Abstract
Animal and human studies suggest a potential link between acid-base status and blood pressure. Contemporary Western diets yield a daily systemic acid load of varying amounts, yet the association with hypertension has never been explored. We prospectively examined the association between the diet-dependent net acid load (also known as the estimated net endogenous acid production) and the risk of incident hypertension among 87 293 women without a history of hypertension in Nurses' Health Study II. We also used the ratio of animal protein intake to potassium intake as an alternative evaluation of diet-dependent net acid load. We identified 15 385 incident cases of hypertension during 995 239 person-years of follow-up. After adjusting for potential confounders, women in the top decile of estimated diet-dependent net acid load had an increased risk of hypertension (relative risk 1.14, 95% confidence interval 1.05–1.24; P for trend = 0.01) compared with women in the bottom decile. In order to test whether the association between estimated diet-dependent net acid load and hypertension is independent of its individual components, additional adjustment for intakes of protein and potassium was made and resulted in a relative risk of 1.23 (95% confidence interval 1.08–1.41, P for trend=0.003) for the top decile of estimated diet-dependent net acid load. Results of the ratio of animal protein intake to potassium intake were similar with those of estimated diet-depend net acid load. In conclusion, a high diet-dependent net acid load is independently associated with a higher risk of incident hypertension.
Keywords: Acid-base equilibrium, hypertension, risk factors, epidemiology, human
Hypertension is the most important modifiable cardiovascular risk factor, contributing to one half of the coronary heart disease and approximately two thirds of the cerebrovascular disease burdens 1. Accordingly, there has been a growing emphasis in national practice guidelines on the importance of preventing hypertension to reduce the public health burden of cardiovascular disease 2. The National Health and Nutrition Examination Survey (NHANES) 1999–2000 data estimated that 65 million individuals in the United States had hypertension, and that number was increasing 3. Therefore, identifying risk factors for hypertension could lead to specific preventive interventions that may favorably affect public health.
Animal and human studies suggest a potential link between acid-base status and blood pressure (BP) 4–8. For example, spontaneously hypertensive rats have lower serum bicarbonate concentrations and lower blood pH compared to control normotensive rats; these acid-base abnormalities precede the development of hypertension 5, 6. This perturbation of acid-base status may arise from increased metabolic acid production 7. Lower renal bicarbonate excretion after administration of sodium citrate was also observed in salt-sensitive men, if compared with salt-resistant men4. More recent population-based studies are also consistent with the hypothesis that increased endogenous acid production results in higher BP 9–11.
Contemporary Western diets contain acid precursors in excess of base precursors, which leads to chronic, low-grade metabolic acidosis12. This diet-dependent net acid load, which is called “estimated net endogenous acid production (NEAP)” 13, is known to be associated with diseases of bone mineralization14. However, its association with hypertension has never been explored. We prospectively examined the association between NEAP and the risk of incident hypertension among 87 293 women without history of hypertension in the Nurses' Health Study II (NHS II).
Methods
Study Population
The NHS II is an ongoing prospective cohort study of 116 430 female registered nurses that began in 1989. Participants are followed via biennial questionnaires that gather information on health-related behaviors and medical events. The follow-up for the cohort exceeded 90% through 2005. This study was approved by the institutional review board at Brigham and Women's Hospital. Receipt of each questionnaire implies participant's consent.
Women were excluded from this analysis if they died before 1991, had prevalent hypertension at baseline, were using blood pressure-lowering medications at baseline but did not report a history of hypertension, or had cancer (except for non-melanoma skin cancer) at baseline. The final study sample included 87 293 women.
Assessment of Diet-Dependent Net Acid Load
Semi-quantitative food frequency questionnaires (FFQ) were used to measure dietary intake and were completed in 1991, 1995, 1999 and 2003. Nutrient intakes were calculated by multiplying the frequency of intake by the nutrient content of the specified portion. Nutrient contents were obtained from the Harvard University food consumption database, which was derived from US Department of Agriculture, manufacturers, and published reports. The reproducibility and validity of the questionnaire by women in a similar cohort (Nurses' Health Study I) has been documented 15, 16, and a similar questionnaire has been shown to be valid and reproducible in men17.
