Dataset Information

Severity of Hypertension Mediates the Association of Hyperuricemia With Stroke in the REGARDS Case Cohort Study.

ABSTRACT: Previous studies do not widely support hyperuricemia as a risk factor for stroke and other cardiovascular diseases. We assessed the relationship between hyperuricemia and ischemic stroke (?900 cases) using a large data set from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). We employed a case-cohort design (incident stroke cases and randomly selected cohort participants) and weighted Cox-proportional hazard models to estimate the association of serum urate level ?6.8 mg/dL (ie, hyperuricemia) and 6.0 to <6.8 mg/dL versus <6.0 mg/dL (reference) with incident stroke. Analyses were stratified by race, gender, and age. Mediation of cardiovascular disease comorbidities on the serum urate-stroke association was tested. Hyperuricemia was associated with stroke (hazard ratio, 1.40 [95% CI, 1.10-1.78]) after adjustment for demographic variables and systolic and diastolic blood pressure. This association was substantially attenuated (hazard ratio, 1.17 [95% CI, 0.90-1.51]) by additional covariate adjustment. In particular, apparent treatment-resistant hypertension (systolic blood pressure ?140 mm Hg or diastolic blood pressure ?90 mm Hg on 3 antihypertensive medications or use of ?4 antihypertensive medications) and the count of antihypertensive medication classes significantly reduced the effect of hyperuricemia on ischemic stroke. Specifically, apparent treatment-resistant hypertension and number of antihypertensive, respectively, mediate 45% and 43% of the association. There was no effect modification in the association between hyperuricemia and stroke by age, race, or gender. We conclude that hyperuricemia may be a risk factor for stroke. The substantial attenuation of this association by apparent treatment-resistant hypertension and number of antihypertensive suggests that severe hypertension may be a mediator.

SUBMITTER: Chaudhary NS

PROVIDER: S-EPMC7122733 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Severity of Hypertension Mediates the Association of Hyperuricemia With Stroke in the REGARDS Case Cohort Study.

Chaudhary Ninad S NS Bridges S Louis SL Saag Kenneth G KG Rahn Elizabeth J EJ Curtis Jeffrey R JR Gaffo Angelo A Limdi Nita A NA Levitan Emily B EB Singh Jasvinder A JA Colantonio Lisandro D LD Howard George G Cushman Mary M Flaherty Matthew L ML Judd Suzanne S Irvin Marguerite R MR Reynolds Richard J RJ

Hypertension (Dallas, Tex. : 1979) 20191202 1

Previous studies do not widely support hyperuricemia as a risk factor for stroke and other cardiovascular diseases. We assessed the relationship between hyperuricemia and ischemic stroke (≈900 cases) using a large data set from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). We employed a case-cohort design (incident stroke cases and randomly selected cohort participants) and weighted Cox-proportional hazard models to estimate the association of serum urate level ≥6. ...[more]

PMID: 31786980

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Project description:BACKGROUND:Hypertension and high triglyceride are two of the most important risk factors for hyperuricemia. Epidemiological records show that hypertension and dyslipidemia often coexist and may significantly increase the risk of target organ damage. However, their combined effect on incident hyperuricemia is poorly understood. Thus, we aimed to investigate the separate and combined effect of hypertension and hypertriglyceridemia on the incidence of hyperuricemia. METHODS:A prospective cohort study of 6424 hyperuricemia-free participants aged 20 to 94 years between August 2009 and October 2017 was performed at Tianjin General Hospital of China. Participants were categorized into four groups by combining hypertension and hypertriglyceridemia status at baseline. The restricted cubic spline fitting Cox regression model was used to evaluate the relationship between blood pressure and triglyceride and hyperuricemia. Cox regression models were performed to calculate hazard ratios (HRs) and 95% confident intervals (CIs) to estimate baseline factors and their association with the incidence of hyperuricemia. A Kaplan-Meier survival analysis was performed to compare the incidence of hyperuricemia among subjects in each separate and combined hypertension and hypertriglyceridemia group. RESULTS:During the 8-year follow-up period, 1259 subjects developed hyperuricemia (20.6%). There existed positive relationships between blood pressure and triglyceride levels and hyperuricemia. This risk factor arising from a combination of the two (HR, 3.02; 95% CI 2.60-3.50) is greater than that from hypertension (HR, 1.48; 95% CI 1.28-1.71) or hypertriglyceridemia (HR, 1.84; 95% CI 1.55-2.18) separately. The Kaplan-Meier survival analysis indicated that combined effect of hypertension and hypertriglyceridemia may predict higher onset of hyperuricemia. CONCLUSION:The combined effect of hypertension and hypertriglyceridemia on the risk of hyperuricemia is much stronger than that by hypertension or hypertriglyceridemia separately. Hypertension combined with hypertriglyceridemia may be an independent and powerful predictor for hyperuricemia.

