlated with changes in glucose, LDL, triglycerides, or weight following either therapy.

CONCLUSIONS

BP response correlated with changes in UA following HCTZ therapy and HDL following atenolol therapy. No other significant correlations were observed between BP response and AMEs, suggesting that these effects generally do not share predictors. Patients should be monitored for AMEs, regardless of BP response.

Background

Despite the promising findings from short-term intervention trials, the long-term effect of habitual fruit and vegetable intake on blood pressure (BP) remains uncertain. We therefore assessed the prospective association between baseline intake of fruits and vegetables and the risk of hypertension in a large cohort of middle-aged and older women.

Methods

We conducted analyses among 28,082 US female health professionals aged ≥39 years, free of cardiovascular disease, cancer, and hypertension at baseline. Baseline intake of fruits and vegetables was assessed using semi-quantitative food frequency questionnaires. Incident hypertension was identified from annual follow-up questionnaires.

Results

During 12.9 years of follow-up, 13,633 women developed incident hypertension. After basic adjustment including age, race, and total energy intake, the hazard ratio and 95% CI of hypertension was 0.97 (0.89-1.05), 0.93 (0.85-1.01), 0.89 (0.82-0.97), and 0.86 (0.78-0.94) comparing women who consumed 2-<4, 4-<6, 6-<8, and ≥8 servings/day of total fruits and vegetables with those consuming <2 servings/day. These associations did not change after additionally adjusting for lifestyle factors but were attenuated after further adjustment for other dietary factors. When fruits and vegetables were analyzed separately, higher intake of all fruits but not all vegetables remained significantly associated with reduced risk of hypertension after adjustment for lifestyle and dietary factors. Adding body mass index to the models eliminated all associations.

Conclusions

Higher intake of fruits and vegetables, as part of a healthy dietary pattern, may only contribute a modest beneficial effect to hypertension prevention, possibly through improvement in body weight regulation.

BACKGROUND

We have shown that the ouabain-sensitive α2 Na,K-ATPase is required for adrenocorticotropic hormone (ACTH)-induced hypertension and gestational blood pressure regulation. It is therefore of interest to explore whether this binding site participates in the development of other forms of hypertension, such as deoxycorticosterone acetate (DOCA)-salt using mutant mice with altered sensitivity to ouabain.

METHODS

Wild-type (α1 ouabain-resistant, α2 ouabain-sensitive: αR/Rα2S/S), α1-resistant, α2-resistant (α1R/Rα2R/R) and α1 -sensitive, α2-resistant (α1S/Sα2R/R) mice were uninephrectomized and implanted with DOCA pellets. The animals were given either tap water or 1% NaCI, and blood pressure was measured before and after DOCA.

RESULTS

DOCA-salt-treated α1R/Rα2R/R mice developed hypertension to the same extent as α1R/Rα2S/S mice (wild type), and the α1S/Sα2R/R mice given DOCA-salt also showed no difference from the other two genotypes. The expression of the α1 isoform was not changed by DOCA-salt treatment in either α1R/Rα2S/S or α1 R/Rα2R/R mice. However, the α2 subunit was expressed at substantially higher levels in the hearts of α1R/Rα2R/R than α1R/Rα2S/S mice, regardless of treatment. Plasma levels of ouabain did not change consistently, but those of marinobufagenin were modestly higher in DOCA-salt treated mice relatively to those without salt.

CONCLUSIONS

The ouabain-binding site of either the α1 or α2 Na,K-ATPase subunit does not play an essential role in the development of DOCA-salt hypertension in this mouse model. These findings indicate that the underlying mechanisms of hypertension induced by DOCA-salt treatment are different from those of ACTH-induced hypertension.

BACKGROUND

Endogenous ouabain (EO) has been linked with long-term changes in sodium balance and cardiovascular structure and function. The biosynthesis of EO involves, cholesterol side-chain cleavage (CYP11A1), 3-β-hydroxysteroid dehydrogenase (HSD3B) with sequential metabolism of pregnenolone and progesterone. Furthermore, the renal excretion of cardiac glycosides is mediated by the organic anion transporter (SLCO4C1) at the basolateral membrane and the P-glycoprotein (PGP) (encoded by MDR1) at the apical membrane of the nephron.

