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1.
Am J Cardiol ; 112(1): 73-8, 2013 Jul 01.
Article in English | MEDLINE | ID: mdl-23597770

ABSTRACT

Myocardial extracellular matrix expansion and reduced coronary flow reserve (CFR) occur in patients with type 2 diabetes mellitus without heart failure or coronary artery disease. Because aldosterone is implicated in the pathophysiology of cardiac fibrosis and vascular injury, the aim of this study was to test the hypothesis that aldosterone is associated with extracellular matrix expansion and reduced CFR in type 2 diabetes mellitus. Patients with type 2 diabetes mellitus without evidence of coronary artery disease were recruited. Blood pressure, lipid management, and glycemic control were optimized over 3 months. Cardiac magnetic resonance imaging with T1 mapping was used to measure myocardial extracellular volume (ECV). Cardiac positron emission tomography was used to assess CFR. On a liberal, 250 mEq/day sodium diet, 24-hour urinary aldosterone and change in serum aldosterone with angiotensin II stimulation were measured. Fifty-three participants with type 2 diabetes (68% men, mean age 53 ± 7 years, mean body mass index 32.2 ± 4.3 kg/m², mean glycosylated hemoglobin 6.8 ± 0.7%, mean systolic blood pressure 126 ± 14 mm Hg) without infarction or ischemia by cardiac magnetic resonance and positron emission tomography were studied. Subjects had impaired CFR (2.51 ± 0.83) and elevated ECV (0.36 ± 0.05), despite normal echocardiographic diastolic function and normal left ventricular function. Myocardial ECV, but not CFR, was positively associated with 24-hour urinary aldosterone excretion (r = 0.37, p = 0.01) and angiotensin II-stimulated aldosterone increase (r = 0.35, p = 0.02). In a best-overall multivariate model (including age, gender, body mass index, glycosylated hemoglobin, and blood pressure), 24-hour urinary aldosterone was the strongest predictor of myocardial ECV (p = 0.004). In conclusion, in patients with type 2 diabetes mellitus without coronary artery disease, aldosterone is associated with myocardial extracellular matrix expansion. These results implicate aldosterone in early myocardial remodeling in type 2 diabetes mellitus.


Subject(s)
Aldosterone/blood , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/pathology , Extracellular Matrix/pathology , Adolescent , Adult , Aged , Biomarkers/blood , Contrast Media , Echocardiography , Electrocardiography , Female , Gadolinium DTPA , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Positron-Emission Tomography
2.
Eur Heart J ; 34(16): 1204-14, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23144048

ABSTRACT

AIMS: The effect of resistant hypertension on outcomes in patients with atherothrombotic disease is currently unknown. Accordingly, we sought to determine the prevalence and outcomes of resistant hypertension in stable hypertensive outpatients with subclinical or established atherothombotic disease enrolled in the international Reduction of Atherothrombosis for Continued Health (REACH) registry. METHODS AND RESULTS: Resistant hypertension was defined as a blood pressure ≥140/90 mmHg at baseline (≥130/80 mmHg if diabetes/renal insufficiency) with the use of ≥3 antihypertensive medications, including a diuretic. The primary outcome was a composite of cardiovascular death, myocardial infarction, or stroke at 4 years. A total of 53 530 hypertensive patients were included. The prevalence of resistant hypertension was 12.7%; 6.2% on 3 antihypertensive agents, 4.6% on 4 agents, and 1.9% on ≥5 agents (mean: 4.7 ± 0.8). In addition to a diuretic, these patients were being treated mostly with ACE-inhibitors/angiotensin receptor blockers (90.1%), beta-blockers (67.0%), and calcium channel blockers (50.8%). Patients with resistant hypertension had a higher risk of the primary endpoint on multivariable analysis [hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.02-1.20; P = 0.017], including an increased non-fatal stroke risk (HR: 1.26; 95% CI: 1.10-1.45; P = 0.0008). Hospitalizations due to congestive heart failure were higher (P < 0.0001). Patients on ≥5 agents had a higher adjusted risk for the primary endpoint when compared with those on ≤3 agents (P = 0.03). CONCLUSION: The presence of resistant hypertension identifies a subgroup of patients with hypertension and atherothrombosis who are at heightened risk for adverse long-term outcomes.


