0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Investigation |

Uric Acid and Insulin Sensitivity and Risk of Incident Hypertension FREE

John P. Forman, MD, MSc; Hyon Choi, MD, DrPH; Gary C. Curhan, MD, ScD
[+] Author Affiliations

Author Affiliations: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (Drs Forman, Choi, and Curhan), and Renal Division, Department of Medicine, Brigham and Women's Hospital (Drs Forman and Curhan), Boston, Massachusetts; Division of Rheumatology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada (Dr Choi); and Department of Epidemiology, Harvard School of Public Health, Boston (Dr Curhan).


Arch Intern Med. 2009;169(2):155-162. doi:10.1001/archinternmed.2008.521.
Text Size: A A A
Published online

Background  Uric acid, insulin sensitivity, and endothelial dysfunction may be important in the development of hypertension. Corresponding circulating biomarkers are associated with risk of hypertension, but because these factors may be interrelated, whether they independently affect risk is unknown.

Methods  In 1496 women aged 32 to 52 years without hypertension at baseline, we prospectively analyzed the associations between fasting plasma levels of uric acid, insulin, triglycerides, the insulin sensitivity index, and 2 biomarkers associated with endothelial dysfunction (homocysteine and soluble intercellular adhesion molecule-1) and the odds of incident hypertension. Odds ratios were adjusted for standard risk factors and then for all biomarkers plus estimated glomerular filtration rate and total cholesterol level. Population-attributable risk was estimated for biomarkers significantly associated with hypertension.

Results  All the biomarkers were associated with incident hypertension after adjustment for standard hypertension risk factors. However, after simultaneously controlling for all the biomarkers, estimated glomerular filtration rate, and total cholesterol level, only uric acid and insulin levels were independently associated with incident hypertension. Comparing the highest and lowest quartiles of uric acid levels, the odds ratio was 1.89 (95% confidence interval, 1.26-2.82). A similar comparison yielded an odds ratio of 2.03 (95% confidence interval, 1.35-3.05) for insulin levels. Using an estimated basal incidence rate of 14.6 per 1000 annually, 30.8% of all hypertension occurring in young women annually is associated with uric acid levels of 3.4 mg/dL or greater (to convert to micromoles per liter, multiply by 59.485). For insulin levels of 2.9 μIU/mL or greater (to convert to picomoles per liter, multiply by 6.945), this proportion is 24.2%.

Conclusions  Differences in uric acid and insulin levels robustly and substantially affect the risk of hypertension in young women. Measuring these biomarkers in clinical practice may identify higher-risk individuals.

Hypertension is highly prevalent, affecting approximately one-third of Americans,1 and is a leading cause of morbidity and mortality.2 The etiology of hypertension is unclear in most patients.3 Proposed pathophysiologic mechanisms include (1) uric acid–induced activation of the renin-angiotensin system and injury to preglomerular renal vessels,4 (2) reduced insulin sensitivity and hyperinsulinemia with altered renal sodium handling and enhanced sympathetic tone,57 and (3) endothelial dysfunction with altered vascular tone and function.811 Measurement of these potential pathophysiologic factors may ultimately lead to identification of high-risk individuals and improved prevention.

Circulating biomarkers related to these 3 pathophysiologic processes, specifically, uric acid,1225 insulin,26,27 and homocysteine,28,29 have been associated with risk of hypertension in most studies. However, because these factors may be interrelated, it is unknown whether they are independently associated with risk of hypertension. Therefore, we measured uric acid, insulin, and triglyceride levels (to compute the insulin sensitivity index)30 and homocysteine and soluble intercellular adhesion molecule-1 (sICAM-1) levels (both associated with endothelial dysfunction)3136 in a prospective nested case-control study of 1496 healthy women aged 32 to 52 years from the second Nurses' Health Study37 to determine whether differences in these biomarkers precede and independently predict the onset of hypertension.

STUDY POPULATION

The second Nurses' Health Study is an ongoing prospective study of 116 671 female registered nurses that began in 1989. Participants are followed up via biennial questionnaires that gather information on health-related behaviors and medical events. Follow-up of participants was greater than 90% through 2005. From 1997 to 1999, 29 616 participants contributed blood samples that were stored in liquid nitrogen (−130°C). We conducted a nested case-control study of incident hypertension in women who contributed blood samples and who did not have prevalent hypertension at the time of blood collection. The institutional review board at Brigham and Women's Hospital approved this study.

We selected cases and controls from among those who met the following criteria at the time of blood collection: (1) blood sample collected after fasting for at least 8 hours, (2) no diagnosis of hypertension, (3) no use of antihypertensive medications, (4) no diagnosis of cancer (except nonmelanoma skin cancer), (5) no diagnosis of either coronary heart disease or diabetes mellitus, and (6) a body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) less than 30. This last eligibility criterion was imposed because a high BMI is a powerful predictor of hypertension37,38 and the biomarkers under study.3943

Using risk set sampling, we selected 750 cases who subsequently developed hypertension and 750 controls who did not. Controls were matched to cases on the following factors: age (within 1 year), race, date of blood sample collection (within 1 month), day of menstrual cycle if premenopausal (within 2 days), and time of day of the blood collection (within 2 hours). In addition, controls were required to have had at least 1 clinician examination during the 2 years before being selected as a control. After excluding 2 pairs with missing biomarker data, the final study population included 748 case-control pairs (N = 1496).

BIOMARKER MEASUREMENT

Uric acid concentration was determined by oxidation with the specific enzyme uricase to form allantoin and hydrogen peroxide (Roche Diagnostics Corporation, Indianapolis, Indiana). The coefficient of variation (CV) using quality control samples was 3.4%. Insulin and triglyceride levels were used as biomarkers of insulin sensitivity and were measured using a radioimmunoassay and standard enzymatic methods, respectively (Roche Diagnostics Corporation); the CVs were 10.4% and 14.1%, respectively. The insulin sensitivity index (glucose disposal rate [M] corrected for fat-free mass, ie, MFFM) was calculated for participants using the following prediction equation, which includes fasting insulin and triglyceride levels (triglyceride levels converted to millimoles per liter):

MFFM = e{2.63 – [0.28 × ln(insulin)] – [0.31 × ln(triglycerides)]}

This calculated MFFM value has been validated30 and has been accepted as an index of insulin sensitivity.44

Homocysteine concentration was measured using an enzymatic assay (Roche Diagnostics Corporation) (CV = 7.4%), and the sICAM-1 level was measured using an enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, Minnesota) (CV = 8.8%). Total cholesterol level was measured using a standard esterase-oxidase method (CV = 5.3%), and creatinine was assayed using a modified version of the Jaffe method (CV = 6.5%). Estimated glomerular filtration rate (eGFR) was determined using the Modification of Diet in Renal Disease Study formula45:

186 × creatinine−1.154 × age−0.203 × 1.212 (if black) × 0.742 (if female)

