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The DASH diet enhances the blood pressure response to losartan in hypertensive patients
AJH
2003; 16:337–342
The DASH Diet Enhances the Blood Pressure Response to Losartan in Hypertensive Patients Paul R. Conlin, Thomas P. Erlinger, Arline Bohannon, Edgar R. Miller III, Lawrence J. Appel, Laura P. Svetkey, and Thomas J. Moore Background: The Dietary Approaches to Stop Hypertension (DASH) diet, which emphasizes fruits, vegetables, and low fat dairy products, significantly lowers blood pressure (BP). We conducted a clinical trial to assess the BP response to the DASH diet with an antihypertensive medication, losartan, in participants with essential hypertension. Methods: A total of 55 hypertensive participants were randomly assigned to 8 weeks of controlled feeding with either a control diet or the DASH diet. Within each diet arm, participants received losartan 50 mg daily or placebo for 4 weeks each, in double blind, randomized, cross-over fashion. Twenty-four-hour ambulatory BP (ABP) was measured at the end of a 2-week run-in period (baseline) and after each 4-week intervention period. Results: There was no significant change in ABP during the placebo period on the control diet (n ⫽ 28) (⫺2.3
R
⫾ 1.5/⫺1.6 ⫾ 1.0 mm Hg), but there was a significant reduction in systolic ABP (⫺5.3 ⫾ 1.5 mm Hg, P ⬍ .05) and no change in DBP (⫺2.5 ⫾ 1.0 mm Hg) on the DASH diet (n ⫽ 27). Losartan significantly reduced ABP on the control diet (⫺6.7 ⫾ 1.5/⫺3.7 ⫾ 1.0 mm Hg, P ⬍ .05) and to a greater extent on the DASH diet (⫺11.7 ⫾ 1.5/⫺6.9 ⫾ 1.0 mm Hg, P ⬍ .05 versus basal and control diet) particularly in African Americans. On the DASH diet, ⌬SBP on losartan was inversely related to basal plasma renin activity (n ⫽ ⫺0.53, P ⫽ .004). Conclusions: The DASH diet enhances the ABP response to losartan in essential hypertension. This effect is particularly marked in African Americans. Am J Hypertens 2003;16:337–342 © 2003 American Journal of Hypertension, Ltd. Key Words: Hypertension, DASH diet, losartan, blood pressure.
ecommendations for hypertension prevention and treatment consistently include lifestyle modifications as both an initial step and as an adjunct to pharmacologic therapy. Dietary interventions have been the mainstay of nonpharmacologic therapy but have traditionally focused on salt restriction and weight loss. The success of these interventions has typically been suboptimal, largely related to the difficulty in achieving and sustaining dietary and lifestyle changes. We previously reported the results of a multicenter study, the Dietary Approaches to Stop Hypertension (DASH) study.1 We showed that a diet emphasizing fruits, vegetables, and low fat dairy products significantly lowers
blood pressure (BP) in individuals with diastolic BP (DBP) between 80 and 95 mm Hg and systolic BP (SBP) ⬍160 mm Hg. The DASH diet was particularly effective in participants with stage 1 systolic or diastolic hypertension.2,3 The importance of these findings was acknowledged by the Sixth Report of the Joint National Committee (JNC-VI), which recommended the DASH diet for prevention and treatment of hypertension.4 The DASH study did not enroll patients with higher levels of BP. Most of these patients, who are currently treated with antihypertensive medication, might achieve additional BP lowering with concomitant use of the DASH diet. The present study was designed to test the hypothesis that the DASH diet enhances the BP response to antihy-
Received September 18, 2002. First decision November 13, 2002. Accepted December 19, 2002. From the Division of Endocrinology, Diabetes and Hypertension (PRC), Brigham and Women’s Hospital, Boston, Massachusetts; Veterans Affairs Boston Healthcare System and Harvard Medical School (PRC), Boston, Massachusetts; Johns Hopkins School of Medicine (TPE, ERM, LJA), Baltimore, Maryland; Duke Hypertension Center (AB, LPS), Duke University Medical Center and the Sarah W. Stedman Center for Nutritional Studies, Durham, North Carolina; and Boston University Medical Center (TJM), Boston, Massachusetts. This project was supported by an unrestricted grant from Merck and
Company, Inc. The authors also acknowledge grant support from the National Heart, Lung and Blood Institute (DK63214, HL57173, HL57114, HL57139, and HL03857) and the General Clinical Research Center Program of the National Center for Research Resources, National Institutes of Health to Brigham and Women’s Hospital (M01-RR02635) and Johns Hopkins University (M01-RR00722).
