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Cardiovascular Risk Factors Increase with Obesity Severity in African American Youth with and without type 2 Diabetes (T2DM)
COSEHC Abstracts LOSS OF OVARIAN HORMONES INCREASES SALT SENSITIVITY IN NORMOTENSIVE WOMEN I.H. Schulman, P. Aranda, L. Raij, M. Veronesi, F.J. Aranda, R. Martin. Veterans Affairs Medical Center and University of Miami Miller School of Medicine (IHS, PA, LR, MV), Miami, FL, and Hypertension and Vascular Risk Unit, University General Hospital (FJA, RM), Malaga, Spain . Salt sensitivity is associated with an elevated risk of developing hypertension and is an independent risk factor for cardiovascular morbidity and mortality. Cross-sectional studies have suggested that postmenopausal women are more salt sensitive than premenopausal women. The purpose of the present study was to investigate prospectively the prevalence of salt sensitivity among healthy premenopausal women and determine whether the loss of ovarian hormones increases salt sensitivity. We enrolled 40 normotensive (systolic blood pressure 127 ⫾ 2, diastolic blood pressure 78 ⫾ 1; Mean ⫾ SEM), non-diabetic women (age 47 ⫾ 0.6) undergoing hysterectomy and ovariectomy for non-neoplastic processes to determine the effect of changes in sodium intake on blood pressure the day before and 4 months after surgical menopause. After a 1-week diet containing 120 mmol/day NaCl, salt loading was achieved with a 2-liter infusion of normal saline, followed by salt depletion produced by 40 mg of intravenous furosemide. A decrease of 10 mm Hg in systolic blood pressure between salt loading and salt depletion was used to define salt sensitivity. Premenopausal salt sensitive women exhibited higher waist/hip ratio (0.85 ⫾ 0.017 vs. 0.82 ⫾ 0.007; P ⫽ 0.001), fasting glucose (105.9 ⫾ 2.9 vs. 98.5 ⫾ 3.1 mg/dL; P ⫽ 0.03), triglycerides (155 ⫾ 35 vs. 90 ⫾ 6 mg/dL; P ⬍ 0.0001), uric acid (4.5 ⫾ 0.22 vs. 3.7 ⫾ 0.16 mg/dL; P ⬍ 0.0001), apoB (145.6 ⫾ 5.4 vs. 112.5 ⫾ 3.3 mg/dL; P ⬍ 0.0001) and microalbuminuria (20.2 ⫾ 7.3 vs. 4.5 ⫾ 1.4 mg/24hr; P ⬍ 0.0001) than salt resistant women. Four months after surgical menopause, none of the women were on hormone replacement and all remained normotensive (systolic blood pressure 127 ⫾ 3, diastolic blood pressure 77 ⫾ 2). However, the prevalence of salt sensitivity was significantly higher after menopause (21 women, 52.5%) than before (9 women, 22.5%, P ⫽ 0.01), because 12 (38.7%) salt resistant women de-
60
veloped salt sensitivity after menopause. Thus, we found that the prevalence of salt sensitivity doubled as early as 4 months after surgical menopause, due to the development of salt sensitivity in previously salt resistant women. The women who developed salt sensitivity did not manifest an increase in blood pressure or in the above markers of cardiovascular risk. However, epidemiological studies indicate that, in most women, development of hypertension does not occur until 5–10 years after menopause. We surmise that the loss of ovarian hormones unmasks a population of women prone to salt sensitivity that with aging would be at higher risk for the development of hypertension and its associated cardiovascular morbidity and mortality. DEFINING COMMUNITY STRATEGIES TO REDUCE THE IMPACT OF CARDIOVASCULAR DISEASE M.A. Moore, T.R. Motley, K. Plumb. Dan River Region Cardiovascular Health Initiative (DRchip), Danville, VA. Strategies are needed to translate research outcomes to community CV benefits. The Dan River Cardiovascular (CV) Health Initiative Program (DRchip), a COSEHC Cardiovascular Center of Excellence, is an NHLBI Education & Dissemination Center, in a high CV mortality community. Four interventions were tested. Interventions: 1) faithbased, business, and community CV risk screening and education; 2) middle school student CV health education, risk factor screening, and physical activity promotion; 3) enhanced physician CV continuing medical education (ECCME) with clinical educational outcomes; 4) community case management (CM) of congestive heart failure (CHF). Study Population: 1) Over 6000 adults over 3 years were CV screened and educated, 2) 431 middle school children were screened annually for 3 years and received 22 hours per year of CV education, 3) 10 of 49 physicians chose to participate in CV ECCME, and 4) 39 hospital CHF patients entered CHF CM. Outcomes: 1) CV adult screening, 45% BP ⬎140/90 mm Hg, 11% blood cholesterol ⬎200 mg, and/or 20% elevated BMI. All referred to medical management. 2) In 2002 among 6th, 7th, and 8th grade middle school children (MSC) the prevalence of overweight (OW) (⬎85th percentile for age/gender) was 19%, 25%, 60% & the prevalence of HBP (⬎90th percentile for age) was 9%, 10%, 15%, respectively. In 2003 the prevalence among 6th, 7th, and 8th grade MSC February 2006 Volume 331 Number 2