ASCERTAINMENT OF OTHER COVARIATES

Age and BMI were obtained from the supplemental questionnaire that accompanied the submitted blood samples. Smoking status (never, past, or current), physical activity, and alcohol intake were ascertained from the biennial questionnaire that immediately followed submission of the blood sample (typically the 1999 biennial questionnaire). Family history of hypertension was obtained from the 1989 questionnaire; race was self-classified. Blood pressure (BP) was reported on the 1999 questionnaire in 9 systolic (SBP) categories (<105, 105-114, 115-124, 125-134, 135-144, 145-154, 155-164, 165-174, and ≥175 mm Hg) and 7 diastolic (DBP) categories (<65, 65-74, 75-84, 85-89, 90-94, 95-104, and ≥105 mm Hg). Based on these categories, we assigned participants a baseline BP using the middle value of each category; for example, if a participant reported her SBP and DBP as 125 to 134 mm Hg and 75 to 84 mm Hg, respectively, she was assigned a BP of 130/80 mm Hg. Self-reported BP in nurses has been previously validated as predictive of future cardiovascular events.46

ASCERTAINMENT OF HYPERTENSION

Clinician-diagnosed hypertension was self-reported by these health professionals on biennial questionnaires. Self-reported hypertension was highly reliable in participants in a similar cohort of nurses; specifically, the accuracy was 100% in a substudy of randomly selected participants who reported the diagnosis.47

Women were considered to have prevalent hypertension at the time of blood collection if they reported hypertension on the biennial questionnaire immediately after blood collection or on any previous questionnaire. For this study of incident hypertension, women with prevalent hypertension were excluded. In addition, women who reported taking antihypertensive medications on the questionnaire given immediately after blood collection were also excluded.

STATISTICAL ANALYSES

Because the continuous baseline variables, including the biomarker levels, were not normally distributed, differences in these variables between cases and controls were analyzed using the Wilcoxon rank sum test. Differences in categorical variables between cases and controls were compared using the χ2 test.

To examine the correlations among age, BMI, and the studied biomarkers, we used Spearman partial correlations, in which pairwise Spearman correlation coefficients were computed after adjusting for the other variables. For example, the Spearman correlation between BMI and uric acid level was adjusted for age, eGFR, and levels of insulin, triglycerides, homocysteine, and sICAM-1.

Associations between the biomarkers and incident hypertension were analyzed with the biomarkers as continuous variables and with the biomarkers divided into quartiles, with the lowest quartile defined as the reference group. We used conditional logistic regression conditioning on the matching factors to generate odds ratios (ORs) and 95% confidence intervals (CIs).

Two types of analyses were conducted. First, each biomarker was analyzed individually (ie, without other biomarkers in the model); the primary analyses adjusted for BMI (continuous), physical activity, alcohol intake, smoking status, and family history of hypertension. Further analyses were performed after adjusting for baseline SBP and DBP. Second, each biomarker was analyzed after also adjusting for eGFR, total cholesterol level, and all the other biomarkers.

Population-attributable risks were calculated for biomarkers using the adjusted quartile-specific OR from the final multivariable models and with the lowest quartile defined as the “unexposed” group. A baseline incidence rate of 14.6 cases per 1000 women annually (1.46% of the population per year) for the unexposed group was estimated using the incidence rate for the parent cohort (the second Nurses' Health Study37). All statistical analyses were conducted using a software program (SAS Institute Inc, version 9.1; Cary, North Carolina).

BASELINE CHARACTERISTICS

The baseline characteristics of the study population by case status are given in Table 1. The median age of the population was 43 years; because this was a matching factor, it did not differ in cases and controls. The median BMI was higher in cases (25.1) compared with controls (23.2). Cases were also less physically active, had higher baseline BP values, and were more likely to have a family history of hypertension. Except for eGFR, all the fasting biomarkers differed between cases and controls at baseline. Cases had higher levels of uric acid, insulin, triglycerides, total cholesterol, homocysteine, and sICAM-1; conversely, cases had lower MFFM scores.

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Study Populationa

Many of the biomarkers were correlated with each other and with age and BMI. The partial (ie, adjusted) Spearman correlation coefficients among these variables are given in Table 2. Besides the expected high correlation between MFFM and levels of insulin and triglycerides (which are used to compute MFFM), the strongest correlations were between BMI and uric acid (r = 0.22), insulin (r = 0.27), triglycerides (r = 0.19), and MFFM (r = −0.35) and between eGFR and uric acid (r = −0.17) and homocysteine (r = −0.20) (P < .001 for all).

Table Graphic Jump LocationTable 2. Partial Spearman Correlations Among Biomarkers, Age, and BMIa
URIC ACID

The median uric acid level was 3.9 mg/dL (to convert to micromoles per liter, multiply by 59.485), and less than 1% of the population had uric acid levels that would be considered abnormally elevated (≥7.0 mg/dL).48,49 After controlling for matching factors and multivariable adjustment for BMI, physical activity, smoking, alcohol intake, and family history of hypertension, every 1-mg/dL increase in uric acid was associated with a 1.33-fold higher odds of incident hypertension (95% CI, 1.15-1.53) (Table 3). When uric acid was examined in quartiles, the OR for the highest compared with the lowest quartile was 2.17 (95% CI, 1.51-3.11) (Table 3). After further adjusting for baseline SBP and DBP, the same comparison remained significant (OR, 1.79; 95% CI, 1.11-2.87).

Table Graphic Jump LocationTable 3. Associations Between Multiple Biomarkers and Risk of Incident Hypertension

Uric acid was also analyzed after further adjusting for eGFR and levels of total cholesterol, triglycerides, insulin, homocysteine, and sICAM-1 (Table 3); the results were attenuated but remained significant. Every 1-mg/dL increase in uric acid level was associated with a 1.25-fold higher odds of incident hypertension (95% CI, 1.06-1.46). The OR for women in the highest compared with the lowest quartile of uric acid level was 1.89 (95% CI, 1.26-2.82).

INSULIN SENSITIVITY

The median values for insulin, triglycerides, and MFFM were 4.6 μIU/mL (to convert to picomoles per liter, multiply by 6.945), 78 mg/dL (to convert to millimoles per liter, multiply by 0.0113), and 9.6, respectively. Six percent of individuals had hyperinsulinemia (ie, an insulin level >13.1 μIU/mL).50 Fewer than 10% of participants had elevated triglyceride levels (≥160 mg/dL), and fewer than 10% of participants had MFFM scores of 6.3 or less (definition of insulin resistance).30

Every 2-μIU/mL higher fasting insulin concentration was associated with a 1.14-fold higher odds of incident hypertension (95% CI, 1.07-1.22) (Table 3). Further controlling for baseline SBP and DBP did not attenuate the association (OR, 1.19; 95% CI, 1.09-1.30). Comparing the highest to the lowest quartile of insulin level, the OR was 2.41 (95% CI, 1.64-3.54) before adjusting for BP and 2.22 (95% CI, 1.37-3.60) after controlling for SBP and DBP. When eGFR and levels of total cholesterol, uric acid, triglycerides, homocysteine, and sICAM-1 were included in the model, the ORs were 1.11 (95% CI, 1.03-1.18) for every 2-μIU/mL higher insulin level and 2.03 (95% CI, 1.35-3.05) comparing the highest to the lowest quartile (Table 3).

