Abstract
Higher uric acid levels are associated with an increased risk for developing hypertension. Higher intake of fructose increases plasma uric acid levels and higher intake of vitamin C reduces uric acid levels, but whether these nutrients are independently associated with the risk for developing hypertension is unknown. We studied this question by analyzing data from participants of three large and independent prospective cohorts: Nurses’ Health Study 1 (n = 88,540), Nurses’ Health Study 2 (n = 97,315), and the Health Professionals Follow-up Study (n = 37,375). Relative risks and 95% confidence intervals for incident hypertension were computed according to quintiles of fructose intake and categories of vitamin C intake using multivariable Cox proportional hazards regression. Fructose intake was not associated with the risk for developing hypertension; the multivariable relative risks (95% confidence intervals) for the highest compared with the lowest quintile of fructose intake were 1.02 (0.99 to 1.06) in Nurses’ Health Study 1, 1.03 (0.98 to 1.08) in Nurses’ Health Study 2, and 0.99 (0.93 to 1.05) in Heath Professionals Follow-up Study. Regarding vitamin C, the relative risks for individuals who consumed ≥1500 mg/d compared with those who consumed <250 mg/d were 0.89 (0.83 to 0.96) in Nurses’ Health Study 1, 1.02 (0.91 to 1.14) in Nurses’ Health Study 2, and 1.06 (0.97 to 1.15) in Health Professionals Follow-up Study. In conclusion, fructose and vitamin C intake do not substantially influence the risk for developing hypertension.
In multiple prospective observational studies, the plasma uric acid level has been found to be an independent risk factor for the development of hypertension.1–14 Experimentation with rats demonstrated that diet-induced mild hyperuricemia, either with oxonic acid or with fructose, increased BP and led to endothelial dysfunction, phenomena that could be reversed with pharmacologic reduction of uric acid.15–18 Studies of humans demonstrated that higher intake of fructose was linearly associated with higher uric acid levels,19–21 whereas greater consumption of vitamin C was linearly associated with lower uric acid levels.22,23 Moreover, higher fructose intake increased the risk for gout24 whereas higher vitamin C intake was inversely related to risk for gout.25 It stands to reason that if uric acid is causally associated with hypertension incidence, then higher intake of fructose and lower intake of vitamin C would be associated with the development of hypertension. Indeed, some investigators have suggested a link between the rising consumption of fructose-sweetened food and beverages with the rising tide of hypertension and the metabolic syndrome.26
A contrasting argument exists, however, because uric acid is a potent antioxidant.27,28 Waring et al.29 first demonstrated that, unlike the rat experiments mentioned, uric acid infusion into healthy humans did not adversely affect endothelial function and subsequently showed that uric acid infusion actually improved endothelial function in patients with diabetes and smokers.30 The antioxidant drug allopurinol, by blocking xanthine oxidase, reduces the formation of not only uric acid but also superoxide31; therefore, it is not clear that studies of allopurinol-induced improvements of endothelial function32–36 should be interpreted simply in terms of uric acid lowering. Indeed, George et al.37 showed that uric acid lowering with allopurinol improved endothelial function in patients with heart failure, but uric acid lowering to a similar degree with probenecid (a uricosuric) had no effect. Thus, it is not clear whether the association between uric acid and hypertension in humans is causal, coincidental, or compensatory.
We prospectively investigated the association between intake of two nutrients that influence plasma uric acid levels, fructose and vitamin C, and risk for developing hypertension in three large cohort studies that together included >200,000 participants: The Nurses’ Health Study 1 (NHS1), the Nurses’ Health Study 2 (NHS2), and the Health Professionals Follow-up Study (HPFS). We hypothesized that a higher intake of fructose would be associated with an increased risk for incident hypertension, whereas a higher intake of vitamin C would be associated with a decreased risk.
RESULTS
Participant Characteristics
In NHS1 in 1984, the median age was 49 yr (interquartile range [IQR] 44 to 56), and the median body mass index (BMI) was 23.4 kg/m2 (IQR 21.4 to 26.3). The median fructose intake (as percentage of total daily energy intake) was 9.3% (IQR 7.5 to 11.4). The median vitamin C intake was 190 mg/d (IQR 117 to 379). In the younger female cohort (NHS2) in 1991, the median age was 36 yr (IQR 32 to 40), and median BMI was 23.0 kg/m2 (IQR 21.0 to 26.1). The median fructose intake was 9.1% (IQR 6.8 to 12.1) of daily energy intake, and the median vitamin C intake was 156 mg/d (IQR 99 to 259). In HPFS in 1986, the median age was 52 yr (IQR 44 to 61), the median BMI was 24.8 kg/m2 (IQR 23.2 to 26.6), the median fructose intake was 9.3% (IQR 7.0 to 12.1) of total daily energy intake, and the median vitamin C intake was 225 mg/d (IQR 136 to 517).