The diet-dependent net acid load was estimated by the formula described by Frassetto et al18: Estimated NEAP (mEq/day) = [54.5×protein (g/day)/potassium (mEq/day)] − 10.2
Based on work by Zwart et al 19, we also used the ratio of animal protein intake to potassium intake (AP/K) as an alternative evaluation of diet-dependent net acid load:
AP/K = animal protein (g/day)/potassium (g/day).
The intake of protein, animal protein and potassium for the calculation were all adjusted for total energy intake by the residual method 20. Potassium from supplements was not included in the calculation, because the vast majority was potassium chloride which does not contribute to dietary-dependant acid load. Information on dietary intake of protein, animal protein and potassium was updated every 4 years as participants returned subsequent FFQs.
Assessment of Other Covariates
Body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), physical activity (metabolic equivalent tasks), smoking status and information on oral contraceptive use were ascertained on the 1991 questionnaire and updated every 4 years. Intakes of alcohol, sodium, calcium, magnesium, folate and vegetable protein were ascertained and updated from the FFQ. Except for intake of alcohol, nutrient values were adjusted for total energy intake by the residual method20.
Assessment of Hypertension
The baseline and biennial follow-up questionnaires inquired about physician-diagnosed hypertension and the year of diagnosis. Self-reported hypertension was found to be highly reliable in a similar cohort of nurses 21. To validate hypertension self-report in NHS II, we obtained relevant medical records from a sub-set of randomly selected NHS II participants who self-reported a new diagnosis of hypertension on the 2005 biennial questionnaire, as well as randomly selected participants who denied this diagnosis in 2005 and in every prior year. The sensitivity of self-reported hypertension was 94%. The specificity of a nurse reporting no diagnosis of hypertension was 85% (unpublished data). Additionally, self-reported hypertension was predictive of subsequent cardiovascular events21. A participant was considered to have prevalent hypertension if she reported this diagnosis on any questionnaire up to and including the 1991 questionnaire, and therefore was excluded from the study. Incident cases included individuals who first reported hypertension on subsequent questionnaires and whose year of diagnosis was after the return of the 1991 questionnaires.
Statistical Analyses
Participants who did not return the 1991 questionnaire for this study were allowed to contribute person-time for later time intervals. Person-time was truncated at the date of hypertension diagnosis, at the date of death, at the date of cancer diagnosis (except for non-melanoma skin cancer), at the first date of anti-hypertensive medication initiation in the absence of hypertension, or June 2005, whichever came first.
The estimated NEAP and AP/K were analyzed in deciles; deciles 2–3, deciles 4–5, deciles 6–7 and deciles 8–9 were merged because the distribution ranges were very narrow. Cox proportional hazards regression models22 were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). Multivariable models were constructed to adjust for potential confounding variables that have been previously associated with incident hypertension (age [continuous], BMI [6 categories], smoking status [past, current, never], family history of hypertension [yes/no], current oral contraceptive use [yes/no], physical activity [quintiles], and intakes of alcohol [6 categories], sodium, calcium, magnesium and folate [quintiles]). Intake of vegetables protein (quintiles) was added to multivariable models of AP/K. To test whether estimated NEAP and AP/K (which are essentially interaction terms of dietary protein and potassium intake) influence hypertension risk independent of their individual components, we also adjusted our estimated NEAP-hypertension models for protein and potassium (both in quintiles), and our AP/K-hypertension models for animal protein and potassium (both in quintiles). We determined P values for trend for each of the exposures of interest by using the median for each category.
We also investigated whether the association between diet-dependent net acid load and hypertension varied according to age (<36 yrs or ≥36 yrs, the cohort median at baseline) and BMI (<25 kg/m2 or ≥25 kg/m2). Stratified multivariable analyses were performed, and appropriate interaction terms were generated to test whether interactions were statistically significant.
All P values are 2-tailed. Statistical tests were performed using SAS version 9.1 for UNIX statistical software package (SAS Institute Inc, Gary, NC).