METHODS

Average 24-h ambulatory blood pressures were recorded in 729 untreated essential hypertensives. Aldosterone (Aldo), EO, urinary Na+, and K+ excretions were determined. Single-nucleotide polymorphism (SNP) and haplotype-based association study was performed with a total of 26 informative SNPs.

RESULTS

Plasma EO was significantly directly related to both day (r = 0.131, P < 0.01) and nighttime diastolic blood pressure (DBP) (r = 0.143, P < 0.01), and remained significantly related after correction for confounders (sex, body mass index, age). Genotype analysis for EO levels and daytime DBP gave significant results for CYP11A1 rs11638442 and MDR1 rs1045642 (T/C Ile1145) in which the minor allele tracked with higher EO levels (T/T 210.3 (147–272) vs. C/C 270.7 (193–366) pmol/l, P < 0.001). Association was found between HSD3B1 polymorphisms and/or haplotypes with blood pressure (systolic blood pressure (SBP) 140.3 (11.7) vs. 143.8 (11.2) mm Hg, P < 0.01) and plasma Aldo (P < 0.05). Haplotype-based analyses support the data of SNP analysis.

CONCLUSIONS

Among patients with essential hypertension, cholesterol side-chain cleavage and MDR1 loci are related to circulating EO and DBP, most likely by influencing EO synthesis and transmembrane transport, respectively. In contrast, variants in HSD3B1 are related with SBP probably via Aldo.

Background

Recent studies suggest a possible association between periodontal disease and hypertension; however, prospective evidence is limited.

Methods

The study population consisted of 31,543 participants of the HPFS prospective cohort who were 40 to 75 years old at baseline, had no prior hypertension history and had complete baseline information on oral health. Information on periodontal disease, hypertension and potential confounders was updated biennially. We used Cox proportional hazards models to study the relation between periodontal disease at baseline, during follow-up, periodontal bone loss severity, baseline number of teeth and tooth loss during follow-up, and the risk of developing hypertension. Multivariate models included age, calendar time, race, comprehensive smoking index, diabetes, alcohol consumption, family history of hypertension, dental profession, BMI, physical activity, fruit and vegetable intake, multivitamin use, calcium, vitamin D and vitamin E intake.

Results

We identified 10,828 cases of incident hypertension over 20 years of follow-up. After adjusting for potential confounders, we did not observe significant associations between incident hypertension and periodontal disease at baseline (RR=1.04; 95% CI: 0.98–1.10), periodontitis during follow-up (RR=1.01; 95% CI: 0.96–1.05), tooth loss during follow-up (RR=1.03; 95% CI: 0.98–1.09), or when comparing men with 0–10 teeth to men with ≥25 teeth at baseline (RR=1.05; 95% CI: 0.91–1.21). Participants reporting severe periodontal bone loss had a relative risk for incident hypertension of 1.02 compared to those without bone loss (95% CI: 0.77–1.35).

Conclusions

We did not observe an association between periodontal disease measures and incident hypertension in this cohort of middle-aged men.

BACKGROUND

Preeclampsia is considered a disease of immunological origin associated with abnormalities in inflammatory cytokines, tumor necrosis factor-α (TNF-α), and activated lymphocytes secreting AT1-AA. Recent studies have also demonstrated that an imbalance of angiogenic factors, soluble fms-like tyrosine kinase (sFlt-1), and sEndoglin, exists in preeclampsia; however, the mechanisms that initiate their overproduction are unclear.

METHODS

To determine the role of immune regulation of these factors, circulating and placental sFlt-1 and/or sEndoglin was examined from pregnant rats chronically treated with TNF-α or AT1-AA. On day 19 of gestation blood pressure was analyzed and serum and tissues were collected. Placental villous explants were excised and cultured on matrigel coated inserts for 24 h and sFlt-1 and sEndoglin was measured from media.

RESULTS

In response to TNF-α-induced hypertension, sFlt-1 increased from 180 ± 5 to 2,907 ± 412 pg/ml. sFlt-1 was also increased from cultured placental explants of TNF-α induced hypertensive pregnant rats (n = 12) (2,544 ± 1,132 pg/ml) vs. explants from normal pregnant (NP) rats (n = 12) (2,189 ± 586 pg/ml) where as sEng was undetectable. Circulating sFlt-1 increased from 245 ± 38 to 3,920 ± 798 pg/ml in response to AT1-AA induced hypertension. sFlt-1 levels were higher (3,400 ± 350 vs. 2,480 ± 900 pg/ml) in placental explants from AT1-AA infused rats (n = 12) than NP rats (n = 7). In addition, sEndoglin increased from 30 ± 2.7 to 44 ± 3.3 pg/ml (P < 0.047) in AT1-AA infused rats but was undetectable in the media of the placental explants.