Baseline characteristics of these participants stratified by quintile of fructose intake and category of vitamin C intake are shown in Tables 1 through 3. With higher consumption of fructose, intakes of alcohol and caffeine were consistently lower and intake of folate was consistently higher in all three cohorts. In NHS2 and HPFS, we observed lower BMI values among those with higher fructose intakes. With higher vitamin C intake, we consistently observed older age and higher folate intake.
Table 1.
Baseline characteristics of the NHS1 cohort in 1984 according to intake of fructose and vitamin C
| Characteristic | Quintiles of Total Fructose Intake, % Total Energy (Median [Range])
|
Categories of Vitamin C Intake (mg/d)
|
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 6.0 (0.1 to 7.2) | 8.1 (7.3 to 8.9) | 9.7 (9.0 to 10.5) | 11.4 (10.6 to 12.6) | 14.3 (12.7 to 37.8) | <250 (n = 39,110) | 250 to 499 (n = 11,064) | 500 to 999 (n = 7315) | 1000 to 1499 (n = 3684) | ≥1500 (n = 1621) | |
| Age (yr; median [IQR]) | 49 (43 to 55) | 49 (43 to 55) | 50 (44 to 56) | 50 (44 to 56) | 50 (44 to 57) | 49 (43 to 55) | 50 (44 to 56) | 50 (45 to 57) | 51 (45 to 57) | 51 (45 to 57) |
| BMI (kg/m2; median [IQR]) | 23.7 (21.6 to 26.6) | 23.6 (21.6 to 26.5) | 23.4 (21.5 to 26.3) | 23.3 (21.3 to 25.8) | 23.0 (21.1 to 25.7) | 23.6 (21.6 to 26.5) | 23.4 (21.4 to 26.1) | 23.0 (21.3 to 25.6) | 23.2 (21.3 to 25.8) | 23.0 (21.0 to 25.8) |
| Physical activity (METS; median [IQR]) | 6.5 (2.3 to 16.7) | 7.6 (2.7 to 19.0) | 8.4 (3.1 to 20.1) | 8.4 (3.1 to 20.2) | 7.9 (2.8 to 20.2) | 6.9 (2.4 to 17.1) | 9.3 (3.4 to 21.3) | 9.5 (3.4 to 20.9) | 10.2 (3.2 to 22.9) | 9.5 (3.4 to 20.9) |
| Alcohol intake, g/d; median [IQR]) | 5.5 (0.9 to 15.8) | 2.9 (0.0 to 10.6) | 2.0 (0.0 to 7.6) | 1.8 (0.0 to 6.0) | 1.1 (0.0 to 3.9) | 2.0 (0.0 to 8.8) | 2.7 (0.0 to 9.5) | 2.7 (0.0 to 10.6) | 2.7 (0.0 to 10.8) | 1.9 (0.0 to 7.8) |
| Caffeine intake (mg/d; median [IQR]) | 357 (165 to 554) | 348 (149 to 467) | 340 (137 to 433) | 269 (118 to 415) | 218 (104 to 404) | 346 (148 to 468) | 296 (129 to 425) | 260 (117 to 413) | 271 (104 to 426) | 189 (69 to 385) |
| Folate intake (μg/d; median [IQR]) | 272 (196 to 427) | 320 (233 to 501) | 342 (247 to 536) | 350 (251 to 552) | 350 (236 to 570) | 276 (206 to 378) | 443 (309 to 649) | 512 (314 to 703) | 520 (310 to 721) | 623 (367 to 872) |
| Current smoker (%) | 33.9 | 33.2 | 30.7 | 29.6 | 26.7 | 30.3 | 31.0 | 33.3 | 33.7 | 35.8 |
| Past smoker (%) | 3.8 | 4.3 | 4.2 | 4.1 | 3.8 | 3.8 | 4.1 | 4.6 | 5.1 | 4.8 |
| Family history of hypertension (%) | 40.5 | 42.1 | 41.4 | 41.5 | 39.0 | 41.5 | 41.0 | 39.7 | 39.4 | 38.8 |
Table 2.