Results
Over the 14 years (995 239 person-years of follow-up), 15 385 incident cases of physician-diagnosed hypertension were reported (15.5 cases per 1000 person-years). Participant characteristics by categories of estimated NEAP are presented in Table 1. Women with higher estimated NEAP had higher BMI, were less physically active, and had lower intakes of alcohol, folate and magnesium. Past and current smoking were more common in lower estimated NEAP categories. Oral contraceptive use was more frequent among the higher categories of estimated NEAP.
Table 1.
Baseline characteristics of the cohort in 1991 by categories of estimated net endogenous acid production*.
| Variables | Deciles of estimated NEAP, mEq/d | |||||
|---|---|---|---|---|---|---|
| D1 | D2–D3 | D4–D5 | D6–D7 | D8–D9 | D10 | |
| Age (yrs) | 37 (34–41) | 37 (33–40) | 36 (33–40) | 36 (32–39) | 35 (32–39) | 35 (31–39) |
| Body mass index (kg/m2) | 22.1 (20.4–24.6) | 22.7 (20.8–25.6) | 22.9 (21.0–25.8) | 23.2 (21.0–26.5) | 23.4 (21.3–27.0) | 23.8 (21.4–28.0) |
| Alcohol consumption (g/d) | 1.1 (0.0–4.8) | 1.1 (0.0–4.7) | 1.1 (0.0–3.8) | 0.9 (0.0–3.1) | 0.9 (0.0–2.8) | 0.0 (0.0–2.0) |
| Physical activity (METs/w) | 17.7 (7.0–37.2) | 15.0 (6.1–30.4) | 13.2 (5.5–27.0) | 12.0 (5.0–25.4) | 11.0 (4.2–23.2) | 9.2 (3.5–20.9) |
| Family history of HTN (%) | 50.4 | 49.9 | 49.9 | 50.0 | 50.5 | 50.3 |
| Current smoker (%) | 16.0 | 14.1 | 12.3 | 11.2 | 10.0 | 10.4 |
| Past smoker (%) | 26.6 | 24.8 | 23.3 | 21.1 | 19.4 | 16.8 |
| Current OC use (%) | 9.9 | 9.5 | 10.5 | 11.1 | 12.6 | 12.8 |
| Dietary factors (per day) | ||||||
| Folate (μg) | 467 (343–715) | 409 (312–650) | 380 (293–620) | 358 (276–595) | 329 (256–564) | 286 (221–504) |
| Sodium (mg) | 2066 (1810–2340) | 2137 (1915–2368) | 2152 (1946–2372) | 2163 (1954–2380) | 2160 (1942–2380) | 2125 (1879–2380) |
| Magnesium (mg) | 352 (305–409) | 327 (287–374) | 314 (276–358) | 301 (265–343) | 286 (252–327) | 262 (228–303) |
| Calcium (mg) | 826 (659–1022) | 851 (685–1072) | 861 (690–1104) | 848 (677–1092) | 823 (651–1063) | 750 (593–960) |
| Total protein (g) | 70.9 (62.4–78.7) | 79.9 (72.4–87.4) | 85.1 (77.3–92.9) | 88.8 (80.6–97.1) | 92.8 (84.0–101.7) | 98.5 (88.3–109.4) |
| Animal protein (g) | 45.4 (36.2–53.6) | 56.2 (48.5–64.0) | 62.3 (54.4–70.3) | 66.7 (58.3–75.3) | 71.5 (62.6–80.9) | 78.5 (68.0–90.1) |
| Vegetable protein(g) | 25.3 (21.8–29.7) | 23.3 (20.5–26.3) | 22.4 (19.8–25.1) | 21.7 (19.2–24.4) | 20.9 (18.3–23.6) | 19.5 (16.8–22.4) |
| Potassium (mg) | 3476 (3118–3853) | 3177 (2883–3476) | 2999 (2729–3277) | 2848 (2583–3109) | 2659 (2404–2914) | 2384 (2119–2655) |
| Estimated NEAP (mEq/d) | 34.4 (30.6–36.7) | 43.5 (41.3–45.3) | 50.1 (48.5–51.6) | 56.1 (54.6–57.7) | 63.7 (61.5–66.4) | 76.0 (72.6–81.6) |
Data are presented as median (inter-quartile range) or percentages; MET, metabolic equivalent; HTN, hypertension; OC, oral contraceptives; NEAP, estimated net endogenous acid production.