of OW had increased to 61%, 46%, and 48% with the prevalence of HBP being 6%, 11%, and 11%, respectively. In response to this MSC data, fried foods and high sugar content juices were removed from school foods and heart healthy alternatives were provided. After-school DRchip physical activity program was begun. MSCs reported improved CV lifestyles. 3) Systolic HBP control was better over 6 months by 10 ECCME physicians compared to 29 non ECCCME physicians.(ECCME: 156.6 vs. 134.7 mm Hg; P ⬍ 0.004) (Non-ECCME physicians 157.7 vs. 139.7; (NS). 4) None of the 39 CHF CM patients returned to the emergency room (ER); 3 readmitted to hospital for terminal care. Conclusions: The community interventions were shown to 1) identify adults with CV risk factors, 2a) identify a high prevalence of OW MSC of whom 10.3% (mean of 3 grades/2 yrs) had HBP, 2b) improved MSC CV lifestyles opportunities, 3) improved systolic HBP control by ECCME physicians, and 4) eliminate hospital ER of CM CHF patients. DISPARITIES IN BLOOD PRESSURE BETWEEN AFRICAN AMERICANS AND NON-HISPANIC WHITE ADULTS WITH TYPE 2 DIABETES: A META-ANALYSIS J. Kirk, L. Passmore, R. D’Agostino Jr, A. Bertoni, R. Bell, V. Narayan. Family and Community Medicine (JK) and Public Health Sciences (LP, RD, AB, RB), Wake Forest University Health Sciences Center, Winston-Salem, NC, and Division of Diabetes Translation (VN), National Center for Chronic Disease Prevention and Health, Rockville, MD. Purpose: Poor blood pressure (BP) control is a risk factor for diabetes micro- and macrovascular complications, and the prevalence of some of these complications is higher among U.S. minority groups. We undertook a meta-analysis comparing BP between African Americans and non-Hispanic whites with diabetes. Methods: Data Sources included PubMed, Web of Science, Cumulative Index to Nursing and Allied Health, the Cochrane Library, Combined Health Information Database, and the Education Resources Information Center. A search of these databases was conducted from 1993 through 2005. Studies of patients with diabetes in which comparisons were made between African Americans and non-Hispanic whites were included. Persons with diabetes aged ⬍18 years and those with prediabetes or gestational diabetes were excluded. We used mean and standard deviation values to conduct a meta-analysis to estimate the difference in systolic and diastolic BP values between African Americans and non-Hispanic whites. Data on sample size, age, gender, geographical location, and study design were also extracted. Results: 117 studies met our search criteria, of which 9 had mean and standard deviation data for BP in African Americans and THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
non-Hispanic whites. A meta-analysis estimated the standardized effect size to be -0.25 (95% confidence interval, -0.30, -0.21) for systolic BP and -0.27 (95% confidence interval, -0.32, -0.21) for diastolic BP. This corresponds to an approximate BP difference between groups of approximately 4.9 mm Hg higher systolic BP and 2.8 mm Hg higher diastolic BP for African Americans. Conclusion: Patients with diabetes who were African Americans had clinically meaningful higher BP across studies than non-Hispanic whites in this meta-analysis. REGULATION OF BRAIN NEPRILYSIN AND ACE2 IN TRANSGENIC RATS DURING AGING M.A. Garcia-Espinosa, S. Vinsant, P.E. Gallagher, C.M. Ferrario, D. Ganten, M.C. Chappell, D.I. Diz. Hypertension & Vascular Disease Center, Wake Forest University Health Sciences Center, Winston-Salem, NC. Angiotensinogen (Aogen), the precursor to angiotensin (Ang) II and Ang-(1–7) is expressed in astrocytes and neurons. Neprilysin and angiotensin-converting enzyme 2 (ACE2) are potential enzymes for Ang-(1–7) formation from Ang I and Ang II respectively. We assessed their regulation in brain during aging in transgenic rats (ASrAogen) with an Aogen antisense behind a glial-promoter. These exhibit a 90% reduction in brain Aogen levels and low blood pressure that is maintained during aging at 16 and 70 weeks in hypothalamus (HYPO) and medulla (MED). HYPO ACE2 mRNA was 45% higher in ASrAogen than control SD rats and higher in older ASrAogen vs. younger rats. Neprilysin mRNA tended to increase during aging and values were 80% higher in ASrAogen vs. SD. In MED, mRNA of both enzymes during aging tended to decrease with no difference between strains. Immunocytochemistry revealed ACE2-staining in both strains localized to circumventricular organs and plexus choroideus. Thus, the ACE2 distribution suggests the enzyme contributes to Ang-(1–7) in cerebrospinal fluid but not neural pathways. Up regulation of mRNA for both enzymes in HYPO of ASrAogen rats may represent compensation for loss of glial-derived peptides. Lack of differences in MED between strains may reflect distinct sources (neural vs. glial) of peptides responsible for enzyme regulation in the two brain areas. CARDIOVASCULAR RISK FACTORS INCREASE WITH OBESITY SEVERITY IN AFRICAN AMERICAN YOUTH WITH AND WITHOUT TYPE 2 DIABETES (T2DM) P. Cowan, P. Velasquez-Mieyer, M. Christensen, S. Perez-Faustinelli. The University of Tennessee Health Science Center, Memphis, TN. Background: The increase in childhood Type 2 Diabetes (T2DM) has paralleled the epidemic in61
Groups
BMI
RBMI (%)
HBA1c
TC (mg/dL)
HDL (mg/dL)
LDL (mg/dL)
TRI (mg/dL)
CRP (mg/L)
FIB (mg/dL)
T2DM (54) Non-DM (44)
40.2 ⫾ 9.8 36.2 ⫾ 9.5
204 ⫾ 47 196 ⫾ 44
8.2 ⫾ 2.7 5.5 ⫾ 0.5a
178 ⫾ 44 170 ⫾ 30
42 ⫾ 11 48 ⫾ 12a
107 ⫾ 28 104 ⫾ 26
129 ⫾ 106 88 ⫾ 31a
0.7 ⫾ 0.8 0.8 ⫾ 1.4
393 ⫾ 83 370 ⫾ 71
Values means ⫾ SD. a P ⬍ 0.05 between groups.