Baseline characteristics of the NHS2 cohort in 1991 according to intake of fructose and vitamin C
| Characteristic | Quintiles of Total Fructose Intake, % Total Energy (Median [Range])
|
Categories of Vitamin C Intake (mg/d)
|
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 5.7 (0.7 to 6.7) | 7.6 (6.8 to 8.3) | 9.1 (8.4 to 9.9) | 10.9 (10.0 to 12.1) | 14.3 (12.2 to 45.9) | <250 (n = 64,851) | 250 to 499 (n = 14,058) | 500 to 999 (n = 5532) | 1000 to 1499 (n = 2773) | ≥1500 (n = 963) | |
| Age (yr; median [IQR]) | 36 (33 to 40) | 36 (33 to 40) | 36 (33 to 40) | 36 (32 to 40) | 36 (32 to 39) | 36 (32 to 40) | 36 (32 to 39) | 37 (33 to 40) | 37 (34 to 41) | 38 (35 to 41) |
| BMI (kg/m2; median [IQR]) | 23.6 (21.4 to 27.3) | 23.3 (21.3 to 26.6) | 23.0 (21.0 to 26.0) | 22.7 (20.7 to 25.6) | 22.3 (20.5 to 25.4) | 23.0 (21.0 to 26.3) | 22.9 (20.8 to 25.8) | 22.6 (20.7 to 25.5) | 22.6 (20.8 to 25.3) | 22.8 (20.6 to 25.8) |
| Physical activity (METS; median [IQR]) | 10.2 (3.9 to 22.6) | 12.4 (5.2 to 26.0) | 13.5 (5.6 to 27.4) | 14.3 (5.9 to 29.5) | 13.1 (4.9 to 28.9) | 11.5 (4.6 to 24.9) | 15.9 (6.8 to 32.6) | 16.3 (7.1 to 32.9) | 16.4 (7.3 to 34.9) | 18.5 (7.7 to 37.1) |
| Alcohol intake, g/d; median [IQR]) | 1.5 (0.0 to 5.7) | 1.1 (0.0 to 4.2) | 0.9 (0.0 to 3.5) | 0.9 (0.0 to 2.9) | 0.0 (0.0 to 2.0) | 0.9 (0.0 to 3.4) | 0.9 (0.0 to 3.5) | 1.0 (0.0 to 4.2) | 1.1 (0.0 to 4.4) | 0.9 (0.0 to 4.1) |
| Caffeine intake (mg/d; median [IQR]) | 217 (89 to 391) | 183 (65 to 382) | 164 (57 to 369) | 152 (52 to 364) | 144 (59 to 351) | 170 (65 to 375) | 150 (50 to 359) | 155 (51 to 365) | 160 (54 to 369) | 142 (32 to 364) |
| Folate intake (μg/d; median [IQR]) | 307 (214 to 492) | 369 (260 to 586) | 404 (279 to 636) | 419 (287 to 662) | 414 (265 to 659) | 328 (235 to 487) | 615 (431 to 847) | 633 (438 to 808) | 617 (401 to 785) | 674 (457 to 962) |
| Current smoker (%) | 16.3 | 11.2 | 10.0 | 9.9 | 13.8 | 12.6 | 9.9 | 12.0 | 14.3 | 12.9 |
| Past smoker (%) | 24.6 | 24.4 | 22.7 | 21.2 | 18.2 | 21.8 | 21.9 | 24.1 | 25.9 | 30.3 |
| Family history of hypertension (%) | 51.0 | 50.5 | 49.8 | 49.8 | 49.4 | 50.0 | 50.1 | 50.8 | 50.0 | 50.9 |
Table 3.
Baseline characteristics of the HPFS cohort in 1986 according to intake of fructose and vitamin C
| Characteristic | Quintiles of Total Fructose Intake, % Total Energy (Median [Range])
|
Categories of Vitamin C Intake (mg/d)
|
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 5.7 (0.5 to 6.9) | 7.8 (7.0 to 8.6) | 9.3 (8.7 to 10.1) | 11.0 (10.2 to 12.1) | 13.9 (12.2 to 36.2) | <250 (n = 19,904) | 250 to 499 (n = 7330) | 500 to 999 (n = 4849) | 1000 to 1499 (n = 2604) | ≥1500 (n = 1875) | |
| Age (yr; median [IQR]) | 52 (44 to 60) | 52 (44 to 61) | 52 (44 to 61) | 52 (44 to 61) | 52 (44 to 61) | 51 (44 to 60) | 52 (44 to 61) | 54 (45 to 62) | 53 (45 to 61) | 53 (45 to 60) |
| BMI (kg/m2; median [IQR]) | 25.1 (23.5 to 27.1) | 25.0 (23.3 to 26.7) | 24.8 (23.2 to 26.6) | 24.6 (23.1 to 26.5) | 24.4 (23.0 to 26.5) | 25.1 (23.4 to 26.9) | 24.8 (23.1 to 26.6) | 24.6 (23.1 to 26.5) | 24.4 (23.0 to 26.3) | 24.4 (22.9 to 26.2) |
| Physical activity (METS; median [IQR]) | 10.4 (3.2 to 25.6) | 12.6 (4.2 to 28.8) | 13.4 (4.6 to 30.3) | 13.9 (4.6 to 32.3) | 13.6 (4.4 to 32.2) | 10.6 (3.4 to 25.9) | 15.1 (5.3 to 33.6) | 14.9 (4.8 to 31.8) | 15.4 (5.7 to 33.9) | 17.6 (6.4 to 35.8) |
| Alcohol intake, g/d; median [IQR]) | 12.8(2.9 to 32.0) | 7.5 (1.8 to 15.9) | 4.7 (0.9 to 12.9) | 3.5 (0.0 to 10.2) | 1.9 (0.0 to 6.8) | 5.5 (0.9 to 14.6) | 5.5 (0.9 to 14.0) | 5.5 (0.9 to 14.0) | 6.0 (1.0 to 15.2) | 5.5 (0.9 to 14.9) |