Subject(s)
Antihypertensive Agents/therapeutic use , Atherosclerosis/complications , Hypertension/etiology , Thrombosis/complications , Aged , Atherosclerosis/mortality , Drug Resistance , Female , Follow-Up Studies , Hospitalization/statistics & numerical data , Humans , Hypertension/drug therapy , Hypertension/mortality , Male , Myocardial Infarction/etiology , Myocardial Infarction/mortality , Stroke/etiology , Stroke/mortality , Thrombosis/mortality , Treatment Outcome
3.
Nature ; 481(7382): 516-9, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22246326

ABSTRACT

Mass spectrometry with stable isotope labels has been seminal in discovering the dynamic state of living matter, but is limited to bulk tissues or cells. We developed multi-isotope imaging mass spectrometry (MIMS) that allowed us to view and measure stable isotope incorporation with submicrometre resolution. Here we apply MIMS to diverse organisms, including Drosophila, mice and humans. We test the 'immortal strand hypothesis', which predicts that during asymmetric stem cell division chromosomes containing older template DNA are segregated to the daughter destined to remain a stem cell, thus insuring lifetime genetic stability. After labelling mice with (15)N-thymidine from gestation until post-natal week 8, we find no (15)N label retention by dividing small intestinal crypt cells after a four-week chase. In adult mice administered (15)N-thymidine pulse-chase, we find that proliferating crypt cells dilute the (15)N label, consistent with random strand segregation. We demonstrate the broad utility of MIMS with proof-of-principle studies of lipid turnover in Drosophila and translation to the human haematopoietic system. These studies show that MIMS provides high-resolution quantification of stable isotope labels that cannot be obtained using other techniques and that is broadly applicable to biological and medical research.


Subject(s)
Cell Division , Mass Spectrometry/methods , Stem Cells/cytology , Stem Cells/metabolism , Animals , Animals, Newborn , DNA/biosynthesis , DNA/genetics , DNA/metabolism , Drosophila melanogaster/cytology , Enterocytes/cytology , Fibroblasts/cytology , Humans , Intestine, Small/cytology , Isotope Labeling , Isotopes , Leukocytes/cytology , Lipid Metabolism , Lymphopoiesis , Mice , Mice, Inbred C57BL , Models, Biological , Stem Cells/pathology , Templates, Genetic , Thymidine/metabolism
4.
Thromb Haemost ; 107(1): 59-68, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22116191

ABSTRACT

A significant proportion of warfarin dose variability is explained by variation in the genotypes of the cytochrome P450 CYP2C9 and the vitamin K epoxide reductase complex, VKORC1, enzymes that influence warfarin metabolism and sensitivity, respectively. We sought to develop an optimal pharmacogenetic warfarin dosing algorithm that incorporated clinical and genetic information. We enroled patients initiating warfarin therapy. Genotyping was performed of the VKORC1, -1639G>A, the CYP2C9*2, 430C>T, and the CYP2C9*3, 1075C>A genotypes. The initial warfarin dosing algorithm (Algorithm A) was based upon established clinical practice and published warfarin pharmacogenetic information. Subsequent dosing algorithms (Algorithms B and Algorithm C) were derived from pharmacokinetic / pharmacodynamic (PK/PD) modelling of warfarin dose, international normalised ratio (INR), clinical and genetic factors from patients treated by the preceding algorithm(s). The primary outcome was the time in the therapeutic range, considered an INR of 1.8 to 3.2. A total of 344 subjects are included in the study analyses. The mean percentage time within the therapeutic range for each subject increased progressively from Algorithm A to Algorithm C from 58.9 (22.0), to 59.7 (23.0), to 65.8 (16.9) percent (p = 0.04). Improvement also occurred in most secondary endpoints, which included the per-patient percentage of INRs outside of the therapeutic range (p = 0.004), the time to the first therapeutic INR (p = 0.07), and the time to achieve stable therapeutic anticoagulation (p < 0.001). In conclusion, warfarin pharmacogenetic dosing can be optimised in real time utilising observed PK/PD information in an adaptive fashion.


Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Mixed Function Oxygenases/genetics , Warfarin/therapeutic use , Adult , Aged , Algorithms , Anticoagulants/therapeutic use , Cytochrome P-450 CYP2C9 , Female , Genotype , Humans , International Normalized Ratio , Male , Middle Aged , Models, Genetic , Nomograms , Pharmacogenetics/methods , Prospective Studies , Vitamin K Epoxide Reductases
5.
Clin Sci (Lond) ; 122(4): 193-202, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21861845

ABSTRACT

AngII (angiotensin II) may contribute to cardiovascular risk in obesity via adverse effects on insulin sensitivity and endothelial function. In the present study, we examined the effects of ARB (angiotensin receptor blocker) therapy (losartan, 100 mg/day) on insulin sensitivity and endothelial function in 53 subjects with stage I hypertension, abdominal obesity and impaired fasting glucose. The study design was a randomized double-blinded parallel design placebo-controlled multi-centre trial of 8 weeks duration. We used the hyperinsulinaemic-euglycaemic clamp technique to measure insulin sensitivity (expressed as the 'M/I' value) and RH-PAT (reactive hyperaemia-peripheral arterial tonometry) to measure endothelial function. Additional measures included HOMA (homoeostasis model assessment)-B, an index of pancreatic ß-cell function, and markers of inflammation [e.g. CRP (C-reactive protein)] and oxidative stress (e.g. F2-isoprostanes). ARB therapy did not alter insulin sensitivity [5.2 (2.7) pre-treatment and 4.6 (1.6) post-treatment] compared with placebo therapy [6.1 (2.9) pre-treatment and 5.3 (2.7) post-treatment; P value not significant], but did improve the HOMA-B compared with placebo therapy (P=0.05). ARB therapy also did not change endothelial function [RH-PAT, 2.15 (0.7) pre-treatment and 2.11 (0.7) post-treatment] compared with placebo therapy [RH-PAT, 1.81 (0.5) pre-treatment and 1.76 (0.7) post-treatment; P value not significant]. Markers of inflammation and oxidative stress were not significantly changed by ARB therapy. In conclusion, ARB therapy did not alter peripheral insulin sensitivity or endothelial function in this cohort of patients with essential hypertension, abdominal obesity and impaired fasting glucose, but did improve pancreatic ß-cell function.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/therapeutic use , Glucose Metabolism Disorders/drug therapy , Hypertension/drug therapy , Losartan/therapeutic use , Obesity, Abdominal/complications , Vasodilation/drug effects , Adult , Angiotensin II Type 1 Receptor Blockers/pharmacology , Blood Pressure/drug effects , Creatinine/blood , Double-Blind Method , Endothelium, Vascular/drug effects , Female , Glucose Metabolism Disorders/complications , Heart Rate/drug effects , Humans , Hypertension/complications , Losartan/pharmacology , Male , Middle Aged , Potassium/blood
6.
Circulation ; 124(1): 17-23, 2011 Jul 05.
Article in English | MEDLINE | ID: mdl-21690489

ABSTRACT

BACKGROUND: Whether individuals with peripheral artery disease (PAD) identified by screening ankle-brachial index benefit from preventive therapies to reduce cardiovascular risk is unknown. We aimed to determine the number of US adults with PAD who are not receiving preventive therapies and whether treatment is associated with reduced mortality in PAD subjects without known cardiovascular disease. METHODS AND RESULTS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 with mortality follow-up through December 31, 2006. We defined PAD as an ankle-brachial index ≤0.90. Of 7458 eligible participants ≥40 years, weighted PAD prevalence was 5.9±0.3% (mean±SE), corresponding to ≈7.1 million US adults with PAD. Statin use was reported in only 30.5±2.5%, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use in 24.9±1.9%, and aspirin use in 35.8±2.9%, corresponding to 5.0 million adults with PAD not taking statins, 5.4 million not taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 4.5 million not receiving aspirin. After adjustment for age, sex, and race/ethnicity, PAD was associated with all-cause mortality (hazard ratio, 2.4; 95% confidence interval, 1.9 to 2.9; P<0.0001). Even after exclusion of individuals with known cardiovascular disease, subjects with PAD had higher mortality rates (16.1±2.1%) than subjects without PAD or cardiovascular disease (4.1±0.3%), with an adjusted hazard ratio of 1.9 (95% confidence interval, 1.3 to 2.8; P=0.001). Among PAD subjects without cardiovascular disease, use of multiple preventive therapies was associated with 65% lower all-cause mortality (hazard ratio, 0.35; 95% confidence interval, 0.20 to 0.86; P=0.02). CONCLUSIONS: Millions of US adults with PAD are not receiving secondary prevention therapies. Treatment with multiple therapies is associated with reduced all-cause mortality.