Project description:Studies suggest that treatment-resistant hypertension is common and increasing in prevalence among US adults. Although hypertension is a risk factor for end-stage renal disease (ESRD), few data are available for the association between treatment-resistant hypertension and ESRD risk.Prospective cohort study.We analyzed data from 9,974 REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study participants treated for hypertension without ESRD at baseline.Treatment-resistant hypertension was defined as uncontrolled blood pressure (BP) with concurrent use of 3 antihypertensive medication classes including a diuretic or use of 4 or more antihypertensive medication classes including a diuretic regardless of BP.Incident ESRD was identified by linkage of REGARDS Study participants with the US Renal Data System.During a baseline in-home study visit, BP was measured twice and classes of antihypertensive medication being taken were determined by pill bottle inspection.During a median follow-up of 6.4 years, there were 152 incident cases of ESRD (110 ESRD cases among 2,147 with treatment-resistant hypertension and 42 ESRD cases among 7,827 without treatment-resistant hypertension). The incidence of ESRD per 1,000 person-years for hypertensive participants with and without treatment-resistant hypertension was 8.86 (95% CI, 7.35-10.68) and 0.88 (95% CI, 0.65-1.19), respectively. After multivariable adjustment, the HR for ESRD comparing hypertensive participants with versus without treatment-resistant hypertension was 6.32 (95% CI, 4.30-9.30). Of participants who developed incident ESRD during follow-up, 72% had treatment-resistant hypertension at baseline.BP, estimated glomerular filtration rate, and albuminuria assessed at a single time.Individuals with treatment-resistant hypertension are at increased risk for ESRD. Appropriate clinical management strategies are needed to treat treatment-resistant hypertension in order to preserve kidney function in this high-risk group.

Project description:Increased plasma uric acid (hyperuricemia) has been associated with worse outcomes for chronic kidney disease (CKD). But some attempts to control uric acid (UA) in large-cohort clinical trials did not produce clinically meaningful benefits for CKD. Some studies suggest that only hyperuricemia with crystals, but not asymptomatic hyperuricemia promotes the progression of CKD. Salt-sensitivity (SS) in blood pressure is a prevalent trait that is sexually dimorphic and results in kidney damage. But the connection between hyperuricemia and SS hypertension (HTN) is still unclear. Here we tested the connection between the two using both male and female Dahl SS rats, a well-establish model of SS HTN. We hypothesized that mild asymptomatic hyperuricemia is beneficial in controlling the progression of SS HTN. A uricase inhibitor, oxonic acid (2%) (Oxo) was used to induce hyperuricemia and high-salt (HS) (4% NaCl) diet was used to induce SS HTN. After 3 weeks, in response to oxonic acid supplementation, both sexes showed a significant increase of UA in plasma compared to their respective HS-only controls (Males: 0.63 ±0.07 vs. 2.17 ±0.34; Females: 0.78 ±0.15 vs. 2.04 ±0.35 mg/dl, HS vs. HS/oxo). Interestingly, only male HS/oxo rats showed a significant increase in uricosuria (Males: 0.23 ±0.03 vs. 0.45 ±0.06; Femaels: 0.26 ±0.06 vs. 0.26 ±0.001 UA/Cre, HS vs. HS/oxo). Moreover, the mild hyperuricemia was associated with a significant attenuation of the progression and magnitude of the mean arterial pressure in male but not female rats (Males: 157 ±3 vs. 136 ±3; Females: 155 ±6 vs. 154 ±5 mmHg, HS vs. HS/oxo). Xanthine oxidase (XO) is one of the enzymes that produce UA, and its activity has been shown to affect HTN as well. Therefore, we examined the level of XO activity in the plasma after the treatment. While there was no difference in the activity based on the diet within each sex, females had significantly lower levels of XO activity compared to males in each of the diets. To further investigate the beneficial phenotype seen in male rats, we evaluate changes in the progression of renal pathology. The HS/oxo group compared to the HS group had a lower kidney weight/body weight ratio and lower protein cast accumulation, indicating lower kidney damage. Furthermore, the HS/Oxo treated males had less oxidative damage in their tubules than the HS-only males. Bulk-RNA seq done on the male kidneys revealed that attenuated HTN phenotype was associated with an increased expression in Mas1 (MAS receptor), Klk-1 (Kallikrein-1), and Pcsk6 (PCSK6 enzyme) which can all lead to the activation of different vasodilatory pathways. Our study showed that in male but not female Dahl SS rats, asymptomatic mild hyperuricemia accompanied by hyperuricosuria ameliorates the progression of SS HTN and protects kidneys from further damage. Thus, our findings challenge the notion of hyperuricemia being inherently detrimental to health and highlight that this is an oversimplified view of UA’s role in disease.

Dataset Information

Severity of Hypertension Mediates the Association of Hyperuricemia With Stroke in the REGARDS Case Cohort Study.

Publications

Severity of Hypertension Mediates the Association of Hyperuricemia With Stroke in the REGARDS Case Cohort Study.

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