Although the fasting triglyceride concentration was also associated with incident hypertension in the base multivariable model (Table 3) and after adjusting for SBP and DBP, the association did not persist when further controlling for eGFR and levels of total cholesterol, uric acid, insulin, homocysteine, and sICAM-1 (Table 3).

Each unit increase in the MFFM score, an estimate of insulin sensitivity, was associated with a lower odds of developing hypertension (OR, 0.89; 95% CI, 0.84-0.93) (Table 3). Women in the highest compared with the lowest quartile had a 48% reduced odds (OR, 0.52; 95% CI, 0.35-0.76). This association persisted after controlling for baseline SBP and DBP; the ORs were 0.88 (95% CI, 0.82-0.94) for each unit increase and 0.54 (95% CI, 0.33-0.90) comparing the highest with the lowest quartile. After further adjusting for eGFR and levels of total cholesterol, uric acid, homocysteine, and sICAM-1, these comparisons yielded ORs of 0.92 (95% CI, 0.87-0.97) and 0.69 (95% CI, 0.46-1.04), respectively (Table 3).

HOMOCYSTEINE AND sICAM-1

The median homocysteine concentration in the study population was 1.57 mg/L; 10% of participants had elevated homocysteine concentrations (>2.03 mg/L).51 The median sICAM-1 level was 241 ng/mL (similar to other populations).5255

After multivariate adjustment, every 0.27 mg/L increase in homocysteine was associated with a 1.13-fold higher odds of incident hypertension (95% CI, 1.05-1.22) (Table 3). When homocysteine was examined in quartiles, the OR for the highest compared with the lowest quartile was 1.38 (95% CI, 0.99-1.93) (Table 3). After further adjusting for baseline SBP and DBP, the ORs were 1.10 (95% CI, 1.00-1.22) and 1.19 (95% CI, 0.77-1.83), respectively. When eGFR and levels of total cholesterol, uric acid, insulin, triglycerides, and sICAM-1 were included in the model, the ORs were 1.08 (95% CI, 0.99-1.18) for each 0.27 mg/L increase and 1.27 (95% CI, 0.86-1.88) comparing the highest with the lowest quartile (Table 3).

Although the sICAM-1 concentration was associated with incident hypertension in the base multivariable model (Table 3) and after adjusting for SBP and DBP, the association did not persist when further controlling for eGFR and levels of total cholesterol, uric acid, insulin, homocysteine, and sICAM-1 (Table 3).

ESTIMATED POPULATION-ATTRIBUTABLE RISK

We estimated the percentage of incident hypertension potentially attributable to higher uric acid and insulin levels, which were the 2 biomarkers independently associated with hypertension (Table 4). The population-attributable risk associated with the top 3 quartiles of uric acid (ie, uric acid ≥3.4 mg/dL) was 6.51 cases of hypertension per 1000 women per year. Given an estimated baseline incidence rate of 14.6 cases per 1000 young women annually, 30.8% of hypertension occurring in young women is associated with a uric acid level of 3.4 mg/dL or greater. The attributable risk associated with insulin levels of 2.9 μIU/mL or greater was 4.65 cases per 1000 young women annually. Therefore, an estimated 24.2% of hypertension occurring in young women is associated with an insulin level of 2.9 μIU/mL or greater.

Table Graphic Jump LocationTable 4. Estimated Population-Attributable Risk of Hypertension Associated With Uric Acid and Insulin Levels

In 1496 nonobese young women without hypertension, diabetes mellitus, or coronary disease at baseline, small differences in uric acid and insulin levels independently predicted clinically important increases in the odds of the subsequent development of hypertension. A substantial magnitude of the population risk may be attributable to higher uric acid and insulin levels. Furthermore, these associations were observed within ranges of these biomarkers that would be considered “normal.”

Higher uric acid concentrations were independently associated with increased odds of developing hypertension. To date, 14 prospective studies1225 have examined this association; of these, 12 studies12,1525 have documented a direct association with either incident hypertension or increase in BP. Most of these studies were not fully adjusted for other physiologic variables, such as renal function, lipid levels, and measures of insulin resistance; controlling for these factors is important given that higher uric acid levels may be coincident with alterations in these other metabolic variables.42,56 Of the 3 studies13,21,23 that fully adjusted for these physiologic variables (eGFR, lipid levels, insulin levels, or insulin resistance), all involved considerably older populations and 2 consisted only of men. Thus, the present study represents the only fully adjusted study consisting of young women.

The proposed mechanism linking uric acid with the onset of hypertension stems from a rat model of moderate hyperuricemia.5759 Mazzali et al59 showed that rats made hyperuricemic developed increases in BP that were reversible by lowering the uric acid concentration. Furthermore, hyperuricemia was associated with endothelial dysfunction, activation of the renin-angiotensin system, and preglomerular vascular disease.5759

However, substantial quantities of circulating uric acid are only a feature of advanced primates in whom the uricase gene is deleted; rodents, in contrast, have very low uric acid levels due to functional uricase.60 Furthermore, uric acid is a powerful antioxidant,61,62 and intravenous infusion of uric acid into humans actually improves endothelial function.63 Thus, it is not clear that the association between uric acid and hypertension is causal. Even if a randomized trial showed that uric acid lowering by xanthine oxidase inhibition decreased BP, this would not establish causality because xanthine oxidase is an important enzyme in the generation of oxidative stress and endothelial dysfunction.64 Indeed, a recent study in patients with heart failure demonstrated that allopurinol use improved endothelial dysfunction, whereas uric acid level lowering to a similar degree using probenecid (a uricosuric) did not.65 Nevertheless, the present data demonstrate that in relatively healthy young women, small differences in plasma uric acid levels, even within the reference range, powerfully predict the development of hypertension.

We also observed direct associations between insulin and triglyceride levels and incident hypertension as well as an inverse association between a validated estimate of the insulin sensitivity index and incident hypertension. Triglyceride levels, however, were not independently associated in the final models. Several studies26,27 have examined the association between measures of insulin sensitivity (or resistance) and the risk of hypertension. In the present study, even after controlling for biomarkers from other proposed pathophysiologic pathways, we observed a strong association between insulin levels (and MFFM) and risk of incident hypertension.