| Caffeine intake (mg/d; median [IQR]) | 205 (64 to 395) | 165 (46 to 377) | 149 (36 to 365) | 143 (34 to 358) | 117 (28 to 349) | 170 (53 to 380) | 146 (32 to 362) | 140 (29 to 356) | 136 (28 to 355) | 89 (17 to 348) |
| Folate intake (μg/d; median [IQR]) | 347 (250 to 516) | 386 (288 to 565) | 405 (301 to 599) | 416 (304 to 620) | 422 (298 to 652) | 326 (248 to 427) | 488 (365 to 671) | 556 (363 to 777) | 597 (368 to 848) | 721 (432 to 1101 |
| Current smoker (%) | 14.2 | 9.2 | 8.0 | 7.4 | 7.5 | 10.7 | 7.8 | 8.1 | 9.1 | 8.2 |
| Past smoker (%) | 46.3 | 42.7 | 39.3 | 36.0 | 33.8 | 40.0 | 39.3 | 39.7 | 43.2 | 41.8 |
| Family history of hypertension (%) | 30.8 | 32.0 | 31.9 | 31.4 | 31.9 | 31.3 | 31.3 | 32.1 | 32.4 | 32.7 |
During 20 yr and 990,646 person-years of follow-up in NHS1, we observed 31,107 incident cases of hypertension. During 14 yr and 1,085,648 person-years of follow-up in NHS2, there were 15,863 new cases of hypertension. During 18 yr and 426,063 person-years of follow-up in HPFS, 11,192 incident cases of hypertension were observed.
Fructose Intake and Hypertension
There was no overall association between intake of fructose and the risk for developing hypertension (Table 4). In multivariable models controlling for age; BMI; physical activity; smoking status; family history of hypertension; total energy intake; and intakes of alcohol, caffeine, folate, and vitamin C, the relative risks (RRs; 95% confidence intervals [CIs]) comparing the highest with lowest quintile were 1.02 (0.99 to 1.06) in NHS1, 1.03 (0.98 to 1.08) in NHS2, and 0.99 (0.93 to 1.05) in HPFS. Additional adjustment for intakes of calcium, magnesium, and potassium did not materially alter the results. Repeating these analyses using cumulative time-averaging of fructose intake did not substantially change the results.
Table 4.
Total fructose intake and risk for incident hypertensiona
| Parameter | Fructose Intake, % Total Energy (Quintiles)
|
||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | |
| NHS1 | |||||
| person-years | 186,935 | 204,417 | 208,345 | 206,060 | 184,889 |
| no. of cases | 6055 | 6427 | 6269 | 6309 | 6047 |
| age- and BMI-adjusted RR (95% CI) | 1.00 (reference) | 0.95 (0.92 to 0.98) | 0.90 (0.87 to 0.93) | 0.92 (0.89 to 0.95) | 0.97 (0.94 to 1.00) |
| multivariable-adjusted RR (95% CI) | 1.00 (reference) | 0.98 (0.94 to 1.01) | 0.94 (0.90 to 0.97) | 0.96 (0.92 to 0.99) | 1.02 (0.99 to 1.06) |
| NHS2 | |||||
| person-years | 215,222 | 217,250 | 217,887 | 218,294 | 216,995 |
| no. of cases | 3600 | 3250 | 3074 | 2816 | 3123 |
| age- and BMI-adjusted RR (95% CI) | 1.00 (reference) | 0.96 (0.91 to 1.00) | 0.96 (0.91 to 1.00) | 0.92 (0.87 to 0.97) | 1.03 (0.98 to 1.08) |
| multivariable-adjusted RR (95% CI) | 1.00 (reference) | 0.98 (0.93 to 1.03) | 0.98 (0.93 to 1.03) | 0.94 (0.89 to 0.99) | 1.03 (0.98 to 1.08) |
| HPFS | |||||
| person-years | 84,933 | 85,452 | 85,387 | 85,023 | 85,268 |
| no. of cases | 2461 | 2213 | 2123 | 2195 | 2200 |
| age- and BMI-adjusted RR (95% CI) | 1.00 (reference) | 0.89 (0.84 to 0.95) | 0.85 (0.80 to 0.91) | 0.88 (0.83 to 0.94) | 0.89 (0.84 to 0.95) |
| multivariable-adjusted RR (95% CI) | 1.00 (reference) | 0.95 (0.89 to 1.00) | 0.93 (0.87 to 0.98) | 0.97 (0.91 to 1.03) | 0.99 (0.93 to 1.05) |
Multivariable models were adjusted for age; BMI; physical activity; smoking status; family history of hypertension; and intakes of alcohol, caffeine, folate, and mutually for fructose and vitamin C.