© 2003 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
Address correspondence and reprint requests to Dr. Paul R. Conlin, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, MA 02115; e-mail: [email protected] 0895-7061/03/$30.00 doi:10.1016/S0895-7061(03)00056-6
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Table 1. Nutrient composition of diets 2100 kcal/day Fat (%) Sat. Fat (%) Protein (%) CHO (%) Fiber (g) Potassium (mg) Magnesium (mg) Calcium (mg) Sodium (g)
Control Diet
DASH Diet
37 16 15 48 9 1700 165 450 3
27 6 18 55 31 4700 500 1240 3
DASH ⫽ Dietary Approaches to Stop Hypertension; CHO ⫽ carbohydrate.
pertensive medication in patients with stages 1 and 2 hypertension. Based on observations (unpublished) that the DASH diet was associated with a small but significant increase in plasma renin activity (PRA) and a significant association between the BP response to the DASH diet and the presence of the G-6A angiotensinogen gene polymorphism,5 we hypothesized that using an agent that interrupts the renin angiotensin system would be effective in conjunction with the DASH diet. The angiotensin receptor blocker losartan was used to explore this question.
Methods Study Population This multicenter feeding study was conducted in a double blind, randomized, placebo controlled manner. Study participants were adults with essential hypertension. The protocol excluded individuals with significant concomitant medical conditions that would interfere with or be affected by participation in the study. Those taking antihypertensive medication were withdrawn from medication before completing two screening visits at least 1 week apart. To be eligible, participants were required to have measurements of mean DBP 90 to 109 mm Hg and mean SBP ⬍180 mm Hg (JNC-VI stages 1 and 2 systolic and diastolic hypertension)4 at each screening visit. Human research committees approved the study at each of the participating centers and all individuals provided written informed consent before entering the study. Study Diets The study diets, outlined in Table 1, have been previously described.1,6 The control diet is typical of what many Americans eat in terms of macronutrient and micronutrient composition. The DASH diet emphasizes fruits, vegetables, and low–fat dairy products; it includes whole grains, poultry, fish, and nuts; and it is reduced in fat, red meat, sweets, and sugar containing beverages. Compared to the control diet, the DASH diet was designed to contain higher amounts of potassium, magnesium, calcium, fiber, and
FIG. 1. Study design. ABP ⫽ ambulatory blood pressure; DASH ⫽ Dietary Approaches to Stop Hypertension.
protein, and lower amounts of saturated fat, total fat, and cholesterol. Both diets contained the same sodium content (approximately 3 g sodium/2100 kcal intake). Study Design Eligible participants began a 2-week run-in period of controlled feeding eating the control diet. This study period was used to determine caloric requirements and participant adherence to the feeding protocol. After the run-in period, participants were randomized in block format (accounting for ethnicity) to continue the control diet (n ⫽ 28) or begin the DASH diet (n ⫽ 27). The diet assignment was continued for 8 weeks and was subdivided into two 4-week treatment periods during which participants were given either losartan 50 mg daily or matching placebo in double blind, randomized, crossover fashion (Fig. 1). For the full 10 weeks of controlled feeding (2 weeks of run-in and 8 weeks of randomized diet feeding), all meals were prepared in metabolic kitchens and supplied to study participants. Compliance with the dietary intervention was assessed by participants’ daily attendance (Monday through Friday) for one on-site meal, attendance at study visits for BP measurement, and self-report of adherence. Caloric intake was adjusted during the study to maintain entry-level weight. All participants were asked to continue with any exercise or physical activities in which they had participated before entry into the study. Study Measurements The primary outcome measurements were 24-h SBP and DBP measured with ambulatory BP monitors (model 90207, SpaceLabs, Redmond, WA). The devices were placed on the nondominant arm and programmed to take readings automatically every 30 min over a 24-h period. Recordings were considered complete if at least 14 acceptable readings were recorded between 6:00 AM and 12:00 AM. Participants who failed to complete this number
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Table 2. Baseline characteristics of study participants Characteristic Number Blood pressure (mm Hg) SBP DBP Age (y) Ethnicity, n (%) African American Non–African American BMI (kg/m2) Female sex (%)
Control Diet
DASH Diet
28
27
150 ⫾ 12 95 ⫾ 4 52 ⫾ 8
151 ⫾ 12 95 ⫾ 6 52 ⫾ 11
18 (64) 10 (36) 30 ⫾ 5 54
17 (63) 10 (37) 32 ⫾ 18 56
SBP ⫽ systolic blood pressure; DBP ⫽ diastolic blood pressure; BMI ⫽ body mass index; other abbreviation as in Table 1. Data are given as mean ⫾ SD.