Subject(s)
Nutrition Surveys , Peripheral Arterial Disease/mortality , Peripheral Arterial Disease/prevention & control , Secondary Prevention/trends , Aged , Angiotensin II Type 2 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Aspirin/therapeutic use , Cardiovascular Diseases/epidemiology , Female , Humans , Male , Peripheral Arterial Disease/drug therapy , Prevalence , Retrospective Studies , Risk Factors , United States
7.
Blood ; 117(10): 2800-6, 2011 Mar 10.
Article in English | MEDLINE | ID: mdl-21239700

ABSTRACT

Anemia and vitamin D deficiency are conditions that both result in significant morbidity and increase with age. The potential relationship between them remains poorly understood, particularly in the elderly. We used the Third National Health and Nutrition Examination Survey to examine the association of vitamin D deficiency with anemia subtypes in persons aged ≥ 60 years. Vitamin D deficiency was defined as serum levels < 20 ng/mL, and anemia was defined according to World Health Organization criteria. Vitamin D deficiency was associated with anemia prevalence independent of age, sex, or race/ethnicity (odds ratio, 1.47; 95% confidence interval, 1.06-2.05; P = .02) and varied significantly by anemia subtype (P overall = .003). The prevalence of vitamin D deficiency was 33.3% in the nonanemic population, 56% in anemia of inflammation (AI; P = .008), and 33.0% in unexplained anemia (P = .55). Non-Hispanic blacks had a 7-fold increased risk of AI compared with whites, and this was partially attenuated after adjusting for vitamin D deficiency. These data show that vitamin D deficiency is associated with specific subtypes of anemia in the elderly, especially in those with AI. Vitamin D may suppress inflammatory pathways, and studies to determine whether vitamin D supplementation ameliorates AI are warranted.


Subject(s)
Anemia/complications , Anemia/epidemiology , Vitamin D Deficiency/complications , Vitamin D Deficiency/epidemiology , Female , Humans , Inflammation/complications , Inflammation/epidemiology , Male , Middle Aged , Nutrition Surveys , Prevalence , Vitamin D/analogs & derivatives , Vitamin D/metabolism , Vitamin D Deficiency/blood
8.
Arterioscler Thromb Vasc Biol ; 31(1): 190-6, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21051665

ABSTRACT

OBJECTIVE: Reduced limb perfusion from arterial stenosis does not adequately account for intermittent claudication symptoms in peripheral artery disease (PAD). Insulin resistance is associated with PAD and may contribute to claudication by impairing skeletal muscle metabolism. We aimed to determine whether skeletal muscle glucose uptake, assessed by [(18)F]fluorodeoxyglucose positron emission tomography, is reduced in patients with claudication. METHODS AND RESULTS: Thirty-seven subjects with PAD and claudication and 11 healthy controls underwent [(18)F]fluorodeoxyglucose-positron emission tomography imaging of the legs during hyperinsulinemic-euglycemic clamp. Calf glucose uptake was quantified by graphical Patlak analysis, and whole-body insulin sensitivity was assessed as the glucose disposal rate (M) from the insulin clamp. Compared with healthy controls, PAD subjects were insulin resistant (M=3.4 mg/kg per minute [interquartile range, 2.7 to 4.8] versus 5.0 [3.7 to 6.6], P=0.019). Calf muscle glucose uptake was significantly lower in PAD compared with healthy subjects (48.6±2.6 µmol/kg per minute versus 62.9±6.5 µmol/kg per minute, P=0.009) and correlated with systemic insulin sensitivity (r=0.37, P=0.03) in PAD subjects. These abnormalities persisted even after exclusion of PAD subjects with diabetes. CONCLUSIONS: Patients with claudication have impaired calf muscle glucose uptake. Future studies are required to assess whether calf muscle insulin resistance contributes to exercise limitation in patients with intermittent claudication.


Subject(s)
Blood Glucose/metabolism , Fluorodeoxyglucose F18 , Intermittent Claudication/metabolism , Muscle, Skeletal/metabolism , Peripheral Arterial Disease/metabolism , Positron-Emission Tomography , Radiopharmaceuticals , Aged , Biological Transport , Boston , Case-Control Studies , Chi-Square Distribution , Diabetes Mellitus/diagnostic imaging , Diabetes Mellitus/metabolism , Female , Glucose Clamp Technique , Humans , Insulin Resistance , Intermittent Claudication/diagnostic imaging , Kinetics , Lower Extremity , Male , Middle Aged , Muscle, Skeletal/blood supply , Muscle, Skeletal/diagnostic imaging , Peripheral Arterial Disease/diagnostic imaging , Predictive Value of Tests
9.
Environ Res ; 110(2): 199-206, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20060521