crease in childhood obesity. T2DM and obesity in adults are associated with increased risk for cardiovascular disease with African-Americans (AA) disproportionately affected. This study evaluated whether obese AA youth with and without T2DM exhibit a similar cardiovascular risk (CVR) profile and if severity of obesity affects the CVR profile. Methods: Overweight AA youth without (Non-DM, n ⫽ 44, 70% female, 13.3 ⫾ 2.8 yr) and with T2DM (n ⫽ 54, 67% female, 14 ⫾ 2.3 yr) underwent a physical examination with resting BP, fasting levels of fibrinogen (FIB), lipids, and HBA1c measured. In a subgroup (n⫽60), C-reactive protein (CRP) levels were obtained. Relative BMI (RBMI) was used as an estimate of percent overweight (BMI/50th percentile BMI on CDC chart*100 for gender and age). Results: Although younger in age (P ⬍ 0.05), the Non-DM group had a similar incidence of elevated FIB (⬎400 mg) (34 vs. 46%), CRP (⬎0.5 mg) (44% vs. 29%), and BP (55% vs. 39%) compared to the T2DM group (P ⫽ NS). Based on National Cholesterol Education Program guidelines, dyslipidemia was present in 81% T2DM compared to 60% Non-DM (X2 ⫽ 5.26, P ⫽ 0.02). In addition to obesity, 88% of Non-DM and 93% of T2DM had at least one additional CVR factor of dyslipidemia, hypertension or elevated FIB. For the entire cohort, higher RBMI was associated with higher FIB (r ⫽ 0.36, P ⫽ 0.001), CRP (r ⫽ 0.50, P ⬍ 0.001), and increased number of CVR factors (r ⫽ 0.34, P ⬍ 0.001) but not lipid levels. Higher HbA1c values were associated with higher triglyceride (r ⫽ 0.33, P ⫽ 0.001) and total cholesterol (r ⫽ 0.30, P ⫽ 0.003). These associations persisted after adjusting for age. The number of CVR factors was similar between groups at comparable RBMI, with both groups exhibiting an increased number of CVR factors at higher RBMI (P ⬍ 0.05). Table 1. Conclusion: Severity of obesity contributes to CVR in overweight AA youth, regardless of concomitant diagnosis of type 2 diabetes, suggesting that control of glycemia, while critical, is insufficient to reduce CVR. The presence of CVR factors prior to manifestation of T2DM might account for the earlier manifestation and higher prevalence of CVD in AA with T2DM. Screening for CVR factors and development of treatment strategies for weight and CVR management are needed for all overweight AA youth regardless of diabetes status. 62
COLLECTING DUCT RENIN IN 2K1C GOLDBLATT HYPERTENSIVE RATS IS UP-REGULATED BY ANGIOTENSIN II INDEPENDENTLY OF HIGH BLOOD PRESSURE M. Prieto-Carrasquero, F. Botros, H. Kobori, L.G. Navar. Hypertension and Renal Center of Excellence, Department of Physiology, Tulane University Health Science Center, New Orleans, LA. Chronic angiotensin II (AngII) infusion leads to hypertension and stimulation of proximal tubule angiotensinogen and augmentation of collecting duct (CD) renin, specifically in principal cells. The present study was performed to determine if the enhancement of CD renin in AngII-dependent hypertension is a direct effect of AngII or primarily due to the elevated arterial blood pressure by evaluating renin mRNA and protein levels separately in renal cortex and medulla of both kidneys in two-kidney, one-clip rats (2K1C) prepared by placing a 0.25 mm clip on left renal artery. After 25 days, systolic blood pressure in 2K1C (n ⫽ 8) was 196 ⫾ 3 mm Hg compared to 116 ⫾ 2 mm Hg in sham-operated rats (n ⫽ 8); kidney (0.2 ⫾ 0.0 vs. 1.0 ⫾ 0.0 DU) but increased in the clipped kidney (1.7 ⫾ 1.0 vs. 1.0 ⫾ 0.0 DU) compared to sham. However, renin immunoreactivity in cortical and medullary CDs increased in both kidneys of 2K1C rats compared to sham (clipped ⫽ 2.8 ⫾ 1.5 cortex; 2.1 ⫾ 1.0 medulla; non-clipped ⫽ 4.6 ⫾ 2.3 cortex; 3.2 ⫾ 0.8 medulla vs. 1.0 ⫾ 0.0 DU) compared to sham. Renin protein levels assessed by Western blot in kidney medulla of 2K1C rats were also increased compared to sham (1.4 ⫾ 0.2 in clipped and 1.5 ⫾ 0.3 in non-clipped). Likewise, renin mRNA levels measured by real-time qRT-PCR were higher in medullary tissue from both kidneys of 2K1C (clipped ⫽ 10 ⫾ 4.0; non-clipped ⫽ 4.3 ⫾ 2.6) compared to sham rats. Increased expression of renin in principal cells of CDs of clipped as well as non- clipped kidneys is consistent with the hypothesis that intrarenal AngII levels stimulate renin in distal nephron segment independently of high blood pressure. The increased distal tubular renin may contribute to increased intrarenal and intratubular AngII formation in AngII-dependent hypertension. Supported by grants from NIH (P20RR017659), HL 26371, AHA-0325269B and the February 2006 Volume 331 Number 2
