Increased serum uric acid (UA) is associated with incident heart failure (HF). However, whether it is a direct effect of UA or an effect of increased xanthine oxidase (XO) is unknown. Because hyperuricemia in hyperinsulinemia is primarily due to impaired renal UA excretion, its association with incident HF would suggest a direct UA effect. In contrast, hyperuricemia in normoinsulinemia is likely due to increased UA production and thus its association with incident HF would suggest an XO effect. To clarify this, we examined the association of hyperuricemia with centrally adjudicated incident HF in Cardiovascular Health Study participants with and without hyperinsulinemia. Of the 5,411 participants ≥65 years of age without baseline HF, 1,491 (28%) had hyperuricemia (serum UA ≥6 mg/dl for women and ≥7 mg/dl for men). Propensity scores for hyperuricemia were estimated using 63 baseline characteristics. Mean serum UA levels were 6.0 and 5.3 mg/dl in those with (n = 2,731) and those without (n = 2,680) hyperinsulinemia (median serum insulin ≥13 mU/L), respectively (p <0.001). Propensity-adjusted hazard ratios (95% confidence intervals) for hyperuricemia-associated incident HF during 8 years of median follow-up were 0.99 (0.83 to 1.18, p = 0.886) and 1.32 (1.04 to 1.67, p = 0.021) for those with and without hyperinsulinemia respectively (p for interaction = 0.014). In conclusion, the absence of an association of hyperuricemia with incident HF in those with hyperinsulinemia (despite a significantly higher mean serum UA) and a significant association in normoinsulinemia suggest that UA has no intrinsic association with incident HF and that it may predict incident HF when it is a marker of increased of XO activity.
Increased serum uric acid (UA) is associated with increased risk of heart failure (HF) and cardiovascular morbidity. However, whether hyperuricemia-associated poor cardiovascular outcomes are due to a direct effect of UA or to an underlying increased xanthine oxidase (XO) activity is unclear. Hyperinsulinemia has been shown to be associated with impaired renal UA clearance. Therefore, it is likely that in those with hyperinsulinemia serum UA may be increased due to decreased elimination of UA rather than its increased production. Thus, an association of hyperuricemia and incident HF in those with hyperinsulinemia will likely represent a direct effect of UA. In contrast, hyperuricemia in those with normoinsulinemia is more likely to be due to increased UA production and thus a marker of increased XO activity. Thus, an association of hyperuricemia with incident HF in those with normoinsulinemia will likely represent an effect of XO. Because XO activity is a known cause of oxidative stress and UA is known for its antioxidant properties, we hypothesized that hyperuricemia-associated increase in incident HF would be observed in those with normoinsulinemia but not in those with hyperinsulinemia. To test this hypothesis, we examined the association of hyperuricemia and incident HF in a cohort of community-dwelling older adults with and without hyperinsulinemia.
Methods
For the present study, we used de-identified public-use copies of the Cardiovascular Health Study (CHS) datasets. The rationale, design, and implementation of the CHS have been previously detailed. Briefly, the CHS is an ongoing prospective epidemiologic study of 5,888 Medicare-eligible community-dwelling adults ≥65 years of age recruited from 4 United States counties. The National Heart, Lung, and Blood Institute sponsored the CHS and provided the current datasets, which include 5,795 participants (93 did not consent to be included in the public-use datasets). Of these, we excluded 255 participants with centrally adjudicated prevalent HF at baseline, 79 participants without data on baseline serum UA, and 50 participants without data on baseline serum insulin. The final sample size for the present analysis was 5,411.
Serum UA levels were measured in a central blood analysis laboratory using a Kodak Ektachem 700 analyzer assay (Eastman Kodak, Rochester, New York). Based on commonly used gender-based cutoffs, we defined hyperuricemia as serum UA levels ≥6 mg/dl for women and ≥7 mg/dl for men. Serum insulin levels were measured by a competitive radioimmunoassay (Diagnostic Products, Corp., Malvern, Pennsylvania). Serum insulin levels ≥13 mU/L (median) was used to define hyperinsulinemia. Of the 5,411 participants, 2,731 had hyperinsulinemia and 2,680 had normoinsulinemia. Data on sociodemographic, clinical, subclinical, and laboratory variables were collected at baseline and have been previously described in details.