of acceptable readings were asked to wear the device for an additional 24-h period. Blood pressure was also measured with a standard mercury sphygmomanometer at baseline and weekly during the protocol. Duplicate seated measurements were obtained in the right arm after 5 min of undisturbed sitting. The mean of duplicate measurements taken on 2 successive days, at the time of ambulatory BP monitor placement and removal, were used for baseline and end of treatment period measurements. Twenty-four-hour urine collections were obtained at the end of each treatment period for measurement of creatinine, sodium, and potassium excretion. Plasma renin activity (PRA) was measured at baseline and after each treatment period, with participants in the sitting position after at least 90 min of upright posture. Statistical Analyses Data were analyzed based on all randomized participants (intent-to-treat) and are expressed as mean ⫾ SE. Changes in ambulatory BP from the end of the run-in period (baseline) to the end of each 4-week treatment period were the primary outcome measures. The study was designed with 80% power to detect a between group difference of 4 mm Hg for DBP and 6 mm Hg for SBP as significant. Analyses used an ANOVA model for repeated measures with adjustment for site, ethnicity, sex, treatment period, and carry-over effects. A value of P ⬍ .05 was considered significant. For analyses by diet and ethicity, corrections for multiple comparisons were applied. The association of PRA and change in BP was assessed by multiple linear regression.
Results A total of 183 individuals were screened for the study; 66 were eligible and started the run-in period. Of these, 55 participants were randomized. All randomized participants
FIG. 2. Twenty-four-hour ambulatory systolic (A) and diastolic (B) blood pressures at baseline and during placebo and losartan treatment. *P ⬍ .05 v baseline; †P ⬍ .05 v placebo. BP ⫽ blood pressure; other abbreviation as in Fig. 1.
completed the study. Baseline demographic characteristics of the 55 randomized participants are shown in Table 2. During the placebo period there was no significant change from baseline in 24-h ambulatory SBP or DBP on the control diet (⌬ BP, ⫺2.3 ⫾ 1.5/⫺1.6 ⫾ 1.0 mm Hg) but there was a significant reduction from baseline in ambulatory SBP (⫺5.3 ⫾ 1.5 mm Hg, P ⬍ .05) and no change in DBP (⫺2.5 ⫾ 1.0 mm Hg) on the DASH diet (Fig. 2). Losartan significantly reduced both SBP and DBP from baseline on the control diet (⌬ BP, ⫺6.7 ⫾ 1.5/⫺3.7 ⫾ 1.0 mm Hg, P ⬍ .05) and on the DASH diet (⌬ BP, ⫺11.7 ⫾ 1.5/⫺6.9 ⫾ 1.0 mm Hg, P ⬍ .05). The SBP and DBP changes from baseline with losartan were significantly greater (P ⬍ .05) on the DASH diet than on the control diet. Clinic BP changed in parallel with ambulatory BP (Table 3). Both SBP (P ⬍ .05) and DBP (P ⫽ .07) were lower in participants on the DASH diet versus the control diet. The DASH diet had greater effects in hypertensive African Americans than in non–African Americans, consistent with prior observations.1 There was a significant interaction of losartan treatment with ethnicity (P ⬍ .001) for both SBP and DBP. Overall, non–African Americans had a greater response to losartan than African Americans. However, the DASH diet substantially augmented the BP response to losartan in African Americans, (Table 4), in whom the interventions were more than additive. In non– African Americans the BP response to losartan did not differ on the DASH or control diets.