After controlling for age, BMI, physical activity and potassium intake, NEAP is positively correlated with protein intake (correlation coefficient=0.96, P<0.001). And NEAP is negatively correlated with potassium intake (correlation coefficient=− 0.96, P<0.001) after controlling for age, BMI, physical activity and protein intake.
Estimated NEAP was positively associated with the risk of incident hypertension in age-adjusted and multivariable-adjusted analyses (Table 2). Compared with those in the lowest decile of estimated NEAP, the multivariable RR of incident hypertension for those in the highest decile of estimated NEAP was 1.14 (95% CI 1.05–1.24; P for trend = 0.01). Additional adjustment for intakes of protein and potassium resulted in a RR of 1.23 (95% CI 1.08–1.41, P for trend=0.003) for the top decile of estimated NEAP.
Table 2.
Estimated net endogenous acid production (NEAP) and risk of incident hypertension.
| Characteristics | Deciles of estimated NEAP | ||||||
|---|---|---|---|---|---|---|---|
| D1 | D2–D3 | D4–D5 | D6–D7 | D8–D9 | D10 | P value for trend | |
| Person years | 91481 | 182950 | 206953 | 208465 | 205620 | 99772 | |
| Number of cases | 1056 | 2406 | 3071 | 3340 | 3631 | 1881 | |
| Age- adjusted relative risk (95% CI) | 1.00 reference | 1.19 (1.10–1.27) | 1.27 (1.18–1.36) | 1.40 (1.30–1.50) | 1.59 (1.48–1.71) | 1.73 (1.60–1.86) | <0.001 |
| Multivariable relative risk* (95% CI) | 1.00 reference | 1.07 (1.00–1.15) | 1.08 (1.00–1.16) | 1.10 (1.03–1.19) | 1.16 (1.08–1.25) | 1.14 (1.05–1.24) | 0.01 |
| Multivariable relative risk† (95%CI) | 1.00 reference | 1.09 (1.01–1.18) | 1.12 (1.03–1.21) | 1.16 (1.05–1.27) | 1.23 (1.10–1.38) | 1.23 (1.08–1.41) | 0.003 |
adjusted for age, body mass index (BMI), physical activity, family history of hypertension, smoking status (current/past), current oral contraceptive use, intake of alcohol, intake of sodium, magnesium, calcium and folate.
adjusted for age, BMI, physical activity, family history of hypertension, smoking status (current/past), current oral contraceptive use, intakes of alcohol, sodium, magnesium, calcium and folate, plus intakes of protein and potassium.
CI, confidence interval.
The Cox proportional hazards models for AP/K showed similar results (Table 3). The multivariable RR comparing those in the top decile with those in the bottom decile was 1.15 (95% CI 1.06–1.25; P for trend = 0.003). After adding intakes of animal protein and potassium to the model, the RR was 1.27 (95% CI 1.09–1.47, P for trend <0.001) for the top decile of AP/K.
Table 3.
The ratio of animal protein intake to potassium intake (AP/K) and risk of incident hypertension.
| Characteristics | Deciles of AP/K | ||||||
|---|---|---|---|---|---|---|---|
| D1 (0.0–15.1) | D2–D3 (15.1–19.2) | D4–D5 (19.2–22.0) | D6–D7 (22.0–25.0) | D8–D9 (25.0–30.0) | D10 (30.0–78.1) | P value for trend | |
| Person years | 101742 | 202094 | 200636 | 198948 | 196705 | 95114 | |
| Number of cases | 1197 | 2790 | 3029 | 3173 | 3375 | 1821 | |
| Age- adjusted relative risk (95% CI) | 1.00 reference | 1.21 (1.13–1.29) | 1.36 (1.27–1.45) | 1.47 (1.37–1.57) | 1.62 (1.52–1.73) | 1.83 (1.70–1.96) | <0.001 |
| Multivariable relative risk* (95% CI) | 1.00 reference | 1.06 (0.99–1.13) | 1.10 (1.02–1.18) | 1.11 (1.03–1.19) | 1.13 (1.05–1.22) | 1.15 (1.06–1.25) | 0.003 |
| Multivariable relative risk† (95%CI) | 1.00 reference | 1.08 (1.00–1.17) | 1.14 (1.04–1.25) | 1.17 (1.06–1.31) | 1.22 (1.08–1.38) | 1.27 (1.09–1.47) | <0.001 |
adjusted for age, BMI, physical activity, family history of hypertension, smoking status (current/past), current oral contraceptive use, intakes of alcohol, sodium, magnesium, calcium, folate and vegetable protein.