CONCLUSIONS

These data suggest that immune factors may serve as an important stimulus for both sFlt-1 and sEndoglin production in response to placental ischemia.

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.

Background

There are few available data on the epidemiology of prehypertension

Objective

To determine racial, clinical, and demographic differences in the prevalence of prehypertension and its cross-sectional association with vascular risk factors.

Methods

Cross-sectional analysis of 5553 prehypertensives, 20351 hypertensive’s, and 4246 non hypertensive participants (age ≥45), from a population-based national cohort study (REGARDS total population 30239, of whom 30150 had adequate blood pressure measurements) enrolled from January 2003-October 2007 with over-sampling from the southeastern Stroke Belt, and black individuals. Baseline data were collected using a combination of telephone interview and in-home evaluation. Prehypertension was defined according to JNC 7 guidelines.

Results

The prevalence of pre-hypertension was associated with age and black race (62.9% in blacks compared to 54.1% in whites). A higher prevalence of pre-hypertension was observed in obese individuals, self-reported heart disease; and, those with elevated hsCRP, diabetes, and microalbuminuria compared to those without these factors. Heavy alcohol consumption in white participants was associated with increased odds of pre-hypertension (OR = 1.32) but was even greater in black participants (OR=2.27).

Conclusion

The prevalence of prehypertension increased by age and African-American race. In addition, a higher prevalence of pre-hypertension was observed with elevated hsCRP, diabetes, microalbuminuria, and those with heavy alcohol consumption compared to those without these factors.

Background

Arterial stiffening is one of the hallmarks of vascular aging, and is an important risk factor for cardiovascular morbidity and mortality. Aging is also associated with bone demineralization. Accumulating evidence indicate that arterial stiffness and bone demineralization might share common pathways. The aims of this study were to evaluate whether the association between arterial stiffness and bone demineralization is independent of age, and to explore putative mechanisms that may mediate their relationship.

Methods

A cross-sectional analysis was performed using data from 321 men (68 ± 12 years) and 312 women (65 ± 13 years) of the Baltimore Longitudinal Study of Aging. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) and cross-sectional cortical bone area (cCSA) was assessed at the level of the mid-tibia with CT imaging.

Results

Age was significantly correlated with PWV in men (r=0.38, p<0.0001) and women (r=0.35, p<0.0001). Age was associated with cCSA in women (r=−0.14, p=0.0008), but not in men. Age-adjusted linear regression analysis showed a significant inverse association between PWV and cCSA, in women but not in men. The association between PWV and cCSA remained significant in women after adjusting for age, mean arterial pressure, obesity, menopause, drugs, alcohol intake, physical activity, renal function, serum calcium, and total estradiol concentration.

Conclusions

Independent of age and other shared risk factors, arterial stiffness is inversely related to cortical bone area in women. The sex-specific signaling and molecular pathways that putatively underlie the cross-talk between central arteries and bone are not completely understood.

BACKGROUND

Few prospective studies have evaluated the risk for incident hypertension (HTN) across the normal range of body mass index (BMI). Even fewer studies included body composition and fat distribution measurements in their analyses. In the Aerobics Center Longitudinal Study, we examined HTN risk in women across a wide spectrum of baseline BMI (kg/m2) values and also studied waist circumference (WC, cm), percent body fat, fat mass (FM, kg), and fat-free mass (FFM, kg) on incident HTN in subgroup analyses.

METHODS

A total of 5,296 healthy normotensive women between 20 and 77 years of age completed a baseline examination during 1971–2004, and were followed for HTN incidence. Incident HTN was identified using mail-back surveys.