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Table 3. Clinic blood pressures Control Diet (n ⴝ 28) Baseline Placebo Losartan
DASH Diet (n ⴝ 27)
SBP
DBP
SBP
DBP
148.7 ⫾ 2.7 147.0 ⫾ 3.2 138.6 ⫾ 3.5*
94.0 ⫾ 0.9 93.2 ⫾ 1.7 87.5 ⫾ 1.6
150.1 ⫾ 3.0 142.0 ⫾ 2.6* 132.2 ⫾ 2.5*†
94.2 ⫾ 1.6 89.2 ⫾ 1.3 85.6 ⫾ 1.7*
Abbreviations as in Tables 1 and 2. Data are given as mean ⫾ SD. * P ⬍ .05 v baseline; † P ⬍ .05 v control diet.
A greater number of losartan treated participants on the DASH diet had clinic BP ⬍140/90 mm Hg than did those on the control diet. In all, 46% (13/28) of those on the control diet with losartan had BP ⬍140/90 mm Hg, whereas 63% (17/27) on the DASH diet with losartan achieved BP ⬍140/90 mm Hg. African Americans showed similar trends: 33% (6/18) on the control diet with losartan and 53% (9/17) on the DASH diet with losartan had BP ⬍140/90 mm Hg. Twenty-four-hour urine potassium excretion showed clear separation between diets, with participants on the DASH diet having significantly higher urine potassium, reflecting the increased fruit and vegetable intake (Table 5). There was no difference in urinary potassium excretion within diets during the placebo and losartan treatment periods. The PRA did not change from baseline after the placebo period on either diet, but it increased significantly (P ⬍ .05) during losartan treatment, similarly on both diets (Table 5). In participants on the DASH diet, the losartan induced change in SBP was significantly but inversely related to baseline PRA (r ⫽ ⫺0.53, P ⫽ .004) (Fig. 3). Those with higher PRA at baseline had a greater fall in SBP in response to the combined DASH diet–losartan interventions. Multiple linear regression, including terms for baseline BP, ethnicity, and intervention period, showed
that this relationship remained significant (P ⬍ .01). The relationship between change in DBP from baseline and baseline PRA was also inverse (P ⫽ .08). No similar relationships were present in individuals on the control diet.
Discussion In this study, the DASH diet with losartan significantly reduced BP in patients with stages 1 and 2 hypertension in comparison to losartan treatment on a control diet background. These results have important implications for the treatment of patients with essential hypertension. Dietary modifications are frequently advocated as an adjunct to antihypertensive therapy, with a focus on sodium restriction.4 Fewer data are available on the effects of dietary patterns such as the DASH diet. Two prior studies assessed the impact of low fat/high fiber diets with or without sodium restriction on BP in treated hypertensive subjects. Significant antihypertensive effects were achieved only with the addition of sodium restriction.7,8 The DASH diet combined with multiple lifestyle changes— exercise, moderate sodium restriction, and weight loss—when compared with a control diet without lifestyle changes is associated with significantly lower BP in treated hypertensive patients.9 Our data show that the
Table 4. Changes in 24-h ambulatory blood pressure from baseline in African Americans and non–African Americans African Americans
Placebo ⌬ SBP Losartan ⌬ SBP Placebo ⌬ DBP Losartan ⌬ DBP
Non–African Americans
Control (n ⴝ 18)
DASH (n ⴝ 17)
Control (n ⴝ 10)
DASH (n ⴝ 10)
⫺2.3 ⫾ 1.9
⫺6.4 ⫾ 1.9
⫺2.2 ⫾ 2.1
⫺3.3 ⫾ 2.2
⫺11.0 ⫾ 1.9*†
⫺11.0 ⫾ 2.2*
⫺12.7 ⫾ 2.2*
⫺1.5 ⫾ 1.4
⫺2.8 ⫾ 1.4
⫺1.8 ⫾ 1.5
⫺2.0 ⫾ 1.5
⫺2.0 ⫾ 1.4
⫺6.1 ⫾ 1.4*†
⫺6.7 ⫾ 1.5*
⫺8.3 ⫾ 1.5*
⫺4.3 ⫾ 1.9*
Abbreviations as in Tables 1–3. Data are given as mean ⫾ SD. * P ⬍ .01 v placebo; † P ⬍ .05 v control diet.