Louisiana Board of Regents Millennium Excellence Fund (2001-06-07). ACUTE INTRA-ARTERIAL ADMINISTRATION OF CHOLESTEROL CAUSES RENAL VASOCONSTRICTION AND ANTINATRIURESIS IN RATS L. Kopkan, M.S. Awayda, D.S.A. Majid. Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA. An increase in circulating cholesterol level concentration chronically induces vascular dysfunction and aggravates the condition of hypertension. However, the mechanistic role of cholesterol in the pathophysiological process of hypertension remains poorly understood. To examine the hypothesis that increased cholesterol influences renal hemodynamic and tubular function leading to sodium retention, we evaluated the renal responses to polyoxyethanylcholesteryl sebacate (PEG-Chol) as well as cholesterol sequestered with methyl-cyclodextrin (MCDChol) at a dose 8g/min/100g of body weight infused directly into the left renal artery of anesthetized male Sprague-Dawley rats for 60 min. Total renal blood flow (RBF) was measured by a Transonic flow probe and regional (cortical, CBF and medullary, MBF) blood flow was measured by laser-Doppler needle flow probes. Glomerular filtration rate (GFR) was determined by inulin clearance. Observed renal responses to acute infusion of PEG-Chol (n ⫽ 6) and MCD-Chol (n ⫽ 6) were similar, therefore these data were combined. Compared to the control period, administration of cholesterol caused slight decreased of 10 ⫾ 2 % in RBF (baseline, B 7.6 ⫾ 0.3 mL/min/g), 8 ⫾ 1 % in CBF (B 210 ⫾ 11 perfusion unit; PU), 7 ⫾ 2 % in MBF (B 67 ⫾ 4 PU) and 5 ⫾ 2 % in GFR (B 0.87 ⫾ 0.03mL/min/g). Moreover, cholesterol infusion also caused marked reductions of 14 ⫾ 2 % in urine flow (B 12.9 ⫾ 0.9 L/min/g), 28 ⫾ 3 % in sodium excretion (B 1.10 ⫾ 0.08 mol/min/g) and 22 ⫾ 2 % in fractional sodium excretion (B 0.87 ⫾ 0.06 %) without affecting potassium excretion. Infusion of vehicle did not cause any changes in renal parameters. These data suggest that hypercholesterolemia compromises the kidney’s ability to excrete sodium appropriately and thus could play a role in the pathophysiology of salt-sensitivity and hypertension. ALTERED STRESS RESPONSES IN RATS WITH LOW GLIAL ANGIOTENSINOGEN S.O. Kasper, A. Sakima, C.M. Ferrario, D. Ganten, D.I. Diz. Hypertension and Vascular Disease Center, Wake Forest University Health Sciences Center, Winston-Salem, NC. Rats with low glial-derived angiotensinogen (ASrAogen) have higher AT1 receptors in subforniTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
cal organ and paraventericular nucleus, brain regions important in stress responses, compared to Sprague-Dawley (SD) rats at 48 and 68 weeks of age consistent with decreased tissue angiotensins (Ang). However, neuronal expression of Ang II and Ang(1–7) in these nuclei is similar between strains. We measured systolic blood pressure (SBP) and baroreflex sensitivity (BRS; bradycardia in response to increase in pressure) in conscious 68 week old rats with intracerebroventricular (i.c.v.) cannulae. SBP averaged 151 mm Hg in SD and 122 mm Hg in ASrAogen rats, confirming their lower resting SBP (P ⬍ 0.05). When ASrAogen animals were handled for connection of i.c.v. catheters or when candesartan but not saline was given, there was an increase in heart rate (HR) and signs of arousal. There were no cardiovascular or behavioral changes in SD animals to either handling or i.c.v. injections. BRS was increased in SD rats after i.c.v. candesartan, but not saline, as previously reported. However, in ASrAogen animals there was a trend for decreased BRS after saline administration, consistent with the observed stress response, which is known to attenuate BRS. Thus, in the absence of glial-derived Ang peptides, intact neural pathways of the brain reninangiotensin system important in stress responses are enhanced and associated with suppression of BRS. PREDICTORS OF BLOOD PRESSURE CONTROL IN PRIMARY CARE PATIENTS T. Santiago, C.A. Plauschinat, F. Frech, D. Carmouche. The Baton Rouge Clinic AMC (TS, DC), Baton Rouge, LA, and Novartis Pharmaceuticals Corporation (CP, FF), East Hanover, NJ. Purpose: Clinical trial evidence has demonstrated the benefits of blood pressure (BP) lowering in reducing cardiovascular-related morbidity and mortality. Despite this fact, BP control in primary care settings remains poor. The purpose of this study was to evaluate BP control and its predictors in a primary care hypertensive population. Methods: Patients with a primary diagnosis for hypertension (ICD-9 401.xx) were randomly selected from medical claims. A retrospective chart review was conducted (n ⫽ 506) to obtain demographic, behavioral, and clinical characteristics. Logistic regression techniques were performed to identify predictors of BP control, defined as systolic ⬍140 mm Hg and diastolic ⬍90 mm Hg (patients with diabetes, systolic ⬍130 mm Hg and diastolic ⬍80 mm Hg). Variables of interest included age, gender, race, body mass index (BMI) medication compliance, tobacco use, diabetes, family history of premature cardiovascular disease, heart failure, dyslipidemia, left ventricular hypertrophy, and stroke. Results: Approximately 55% of the random sample was female with a mean 63
age of 63 ⫾ 14 (SD) years. The mean number of cardiovascular risk factors was 2.7. A majority (61%, n⫽309) of patients had controlled BP. After controlling for age and gender, having diabetes (n ⫽ 99) reduced the odds of achieving BP control by 86% (95% CI 0.08 – 0.24) when compared to patients with BP control. Patients with poor medication compliance reported in their charts (n ⫽ 38) reduced the odds of control by 65% (95% CI 0.17– 0.72). Other variables, including race (OR 0.93, 95% CI 0.82–
64
1.05) and BMI (OR 0.96, 95% CI 0.93–1.00), were not significant predictors of BP control. Conclusion: BP control in this hypertensive population was higher than previous estimates of 31% (NHANES 1999 – 2000). Hypertensive patients with diabetes and poor medication compliance are at an increased risk for uncontrolled BP. Identification, education, and more aggressive treatment of this high-risk population may reduce future cardiovascular-related complications and mortality.