RESULTS

A total of 592 women reported HTN during a mean 16.7 years of follow-up. Higher BMI, even within the “normal” range, was associated with greater risk of HTN. Compared with women in the lowest fifth of BMI (18.5–20.0 kg/m2), the hazard ratios (HRs) (95% confidence interval (CI)) of developing HTN for women with a BMI of 20.1–21.2, 21.3–22.5, 22.6–24.7, and >24.7 were 1.19 (0.89–1.60), 1.33 (0.99–1.78), 1.36 (1.03–1.81), and 2.01 (1.52–2.66), respectively (Ptrend < 0.001). In a subgroup (n = 3,189) with complete data on all the five adiposity measures, significant positive associations with HTN were seen across incremental fifths of BMI, percent body fat, and FM (Ptrend < 0.05 each), but not WC and FFM.

CONCLUSIONS

Clinicians should emphasize the importance of weight management for the primary prevention of HTN in women.

Preeclampsia is a pregnancy-induced hypertensive disorder characterized by proteinuria and widespread maternal endothelial dysfunction. It remains one of the most common disorders in pregnancy and remains one of the leading causes of maternal and fetal morbidity. Recent research has revealed that placental insufficiency, resulting in hypoxia and ischemia, is a central causative pathway in the development of the disorder. In response, the placenta secretes soluble substances into the maternal circulation which are responsible for the symptomatic phase of the disease. Among the most well characterized factors in the disease pathology are the anti-angiogenic protein soluble fms-like tyrosine kinase-1 (sFlt-1), inflammatory cytokines, and agonistic angiotensin II type-1 receptor autoantibodies. Each of these factors has been shown to induce hypertension experimentally through the production of endothelin-1 (ET-1), a powerful vasoconstrictor. Antagonism of the endothelin-A receptor has proved beneficial in numerous animal models of gestational hypertension, and it remains an intriguing target for pharmacological intervention in preeclampsia.

BACKGROUND

Studies were performed to determine if early treatment with an angiotensin II (Ang II) receptor blocker (ARB), olmesartan, prevents the onset of microalbuminuria by attenuating glomerular podocyte injury in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with type 2 diabetes mellitus.

METHODS

OLETF rats were treated with either a vehicle, olmesartan (10 mg/kg/ day) or a combination of nonspecific vasodilators (hydralazine 15 mg/ kg/day, hydrochlorothiazide 6 mg/kg/day, and reserpine 0.3 mg/kg/ day; HHR) from the age of 7–25 weeks.

RESULTS

OLETF rats were hypertensive and had microalbuminuria from 9 weeks of age. At 15 weeks, OLETF rats had higher Ang II levels in the kidney, larger glomerular desmin-staining areas (an index of podocyte injury), and lower gene expression of nephrin in juxtamedullary glomeruli, than nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. At 25 weeks, OLETF rats showed overt albuminuria, and higher levels of Ang II in the kidney and larger glomerular desmin-staining areas in superficial and juxtamedullary glomeruli compared to LETO rats. Reductions in mRNA levels of nephrin were also observed in superficial and juxtamedullary glomeruli. Although olmesartan did not affect glucose metabolism, it decreased blood pressure and prevented the renal changes in OLETF rats. HHR treatment also reduced blood pressure, but did not affect the renal parameters.

CONCLUSIONS

This study demonstrated that podocyte injury occurs in juxtamedullary glomeruli prior to superficial glomeruli in type 2 diabetic rats with microalbuminuria. Early treatment with an ARB may prevent the onset of albuminuria through its protective effects on juxtamedullary glomerular podocytes.

Background

The reasons for racial/ethnic disparities in hypertension prevalence in the U.S are poorly understood.

Methods

Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), we investigated whether individual and neighborhood-level chronic stressors contribute to these disparities in cross-sectional analyses. The sample consisted of 2679 MESA participants (45–84yrs) residing in Baltimore, New York, and North Carolina. Hypertension was defined as systolic or diastolic blood pressure ≥140 or 90mmHg, or taking anti-hypertensive medications. Individual-level chronic stress was measured by self-reported chronic burden and perceived major and everyday discrimination. A measure of neighborhood (census tract) chronic stressors (i.e. physical disorder, violence) was developed using data from a telephone survey conducted with other residents of MESA neighborhoods. Binomial regression was used to estimate associations between hypertension and race/ethnicity before and after adjustment for individual and neighborhood stressors.