ABSTRACT

BACKGROUND: It is unclear whether environmental cadmium exposure is associated with cardiovascular disease, although recent data suggest associations with myocardial infarction and peripheral arterial disease. OBJECTIVE: The objective of this study was to evaluate the association of measured cadmium exposure with stroke and heart failure (HF) in the general population. METHODS: We analyzed data from 12,049 participants, aged 30 years and older, in the 1999-2006 National Health and Nutrition Examination Survey (NHANES) for whom information was available on body mass index, smoking status, alcohol consumption, and socio-demographic characteristics. RESULTS: At their interviews, 492 persons reported a history of stroke, and 471 a history of HF. After adjusting for demographic and cardiovascular risk factors, a 50% increase in blood cadmium corresponded to a 35% increased odds of prevalent stroke [OR: 1.35; 95% confidence interval (CI): 1.12-1.65] and a 50% increase in urinary cadmium corresponded to a 9% increase in prevalent stroke [OR: 1.09; 95% CI: 1.00-1.19]. This association was higher among women [OR: 1.38; 95% CI: 1.11-1.72] than men [OR: 1.30; 95% CI: 0.93-1.79] (p-value for interaction=0.05). A 50% increase in blood cadmium corresponded to a 48% increased odds of prevalent HF [OR: 1.48; 95% CI: 1.17-1.87] and a 50% increase in urinary cadmium corresponded to a 12% increase in prevalent HF [OR: 1.12; 95% CI: 1.03-1.20], with no difference in sex-specific associations. CONCLUSIONS: Environmental exposure to cadmium was associated with significantly increased stroke and heart failure prevalence. Cadmium exposure may increase these important manifestations of cardiovascular disease.


Subject(s)
Cadmium Poisoning/epidemiology , Cadmium/blood , Cadmium/urine , Environmental Exposure/adverse effects , Heart Failure/epidemiology , Stroke/epidemiology , Adult , Cadmium Poisoning/blood , Cadmium Poisoning/urine , Cross-Sectional Studies , Female , Heart Failure/blood , Heart Failure/chemically induced , Heart Failure/urine , Humans , Logistic Models , Male , Multivariate Analysis , Nutrition Surveys , Prevalence , Stroke/blood , Stroke/chemically induced , Stroke/urine , Surveys and Questionnaires , United States/epidemiology
11.
Arch Intern Med ; 169(6): 588-94, 2009 Mar 23.
Article in English | MEDLINE | ID: mdl-19307522

ABSTRACT

BACKGROUND: Red blood cell distribution width (RDW), an automated measure of red blood cell size heterogeneity (eg, anisocytosis) that is largely overlooked, is a newly recognized risk marker in patients with established cardiovascular disease (CVD). It is unknown whether RDW is associated with mortality in the general population or whether this association is specific to CVD. METHODS: We examined the association of RDW with all-cause mortality and with CVD, cancer, and chronic lower respiratory tract disease mortality in 15 852 adult participants in the Third National Health and Nutrition Examination Survey (1988-1994), a nationally representative sample of the US population. Mortality status was obtained by matching to the National Death Index, with follow-up through December 31, 2000. RESULTS: Estimated mortality rates increased 5-fold from the lowest to the highest quintile of RDW after accounting for age and 2-fold after multivariable adjustment (P(trend) < .001 for each). A 1-SD increment in RDW (0.98%) was associated with a 23% greater risk of all-cause mortality (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.18-1.28) after multivariable adjustment. The RDW was also associated with risk of death due to CVD (HR, 1.22; 95% CI, 1.14-1.31), cancer (1.28; 1.21-1.36), and chronic lower respiratory tract disease (1.32; 1.17-1.49). CONCLUSIONS: Higher RDW is associated with increased mortality risk in this large, community-based sample, an association not specific to CVD. Study of anisocytosis may, therefore, yield novel pathophysiologic insights, and measurement of RDW may contribute to risk assessment.