The primary outcome for this study was definite new-onset HF. The process of adjudication of HF in the CHS has been very well documented in the literature. Briefly, participants were asked about self-reports of a physician diagnosis of HF during semiannual visits. The CHS events committee later adjudicated the diagnosis of HF through examination of participants’ medical records for evidence suggestive of HF and follow-up surveillances.
For descriptive analyses, we used Pearson chi-square and Student’s t tests as appropriate. We used a nonparsimonious multivariable logistic regression model to estimate propensity scores for hyperuricemia (for each of the 5,411 participants), which is the conditional probability of having hyperuricemia given a set of measured baseline characteristics. In the model hyperuricemia was the dependent variable and 63 baseline characteristics and a significant interaction term (between age and baseline serum creatinine) were covariates. To determine if the association between hyperuricemia and incident HF varied by the presence of hyperinsulinemia, we formally tested for 2-way interaction using a Cox regression model. In the model, incident HF was the dependent variable, and hyperuricemia and hyperinsulinemia were entered as main effect terms, in addition to an interaction term for the 2. To determine independence of the interaction between hyperuricemia and hyperinsulinemia, we adjusted the model for propensity score, which is a composite score for the 63 measured baseline characteristics. To determine the association between hyperuricemia and incident HF in those with and without hyperinsulinemia, we then repeated our Cox regression model separately in those groups. All statistical tests were 2-sided, and tests with p value <0.05 were considered statistically significant. Confidence intervals (CIs) were computed based on a 95% confidence levels. SPSS 15 for Windows (SPSS, Inc., Chicago, Illinois) was used for all data analysis.
Results
Our study cohort had a mean age of 73 ± 6 years; 58% were women and 15% were African-American. Baseline characteristics by hyperuricemia, in those with and without hyperinsulinemia, are listed in Table 1 . Prevalences of hyperuricemia were 18% (470 of 2,680) and 37% (1,021 of 2,731) in those with normoinsulinemia and hyperinsulinemia, respectively. Mean ± SD serum UA (6.0 ± 1.5 vs 5.3 ± 1.4 mg/dl, p <0.001), creatinine (1.0 ± 0.4 vs 0.9 ± 0.4 mg/dl, p <0.001), and insulin (24.0 ± 33.0 vs 9.2 ± 2.0 μIU/ml, p <0.001) levels were higher for those with hyperinsulinemia than for those without.
| Serum Insulin Level <13 mU/L | Serum Insulin Level ≥13 mU/L | |||||
|---|---|---|---|---|---|---|
| Variable | Normouricemia (n = 2,210) | Hyperuricemia (n = 470) | p Value | Normouricemia (n = 1,710) | Hyperuricemia ⁎ (n = 1,021) | p Value |
| Age (years) | 73 ± 6 | 75 ± 6 | <0.001 | 73 ± 5 | 73 ± 6 | 0.101 |
| Women | 1,300 (59%) | 258 (55%) | 0.117 | 948 (55%) | 611 (60%) | 0.024 |
| African-American | 335 (15%) | 81 (17%) | 0.259 | 216 (13%) | 166 (16%) | 0.008 |