Vitamin C Intake and Hypertension
There was no overall association between intake of vitamin C and the risk for developing hypertension (Table 5). In multivariable models controlling for age; BMI; physical activity; smoking status; family history of hypertension; total energy intake; and intakes of alcohol, caffeine, folate, and fructose, the RR (95% CI) comparing women in NHS1 whose vitamin C intake was ≥1500 mg/d with those whose intake was <250 mg/d was 0.89 (0.83 to 0.96); however, this relation was nonlinear (P = 0.76 for trend; Table 5). Comparing individuals whose daily consumption of vitamin C was ≥1500 mg with those whose intake was <250 mg in the other two cohorts, the RRs (95% CIs) were 1.02 (0.91 to 1.14) in NHS2 and 1.06 (0.97 to 1.15) in HPFS. Repeating these analyses using cumulative time-averaging of vitamin C intake did not materially change the results.
Table 5.
Total vitamin C intake and risk for incident hypertensiona
| Parameter | Vitamin C Intake (mg/d)
|
||||
|---|---|---|---|---|---|
| <250 | 250 to 499 | 500 to 999 | 1000 to 1499 | ≥1500 | |
| NHS1 | |||||
| person-years | 577,627 | 191,187 | 129,511 | 67,826 | 24,498 |
| no. of cases | 17,739 | 6074 | 4370 | 2238 | 686 |
| age- and BMI-adjusted RR (95% CI) | 1.00 (reference) | 1.01 (0.98 to 1.04) | 1.05 (1.02 to 1.08) | 1.02 (0.97 to 1.06) | 0.89 (0.83 to 0.95) |
| multivariable-adjusted RR (95% CI) | 1.00 (reference) | 1.01 (0.98 to 1.04) | 1.04 (1.01 to 1.08) | 1.01 (0.97 to 1.06) | 0.89 (0.83 to 0.96) |
| NHS2 | |||||
| person-years | 750,110 | 171,609 | 91,826 | 53,765 | 18,339 |
| no. of cases | 10,672 | 2538 | 1446 | 900 | 307 |
| age- and BMI-adjusted RR (95% CI) | 1.00 (reference) | 1.06 (1.01 to 1.10) | 1.04 (0.98 to 1.10) | 1.04 (0.97 to 1.11) | 1.01 (0.90 to 1.13) |
| multivariable-adjusted RR (95% CI) | 1.00 (reference) | 1.07 (1.02 to 1.12) | 1.04 (0.99 to 1.11) | 1.05 (0.98 to 1.13) | 1.02 (0.91 to 1.14) |
| HPFS | |||||
| person-years | 225,181 | 83,481 | 59,920 | 34,691 | 22,794 |
| no. of cases | 5756 | 2161 | 1662 | 986 | 627 |
| age- and BMI-adjusted RR (95% CI) | 1.00 (reference) | 0.98 (0.93 to 1.03) | 1.02 (0.96 to 1.08) | 1.04 (0.97 to 1.12) | 1.03 (0.94 to 1.12) |
| multivariable-adjusted RR (95% CI) | 1.00 (reference) | 1.01 (0.96 to 1.07) | 1.04 (0.98 to 1.10) | 1.05 (0.98 to 1.13) | 1.06 (0.97 to 1.15) |
Multivariable models were adjusted for age; BMI; physical activity; smoking status; family history of hypertension; and intakes of alcohol, caffeine, folate, and mutually for fructose and vitamin C.
We also reanalyzed these cohorts after dividing the lowest category (<250 mg/d) into two categories (<100 and 100 to 249 mg/d) and redefining the reference group as <100 mg/d. The results were not materially changed from our primary analyses. Comparing individuals whose intake of vitamin C was ≥1500 mg/d with those whose consumed <100 mg/d, the adjusted RRs (95% CI) were 0.90 (0.84 to 0.98) in NHS1, 1.01 (0.89 to 1.15) in NHS2, and 1.05 (0.95 to 1.17) in HPFS.
In a secondary analysis, we excluded women and men who took supplemental vitamin C (including multivitamin users) and analyzed the association between dietary intake of vitamin C and incident hypertension. Comparing individuals whose daily dietary consumption of vitamin C was ≥250 mg to those whose consumed <100 mg/d, the adjusted RRs (95% CI) were 1.05 (0.97 to 1.14) in NHS1, 1.06 (0.92 to 1.23) in NHS2, and 0.99 (0.84 to 1.17) in HPFS.