Several theories exist to explain how insulin may promote hypertension. First, hyperinsulinemia may disinhibit the sympathetic nervous system.6 Several placebo-controlled studies using euglycemic clamp techniques demonstrated that insulin infusion is associated with an increase in plasma norepinephrine concentrations and SBP.5,7 Second, insulin may stimulate the renin-angiotensin system and enhance renal sodium reabsorption. Euglycemic clamp studies7,66 have shown that insulin infusion increases plasma-renin activity and angiotensin II levels. Furthermore, insulin infusion into healthy individuals leads to a reduction in sodium excretion.6769

Higher levels of homocysteine and sICAM-1 are associated with endothelial dysfunction,3136 and, in turn, endothelial dysfunction has been proposed as a risk factor for hypertension.70 Only 2 prospective analyses28,29 have examined the association between homocysteine concentrations and the risk of incident hypertension; none have examined sICAM-1. Neither of the homocysteine studies observed an association with hypertension. Although we noted significant associations between homocysteine and sICAM-1 levels and incident hypertension after adjustment for standard risk factors and BP, these associations were no longer significant after the other biomarkers were considered.

The present study has limitations that deserve mention. First, we relied on self-reported hypertension and did not directly measure the BP of the participants; however, all the participants are registered nurses, and hypertension reporting by nurses is highly accurate.47 Second, controls may have been misclassified if they were unaware of existing hypertension, but because we required controls to have had a clinician examination during follow-up, this possibility is reduced. Furthermore, this sort of misclassification tends to produce less significant results; therefore, the present findings may represent an underestimate of true associations. Third, because the CVs for the insulin and triglyceride assays were greater than 10%, measurement error (and, as a result, misclassification of these biomarker levels) may have occurred. Because measurement error is typically random, this type of misclassification would also tend to produce less significant results; therefore, the observed associations between insulin levels, MFFM, and hypertension risk may indeed represent underestimations of the true relations. Fourth, we lacked information about the inflammatory biomarker C-reactive protein, which was observed in a previous study71 of women to be associated with hypertension; however, that study did not adjust for uric acid levels or markers of insulin sensitivity. Moreover, the present study included sICAM-1, which is also considered to be a prominent inflammatory biomarker.54,55 Fifth, we purposefully restricted the sample to women with BMI values less than 30. Although this limits the generalizability of the findings to nonobese women, other studies20,72,73 have suggested that the associations between a variety of these biomarkers and hypertension are stronger in leaner individuals. Finally, the study population was almost entirely white. Therefore, the findings are not necessarily generalizable to other races.

In conclusion, small differences in uric acid levels and insulin sensitivity, even within ranges considered normal, are robustly and substantially associated with an increased risk of hypertension in young women. Measuring these biomarkers in clinical practice may identify higher-risk individuals. Future studies are required to determine whether strategies to lower the levels of these biomarkers translate into a lower risk of hypertension.

Correspondence: John P. Forman, MD, MSc, Channing Laboratory, Third Floor, 181 Longwood Ave, Boston, MA 02115 (jforman@partners.org).

Accepted for Publication: July 3, 2008.

Author Contributions: Dr Forman had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Forman, Choi, and Curhan. Acquisition of data: Forman and Choi. Analysis and interpretation of data: Forman, Choi, and Curhan. Drafting of the manuscript: Forman. Critical revision of the manuscript for important intellectual content: Forman, Choi, and Curhan. Statistical analysis: Forman and Curhan. Obtained funding: Forman, Choi, and Curhan. Administrative, technical, and material support: Forman and Curhan. Study supervision: Curhan.

Financial Disclosures: None.

Funding/Support: This study was supported by grant 0535401T from the American Heart Association, grants HL079929 and CA50385 from the National Institutes of Health, and funding from TAP Pharmaceuticals.