Subject(s)
Cardiovascular Diseases/mortality , Erythrocytes/cytology , Lung Diseases/mortality , Neoplasms/mortality , Adult , Aged , C-Reactive Protein/metabolism , Cardiovascular Diseases/blood , Cardiovascular Diseases/pathology , Cell Size , Female , Humans , Lung Diseases/blood , Lung Diseases/pathology , Male , Middle Aged , Neoplasms/blood , Neoplasms/pathology , Nutrition Surveys , Prospective Studies , Risk Factors , United States/epidemiology , Young Adult
12.
Am J Med ; 121(9): 781-788.e1, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18724968

ABSTRACT

BACKGROUND: Bilirubin inhibits experimental atherosclerosis, is inversely associated with carotid plaque burden, and confers neuroprotection in experimental stroke. Clinical data addressing the association of bilirubin with stroke are not available. We hypothesized that higher bilirubin levels would be associated with reduced stroke prevalence and improved stroke outcomes. METHODS: We used the National Health and Nutrition Examination Survey 1999 to 2004, a nationally representative cross-sectional examination of the United States civilian population, to examine the association of bilirubin with stroke. Of 13,214 adult participants with data on stroke history, serum total bilirubin level, and stroke risk factors, 453 reported a history of stroke. Of these, 138 participants reported an adverse stroke outcome, defined as a long-term health problem or disability due to stroke. We performed multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) with adjustment for demographic characteristics and stroke risk factors. RESULTS: After multivariable adjustment, a 1.71 micromol/L (0.1 mg/dL) increment in bilirubin level was associated with a 9% reduced odds of stroke (OR 0.91; 95% CI, 0.86-0.96) among all participants and with a 10% reduced odds of an adverse stroke outcome (OR 0.90; 95% CI, 0.80-1.00) among participants with a history of stroke. CONCLUSIONS: These results suggest that a higher serum total bilirubin level is associated with reduced stroke prevalence and improved stroke outcomes. Our findings support the hypothesis that bilirubin may protect from stroke events and from neurologic damage in stroke.


Subject(s)
Bilirubin/blood , Stroke/blood , Stroke/epidemiology , Adult , Aged , Blood Pressure Determination , Cross-Sectional Studies , Female , Humans , Logistic Models , Male , Middle Aged , Nutrition Surveys , Odds Ratio , Prevalence , Risk Factors , United States/epidemiology
13.
Circulation ; 118(1): 33-41, 2008 Jul 01.
Article in English | MEDLINE | ID: mdl-18559705

ABSTRACT

BACKGROUND: Although the role of inflammation in the pathophysiology of peripheral arterial disease (PAD) is well established, the contribution of insulin resistance (IR) to PAD is less clear. We hypothesized that IR is associated with PAD and that the presence of IR would influence the association between C-reactive protein (CRP) and PAD, an association established predominantly in healthy individuals. METHODS AND RESULTS: We analyzed data from 3242 adults in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 who underwent measurement of ankle brachial index, CRP, and fasting glucose and insulin, enabling calculation of homeostasis model of IR (HOMA-IR). Odds ratios (ORs) and 95% CIs were estimated by logistic regression. The mean prevalence of PAD (defined as an ankle brachial index 3 mg/L) also was strongly associated with PAD (OR, 2.2; 95% CI, 1.3 to 3.6; P=0.003 versus CRP <1 mg/L). Stratifying subjects on the basis of median HOMA-IR, we found that CRP >3 mg/L was no longer significantly associated with PAD in subjects with IR (OR, 1.3; 95% CI, 0.8 to 2.1; P=0.3, P for interaction=0.08). CONCLUSIONS: These findings demonstrate that IR is strongly and independently associated with PAD. Furthermore, IR modifies the association of inflammation with PAD. These data establish a role of IR in PAD and highlight the relative importance of inflammation in patients with and without IR.


Subject(s)
Health Surveys , Inflammation/complications , Insulin Resistance , Peripheral Vascular Diseases/complications , Adult , Aged , Blood Glucose/analysis , Blood Pressure , C-Reactive Protein/analysis , Comorbidity , Humans , Inflammation/blood , Inflammation/epidemiology , Logistic Models , Middle Aged , Nephelometry and Turbidimetry/methods , Nutrition Surveys , Odds Ratio , Peripheral Vascular Diseases/blood , Peripheral Vascular Diseases/epidemiology , Sensitivity and Specificity , United States/epidemiology
14.
Arterioscler Thromb Vasc Biol ; 28(1): 166-72, 2008 Jan.
Article in English | MEDLINE | ID: mdl-17975120