February 2006 Volume 331 Number 2
60
veloped salt sensitivity after menopause. Thus, we found that the prevalence of salt sensitivity doubled as early as 4 months after surgical menopause, due to the development of salt sensitivity in previously salt resistant women. The women who developed salt sensitivity did not manifest an increase in blood pressure or in the above markers of cardiovascular risk. However, epidemiological studies indicate that, in most women, development of hypertension does not occur until 5–10 years after menopause. We surmise that the loss of ovarian hormones unmasks a population of women prone to salt sensitivity that with aging would be at higher risk for the development of hypertension and its associated cardiovascular morbidity and mortality. DEFINING COMMUNITY STRATEGIES TO REDUCE THE IMPACT OF CARDIOVASCULAR DISEASE M.A. Moore, T.R. Motley, K. Plumb. Dan River Region Cardiovascular Health Initiative (DRchip), Danville, VA. Strategies are needed to translate research outcomes to community CV benefits. The Dan River Cardiovascular (CV) Health Initiative Program (DRchip), a COSEHC Cardiovascular Center of Excellence, is an NHLBI Education & Dissemination Center, in a high CV mortality community. Four interventions were tested. Interventions: 1) faithbased, business, and community CV risk screening and education; 2) middle school student CV health education, risk factor screening, and physical activity promotion; 3) enhanced physician CV continuing medical education (ECCME) with clinical educational outcomes; 4) community case management (CM) of congestive heart failure (CHF). Study Population: 1) Over 6000 adults over 3 years were CV screened and educated, 2) 431 middle school children were screened annually for 3 years and received 22 hours per year of CV education, 3) 10 of 49 physicians chose to participate in CV ECCME, and 4) 39 hospital CHF patients entered CHF CM. Outcomes: 1) CV adult screening, 45% BP ⬎140/90 mm Hg, 11% blood cholesterol ⬎200 mg, and/or 20% elevated BMI. All referred to medical management. 2) In 2002 among 6th, 7th, and 8th grade middle school children (MSC) the prevalence of overweight (OW) (⬎85th percentile for age/gender) was 19%, 25%, 60% & the prevalence of HBP (⬎90th percentile for age) was 9%, 10%, 15%, respectively. In 2003 the prevalence among 6th, 7th, and 8th grade MSC February 2006 Volume 331 Number 2
of OW had increased to 61%, 46%, and 48% with the prevalence of HBP being 6%, 11%, and 11%, respectively. In response to this MSC data, fried foods and high sugar content juices were removed from school foods and heart healthy alternatives were provided. After-school DRchip physical activity program was begun. MSCs reported improved CV lifestyles. 3) Systolic HBP control was better over 6 months by 10 ECCME physicians compared to 29 non ECCCME physicians.(ECCME: 156.6 vs. 134.7 mm Hg; P ⬍ 0.004) (Non-ECCME physicians 157.7 vs. 139.7; (NS). 4) None of the 39 CHF CM patients returned to the emergency room (ER); 3 readmitted to hospital for terminal care. Conclusions: The community interventions were shown to 1) identify adults with CV risk factors, 2a) identify a high prevalence of OW MSC of whom 10.3% (mean of 3 grades/2 yrs) had HBP, 2b) improved MSC CV lifestyles opportunities, 3) improved systolic HBP control by ECCME physicians, and 4) eliminate hospital ER of CM CHF patients. DISPARITIES IN BLOOD PRESSURE BETWEEN AFRICAN AMERICANS AND NON-HISPANIC WHITE ADULTS WITH TYPE 2 DIABETES: A META-ANALYSIS J. Kirk, L. Passmore, R. D’Agostino Jr, A. Bertoni, R. Bell, V. Narayan. Family and Community Medicine (JK) and Public Health Sciences (LP, RD, AB, RB), Wake Forest University Health Sciences Center, Winston-Salem, NC, and Division of Diabetes Translation (VN), National Center for Chronic Disease Prevention and Health, Rockville, MD. Purpose: Poor blood pressure (BP) control is a risk factor for diabetes micro- and macrovascular complications, and the prevalence of some of these