Fields  LEBurt  VLCutler  JAHughes  JRoccella  EJSorlie  P The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension 2004;44 (4) 398- 404
PubMed
Chobanian  AVBakris  GLBlack  HR  et al. National High Blood Pressure Education Program Coordinating Committee, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289 (19) 2560- 2572
PubMed
Oparil  SZaman  MACalhoun  DA Pathogenesis of hypertension. Ann Intern Med 2003;139 (9) 761- 776
PubMed
Johnson  RJFeig  DIHerrera-Acosta  JKang  DH Resurrection of uric acid as a causal risk factor in essential hypertension. Hypertension 2005;45 (1) 18- 20
PubMed
Kern  WFittje  AFohr  WKerner  WBorn  JFehm  HL Increase in systolic blood pressure and catecholamine level during hyperinsulinemia in a placebo-controlled euglycemic clamp in healthy subjects. Exp Clin Endocrinol Diabetes 2000;108 (8) 498- 505
PubMed
Reaven  GMLithell  HLandsberg  L Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996;334 (6) 374- 381
PubMed
Rooney  DPEdgar  JDSheridan  BAtkinson  ABBell  PM The effects of low dose insulin infusions on the renin angiotensin and sympathetic nervous systems in normal man. Eur J Clin Invest 1991;21 (4) 430- 435
PubMed
Furchgott  RFZawadzki  JV The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288 (5789) 373- 376
PubMed
Kojda  GHarrison  D Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure. Cardiovasc Res 1999;43 (3) 562- 571
PubMed
Kubes  PSuzuki  MGranger  DN Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 1991;88 (11) 4651- 4655
PubMed
Radomski  MWPalmer  RMMoncada  S Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 1987;2 (8567) 1057- 1058
PubMed
Alper  AB  JrChen  WYau  LSrinivasan  SRBerenson  GSHamm  LL Childhood uric acid predicts adult blood pressure: the Bogalusa Heart Study. Hypertension 2005;45 (1) 34- 38
PubMed
Forman  JPChoi  HCurhan  GC Plasma uric acid level and risk for incident hypertension among men. J Am Soc Nephrol 2007;18 (1) 287- 292
PubMed
Hunt  SCStephenson  SHHopkins  PNWilliams  RR Predictors of an increased risk of future hypertension in Utah: a screening analysis. Hypertension 1991;17 (6, pt 2) 969- 976
PubMed
Jossa  FFarinaro  EPanico  S  et al.  Serum uric acid and hypertension: the Olivetti Heart Study. J Hum Hypertens 1994;8 (9) 677- 681
PubMed
Kahn  HAMedalie  JHNeufeld  HNRiss  EGoldbourt  U The incidence of hypertension and associated factors: the Israel Ischemic Heart Disease study. Am Heart J 1972;84 (2) 171- 182
PubMed
Krishnan  EKwoh  CKSchumacher  HRKuller  L Hyperuricemia and incidence of hypertension among men without metabolic syndrome. Hypertension 2007;49 (2) 298- 303
PubMed
Masuo  KKawaguchi  HMikami  HOgihara  TTuck  ML Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension 2003;42 (4) 474- 480
PubMed
Mellen  PBBleyer  AJErlinger  TP  et al.  Serum uric acid predicts incident hypertension in a biethnic cohort: the Atherosclerosis Risk in Communities study. Hypertension 2006;48 (6) 1037- 1042
PubMed
Nakanishi  NOkamoto  MYoshida  HMatsuo  YSuzuki  KTatara  K Serum uric acid and risk for development of hypertension and impaired fasting glucose or type II diabetes in Japanese male office workers. Eur J Epidemiol 2003;18 (6) 523- 530
PubMed
Perlstein  TSGumieniak  OWilliams  GH  et al.  Uric acid and the development of hypertension: the Normative Aging Study. Hypertension 2006;48 (6) 1031- 1036
PubMed
Selby  JVFriedman  GDQuesenberry  CP  Jr Precursors of essential hypertension: pulmonary function, heart rate, uric acid, serum cholesterol, and other serum chemistries. Am J Epidemiol 1990;131 (6) 1017- 1027
PubMed
Shankar  AKlein  RKlein  BENieto  FJ The association between serum uric acid level and long-term incidence of hypertension: population-based cohort study. J Hum Hypertens 2006;20 (12) 937- 945
PubMed
Sundström  JSullivan  LD'Agostino  RBLevy  DKannel  WBVasan  RS Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension 2005;45 (1) 28- 33
PubMed
Taniguchi  YHayashi  TTsumura  KEndo  GFujii  SOkada  K Serum uric acid and the risk for hypertension and type 2 diabetes in Japanese men: the Osaka Health Survey. J Hypertens 2001;19 (7) 1209- 1215
PubMed
Arnlöv  JPencina  MJNam  BH  et al.  Relations of insulin sensitivity to longitudinal blood pressure tracking: variations with baseline age, body mass index, and blood pressure. Circulation 2005;112 (12) 1719- 1727
PubMed
Hu  FBStampfer  MJ Insulin resistance and hypertension: the chicken-egg question revisited. Circulation 2005;112 (12) 1678- 1680
PubMed
Bowman  TSGaziano  JMStampfer  MJSesso  HD Homocysteine and risk of developing hypertension in men. J Hum Hypertens 2006;20 (8) 631- 634
PubMed
Sundström  JSullivan  LD'Agostino  RB  et al.  Plasma homocysteine, hypertension incidence, and blood pressure tracking: the Framingham Heart Study. Hypertension 2003;42 (6) 1100- 1105
PubMed
McAuley  KAWilliams  SMMann  JI  et al.  Diagnosing insulin resistance in the general population. Diabetes Care 2001;24 (3) 460- 464
PubMed
Brevetti  GMartone  VDde Cristofaro  T  et al.  High levels of adhesion molecules are associated with impaired endothelium-dependent vasodilation in patients with peripheral arterial disease. Thromb Haemost 2001;85 (1) 63- 66
PubMed
Gearing  AJHemingway  IPigott  RHughes  JRees  AJCashman  SJ Soluble forms of vascular adhesion molecules, E-selectin, ICAM-1, and VCAM-1: pathological significance. Ann N Y Acad Sci 1992;667324- 331
PubMed
Holmlund  AHulthe  JMillgård  JSarabi  MKahan  TLind  L Soluble intercellular adhesion molecule-1 is related to endothelial vasodilatory function in healthy individuals. Atherosclerosis 2002;165 (2) 271- 276
PubMed
Nawawi  HOsman  NSAnnuar  RKhalid  BAYusoff  K Soluble intercellular adhesion molecule-1 and interleukin-6 levels reflect endothelial dysfunction in patients with primary hypercholesterolaemia treated with atorvastatin. Atherosclerosis 2003;169 (2) 283- 291
PubMed
Tawakol  AOmland  TGerhard  MWu  JTCreager  MA Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 1997;95 (5) 1119- 1121
PubMed
Woo  KSChook  PLolin  YI  et al.  Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation 1997;96 (8) 2542- 2544
PubMed
Rich-Edwards  JWGoldman  MBWillett  WCHunter  DJStampfer  MJColditz  GAManson  JE Adolescent body mass index and infertility caused by ovulatory disorder. Am J Obstet Gynecol 1994;171 (1) 171- 177
Gelber  RPGaziano  JMManson  JEBuring  JESesso  HD A prospective study of body mass index and the risk of developing hypertension in men. Am J Hypertens 2007;20 (4) 370- 377