ABSTRACT

BACKGROUND: Bilirubin, with recently recognized antioxidant and antiinflammatory activity, has emerged as a candidate for atheroprotection. We hypothesized that higher levels of bilirubin would reduce susceptibility to peripheral arterial disease (PAD). METHODS AND RESULTS: We analyzed 7075 adults with data available on the ankle brachial index, serum total bilirubin level, and PAD risk factors in the National Health and Nutrition Examination Survey (1999 to 2004), a nationally representative cross-sectional examination of the United States population. A 0.1 mg/dL increase in bilirubin level was associated with a 6% reduction in the odds of PAD (OR 0.94 [95% CI 0.90 to 0.98]) after adjustment for age, gender, race/ethnicity, smoking status, diabetes, hypertension, hypercholesterolemia, chronic kidney disease, CRP, and homocysteine. This result was not dependent on bilirubin levels above the reference range, liver disease, or alcohol intake. The inverse association of bilirubin with PAD tended to be stronger among men (OR 0.90 [95% CI 0.85 to 0.96]) compared with women (OR 0.97 [95% CI 0.91 to 1.04]; P(interaction)=0.05), and was stronger among active smokers (OR 0.81 [95% CI 0.73 to 0.90]) compared with nonsmokers (OR 0.97 [95% CI 0.93 to 1.02]; P(interaction)<0.01). CONCLUSIONS: Increased serum total bilirubin level is associated with reduced PAD prevalence. This result is consistent with the hypothesis that bilirubin is protective from PAD.


Subject(s)
Bilirubin/blood , Peripheral Vascular Diseases/blood , Peripheral Vascular Diseases/epidemiology , Adult , Aged , Blood Pressure Determination/methods , Brachial Artery/physiology , Cross-Sectional Studies , Female , Humans , Lower Extremity/physiopathology , Male , Middle Aged , Nutrition Surveys , Odds Ratio , Peripheral Vascular Diseases/prevention & control , Prevalence , United States/epidemiology
16.
J Am Soc Nephrol ; 18(3): 944-51, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17287426

ABSTRACT

Insulin stimulates the renin-angiotensin system and induces renal vasodilation. The relationship between these opposing influences of insulin on renal vascular tone has not been explored. A hyperinsulinemic euglycemic clamp and sham insulin clamp each of 270 min duration were performed in 15 healthy individuals during high sodium balance. An angiotensin receptor blocker was administered at time 180 min. Renal plasma flow and plasma renin activity were measured serially. The response to insulin or sham insulin infusion was defined as the change from time 0 to 180 min; the response to angiotensin receptor blockade (ARB) was defined as the change from time 180 to 270 min. Insulin infusion increased plasma renin activity (P < 0.01) and renal plasma flow (P < 0.01); the latter effect plateaued by time 150 min. ARB caused a greater vasodilator response during insulin infusion compared with during sham insulin infusion (P = 0.02). Increasing renin response to insulin predicted blunting of the renal vasodilator response to insulin infusion (R(2) = 0.36, P = 0.02) and sensitizing of the renal vasodilator response to ARB during insulin infusion (R(2) = 0.59, P < 0.01). Insulin-induced activation of the renin-angiotensin system modulates insulin-induced renal vasodilation in healthy individuals. Further studies are warranted to address this balance in states of insulin resistance and the possible implications for the association of insulin resistance with risk for chronic kidney disease.


Subject(s)
Insulin Resistance/physiology , Insulin/pharmacology , Kidney/drug effects , Renin-Angiotensin System/drug effects , Vasodilation/drug effects , Angiotensin Receptor Antagonists , Blood Pressure/drug effects , Female , Humans , Kidney/blood supply , Male , Potassium/blood , Regional Blood Flow/drug effects , Renin/blood
17.
Hypertension ; 49(3): 461-6, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17224473

ABSTRACT

Accumulating evidence suggests that genes of the hypothalamic-pituitary-thyroid pathway influence susceptibility to hypertension. Type 2 iodothyronine deiodinase is responsible for the conversion of thyroxine to tri-iodothyronine for use in peripheral tissues. The present study evaluated whether a type 2 iodothyronine deiodinase nonsynonymous polymorphism, threonine 92 to alanine (Thr92Ala), is a determinant of hypertension susceptibility. A total of 372 euthyroid subjects were genotyped for Thr92Ala polymorphism using the Sequenom MassARRAY platform. Associations with hypertension and hypertension-related intermediate phenotypes were performed with generalized estimating equations. Type 2 iodothyronine deiodinase Thr92Ala allele frequencies differed significantly between hypertensive and normotensive subjects, with an excess of Ala92 carriers in hypertensive compared with normotensive subjects (64.8% versus 47.1%; P=0.011). Adjusted for age, gender and race, the estimated odds ratio for hypertension in Ala92 allele carriers compared with Thr92 homozygotes was 2.11 (95% CI: 1.15 to 3.89). Among euthyroid adults, the common Ala92 allele of the type 2 iodothyronine deiodinase increases risk for the development of hypertension. These data support an important role for genetic variation in the hypothalamic-pituitary-thyroid pathway in influencing susceptibility to hypertension.