Results

The prevalence of hypertension was 59.5% in African Americans (AA), 43.9% in Hispanics, and 42.0% in whites. Age and sex adjusted relative prevalences of hypertension (compared to whites) were 1.30 [95% Confidence Interval (CI): 1.22–1.38] for AA and 1.16 [95% CI: 1.04–1.31] for Hispanics. Adjustment for neighborhood stressors reduced these to 1.17 [95% CI: 1.11–1.22] and 1.09 [95% CI: 1.00–1.18] respectively. Additional adjustment for individual-level stressors, acculturation, income, education, and other neighborhood features only slightly reduced these associations.

Conclusion

Neighborhood chronic stressors may contribute to race/ethnic differences in hypertension prevalence in the U.S.

We provide an overview of ongoing discovery efforts in the genetics of blood pressure (BP) and hypertension (HTN) traits. Two large genome-wide association meta-analyses of individuals of European descent were recently published, revealing ~13 new loci for BP traits. Only two of these loci harbor genes in a pathway known to affect BP (CYP17A1 and NPPA/NPPB). Functional variants in these loci are still unknown. Few genome-wide association studies (GWAS) of complex diseases have been published from non-European populations. The study of populations with different evolutionary history and linkage disequilibrium (LD) structure, such as individuals of African ancestry, may provide an opportunity to further narrow these regions to identify the causal gene(s). Several collaborative efforts toward discovery of low-frequency variants and copy number variation for BP traits are currently underway. As evidence for new loci for complex diseases accumulates the assessment of the epidemiologic architecture of these variants in populations assumes higher priority. The impact of public health–relevant contexts such as diet, physical activity, psychosocial factors, and aging has not been examined for most common variants associated with BP.

Objective

High dose fish oil supplementation reduces blood pressure (BP) in hypertensive patients. The current study examines how modest variations in omega-3 fatty acid intake may affect BP in a healthy community sample.

Methods

Study participants included 265 Pittsburgh-area adults 30–54 years of age (11% black, 51% female) not taking omega-3 fatty acid supplements or antihypertensive medications. Standardized assessments of clinic and 24-hour ambulatory BP, and pulse rate were obtained. Docosahexanenoic acid (DHA) and eicosapentaenoic acid (EPA) in fasting serum phospholipids were measured by capillary gas chromatography. Regression analyses controlled for age, gender, race, BMI, self-reported sodium intake and physical activity.

Results

Participants included 181 (68%) normotensives, 64 (25%) prehypertensives, and 18 (7%) persons with untreated hypertension. DHA was inversely associated with clinic diastolic (β=−0.121, p= 0.03), awake ambulatory diastolic BP (β=−0.164, p= 0.004), and 24-hour diastolic BP (β=−0.135, p=0.02). A two standard deviation greater DHA was associated with 2.1 mm Hg lower clinic and 2.3 mm Hg lower awake ambulatory diastolic BP. In addition, DHA was inversely associated with pulse rate measured at rest in the clinic. EPA was related to clinic pulse rate but not clinic or ambulatory BP.

Conclusion

In this sample of American adults not on antihypertensive medications, a modest, inverse association was found between DHA exposure and both clinic and ambulatory diastolic BP. Therefore, increasing DHA consumption through diet modification rather than large dose supplementation represents a candidate strategy for future studies of hypertension prevention.

The objective of this study was to determine the impact of stress reduction on blood pressure (BP) in adolescents by the Transcendental Meditation (TM) program. African-American adolescents (aged 16.2 ± 1.3 years) with high normal systolic BP were randomly assigned to either 4-month TM (n = 50) or health education control (n = 50) groups. Ambulatory 24-h BP measures were recorded at pretest, 2- and 4-month post-tests, and 4-month follow-up. Greater decreases in daytime systolic BP (P < .04) and diastolic BP (P < .06) in the TM group compared with the control group across the visits demonstrate a beneficial impact of the TM program in youth at risk for the development of hypertension.

BACKGROUND

Much of the interindividual variation in left ventricular (LV) structure and function is unexplained by established risk factors and may be due to novel or genetic factors. We used pedigree information from 454 tandem markers across the genome to estimate the heritability and linkage of various echocardiographic measures of LV structure and function in a cohort of African-American hypertensive siblings.

METHODS

LV mass was calculated according to the American Society of Echocardiography (ASE) simplified cubed equation and indexed to height2.7. Fractional shortening (FS) was calculated as the percent change in the internal diameter between diastole and systole. Ejection fraction (EF) was calculated from ventricular diameters. Peak mitral early and late diastolic filling velocities were measured from the transmitral pulsed Doppler profile. The maximum-likelihood heritability estimate for each phenotype was obtained using a variance components method. Linkage analyses were performed using the multipoint variance components-based approach.