PubMed
Huang  ZWillett  WCManson  JE  et al.  Body weight, weight change, and risk for hypertension in women. Ann Intern Med 1998;128 (2) 81- 88
PubMed
Høieggen  AAlderman  MHKjeldsen  SE  et al. LIFE Study Group, The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004;65 (3) 1041- 1049
PubMed
Li  CFord  ES McGuire  LCMokdad  AHLittle  RRReaven  GM Trends in hyperinsulinemia among nondiabetic adults in the U.S. Diabetes Care 2006;29 (11) 2396- 2402
PubMed
Marchesi  SVaudo  GLupattelli  G  et al.  Fat distribution and endothelial function in normal-overweight menopausal women. J Clin Pharm Ther 2007;32 (5) 477- 482
PubMed
Moriarity  JTFolsom  ARIribarren  CNieto  FJRosamond  WD Serum uric acid and risk of coronary heart disease: Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 2000;10 (3) 136- 143
PubMed
Shai  IPischon  THu  FBAscherio  ARifai  NRimm  EB Soluble intercellular adhesion molecules, soluble vascular cell adhesion molecules, and risk of coronary heart disease. Obesity 2006;14 (11) 2099- 2106
PubMed
Davies  MJBaer  DJJudd  JTBrown  EDCampbell  WSTaylor  PR Effects of moderate alcohol intake on fasting insulin and glucose concentrations and insulin sensitivity in postmenopausal women: a randomized controlled trial. JAMA 2002;287 (19) 2559- 2562
PubMed
Levey  ASBosch  JPLewis  JBGreene  TRogers  NRoth  DModification of Diet in Renal Disease Study Group, A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130 (6) 461- 470
PubMed
Fiebach  NHHebert  PRStampfer  MJ  et al.  A prospective study of high blood pressure and cardiovascular disease in women. Am J Epidemiol 1989;130 (4) 646- 654
PubMed
Colditz  GAMartin  PStampfer  MJ  et al.  Validation of questionnaire information on risk factors and disease outcomes in a prospective cohort study of women. Am J Epidemiol 1986;123 (5) 894- 900
PubMed
Choi  HKLiu  SCurhan  G Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2005;52 (1) 283- 289
PubMed
Wortmann  RL Recent advances in the management of gout and hyperuricemia. Curr Opin Rheumatol 2005;17 (3) 319- 324
PubMed
Li  CFord  ESMeng  YXMokdad  AHReaven  GM Does the association of the triglyceride to high-density lipoprotein cholesterol ratio with fasting serum insulin differ by race/ethnicity? Cardiovasc Diabetol 2008;74
PubMed10.1186/1475-2840-7-4
Kang  SSWong  PWMalinow  MR Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 1992;12279- 298
PubMed
Grewal  JChan  SFrohlich  JMancini  GB Assessment of novel risk factors in patients at low risk for cardiovascular events based on Framingham risk stratification. Clin Invest Med 2003;26 (4) 158- 165
PubMed
Hoogeveen  RCBallantyne  CMBang  H  et al.  Circulating oxidised low-density lipoprotein and intercellular adhesion molecule-1 and risk of type 2 diabetes mellitus: the Atherosclerosis Risk in Communities Study. Diabetologia 2007;50 (1) 36- 42
PubMed
Hulthe  JWikstrand  JMattsson-Hultén  LFagerberg  B Circulating ICAM-1 (intercellular cell-adhesion molecule 1) is associated with early stages of atherosclerosis development and with inflammatory cytokines in healthy 58-year-old men: the Atherosclerosis and Insulin Resistance (AIR) study. Clin Sci (Lond) 2002;103 (2) 123- 129
PubMed
Tzoulaki  IMurray  GDLee  AJRumley  ALowe  GDFowkes  FG C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh Artery Study. Circulation 2005;112 (7) 976- 983
PubMed
Iribarren  CFolsom  AREckfeldt  JH McGovern  PGNieto  FJ Correlates of uric acid and its association with asymptomatic carotid atherosclerosis: the ARIC study. Ann Epidemiol 1996;6 (4) 331- 340
PubMed
Kang  DHNakagawa  TFeng  L  et al.  A role for uric acid in the progression of renal disease. J Am Soc Nephrol 2002;13 (12) 2888- 2897
PubMed
Khosla  UMZharikov  SFinch  JL  et al.  Hyperuricemia induces endothelial dysfunction. Kidney Int 2005;67 (5) 1739- 1742
PubMed
Mazzali  MHughes  JKim  YG  et al.  Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001;38 (5) 1101- 1106
PubMed
Johnson  RJTitte  SCade  JRRideout  BAOliver  WJ Uric acid, evolution and primitive cultures. Semin Nephrol 2005;25 (1) 3- 8
PubMed
Maxwell  SRThomason  HSandler  D  et al.  Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus. Eur J Clin Invest 1997;27 (6) 484- 490
PubMed
Scott  GSCuzzocrea  SGenovese  TKoprowski  HHooper  DC Uric acid protects against secondary damage after spinal cord injury. Proc Natl Acad Sci U S A 2005;102 (9) 3483- 3488
PubMed
Waring  WS McKnight  JAWebb  DJMaxwell  SR Uric acid restores endothelial function in patients with type 1 diabetes and regular smokers. Diabetes 2006;55 (11) 3127- 3132
PubMed
Paravicini  TMTouyz  RM Redox signaling in hypertension. Cardiovasc Res 2006;71 (2) 247- 258
PubMed
George  JCarr  EDavies  JBelch  JJStruthers  A High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 2006;114 (23) 2508- 2516
PubMed
Perlstein  TSGerhard-Herman  MHollenberg  NKWilliams  GHThomas  A Insulin induces renal vasodilation, increases plasma renin activity, and sensitizes the renal vasculature to angiotensin receptor blockade in healthy subjects. J Am Soc Nephrol 2007;18 (3) 944- 951
PubMed
DeFronzo  RACooke  CRAndres  RFaloona  GRDavis  PJ The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest 1975;55 (4) 845- 855
PubMed
Nørgaard  KJensen  TSkøtt  P  et al.  Effects of insulin on renal haemodynamics and sodium handling in normal subjects. Scand J Clin Lab Invest 1991;51 (4) 367- 376
PubMed
Skøtt  PHother-Nielsen  OBruun  NE  et al.  Effects of insulin on kidney function and sodium excretion in healthy subjects. Diabetologia 1989;32 (9) 694- 699
PubMed
Rossi  RChiurlia  ENuzzo  ACioni  EOrigliani  GModena  MG Flow-mediated vasodilation and the risk of developing hypertension in healthy postmenopausal women. J Am Coll Cardiol 2004;44 (8) 1636- 1640
PubMed
Sesso  HDBuring  JERifai  NBlake  GJGaziano  JMRidker  PM C-reactive protein and the risk of developing hypertension. JAMA 2003;290 (22) 2945- 2951
PubMed
Liese  ADMayer-Davis  EJChambless  LE  et al. Atherosclerosis Risk in Communities Study Investigators, Elevated fasting insulin predicts incident hypertension: the ARIC study. J Hypertens 1999;17 (8) 1169- 1177
PubMed
Shetterly  SMRewers  MHamman  RFMarshall  JA Patterns and predictors of hypertension incidence among Hispanics and non-Hispanic whites: the San Luis Valley Diabetes Study. J Hypertens 1994;12 (9) 1095- 1102
PubMed