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Table 5. Plasma renin activity and 24-h urine potassium excretion Control Diet Plasma renin activity (ng/mL/h) Urine potassium (mmol/24 h)
DASH Diet
Baseline
Placebo
Losartan
Baseline
Placebo
Losartan
1.1 ⫾ 0.9
1.5 ⫾ 1.9
4.1 ⫾ 7.3*
0.7 ⫾ 0.7
0.8 ⫾ 0.7
3.4 ⫾ 4.3*
ND
38 ⫾ 19
ND
53 ⫾ 25†
58 ⫾ 28†
40 ⫾ 17
ND ⫽ not determined; other abbreviation as in Tables 1– 4. Data are given as mean ⫾ SD. * P ⬍ .05 v placebo and baseline; † P ⬍ .05 v control diet.
DASH diet alone lowers BP and augments the BP response to losartan in patients with stages 1 and 2 hypertension. This study showed effects of the DASH diet that were qualitatively similar to findings from the hypertensive subgroups (stage 1 systolic or diastolic hypertension) in the DASH study1–3,10 and the DASH-Sodium study.11 The changes that we observed in clinic BP were less than those observed in hypertensive patients in the DASH study2,3 but were greater than those observed in hypertensive subjects in the DASH-Sodium trial.11 However, the present study involved patients with higher levels of BP and also enrolled fewer participants than either the DASH study or DASH-Sodium study, potentially contributing to more variability in the BP responses. The BP response to losartan on the control diet differed by ethnicity. Non–African Americans experienced a greater effect than did African Americans. The lesser effect of losartan in African Americans on the control diet is consistent with prior observations showing lesser BP effects with agents that block the renin-angiotensin system in African Americans than in non–African Americans.12,13 These differences by ethnicity may be negated by concomitant administration of a diuretic14,15 or sodium restriction. In our study, the BP response to losartan with the DASH diet was similar in both ethnic subgroups. Thus, the DASH diet neutralizes ethnic differences in the BP response to losartan.
FIG. 3. Regression relationship between the change in systolic blood pressure (SBP) and baseline plasma renin activity (PRA).
Although this study was not designed to elucidate the mechanism(s) for an amplified effect of the DASH diet with losartan, an interaction with the renin-angiotensin system is suggested by the relationship between baseline PRA and the BP response to the DASH diet and losartan. Those participants with higher baseline PRA, regardless of ethnicity, had greater BP responses to the DASH diet and losartan. We recently reported an association between the BP response to the DASH diet and the G-6A angiotensinogen gene polymorphism,5 which is associated with increased angiotensinogen levels16,17 and enhanced BP responses to sodium restriction18 and ACE-inhibition.19 African Americans have a much higher prevalence of the G-6A polymorphism than nonminorities,20 and it is also this ethnic subgroup that had the greatest response to the DASH diet.1,11 The nutrients responsible for an interaction between the DASH diet and the renin-angiotensin system cannot be directly ascertained. Still, it is worthwhile to consider this issue in view of the evidence that certain dietary factors may affect renin-angiotensin system function. Two nutrients that may play a role are potassium and calcium. Studies have evaluated the effects of potassium intake on renin-angiotensin system activity and suggest that an interaction exists.21,22 Hollenberg et al.21 showed that a low potassium intake (40 mmol/day) reduced renal blood flow and blunted the vascular response to angiotensin II, consistent with an increase in renin-angiotensin system activity. Potassium supplementation significantly lowers BP23 and significantly increases PRA.23 Similarly, a relationship between dietary calcium, calcium regulating hormones, and the renin-angiotensin system has been known for some time.24 Oral calcium administration significantly increases PRA and suppresses calcium regulating hormones (ie, parathyroid hormone and 1,25 dihydroxyvitamin D).25 Despite these observations, the available evidence does not clarify the specific nutrients responsible for effects of the DASH diet on BP or renin-angiotensin system activity. As such, an interactive effect among nutrients is quite plausible, as has been suggested in other clinical trials of the effects of diet on BP.26 Our results show that the DASH diet with losartan significantly lowers BP in patients with stages 1 and 2 hypertension. This effect is particularly marked in African
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Americans. For hypertensive individuals, adopting the DASH diet may further lower BP and lead to better control rates.
References 1.
Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, Bray GA, Vogt TM, Cutler JA, Windhauser MM, Lin PH, Karanja N: A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997;336:1117–1124. 2. Conlin PR, Chow D, Miller ER III, Svetkey LP, Lin PH, Harsha DW, Moore TJ, Sacks FM, Appel LJ, for the DASH Research Group: The effect of dietary patterns on blood pressure control in hypertensive patients: results from the Dietary Approaches to Stop Hypertension (DASH) Trial. Am J Hypertens 2000;13:949–955. 3. Moore TM, Conlin PR, Ard J, Svetkey LP: The DASH diet is effective treatment for stage 1 isolated systolic hypertension. Hypertension 2001;38:155–158. 4. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of high blood pressure. Arch Intern Med 1997;157:2413–2445. 5. Svetkey LP, Moore TJ, Simons-Morton DG, Appel LJ, Bray GA, Sacks FM, Ard JD, Mortensen RM, Mitchell SR, Conlin PR, Kesari M: Angiotensinogen genotype and BP response in the Dietary Approaches to Stop Hypertension (DASH) study. J Hypertens 2001; 19:1949–1956. 6. Sacks F, Obarzanek E, Windhauser M, Svetkey LP, Vollmer WM, McCullough M, Karanja N, Lin PH, Steele P, Proschan MA, Evans MA, Appel LJ, Bray GA, Vogt TM, Moore TJ: Rationale and design of the dietary approaches to stop hypertension trial. Ann Epidemiol 1995;5:108–118. 7. Sciarrone SE, Beilin LJ, Rouse IL, Rogers PB: A factorial study of salt restriction and a low-fat/high-fibre diet in hypertensive subjects. J Hypertens 1992;10:287–298. 8. Little P, Girling G, Hasler A, Trafford A, Craven A: A controlled trial of a low sodium, low fat, high fibre diet in treated hypertensive patients: the efficacy of multiple dietary intervention. Postgrad Med J 1990;66:616–621. 9. Miller ER III, Erlinger TP, Young DR, Jehn M, Charleston J, Rhodes D, Wasan SK, Appel LJ: Results of the Diet, Exercise, and Weight Loss Intervention Trial (DEW-IT). Hypertension 2002;40: 612–618. 10. Moore TJ, Vollmer WM, Appel LJ, Sacks FM, Svetkey LP, Vogt TM, Conlin PR, Simons-Morton D, Carter-Edwards L, Harsha DM: Effect of dietary patterns on ambulatory blood pressure: results from the DASH study. Hypertension 1999;34:472–477. 11. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER III, Simons-Morton DG, Karanja N, Lin P-H, for the DASH-Sodium collaborative research group: a clinical trial of the effects on blood pressure of reduced dietary sodium and the DASH dietary pattern (the DASH-Sodium trial). N Eng J Med 2001;344:3–10. 12. Weir MR, Gray JM, Paster R, Saunders E: Differing mechanisms of action of angiotensin-converting enzyme inhibition in black and white hypertensive patients. The Trandolapril Multicenter Study Group. Hypertension 1995;26:124–130.
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13. Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, Hamburger RJ, Fye C, Lakshman R, Gottdiener J, Ramirez EA, Henderson WG, for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents: Singledrug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med 1993;328:914– 921. 14. Middlemost SJ, Tager R, Davis J, Sareli P: Effectiveness of enalapril in combination with low-dose hydrochlorothiazide versus enalapril alone for mild to moderate systemic hypertension in black patients. Am J Cardiol 1994;73:1092–1097. 15. Dahlof B, Hansson L, Acosta JH, Bolzano K, Fairhurst G, Ferreira C, Kaarsalo E, Silva MC, Simone A: Controlled trial of enalapril and hydrochlorothiazide in 200 hypertensive patients. Am J Hypertens 1988;1:38–41. 16. Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, Hunt SC, Hopkins PN, Williams RR, Lalouel JM: Molecular basis of human hypertension: role of angiotensinogen. Cell 1992;71:169–180. 17. Bloem LJ, Foroud TM, Ambrosius WT, Hanna MP, Tewksbury DA, Pratt JH: Association of the angiotensinogen gene to serum angiotensinogen in blacks and whites. Hypertension 1997;29:1078–1082. 18. Hunt SC, Cook NR, Oberman A, Cutler JA, Hennekens CH, Allender PS, Walker WG, Whelton PK, Williams RR: Angiotensinogen genotype, sodium reduction, weight loss, and prevention of hypertension: trials of hypertension prevention, phase II. Hypertension 1998;32:393–401. 