| Current smoker | 295 (13%) | 51 (11%) | 0.143 | 194 (11%) | 115 (11%) | 0.948 |
| Alcohol intake (units/week) | 3 ± 6 | 4 ± 9 | 0.001 | 2 ± 6 | 2 ± 6 | 0.498 |
| Body mass index (kg/m 2 ) | 25 ± 3 | 26 ± 4 | <0.001 | 28 ± 4 | 29 ± 4 | <0.001 |
| Self-reported general health | 408 (19%) | 124 (26%) | <0.001 | 426 (25%) | 305 (30%) | 0.005 |
| Co-morbidities | ||||||
| Hypertension | 1,086 (49%) | 306 (65%) | <0.001 | 1,006 (59%) | 749 (73%) | <0.001 |
| Acute myocardial infarction | 121 (6%) | 53 (11%) | <0.001 | 167 (10%) | 95 (9%) | 0.692 |
| Diabetes mellitus | 137 (6%) | 40 (9%) | 0.067 | 414 (24%) | 238 (23%) | 0.593 |
| Chronic kidney disease | 283 (13%) | 193 (41%) | <0.001 | 272 (16%) | 386 (38%) | <0.001 |
| Stroke | 57 (3%) | 29 (6%) | <0.001 | 66 (4%) | 51 (5%) | 0.156 |
| Atrial fibrillation | 42 (2%) | 11 (2%) | 0.534 | 34 (2%) | 27 (3%) | 0.262 |
| Clinical findings | ||||||
| Pulse (beats/min) | 66 ± 11 | 67 ± 11 | 0.231 | 69 ± 11 | 69 ± 11 | 0.282 |
| Systolic blood pressure (mm Hg) | 135 ± 22 | 139 ± 23 | <0.001 | 137 ± 21 | 138 ± 21 | 0.621 |
| Diastolic blood pressure (mm Hg) | 70 ± 11 | 71 ± 11 | 0.189 | 71 ± 11 | 71 ± 12 | 0.390 |
| Medications | ||||||
| Angiotensin-converting enzyme inhibitors | 104 (5%) | 31 (7%) | 0.089 | 123 (7%) | 87 (9%) | 0.208 |
| β blocker | 203 (9%) | 80 (17%) | <0.001 | 214 (13%) | 193 (19%) | <0.001 |
| Aspirin | 59 (3%) | 13 (3%) | 0.907 | 70 (4%) | 25 (2%) | 0.023 |
| Statin | 42 (2%) | 7 (2%) | 0.546 | 43 (3%) | 29 (3%) | 0.607 |
| Nonsteroidal anti-inflammatory drugs | 250 (11%) | 74 (16%) | 0.007 | 199 (12%) | 162 (16%) | 0.002 |
| Loop diuretics | 41 (2%) | 36 (8%) | <0.001 | 71 (4%) | 109 (11%) | <0.001 |
| Thiazide diuretics | 157 (7%) | 73 (16%) | <0.001 | 176 (10%) | 205 (20%) | <0.001 |
| Serum chemistry tests | ||||||
| Uric acid (mg/dl) | 4.8 ± 1.0 | 7.3 ± 1.0 | <0.001 | 5.1 ± 0.9 | 7.5 ± 1.1 | <0.001 |
| Glucose (mg/dl) | 101 ± 26 | 104 ± 23 | 0.068 | 120 ± 44 | 118 ± 40 | 0.474 |
| Insulin (mU/L) | 9 ± 2 | 10 ± 2 | <0.001 | 24 ± 33 | 25 ± 31 | 0.375 |
| Creatinine (mg/dl) | 0.9 ± 0.3 | 1.1 ± 0.5 | <0.001 | 0.9 ± 0.4 | 1.1 ± 0.4 | <0.001 |
| Potassium (mEq/L) | 4.2 ± 0.3 | 4.2 ± 0.4 | 0.259 | 4.2 ± 0.4 | 4.1 ± 0.4 | <0.001 |
| Cholesterol (mg/dl) | 210 ± 37 | 218 ± 42 | <0.001 | 211 ± 38 | 215 ± 43 | 0.010 |
| Low-density lipoprotein (mg/dl) | 128 ± 34 | 134 ± 37 | <0.001 | 131 ± 40 | 133 ± 40 | 0.091 |
| High-density lipoprotein (mg/dl) | 59 ± 16 | 56 ± 17 | 0.001 | 51 ± 14 | 49 ± 13 | <0.001 |
| Triglyceride (mg/dl) | 116 ± 51 | 135 ± 68 | <0.001 | 151 ± 90 | 174 ± 87 | <0.001 |
| Albumin (g/dl) | 4.0 ± 0.3 | 4.0 ± 0.3 | 0.406 | 4.0 ± 0.3 | 4.0 ± 0.3 | <0.001 |
| Fibrinogen (mg/dl) | 314 ± 63 | 323 ± 65 | 0.003 | 325 ± 66 | 337 ± 69 | <0.001 |
| Interleukin (pg/dl) | 1.9 ± 1.7 | 2.2 ± 1.8 | 0.001 | 2.2 ± 1.7 | 2.6 ± 2.1 | <0.001 |
| C-reactive protein (mg/L) | 3.6 ± 6.3 | 5.1 ± 7.6 | <0.001 | 5.0 ± 9.7 | 6.1 ± 8.6 | 0.002 |
| Left ventricular hypertrophy by electrocardiogram | 78 (4%) | 29 (6%) | 0.008 | 61 (4%) | 63 (6%) | 0.002 |
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