Figures

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of the Study Populationa
Table Graphic Jump LocationTable 2. Partial Spearman Correlations Among Biomarkers, Age, and BMIa
Table Graphic Jump LocationTable 3. Associations Between Multiple Biomarkers and Risk of Incident Hypertension
Table Graphic Jump LocationTable 4. Estimated Population-Attributable Risk of Hypertension Associated With Uric Acid and Insulin Levels

References

Fields  LEBurt  VLCutler  JAHughes  JRoccella  EJSorlie  P The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension 2004;44 (4) 398- 404
PubMed
Chobanian  AVBakris  GLBlack  HR  et al. National High Blood Pressure Education Program Coordinating Committee, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289 (19) 2560- 2572
PubMed
Oparil  SZaman  MACalhoun  DA Pathogenesis of hypertension. Ann Intern Med 2003;139 (9) 761- 776
PubMed
Johnson  RJFeig  DIHerrera-Acosta  JKang  DH Resurrection of uric acid as a causal risk factor in essential hypertension. Hypertension 2005;45 (1) 18- 20
PubMed
Kern  WFittje  AFohr  WKerner  WBorn  JFehm  HL Increase in systolic blood pressure and catecholamine level during hyperinsulinemia in a placebo-controlled euglycemic clamp in healthy subjects. Exp Clin Endocrinol Diabetes 2000;108 (8) 498- 505
PubMed
Reaven  GMLithell  HLandsberg  L Hypertension and associated metabolic abnormalities: the role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996;334 (6) 374- 381
PubMed
Rooney  DPEdgar  JDSheridan  BAtkinson  ABBell  PM The effects of low dose insulin infusions on the renin angiotensin and sympathetic nervous systems in normal man. Eur J Clin Invest 1991;21 (4) 430- 435
PubMed
Furchgott  RFZawadzki  JV The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288 (5789) 373- 376
PubMed
Kojda  GHarrison  D Interactions between NO and reactive oxygen species: pathophysiological importance in atherosclerosis, hypertension, diabetes and heart failure. Cardiovasc Res 1999;43 (3) 562- 571
PubMed
Kubes  PSuzuki  MGranger  DN Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A 1991;88 (11) 4651- 4655
PubMed
Radomski  MWPalmer  RMMoncada  S Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 1987;2 (8567) 1057- 1058
PubMed
Alper  AB  JrChen  WYau  LSrinivasan  SRBerenson  GSHamm  LL Childhood uric acid predicts adult blood pressure: the Bogalusa Heart Study. Hypertension 2005;45 (1) 34- 38
PubMed
Forman  JPChoi  HCurhan  GC Plasma uric acid level and risk for incident hypertension among men. J Am Soc Nephrol 2007;18 (1) 287- 292
PubMed
Hunt  SCStephenson  SHHopkins  PNWilliams  RR Predictors of an increased risk of future hypertension in Utah: a screening analysis. Hypertension 1991;17 (6, pt 2) 969- 976
PubMed
Jossa  FFarinaro  EPanico  S  et al.  Serum uric acid and hypertension: the Olivetti Heart Study. J Hum Hypertens 1994;8 (9) 677- 681
PubMed
Kahn  HAMedalie  JHNeufeld  HNRiss  EGoldbourt  U The incidence of hypertension and associated factors: the Israel Ischemic Heart Disease study. Am Heart J 1972;84 (2) 171- 182
PubMed
Krishnan  EKwoh  CKSchumacher  HRKuller  L Hyperuricemia and incidence of hypertension among men without metabolic syndrome. Hypertension 2007;49 (2) 298- 303
PubMed
Masuo  KKawaguchi  HMikami  HOgihara  TTuck  ML Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension 2003;42 (4) 474- 480
PubMed
Mellen  PBBleyer  AJErlinger  TP  et al.  Serum uric acid predicts incident hypertension in a biethnic cohort: the Atherosclerosis Risk in Communities study. Hypertension 2006;48 (6) 1037- 1042
PubMed
Nakanishi  NOkamoto  MYoshida  HMatsuo  YSuzuki  KTatara  K Serum uric acid and risk for development of hypertension and impaired fasting glucose or type II diabetes in Japanese male office workers. Eur J Epidemiol 2003;18 (6) 523- 530
PubMed
Perlstein  TSGumieniak  OWilliams  GH  et al.  Uric acid and the development of hypertension: the Normative Aging Study. Hypertension 2006;48 (6) 1031- 1036
PubMed
Selby  JVFriedman  GDQuesenberry  CP  Jr Precursors of essential hypertension: pulmonary function, heart rate, uric acid, serum cholesterol, and other serum chemistries. Am J Epidemiol 1990;131 (6) 1017- 1027
PubMed
Shankar  AKlein  RKlein  BENieto  FJ The association between serum uric acid level and long-term incidence of hypertension: population-based cohort study. J Hum Hypertens 2006;20 (12) 937- 945
PubMed
Sundström  JSullivan  LD'Agostino  RBLevy  DKannel  WBVasan  RS Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension 2005;45 (1) 28- 33
PubMed
Taniguchi  YHayashi  TTsumura  KEndo  GFujii  SOkada  K Serum uric acid and the risk for hypertension and type 2 diabetes in Japanese men: the Osaka Health Survey. J Hypertens 2001;19 (7) 1209- 1215
PubMed
Arnlöv  JPencina  MJNam  BH  et al.  Relations of insulin sensitivity to longitudinal blood pressure tracking: variations with baseline age, body mass index, and blood pressure. Circulation 2005;112 (12) 1719- 1727
PubMed
Hu  FBStampfer  MJ Insulin resistance and hypertension: the chicken-egg question revisited. Circulation 2005;112 (12) 1678- 1680
PubMed
Bowman  TSGaziano  JMStampfer  MJSesso  HD Homocysteine and risk of developing hypertension in men. J Hum Hypertens 2006;20 (8) 631- 634
PubMed
Sundström  JSullivan  LD'Agostino  RB  et al.  Plasma homocysteine, hypertension incidence, and blood pressure tracking: the Framingham Heart Study. Hypertension 2003;42 (6) 1100- 1105
PubMed
McAuley  KAWilliams  SMMann  JI  et al.  Diagnosing insulin resistance in the general population. Diabetes Care 2001;24 (3) 460- 464
PubMed
Brevetti  GMartone  VDde Cristofaro  T  et al.  High levels of adhesion molecules are associated with impaired endothelium-dependent vasodilation in patients with peripheral arterial disease. Thromb Haemost 2001;85 (1) 63- 66
PubMed
Gearing  AJHemingway  IPigott  RHughes  JRees  AJCashman  SJ Soluble forms of vascular adhesion molecules, E-selectin, ICAM-1, and VCAM-1: pathological significance. Ann N Y Acad Sci 1992;667324- 331
PubMed
Holmlund  AHulthe  JMillgård  JSarabi  MKahan  TLind  L Soluble intercellular adhesion molecule-1 is related to endothelial vasodilatory function in healthy individuals. Atherosclerosis 2002;165 (2) 271- 276
PubMed
Nawawi  HOsman  NSAnnuar  RKhalid  BAYusoff  K Soluble intercellular adhesion molecule-1 and interleukin-6 levels reflect endothelial dysfunction in patients with primary hypercholesterolaemia treated with atorvastatin. Atherosclerosis 2003;169 (2) 283- 291
PubMed
Tawakol  AOmland  TGerhard  MWu  JTCreager  MA Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 1997;95 (5) 1119- 1121
PubMed
Woo  KSChook  PLolin  YI  et al.  Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans. Circulation 1997;96 (8) 2542- 2544
PubMed
Rich-Edwards  JWGoldman  MBWillett  WCHunter  DJStampfer  MJColditz  GAManson  JE Adolescent body mass index and infertility caused by ovulatory disorder. Am J Obstet Gynecol 1994;171 (1) 171- 177