RESULTS

There was moderate heritability for LV mass index (34%), interventricular septal thickness (29%), diastolic diameter (42%), EF (40%), FS (39%), and mitral early and late diastolic filling velocities (37 and 45%, respectively). The greatest evidence of genetic linkage was observed for LV mass index on chromosome 3 (logarithm of odds (LOD) score = 2.38), LV EF on chromosome 12 (LOD score = 2.39), and mitral E-wave velocity (MVE) on chromosome 19 (LOD score = 2.69).

CONCLUSIONS

In this African-American cohort of hypertensive siblings, the greatest evidence for linkage of LV structure and function was on chromosomes 3, 12, and 19.

BACKGROUND

We recently reported that aldosterone-induced cellular senescence via an increase in p21, a cyclin-dependent kinase (CDK) inhibitor, in rat kidney and cultured human proximal tubular cells. In the present study, we investigated the contribution of aldosterone to the renal p21 expression and senescence during the development of angiotensin II (AngII)-induced hypertension.

METHODS

Mice received 1% salt in drinking water and vehicle or AngII, and were divided into five groups: 1, vehicle; 2, AngII; 3, AngII+olmesartan; 4, AngII+eplerenone; and 5, AngII+hydralazine.

RESULTS

Plasma aldosterone levels were increased by AngII infusion. Eplerenone further elevated the plasma aldosterone level, but olmesartan and hydralazine did not. AngII group showed significant increase in blood pressure compared to vehicle. Olmesartan and hydralazine, but not eplerenone, suppressed the AngII-salt hypertension. The increase in urinary protein excretion by AngII-salt was suppressed only by olmesartan. AngII with high salt induced a greater expression of p21 mRNA in the kidney than vehicle. Olmesartan abolished the increase in p21 expression, whereas neither eplerenone nor hydralazine affected it. AngII with high salt did not change the expression of p16, another CDK inhibitor. The mice lacking p21 showed identical changes on blood pressure and albuminuria in response to AngII with high salt compared to wild type.

CONCLUSION

These results suggest that aldosterone does not predominantly contribute to renal p21 expression and senescence during the development of AngII-salt hypertension, and that the increase in p21 in the kidney is not likely involved in the development of hypertension and albuminuria.

BACKGROUND

Central arterial stiffness is increasingly recognized as an important predictor of cardiovascular events and mortality in older adults; however, few studies have evaluated the association of arterial stiffness with mobility decline, a common consequence of vascular disease.

METHODS

We analyzed the association of pulse wave velocity (PWV), a measure of aortic stiffness, with longitudinal gait speed over seven years in 2,172 participants in the Health, Aging and Body Composition (Health ABC) Study (mean age ± SD 73.6 ± 2.9 years, 48% men, 39% black).

RESULTS

In mixed-effects models adjusted for demographics, each SD (396 cm/s) higher PWV was associated with 0.015 (SE 0.004) m/s slower gait at baseline and throughout the study period in the full cohort (p < 0.001); this relationship was largely explained by hypertension and other vascular risk factors. Among participants with peripheral arterial disease (PAD) (n = 261; 12.7%) each SD higher PWV was independently associated with 0.028 (SE 0.010) m/s slower gait speed at baseline and throughout the study period (p < 0.01).

CONCLUSIONS

These findings suggest that aortic stiffness may be especially detrimental to mobility in older adults with already compromised arterial function.

Background

We have previously documented that central Angiotensin type 2 receptors (AT2R) negatively modulate sympathetic outflow and arterial blood pressure (BP). In the current study, we determined the effects of intracerebroventricular (icv) infusion of Compound 21 (C21), the first selective non-peptide AT2R agonist, on norepinephrine (NE) excretion and BP in rats.

Methods

C21 was icv infused by a Micro-osmotic pump for 7 days. Urinary NE concentration was measured using the Norepinephrine Enzyme Immunoassay kit. BP was recorded by radiotelemetry. After 7 days, the rats were euthanized and three sympathetic relevant brain regions and cerebral cortex were micro-punched to measure nNOS protein expression by Western Blot. In addition, the influence of C21 on neuronal potassium current (IKv) was determined by whole cell patch-clamp in a neuron cell-line, CATH.a.