complications is higher among U.S. minority groups. We undertook a meta-analysis comparing BP between African Americans and non-Hispanic whites with diabetes. Methods: Data Sources included PubMed, Web of Science, Cumulative Index to Nursing and Allied Health, the Cochrane Library, Combined Health Information Database, and the Education Resources Information Center. A search of these databases was conducted from 1993 through 2005. Studies of patients with diabetes in which comparisons were made between African Americans and non-Hispanic whites were included. Persons with diabetes aged ⬍18 years and those with prediabetes or gestational diabetes were excluded. We used mean and standard deviation values to conduct a meta-analysis to estimate the difference in systolic and diastolic BP values between African Americans and non-Hispanic whites. Data on sample size, age, gender, geographical location, and study design were also extracted. Results: 117 studies met our search criteria, of which 9 had mean and standard deviation data for BP in African Americans and THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
non-Hispanic whites. A meta-analysis estimated the standardized effect size to be -0.25 (95% confidence interval, -0.30, -0.21) for systolic BP and -0.27 (95% confidence interval, -0.32, -0.21) for diastolic BP. This corresponds to an approximate BP difference between groups of approximately 4.9 mm Hg higher systolic BP and 2.8 mm Hg higher diastolic BP for African Americans. Conclusion: Patients with diabetes who were African Americans had clinically meaningful higher BP across studies than non-Hispanic whites in this meta-analysis. REGULATION OF BRAIN NEPRILYSIN AND ACE2 IN TRANSGENIC RATS DURING AGING M.A. Garcia-Espinosa, S. Vinsant, P.E. Gallagher, C.M. Ferrario, D. Ganten, M.C. Chappell, D.I. Diz. Hypertension & Vascular Disease Center, Wake Forest University Health Sciences Center, Winston-Salem, NC. Angiotensinogen (Aogen), the precursor to angiotensin (Ang) II and Ang-(1–7) is expressed in astrocytes and neurons. Neprilysin and angiotensin-converting enzyme 2 (ACE2) are potential enzymes for Ang-(1–7) formation from Ang I and Ang II respectively. We assessed their regulation in brain during aging in transgenic rats (ASrAogen) with an Aogen antisense behind a glial-promoter. These exhibit a 90% reduction in brain Aogen levels and low blood pressure that is maintained during aging at 16 and 70 weeks in hypothalamus (HYPO) and medulla (MED). HYPO ACE2 mRNA was 45% higher in ASrAogen than control SD rats and higher in older ASrAogen vs. younger rats. Neprilysin mRNA tended to increase during aging and values were 80% higher in ASrAogen vs. SD. In MED, mRNA of both enzymes during aging tended to decrease with no difference between strains. Immunocytochemistry revealed ACE2-staining in both strains localized to circumventricular organs and plexus choroideus. Thus, the ACE2 distribution suggests the enzyme contributes to Ang-(1–7) in cerebrospinal fluid but not neural pathways. Up regulation of mRNA for both enzymes in HYPO of ASrAogen rats may represent compensation for loss of glial-derived peptides. Lack of differences in MED between strains may reflect distinct sources (neural vs. glial) of peptides responsible for enzyme regulation in the two brain areas. CARDIOVASCULAR RISK FACTORS INCREASE WITH OBESITY SEVERITY IN AFRICAN AMERICAN YOUTH WITH AND WITHOUT TYPE 2 DIABETES (T2DM) P. Cowan, P. Velasquez-Mieyer, M. Christensen, S. Perez-Faustinelli. The University of Tennessee Health Science Center, Memphis, TN. Background: The increase in childhood Type 2 Diabetes (T2DM) has paralleled the epidemic in61
Groups
BMI
RBMI (%)
HBA1c
TC (mg/dL)
HDL (mg/dL)
LDL (mg/dL)
TRI (mg/dL)
CRP (mg/L)
FIB (mg/dL)
T2DM (54) Non-DM (44)
40.2 ⫾ 9.8 36.2 ⫾ 9.5
204 ⫾ 47 196 ⫾ 44
8.2 ⫾ 2.7 5.5 ⫾ 0.5a
178 ⫾ 44 170 ⫾ 30
42 ⫾ 11 48 ⫾ 12a
107 ⫾ 28 104 ⫾ 26
129 ⫾ 106 88 ⫾ 31a
0.7 ⫾ 0.8 0.8 ⫾ 1.4
393 ⫾ 83 370 ⫾ 71
Values means ⫾ SD. a P ⬍ 0.05 between groups.