DISCUSSION
Among three large prospective cohorts comprising >200,000 participants who were followed for 14 to 20 yr, we found no association between the intakes of either fructose or vitamin C and the risk for incident hypertension. Several studies have demonstrated that foods high in fructose are associated with higher uric acid levels; for example, in both the Third National Health and Nutrition Examination Survey (NHANES III) and 2001 to 2002 NHANES, those with the highest compared with the lowest consumption of sweetened soft drinks had approximately 0.4-mg/dl higher uric acid levels.19,21 In HPFS, fructose intake was linearly associated with higher uric acid levels.20 Fructose shares ethanol's urate-raising mechanism in which uric acid production is induced by increased ATP degradation to AMP, a uric acid precursor.38 Fructose phosphorylation in the liver depletes hepatocyte ATP, thereby limiting regeneration of ATP from ADP; increased levels of ADP then serve as substrates for the purine degradation pathway, which results in uric acid formation.39 Thus, within minutes after fructose infusion, plasma (and later urinary) uric acid concentrations are increased.40 In conjunction with purine nucleotide depletion, rates of purine synthesis de novo are accelerated, thus potentiating uric acid production.41 In contrast, glucose and other simple sugars do not have the same effect.26
Vitamin C, conversely, decreases uric acid concentrations. In a subset of 1387 men from HPFS with measured uric acid levels, those consuming ≥1000 mg/d vitamin C had an adjusted plasma uric acid level of 5.7 mg/dl, compared with 6.2 mg/dl among men whose vitamin C intake was <250 mg/d.42 Similarly, a randomized trial of middle-aged men and women demonstrated that 500 mg/d vitamin C supplementation for 8 wk reduced uric acid levels by 0.5 mg/dl.23 This reduction likely occurs via a uricosuric effect. Vitamin C and uric acid both are reabsorbed by anion-exchange transporters in the proximal tubule.23 A higher vitamin C concentration in the glomerular filtrate may competitively inhibit uric acid reabsorption.43 Recent advances in our understanding of the molecular mechanisms of renal uric acid transport suggest that the uricosuric effect of vitamin C may be mediated by cis inhibition of the uric acid transporter 1 (the key target of typical uricosuric agents),44 a sodium-dependent anion co-transporter (e.g., SLC5A8/A12),45 or both in the proximal tubules.38 Furthermore, higher intake of vitamin C may increase the GFR,23,46,47 thereby potentiating the uricosuric effect.
In addition, higher fructose and vitamin C intakes both influence the risk for developing gout, a disease that is caused by uric acid. In the HPFS cohort, the highest compared with the lowest quintile of fructose intake (as we have studied here) was associated with an 81% increased risk for developing gout (P < 0.001).24 Compared with men in HPFS whose vitamin C intake was <250 mg/d, the RR for those who consumed ≥1500 mg/d was 0.55 (95% CI 0.38 to 0.80; H. Choi, personal communication, November 30, 2007). In a case-control study, vitamin C intake in the highest compared with lowest tertile was associated with a RR for gout of 0.31 (95% CI 0.15 to 0.65)25; therefore, the variation in population consumption of these nutrients, including one population from the current analysis, is sufficient to lead to significant differences in risk for gout.
Higher uric acid levels are independently associated with an increased risk for developing hypertension. In total, 14 studies have examined this association, and all but two have documented this association. Thus, analogous to the relations between fructose and vitamin C to uric acid and gout, one would argue that fructose and vitamin C ought to be associated with hypertension if uric acid were causally associated with hypertension. Indeed, rat models seem to show that this is the case. In contrast, we found no association between these nutrients and hypertension.
One potential explanation for this paradox is the following hypothesis: Uric acid, per se, is not pathogenic in the development of hypertension in humans; however, uric acid is a sensitive marker of oxidative stress/endothelial dysfunction, and oxidative stress/endothelial dysfunction may be involved in the pathogenesis of hypertension. Indeed, uric acid is a potent antioxidant and does not cause endothelial function in humans, in contrast to rodents.16,27–29 Furthermore, uric acid infusion in smokers and patients with type 1 diabetes led to an improvement in endothelial dysfunction despite a two-fold increase in the serum uric acid concentration.30
Uric acid may instead be a sensitive marker of cellular oxidative stress and endothelial dysfunction. Xanthine oxidase, which catalyzes the conversion of xanthine to hypoxanthine and, subsequently, hypoxanthine to uric acid, is regulated by various factors that are typically thought to exert a detrimental influence on the vasculature. Specifically, NAD(P)H oxidase, the enzyme chiefly responsible for generating intracellular reactive oxygen species,31 upregulates the activity of xanthine oxidase, potentially mediated by the production of hydrogen peroxide.48 Nitric oxide, in contrast, suppresses the activity of xanthine oxidase.49 Furthermore, angiotensin II signaling increases xanthine oxidase activity, potentially through its stimulatory effect on NAD(P)H oxidase,50 as do interferons and LPS.51,52 Taken together, xanthine oxidase activity and, consequently, circulating levels of uric acid may be a consequence rather than a cause of vascular insult. Xanthine oxidase may also contribute to oxidative stress by producing reactive oxygen species as byproducts of its catalytic activity31; therefore, the benefits of xanthine oxidase inhibition on endothelial function may not be a consequence of lower uric acid levels but rather a function of a decrease in cellular oxidative stress. This argument is supported by the work of George et al.,37 who demonstrated that treatment of patients with heart failure with allopurinol improved endothelial function five-fold, whereas lowering the uric acid concentration to a similar degree with probenecid (a uricosuric) had no effect on endothelial function.