adjusted for age, BMI, physical activity, family history of hypertension, smoking status (current/past), current oral contraceptive use, intake of alcohol, intake of sodium, magnesium, calcium, folate and vegetable protein, plus intake of animal protein and potassium.
CI, confidence interval.
The association between estimated NEAP and risk of incident hypertension was greater among women with a BMI less than 25 kg/m2 (P value for interaction <0.001). The multivariable RR for the top decile of estimated NEAP was 1.27 (95% CI 1.00–1.62) among those with BMI < 25 kg/m2, and was 1.21 (95% CI 1.02–1.43) among those with BMI ≥ 25 kg/m2. We did not observe effect modification by age (P value for interaction = 0.88).
Discussion
In our prospective study of 87 293 women followed for 14 years, we found that a higher diet-dependent net acid load was independently associated with the risk of incident hypertension. The association remained significant after controlling for dietary factors such as sodium, magnesium, calcium, folate, protein and potassium. To the best of our knowledge, this is the first prospective study to report an association between diet-dependent net acid load and the risk of incident hypertension.
Evidence from several rat models of hypertension and salt-sensitive humans indicate an association between acid-base status and hypertension. For example, plasma pH and bicarbonate were lower in spontaneously hypertensive rats than in normotensive rats, and these acid-base abnormalities preceded the development of hypertension 5, 6. Metabolic studies demonstrated increased renal net acid excretion in Dahl/Rapp salt-sensitive rats compared with their salt-resistant counterparts, which might be explained by increased endogenous acid production 7. A metabolic study of 24 normotensive men by Sharma et al. 4 demonstrated similar findings in humans. The renal bicarbonate excretion after administration of sodium citrate was markedly lower in the salt-sensitive than in the salt-resistant men during both the low-salt and high-salt diets (reduced by 46% and 32%, respectively). Because those men had normal renal function, and because the salt-sensitive men had comparatively lower arterial plasma pH and bicarbonate levels than the salt-resistant men 8, the authors hypothesized that the decreased renal bicarbonate excretion was a compensation for increased endogenous acid production.
More recent data from population-based studies show that several metabolic indicators of “sub-clinical” metabolic acidosis are associated with increased BP. First, among more than 3000 participants of three large cohort studies, participants with hypocitraturia (<320 mg/day) were 2.5 times more likely to have prevalent hypertension than those without hypocitraturia11. Acid-base status is the dominant regulator of urinary citrate excretion. The lower urinary citrate could result from systemic acidosis, and the associated decrease in the intracellular pH of renal proximal tubular cells leads to increased re-absorption of the filtered citrate 23. Second, a study of 5043 participants from NHANES revealed that every 1 mEq/L increase in the serum anion gap was associated with a significant 0.48 mm Hg higher systolic BP independent of age, gender,BMI and renal function 10. This positive association between serum anion gap and higher blood pressure has also been confirmed in a distinct cohort9.
Our study suggests that NEAP estimated from diet is an independent risk factor of incident hypertension. Under ordinary physiological circumstances, composition of the diet is a major determinant of the daily NEAP, which in turn determines the degree of perturbation in systemic acid-base equilibrium18. The rate of sulfuric acid production from protein metabolism and the rate of bicarbonate generation from metabolism of intestinally absorbed potassium salts of organic acids are major components of the NEAP18. Thus the diet-dependent net acid load could be predicted from the dietary protein and potassium 13, 18, and NEAP is already known to adversely influence bone health in several studies14. Because the sulfur content of vegetable proteins is much more variable than that of animal proteins 24, and because a recent study showed that the ratio of animal protein intake to potassium intake more consistently predicted directional changes in bone markers than the ratio of total protein intake to potassium intake 19, we also used AP/K as an estimation of the diet-dependent net acid load. The results from AP/K were not materially different from results of estimated NEAP. The reason why estimated NEAP and AP/K showed similar results may stem from the lower between-person variability in vegetable protein intake compared with the higher variability in animal protein intake. Furthermore, because animal protein intake is a much larger contributor to total protein than vegetable protein, the estimated NEAP and AP/K were highly correlated (r=0.95, P<0.001). Along those lines, in the study of Frassetto el al 18, the correlation of urinary sulfate excretion with animal protein content was only marginally stronger than with total protein content (r = 0.88 compared with 0.84).