crease in childhood obesity. T2DM and obesity in adults are associated with increased risk for cardiovascular disease with African-Americans (AA) disproportionately affected. This study evaluated whether obese AA youth with and without T2DM exhibit a similar cardiovascular risk (CVR) profile and if severity of obesity affects the CVR profile. Methods: Overweight AA youth without (Non-DM, n ⫽ 44, 70% female, 13.3 ⫾ 2.8 yr) and with T2DM (n ⫽ 54, 67% female, 14 ⫾ 2.3 yr) underwent a physical examination with resting BP, fasting levels of fibrinogen (FIB), lipids, and HBA1c measured. In a subgroup (n⫽60), C-reactive protein (CRP) levels were obtained. Relative BMI (RBMI) was used as an estimate of percent overweight (BMI/50th percentile BMI on CDC chart*100 for gender and age). Results: Although younger in age (P ⬍ 0.05), the Non-DM group had a similar incidence of elevated FIB (⬎400 mg) (34 vs. 46%), CRP (⬎0.5 mg) (44% vs. 29%), and BP (55% vs. 39%) compared to the T2DM group (P ⫽ NS). Based on National Cholesterol Education Program guidelines, dyslipidemia was present in 81% T2DM compared to 60% Non-DM (X2 ⫽ 5.26, P ⫽ 0.02). In addition to obesity, 88% of Non-DM and 93% of T2DM had at least one additional CVR factor of dyslipidemia, hypertension or elevated FIB. For the entire cohort, higher RBMI was associated with higher FIB (r ⫽ 0.36, P ⫽ 0.001), CRP (r ⫽ 0.50, P ⬍ 0.001), and increased number of CVR factors (r ⫽ 0.34, P ⬍ 0.001) but not lipid levels. Higher HbA1c values were associated with higher triglyceride (r ⫽ 0.33, P ⫽ 0.001) and total cholesterol (r ⫽ 0.30, P ⫽ 0.003). These associations persisted after adjusting for age. The number of CVR factors was similar between groups at comparable RBMI, with both groups exhibiting an increased number of CVR factors at higher RBMI (P ⬍ 0.05). Table 1. Conclusion: Severity of obesity contributes to CVR in overweight AA youth, regardless of concomitant diagnosis of type 2 diabetes, suggesting that control of glycemia, while critical, is insufficient to reduce CVR. The presence of CVR factors prior to manifestation of T2DM might account for the earlier manifestation and higher prevalence of CVD in AA with T2DM. Screening for CVR factors and development of treatment strategies for weight and CVR management are needed for all overweight AA youth regardless of diabetes status. 62
COLLECTING DUCT RENIN IN 2K1C GOLDBLATT HYPERTENSIVE RATS IS UP-REGULATED BY ANGIOTENSIN II INDEPENDENTLY OF HIGH BLOOD PRESSURE M. Prieto-Carrasquero, F. Botros, H. Kobori, L.G. Navar. Hypertension and Renal Center of Excellence, Department of Physiology, Tulane University Health Science Center, New Orleans, LA. Chronic angiotensin II (AngII) infusion leads to hypertension and stimulation of proximal tubule angiotensinogen and augmentation of collecting duct (CD) renin, specifically in principal cells. The present study was performed to determine if the enhancement of CD renin in AngII-dependent hypertension is a direct effect of AngII or primarily due to the elevated arterial blood pressure by evaluating renin mRNA and protein levels separately in renal cortex and medulla of both kidneys in two-kidney, one-clip rats (2K1C) prepared by placing a 0.25 mm clip on left renal artery. After 25 days, systolic blood pressure in 2K1C (n ⫽ 8) was 196 ⫾ 3 mm Hg compared to 116 ⫾ 2 mm Hg in sham-operated rats (n ⫽ 8); kidney (0.2 ⫾ 0.0 vs. 1.0 ⫾ 0.0 DU) but increased in the clipped kidney (1.7 ⫾ 1.0 vs. 1.0 ⫾ 0.0 DU) compared to sham. However, renin immunoreactivity in cortical and medullary CDs increased in both kidneys of 2K1C rats compared to sham (clipped ⫽ 2.8 ⫾ 1.5 cortex; 2.1 ⫾ 1.0 medulla; non-clipped ⫽ 4.6 ⫾ 2.3 cortex; 3.2 ⫾ 0.8 medulla vs. 1.0 ⫾ 0.0 DU) compared to sham. Renin protein levels assessed by Western blot in kidney medulla of 2K1C rats were also increased compared to sham (1.4 ⫾ 0.2 in clipped and 1.5 ⫾ 0.3 in non-clipped). Likewise, renin mRNA levels measured by real-time qRT-PCR were higher in medullary tissue from both kidneys of 2K1C (clipped ⫽ 10 ⫾ 4.0; non-clipped ⫽ 4.3 ⫾ 2.6) compared to sham rats. Increased expression of renin in principal cells of CDs of clipped as well as non- clipped kidneys is consistent with the hypothesis that intrarenal AngII levels stimulate renin in distal nephron segment independently of high blood pressure. The increased distal tubular renin may contribute to increased intrarenal and intratubular AngII formation in AngII-dependent hypertension. Supported by grants from NIH (P20RR017659), HL 26371, AHA-0325269B and the February 2006 Volume 331 Number 2