Gelber  RPGaziano  JMManson  JEBuring  JESesso  HD A prospective study of body mass index and the risk of developing hypertension in men. Am J Hypertens 2007;20 (4) 370- 377
PubMed
Huang  ZWillett  WCManson  JE  et al.  Body weight, weight change, and risk for hypertension in women. Ann Intern Med 1998;128 (2) 81- 88
PubMed
Høieggen  AAlderman  MHKjeldsen  SE  et al. LIFE Study Group, The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004;65 (3) 1041- 1049
PubMed
Li  CFord  ES McGuire  LCMokdad  AHLittle  RRReaven  GM Trends in hyperinsulinemia among nondiabetic adults in the U.S. Diabetes Care 2006;29 (11) 2396- 2402
PubMed
Marchesi  SVaudo  GLupattelli  G  et al.  Fat distribution and endothelial function in normal-overweight menopausal women. J Clin Pharm Ther 2007;32 (5) 477- 482
PubMed
Moriarity  JTFolsom  ARIribarren  CNieto  FJRosamond  WD Serum uric acid and risk of coronary heart disease: Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 2000;10 (3) 136- 143
PubMed
Shai  IPischon  THu  FBAscherio  ARifai  NRimm  EB Soluble intercellular adhesion molecules, soluble vascular cell adhesion molecules, and risk of coronary heart disease. Obesity 2006;14 (11) 2099- 2106
PubMed
Davies  MJBaer  DJJudd  JTBrown  EDCampbell  WSTaylor  PR Effects of moderate alcohol intake on fasting insulin and glucose concentrations and insulin sensitivity in postmenopausal women: a randomized controlled trial. JAMA 2002;287 (19) 2559- 2562
PubMed
Levey  ASBosch  JPLewis  JBGreene  TRogers  NRoth  DModification of Diet in Renal Disease Study Group, A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130 (6) 461- 470
PubMed
Fiebach  NHHebert  PRStampfer  MJ  et al.  A prospective study of high blood pressure and cardiovascular disease in women. Am J Epidemiol 1989;130 (4) 646- 654
PubMed
Colditz  GAMartin  PStampfer  MJ  et al.  Validation of questionnaire information on risk factors and disease outcomes in a prospective cohort study of women. Am J Epidemiol 1986;123 (5) 894- 900
PubMed
Choi  HKLiu  SCurhan  G Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition Examination Survey. Arthritis Rheum 2005;52 (1) 283- 289
PubMed
Wortmann  RL Recent advances in the management of gout and hyperuricemia. Curr Opin Rheumatol 2005;17 (3) 319- 324
PubMed
Li  CFord  ESMeng  YXMokdad  AHReaven  GM Does the association of the triglyceride to high-density lipoprotein cholesterol ratio with fasting serum insulin differ by race/ethnicity? Cardiovasc Diabetol 2008;74
PubMed10.1186/1475-2840-7-4
Kang  SSWong  PWMalinow  MR Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 1992;12279- 298
PubMed
Grewal  JChan  SFrohlich  JMancini  GB Assessment of novel risk factors in patients at low risk for cardiovascular events based on Framingham risk stratification. Clin Invest Med 2003;26 (4) 158- 165
PubMed
Hoogeveen  RCBallantyne  CMBang  H  et al.  Circulating oxidised low-density lipoprotein and intercellular adhesion molecule-1 and risk of type 2 diabetes mellitus: the Atherosclerosis Risk in Communities Study. Diabetologia 2007;50 (1) 36- 42
PubMed
Hulthe  JWikstrand  JMattsson-Hultén  LFagerberg  B Circulating ICAM-1 (intercellular cell-adhesion molecule 1) is associated with early stages of atherosclerosis development and with inflammatory cytokines in healthy 58-year-old men: the Atherosclerosis and Insulin Resistance (AIR) study. Clin Sci (Lond) 2002;103 (2) 123- 129
PubMed
Tzoulaki  IMurray  GDLee  AJRumley  ALowe  GDFowkes  FG C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: Edinburgh Artery Study. Circulation 2005;112 (7) 976- 983
PubMed
Iribarren  CFolsom  AREckfeldt  JH McGovern  PGNieto  FJ Correlates of uric acid and its association with asymptomatic carotid atherosclerosis: the ARIC study. Ann Epidemiol 1996;6 (4) 331- 340
PubMed
Kang  DHNakagawa  TFeng  L  et al.  A role for uric acid in the progression of renal disease. J Am Soc Nephrol 2002;13 (12) 2888- 2897
PubMed
Khosla  UMZharikov  SFinch  JL  et al.  Hyperuricemia induces endothelial dysfunction. Kidney Int 2005;67 (5) 1739- 1742
PubMed
Mazzali  MHughes  JKim  YG  et al.  Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001;38 (5) 1101- 1106
PubMed
Johnson  RJTitte  SCade  JRRideout  BAOliver  WJ Uric acid, evolution and primitive cultures. Semin Nephrol 2005;25 (1) 3- 8
PubMed
Maxwell  SRThomason  HSandler  D  et al.  Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus. Eur J Clin Invest 1997;27 (6) 484- 490
PubMed
Scott  GSCuzzocrea  SGenovese  TKoprowski  HHooper  DC Uric acid protects against secondary damage after spinal cord injury. Proc Natl Acad Sci U S A 2005;102 (9) 3483- 3488
PubMed
Waring  WS McKnight  JAWebb  DJMaxwell  SR Uric acid restores endothelial function in patients with type 1 diabetes and regular smokers. Diabetes 2006;55 (11) 3127- 3132
PubMed
Paravicini  TMTouyz  RM Redox signaling in hypertension. Cardiovasc Res 2006;71 (2) 247- 258
PubMed
George  JCarr  EDavies  JBelch  JJStruthers  A High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 2006;114 (23) 2508- 2516
PubMed
Perlstein  TSGerhard-Herman  MHollenberg  NKWilliams  GHThomas  A Insulin induces renal vasodilation, increases plasma renin activity, and sensitizes the renal vasculature to angiotensin receptor blockade in healthy subjects. J Am Soc Nephrol 2007;18 (3) 944- 951
PubMed
DeFronzo  RACooke  CRAndres  RFaloona  GRDavis  PJ The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest 1975;55 (4) 845- 855
PubMed
Nørgaard  KJensen  TSkøtt  P  et al.  Effects of insulin on renal haemodynamics and sodium handling in normal subjects. Scand J Clin Lab Invest 1991;51 (4) 367- 376
PubMed
Skøtt  PHother-Nielsen  OBruun  NE  et al.  Effects of insulin on kidney function and sodium excretion in healthy subjects. Diabetologia 1989;32 (9) 694- 699
PubMed
Rossi  RChiurlia  ENuzzo  ACioni  EOrigliani  GModena  MG Flow-mediated vasodilation and the risk of developing hypertension in healthy postmenopausal women. J Am Coll Cardiol 2004;44 (8) 1636- 1640
PubMed
Sesso  HDBuring  JERifai  NBlake  GJGaziano  JMRidker  PM C-reactive protein and the risk of developing hypertension. JAMA 2003;290 (22) 2945- 2951
PubMed
Liese  ADMayer-Davis  EJChambless  LE  et al. Atherosclerosis Risk in Communities Study Investigators, Elevated fasting insulin predicts incident hypertension: the ARIC study. J Hypertens 1999;17 (8) 1169- 1177
PubMed
Shetterly  SMRewers  MHamman  RFMarshall  JA Patterns and predictors of hypertension incidence among Hispanics and non-Hispanic whites: the San Luis Valley Diabetes Study. J Hypertens 1994;12 (9) 1095- 1102
PubMed

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 29

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
Clinical Scenario

Users' Guides to the Medical Literature
Example 1: Diabetes and Target Blood Pressure