Dietary intake of protein itself has been reported to be associated with blood pressure, and the direction of the association may depend on the amount and the type of protein consumed 25. Higher potassium intake has also been associated with reduced BP in some studies 26, 27. Since NEAP is essentially an interaction term of dietary protein and potassium intake, we further adjusted for intakes of protein and potassium in our models. The RRs were still significant, suggesting NEAP is associated with risk of hypertension even after controlling for intakes of protein and potassium. The estimated NEAP of the Dietary Approaches to Stop Hypertension (DASH) diet 28 was 34.8 mEq/day, which is close to the median of lowest category of estimated NEAP in present study. Hence, low NEAP might be an alternative mechanism of the BP-lowering effect of the DASH diet.
In addition to Frassetto's equation used in the present study, there are also several other algorithms for estimating NEAP from the composition of the diet13. Detailed data of diet composition and/or anthropometric data are needed for those algorithms, which limits their use in population-based studies, and there are no data suggesting the superiority of these algorithms. The Frassetto's equation has been validated by renal net acid excretion, which is one of the best available estimates of NEAP13. Importantly, the concept of Frassettso's equation makes it possible to develop simple dietary guidelines for regulating NEAP.
Our study has limitations. First, we relied on self-reported hypertension and did not directly measure the blood pressure of our participants; however, all participants are registered nurses, and we demonstrated that hypertension reporting by participants of this cohort is highly sensitive21. Nonetheless, the specificity of hypertension reporting may have resulted in the misclassification of a few truly hypertensive individuals as being non-hypertensive controls; however, such misclassification would tend to diminish the magnitude of the odds ratio. Therefore, our findings may indeed be an underestimate of the true association. Second, despite the validity of our FFQs to compute dietary intake, the instrument is imperfect and may result in some misclassification of estimated NEAP and AP/K. However, this type of misclassification is likely to be random resulting in a RR closer to 1.0; thus, the true RR may in fact be larger than what we report. Third, our population was almost entirely white and exclusively female; thus our results may not be generalizable to other populations. Fourth, we do not have information on renal function, which plays a central role in acid base homeostasis. However, a study in a subset of these participants indicated that the prevalence of renal dysfunction was vanishingly small29. Additionally, we excluded women from our analysis who had hypertension at baseline. For these reasons, we doubt that renal dysfunction was sufficiently prevalent in this population to influence our results. Fifth, we lack data regarding potential metabolic indicators of increased NEAP, such as serum anion gap and bicarbonate. Finally, our study was observational; thus we cannot exclude the possibility of residual confounding.
Perspectives
Our prospective analysis suggests that a higher diet-dependent net acid load is independently associated with an increased risk of incident hypertension. Women eating “typical” American diets are already at increased risk for incident hypertension, and thus these results have substantial public health implications. Our findings should be tested in randomized trials to determine whether dietary interventions to reduce diet-dependent net acid load (e.g. increase intake of foods which supply alkali, such fruits and vegetables; decrease intake of foods which have a high acid load, such as meat and cheeses; and increasing the ratio of potassium to protein in diets) or perhaps treatment with alkalizing supplements could reduce the risk of hypertension.
Acknowledgements
None
Sources of Funding This study was funded by the American Heart Association grant 0535401T, NIH grants HL079929-01 and CA50385, and the Beijing NOVA program from the Beijing Municipal Science and Technology Commission. Additionally this work has been made possible through the International Society of Nephrology-funded Fellowship (LZh).
Footnotes
Conflict of Interest None
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