Louisiana Board of Regents Millennium Excellence Fund (2001-06-07). ACUTE INTRA-ARTERIAL ADMINISTRATION OF CHOLESTEROL CAUSES RENAL VASOCONSTRICTION AND ANTINATRIURESIS IN RATS L. Kopkan, M.S. Awayda, D.S.A. Majid. Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA. An increase in circulating cholesterol level concentration chronically induces vascular dysfunction and aggravates the condition of hypertension. However, the mechanistic role of cholesterol in the pathophysiological process of hypertension remains poorly understood. To examine the hypothesis that increased cholesterol influences renal hemodynamic and tubular function leading to sodium retention, we evaluated the renal responses to polyoxyethanylcholesteryl sebacate (PEG-Chol) as well as cholesterol sequestered with methyl-cyclodextrin (MCDChol) at a dose 8g/min/100g of body weight infused directly into the left renal artery of anesthetized male Sprague-Dawley rats for 60 min. Total renal blood flow (RBF) was measured by a Transonic flow probe and regional (cortical, CBF and medullary, MBF) blood flow was measured by laser-Doppler needle flow probes. Glomerular filtration rate (GFR) was determined by inulin clearance. Observed renal responses to acute infusion of PEG-Chol (n ⫽ 6) and MCD-Chol (n ⫽ 6) were similar, therefore these data were combined. Compared to the control period, administration of cholesterol caused slight decreased of 10 ⫾ 2 % in RBF (baseline, B 7.6 ⫾ 0.3 mL/min/g), 8 ⫾ 1 % in CBF (B 210 ⫾ 11 perfusion unit; PU), 7 ⫾ 2 % in MBF (B 67 ⫾ 4 PU) and 5 ⫾ 2 % in GFR (B 0.87 ⫾ 0.03mL/min/g). Moreover, cholesterol infusion also caused marked reductions of 14 ⫾ 2 % in urine flow (B 12.9 ⫾ 0.9 L/min/g), 28 ⫾ 3 % in sodium excretion (B 1.10 ⫾ 0.08 mol/min/g) and 22 ⫾ 2 % in fractional sodium excretion (B 0.87 ⫾ 0.06 %) without affecting potassium excretion. Infusion of vehicle did not cause any changes in renal parameters. These data suggest that hypercholesterolemia compromises the kidney’s ability to excrete sodium appropriately and thus could play a role in the pathophysiology of salt-sensitivity and hypertension. ALTERED STRESS RESPONSES IN RATS WITH LOW GLIAL ANGIOTENSINOGEN S.O. Kasper, A. Sakima, C.M. Ferrario, D. Ganten, D.I. Diz. Hypertension and Vascular Disease Center, Wake Forest University Health Sciences Center, Winston-Salem, NC. Rats with low glial-derived angiotensinogen (ASrAogen) have higher AT1 receptors in subforniTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
cal organ and paraventericular nucleus, brain regions important in stress responses, compared to Sprague-Dawley (SD) rats at 48 and 68 weeks of age consistent with decreased tissue angiotensins (Ang). However, neuronal expression of Ang II and Ang(1–7) in these nuclei is similar between strains. We measured systolic blood pressure (SBP) and baroreflex sensitivity (BRS; bradycardia in response to increase in pressure) in conscious 68 week old rats with intracerebroventricular (i.c.v.) cannulae. SBP averaged 151 mm Hg in SD and 122 mm Hg in ASrAogen rats, confirming their lower resting SBP (P ⬍ 0.05). When ASrAogen animals were handled for connection of i.c.v. catheters or when candesartan but not saline was given, there was an increase in heart rate (HR) and signs of arousal. There were no cardiovascular or behavioral changes in SD animals to either handling or i.c.v. injections. BRS was increased in SD rats after i.c.v. candesartan, but not saline, as previously reported. However, in ASrAogen animals there was a trend for decreased BRS after saline administration, consistent with the observed stress response, which is known to attenuate BRS. Thus, in the absence of glial-derived Ang peptides, intact neural pathways of the brain reninangiotensin system important in stress responses are enhanced and associated with suppression of BRS. PREDICTORS OF BLOOD PRESSURE CONTROL IN PRIMARY CARE PATIENTS T. Santiago, C.A. Plauschinat, F. Frech, D. Carmouche. The Baton Rouge Clinic AMC (TS, DC), Baton Rouge, LA, and Novartis Pharmaceuticals Corporation (CP, FF), East Hanover, NJ. Purpose: Clinical trial evidence has demonstrated the benefits of blood pressure (BP) lowering in reducing cardiovascular-related morbidity and mortality. Despite this fact, BP control in primary care settings remains poor. The purpose of this study was to evaluate BP control and its predictors in a primary care hypertensive population. Methods: Patients with a primary diagnosis for hypertension (ICD-9 401.xx) were randomly selected from medical claims. A retrospective chart review was conducted (n ⫽ 506) to obtain demographic, behavioral, and clinical characteristics. Logistic regression techniques were performed to identify predictors of BP control, defined as systolic ⬍140 mm Hg and diastolic ⬍90 mm Hg (patients with diabetes, systolic ⬍130 mm Hg and diastolic ⬍80 mm Hg). Variables of interest included age, gender, race, body mass index (BMI) medication compliance, tobacco use, diabetes, family history of premature cardiovascular disease, heart failure, dyslipidemia, left ventricular hypertrophy, and stroke. Results: Approximately 55% of the random sample was female with a mean 63
age of 63 ⫾ 14 (SD) years. The mean number of cardiovascular risk factors was 2.7. A majority (61%, n⫽309) of patients had controlled BP. After controlling for age and gender, having diabetes (n ⫽ 99) reduced the odds of achieving BP control by 86% (95% CI 0.08 – 0.24) when compared to patients with BP control. Patients with poor medication compliance reported in their charts (n ⫽ 38) reduced the odds of control by 65% (95% CI 0.17– 0.72). Other variables, including race (OR 0.93, 95% CI 0.82–
64
1.05) and BMI (OR 0.96, 95% CI 0.93–1.00), were not significant predictors of BP control. Conclusion: BP control in this hypertensive population was higher than previous estimates of 31% (NHANES 1999 – 2000). Hypertensive patients with diabetes and poor medication compliance are at an increased risk for uncontrolled BP. Identification, education, and more aggressive treatment of this high-risk population may reduce future cardiovascular-related complications and mortality.
February 2006 Volume 331 Number 2