A second possibility is that fructose protects against hypertension through some as-yet-unknown mechanism, thereby canceling out a true causal association between uric acid and hypertension. Likewise, if vitamin C promotes hypertension incidence through an unknown mechanism, then any protective effect of vitamin C through lowering of uric acid could have been missed by our analysis; however, vitamin C is proposed to promote and stabilize endothelial nitric oxide,53 enhance vascular prostacyclin production,54 and behave as an antioxidant in blood.55 Because these actions would hypothetically protect against hypertension, our finding that higher vitamin C intakes were not associated with a lower risk for hypertension argues against a hidden causal association between uric acid and hypertension.
This study has limitations that deserve mention. First, we did not directly measure the participants’ BP, and the diagnosis of hypertension was self-reported; however, self-reported hypertension is highly reliable in these cohorts of health professionals. Second, in any study with null findings, the possibility that random misclassification of the exposure (i.e., fructose and vitamin C intake) could mask a true association must be considered. Nevertheless, the large number of participants (and high level of statistical power), the reliability of dietary reporting as assessed by the food frequency questionnaire (FFQ), the long follow-up, and the similar null findings among three large independent cohorts provides assurance that an important association was unlikely to have been missed. Finally, it is possible that the magnitude of the influence of fructose and vitamin C intake on the plasma uric acid concentration is too weak to translate into meaningful differences in risk for hypertension; however, the same dietary comparisons in these cohorts yielded substantial associations with risk for gout, a disease caused by higher uric acid levels. Furthermore, the observational studies examining uric acid and hypertension demonstrated that small changes significantly influence risk.
In conclusion, higher intakes of fructose and vitamin C are not associated with risk for developing hypertension. These findings confer doubt on the hypothesis that uric acid is causally associated with hypertension. A randomized, placebo-controlled trial comparing uric acid lowering not simply through xanthine oxidase inhibition but also by a uricosuric is needed to shed more light on this question.
CONCISE METHODS
Study Populations
The cohort of older women (NHS1) was assembled in 1976, when 121,700 female nurses aged 30 to 55 yr returned an initial questionnaire.56 The younger female cohort (NHS2) was assembled in 1989, when 116,671 female registered nurses aged 25 to 42 yr returned a mailed questionnaire.57 In 1986, 51,529 male health professionals who were aged 40 to 75 yr and returned an initial questionnaire were enrolled in HPFS.58 Since the inception of these cohorts, subsequent questionnaires have been mailed every 2 yr to update information on health-related behavior and medical events. Detailed dietary information has been collected every 4 yr using a semiquantitative FFQ.59 Follow-up for this analysis was 20 yr for NHS1 (1984 to 2004), 14 yr for NHS2 (1991 to 2005), and 18 yr for HPFS (1986 to 2004). Individuals from these cohorts with prevalent hypertension at baseline (1984, 1991, and 1986 depending on cohort) were excluded from this analysis. The institutional review board at Brigham and Women's Hospital reviewed and approved this study, and participants provided implied consent by virtue of returning their questionnaires.
Ascertainment of Dietary Intake
To assess dietary intake of fructose and vitamin C, we used a validated FFQ that inquired about the average use of >130 foods and beverages during the previous year.60–62 The baseline dietary questionnaires were completed in 1984 (NHS1), 1991 (NHS2), and 1986 (HPFS) and were updated every 4 yr. Nutrient intakes were computed by multiplying the frequency of use response for individual foods or supplements by the nutrient content of the specified portion sizes. Values for nutrients were derived from the US Department of Agriculture sources and supplemented with information from manufacturers.
Fructose exists both as a monosaccharide and as half of the disaccharide sucrose; fructose is liberated from sucrose in the small intestine; therefore, using FFQs, we computed the percentage of total caloric intake from fructose as equal to the percentage of caloric intake obtained from free fructose plus half the percentage of caloric intake obtained from sucrose. In NHS1 at baseline, orange and other fruit juices (18.7%), apples (11.1%), sugar-sweetened cola and other soft drinks (11.0%), other sugar sweetened beverages (5.9%), bananas (5.8%), raisins (3.6%), and oranges (3.1%) contributed 59.2% of all fructose consumed by the cohort. In NHS2 at baseline, the largest contributors to total fructose consumption were sugar-sweetened cola and other soft drinks (20.0%), orange and other fruit juices (18.7%), apples (10.5%), bananas (5.5%), other sugar-sweetened beverages (5.3%), yogurt (3.9%), and raisins (3.8%), accounting for 67.7% of fructose intake. In HPFS at baseline, orange and other fruit juices (18.0%), sugar-sweetened cola and other soft drinks (12.8%), apples (11.6%), bananas (6.9%), raisins (4.7%), other sugar-sweetened beverages (4.4%), and oranges (3.3%) contributed 61.7% of all fructose consumed. In all three cohorts, the contributions to total vitamin C intake were heavily influenced by vitamin C supplements (46.2% in NHS1, 35.1% in NHS2, and 50.4% in HPFS), multivitamin supplements (11.8% in NHS1, 13.4% in NHS2, and 10.6% in HPFS), and orange juice (8.1% in NHS1, 9.7% in NHS2, and 8.6% in HPFS).