Results

(1) icv treatment of C21 significantly decreased NE concentration and amount in nighttime urine but had no effect in daytime urine. (2) C21 treated rats exhibited a slight but significant decrease in BP. (3) The effects of C21 on NE excretion and BP were abolished by AT2R antagonist, PD123319, and nitric oxide synthase (NOS) inhibitor, L-NAME. (4) C21 treatment significantly up regulated nNOS expression in the PVN and RVLM, but not in the NTS and cerebral cortex. (5) In CATH.a neurons, C21 treatment significantly increased IKv, which was completely abolished by PD123319 and L-NAME.

Conclusion

These results demonstrate a central inhibitory influence of C21 on sympathetic outflow via a nNOS dependent mechanism, which might be mediated by facilitating neuronal potassium channel.

Background

Nitric oxide (NO)-dependent vasodilation is impaired in middle cerebral arteries (MCas) from Dahl salt-sensitive (SS) rats that are fed normal salt (NS) diet, due to low plasma renin activity and chronic exposure to low plasma angiotensin II (aNG II) levels. NO-dependent vasodilator responses are rescued in MCas from Ren1-BN congenic rats, which have a 2.0 Mbp portion of Brown Norway (BN) chromosome 13 containing the renin gene introgressed onto the Dahl SS genetic background.

Methods

Vascular superoxide levels were measured with dihydroethidium (DHE) fluorescence in basilar arteries from 10- to 14-week-old, male Dahl SS and Ren1-BN congenic rats that fed NS diet. Nicotinamide adenine dinucleotide phosphate (NaDPH) oxidase and xanthine oxidase (XO) activity were also measured in cerebral artery tissue homogenates. Expression of the superoxide dismutase (SOD) enzymes was evaluated via western blotting in cerebral arteries from the two rat strains.

results

Superoxide levels were significantly higher in basilar arteries from Dahl SS rats compared to Ren1-BN congenic rats. NaDPH oxidase and XO activity were similar between the two rat strains. Cu/Zn SOD expression was significantly higher in cerebral arteries from Ren1-BN congenic rats vs. those from Dahl SS rats. The expression of Mn-SOD was similar in cerebral arteries from both strains.

conclusions

These findings suggest that introgressing the BN renin allele onto the Dahl SS genetic background to restore normal activity of the renin-angiotensin system (RaS) protects NO-dependent vascular relaxation in cerebral arteries by increasing the expression of Cu/Zn SOD and lowering vascular superoxide levels.

BACKGROUND

Pre-eclampsia (PE) is a serious hypertensive disorder of pregnancy characterized by excessive production of a soluble form of the vascular endothelial growth factor (VEGF) receptor-1, termed soluble fms-like tyrosine kinase-1 (sFlt-1). This placental-derived factor is believed to be a key contributor to the clinical features of PE. Women with PE are also characterized by the presence of autoantibodies, termed angiotensin type 1 receptor activating autoantibody (AT1-AA), that activate the major angiotensin receptor, AT1. These autoantibodies cause clinical features of PE and elevated sFlt-1 when injected into pregnant mice. The research reported here used this autoantibody-injection model of PE to assess the therapeutic potential of recombinant VEGF121, a relatively stable form of the natural ligand.

METHODS

Immunoglobulin G (IgG) from women with PE was injected into pregnant mice with or without continuous infusion of recombinant VEGF121. Injected mice were monitored for symptoms of PE.

RESULTS

As a result of infusion of recombinant VEGF121 autoantibody-induced hypertension (systolic blood pressure) was reduced from 159 ± 5 to 124 ± 5 mm Hg, proteinuria from 111 ± 16 to 40 ± 5 mg protein/mg creatinine and blood urea nitrogen levels from 31 ± 1 mg/ dl to 18 ± 2 mg/dl, P < 0.05. Histological analysis revealed that autoantibody-induced glomerular damage including the narrowing of Bowman’s space and occlusion of capillary loop spaces was largely prevented by VEGF121 infusion. Finally, impaired placental angiogenesis resulting from AT1-AA injection was significantly improved by VEGF121 infusion.

CONCLUSIONS

The infusion of recombinant VEGF121 significantly attenuated autoantibody-induced features of PE.