Subject(s)
Hypertension/genetics , Iodide Peroxidase/genetics , Adult , Alleles , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Polymorphism, Genetic , Iodothyronine Deiodinase Type II
18.
Hypertension ; 48(6): 1031-6, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17060508

ABSTRACT

Experimental evidence supports a causative role for uric acid in the pathogenesis of hypertension. Prospective studies have variably adjusted for relevant confounders and have been of relatively limited duration. We prospectively examined the relationship between uric acid level and the development of hypertension in the Normative Aging Study, a longitudinal cohort of healthy adult men. Of the 2280 initial men in the Normative Aging Study, 2062 had available information for inclusion in the analysis. Cox proportional hazards model was used to examine the relationship between baseline serum uric acid level and the development of hypertension adjusting for age, body mass index, abdominal circumference, smoking, alcohol, plasma triglycerides, total cholesterol, and plasma glucose. A total of 892 men developed hypertension over a mean of 21.5 years of follow-up. Serum uric acid level independently predicted the development of hypertension in age-adjusted (relative risk [RR]: 1.10; 95% CI: 1.06 to 1.15: P<0.001) and multivariable (RR: 1.05; 95% CI: 1.01 to 1.10; P=0.02) models. Among 1277 men at risk for the development of hypertension at the time of their first serum creatinine measurement, 508 (39.8%) developed hypertension over a mean of 10.3+/-5.5 years of follow-up. Additionally adjusting for calculated glomerular filtration rate in this subset, serum uric acid remained associated with the development of hypertension (RR: 1.06; 95% CI: 1.01 to 1.12; P=0.03). The baseline serum uric acid level is a durable marker of risk for the development of hypertension. The association is independent of elements of the metabolic syndrome, alcohol intake, and renal function.


Subject(s)
Aging/physiology , Hypertension/etiology , Hyperuricemia/complications , Uric Acid/adverse effects , Adult , Aged , Aged, 80 and over , Follow-Up Studies , Humans , Hypertension/blood , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Uric Acid/blood
19.
Hypertension ; 48(5): 892-900, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17015767

ABSTRACT

Two genetic variants of the beta-2 adrenergic receptor, 46G>A and 79C>G, affect agonist-mediated receptor downregulation and vascular reactivity. We determined whether these variants were associated with hypertension, per se, blood pressure response to dietary sodium, 2 forms of salt-sensitive hypertension (low renin and nonmodulation), and the activity of the renin-angiotensin-aldosterone system. Included are 280 hypertensive and 65 normotensive white subjects who had the 2 beta-2 adrenergic receptor genotypes available. Of all subjects, 171 hypertensive and 48 normotensive subjects had complete data for intermediate phenotyping and blood pressure evaluation on high- and low-sodium balance. The beta-2 adrenergic receptor variants were not associated with hypertension per se. However, among hypertensive subjects, the change (from low to high sodium balance) in mean arterial pressure differed significantly by genotype and by diplotype. Compared with all of the other diplotypes combined, 46AA/79CC was associated with a greater change in blood pressure. Furthermore, this diplotype was associated with low-renin (LR) hypertension (identifying 32% of the LR hypertensives), higher plasma aldosterone, and lower plasma renin and serum potassium levels. In conclusion, the 46AA/79CC diplotype is associated with greater blood pressure response to dietary sodium and higher odds of LR hypertension. We propose that the mechanism for the observed association is inadequate suppression of aldosterone with salt intake, implicating the beta-2 adrenergic receptor in the regulation of aldosterone secretion. This hypothesis was confirmed in isolated glomerulosa cells, where beta-2 adrenergic receptor stimulation increased aldosterone secretion, whereas blockade reduced the stimulated aldosterone response. Importantly, this association could only be detected with an intermediate and not a distant phenotype.


Subject(s)
Hypertension/genetics , Receptors, Adrenergic, beta-2/genetics , Sodium Chloride, Dietary , Adolescent , Adult , Aged , Animals , Female , Genetic Variation , Humans , Hypertension/chemically induced , Hypertension/metabolism , Middle Aged , Phenotype , Polymorphism, Genetic , Rats , Rats, Wistar , Receptors, Adrenergic, beta-2/physiology
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