Food intake assessed by these dietary questionnaires were validated previously in these cohorts against either two or four 1-wk diet records.61,62 Specifically for fructose intake, the deattenuated correlation coefficients between the intakes measured by our FFQs and diet records for dietary exposures of interest were 0.84 for sugar-sweetened cola, 0.55 for other sugar-sweetened soft drinks, 0.78 for orange juice, 0.70 for apples, 0.76 for oranges, 0.95 for bananas, 0.59 for raisins, and 0.89 for other fruit juices.60 For vitamin C intake, the deattenuated correlation coefficients for total vitamin C intake between the dietary records and the questionnaires were 0.75 in women and 0.92 in men.61,62
Each participant's fructose and vitamin C intake was originally measured using the first FFQ (1984, 1991, and 1986). With each subsequent FFQ during follow-up, a participant's fructose and vitamin C intake was recalculated to reflect the most recent dietary information. For the purposes of a sensitivity analysis, we also examined time-averaged intake of fructose and vitamin C, whereby the fructose and vitamin C intake computed from each subsequent FFQ was combined with intakes computed from previous FFQs to create a weighted average (weighted by time).
Ascertainment of Other Factors
Age, BMI (calculated as weight in kilograms divided by height in meters squared), smoking status, physical activity, and dietary covariates (intakes of alcohol, caffeine, and folate) were ascertained from questionnaires and updated at each time point that fructose and vitamin C intake were updated. Questionnaire-derived information about these covariates, like fructose and vitamin C, was also previously validated, with correlations of 0.97 for weight and 0.79 for physical activity, and among dietary variables, correlations ranged from 0.77 for folate to 0.90 for alcohol.57,61–63 Family history of hypertension was available on the 1992 (NHS1), 1989 (NHS2), and 1990 (HPFS) questionnaires.
Ascertainment of Hypertension
The baseline and follow-up biennial questionnaires asked participants to report whether a clinician had made a new diagnosis of hypertension during the preceding 2 yr. Self-reported hypertension was shown to be highly reliable in NHS1 and HPFS.64,65 In a subset of women who reported hypertension, medical record review confirmed a documented systolic and diastolic BP >140 and 90 mmHg, respectively, in 100%; among the men, 100% of a subset who reported hypertension also had the diagnosis confirmed by medical record review.64,65 In addition, self-reported hypertension was highly predictive of subsequent cardiovascular events. A participant was considered to have prevalent hypertension when he or she reported this diagnosis on any questionnaire up to and including the 1984 (NHS1), 1991 (NHS2), or 1986 (HPFS) questionnaire. Participants with prevalent hypertension were excluded. Cases included individuals who first reported hypertension on subsequent questionnaires and whose year of diagnosis postdated the return of the 1984, 1991, or 1986 questionnaire.
Statistical Analysis
Total fructose intake was divided into quintiles (of percentage of total energy intake) for the primary analysis. We categorized total daily vitamin C intake (in mg/d) originally into five categories: <250, 250 to 499, 500 to 999, 1000 to 1499, and ≥1500. These categories were chosen on the basis of the previous observation that the inverse relation between vitamin C intake and gout (a uric acid–associated disease) was manifest at intakes of ≥250 mg/d and not at lower levels (H. Choi, personal communication, November 30, 2007). Nevertheless, we performed secondary analyses using a lower reference group of vitamin C intake (<100 mg/d).
For each participant, person-months of follow-up were counted from the date of return of the first questionnaire to the date of return of the last questionnaire and allocated according to exposure status. Person-time was truncated when an event occurred. Participants were censored at the date of death, or, if they did not return a subsequent questionnaire, then they were censored at the date the subsequent questionnaire was mailed. Participants who did not provide dietary information at baseline but provided this information at subsequent questionnaire cycles contributed person-time during those periods in which dietary information was prospectively available.
Multivariable RRs were calculated using Cox proportional hazards regression. Multivariable models were adjusted for variables that have been hypothesized to be associated with hypertension (age [continuous], BMI [six categories], physical activity [quintiles], smoking status [past, current, never], family history of hypertension [yes/no], oral contraceptive use [NHS2, yes/no], alcohol intake [six categories], and intakes of caffeine and folate [quintiles]). In addition, we adjusted our multivariable models for total caloric intake and mutually for both fructose and vitamin C intake. For all RRs, we calculated 95% CIs. All P values are two-tailed. Statistical tests were performed using SAS 9.1 (SAS Institute Inc., Cary, NC).
DISCLOSURES
In addition to the American Heart Association and the National Institutes of Health, the authors receive grant support from TAP Pharmaceuticals. None of the funding agencies (American Heart Association, National Institutes of Health, TAP Pharmaceuticals) had any role in the collection, management, analysis, or interpretation of the data and had no role in the preparation, review, or approval of the manuscript.
Acknowledgments
This study was funded by American Heart Association grant 0535401T and National Institutes of Health grants HL079929, CA87969, CA50385, HL35464, and CA550750.
Published online ahead of print. Publication date available at www.jasn.org.
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