19. Hingorani AD, Jia H, Stevens PA, Hopper R, Dickerson JE, Brown MJ: Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition. J Hypertens 1995;13:1602–1609. 20. Rotimi C, Cooper R, Ogunbiyi O, Morrison L, Ladipo M, Tewksbury D, Ward R: Hypertension, serum angiotensinogen, and molecular variants of the angiotensinogen gene among Nigerians. Circulation 1997;95:2348–2350. 21. Hollenberg NK, Williams GH, Burger B: The influence of potassium on the renal vasculature and the adrenal gland and their responsiveness to angiotensin II in normal man. Clin Sci Mol Med 1975;49:527–534. 22. Langford HG, Cushman WC, Hsu H: Chronic effect of KCl on black-white differences in plasma renin activity, aldosterone, and urinary electrolytes. Am J Hypertens 1991;4:399–403. 23. Whelton PK, He J, Cutler JA, Brancati FL, Appel LJ, Follmann D, Klag MJ: Effects of oral potassium on blood pressure. Meta-analysis of randomized controlled clinical trials. JAMA 1997;277:1624– 1632. 24. Resnick LM, Muller FB, Laragh JH: Calcium-regulating hormones in essential hypertension. Relation to plasma renin activity and sodium metabolism. Ann Intern Med 1986;105:649–654. 25. Petrov V, Lijnen P: Modification of intracellular calcium and plasma renin by dietary calcium in men. Am J Hypertens 1999;12: 1217–1224. 26. Resnick LM, Oparil S, Chait A, Haynes RB, Kris-Etherton P, Stern JS, Clark S, Holcomb S, Hatton DC, Metz JA, McMahon M, Pi-Sunyer FX, McCarron DA: Factors affecting blood pressure responses to diet: the Vanguard study. Am J Hypertens 2000;13: 956–965.
2003; 16:337–342
The DASH Diet Enhances the Blood Pressure Response to Losartan in Hypertensive Patients Paul R. Conlin, Thomas P. Erlinger, Arline Bohannon, Edgar R. Miller III, Lawrence J. Appel, Laura P. Svetkey, and Thomas J. Moore Background: The Dietary Approaches to Stop Hypertension (DASH) diet, which emphasizes fruits, vegetables, and low fat dairy products, significantly lowers blood pressure (BP). We conducted a clinical trial to assess the BP response to the DASH diet with an antihypertensive medication, losartan, in participants with essential hypertension. Methods: A total of 55 hypertensive participants were randomly assigned to 8 weeks of controlled feeding with either a control diet or the DASH diet. Within each diet arm, participants received losartan 50 mg daily or placebo for 4 weeks each, in double blind, randomized, cross-over fashion. Twenty-four-hour ambulatory BP (ABP) was measured at the end of a 2-week run-in period (baseline) and after each 4-week intervention period. Results: There was no significant change in ABP during the placebo period on the control diet (n ⫽ 28) (⫺2.3
R
⫾ 1.5/⫺1.6 ⫾ 1.0 mm Hg), but there was a significant reduction in systolic ABP (⫺5.3 ⫾ 1.5 mm Hg, P ⬍ .05) and no change in DBP (⫺2.5 ⫾ 1.0 mm Hg) on the DASH diet (n ⫽ 27). Losartan significantly reduced ABP on the control diet (⫺6.7 ⫾ 1.5/⫺3.7 ⫾ 1.0 mm Hg, P ⬍ .05) and to a greater extent on the DASH diet (⫺11.7 ⫾ 1.5/⫺6.9 ⫾ 1.0 mm Hg, P ⬍ .05 versus basal and control diet) particularly in African Americans. On the DASH diet, ⌬SBP on losartan was inversely related to basal plasma renin activity (n ⫽ ⫺0.53, P ⫽ .004). Conclusions: The DASH diet enhances the ABP response to losartan in essential hypertension. This effect is particularly marked in African Americans. Am J Hypertens 2003;16:337–342 © 2003 American Journal of Hypertension, Ltd. Key Words: Hypertension, DASH diet, losartan, blood pressure.
ecommendations for hypertension prevention and treatment consistently include lifestyle modifications as both an initial step and as an adjunct to pharmacologic therapy. Dietary interventions have been the mainstay of nonpharmacologic therapy but have traditionally focused on salt restriction and weight loss. The success of these interventions has typically been suboptimal, largely related to the difficulty in achieving and sustaining dietary and lifestyle changes. We previously reported the results of a multicenter study, the Dietary Approaches to Stop Hypertension (DASH) study.1 We showed that a diet emphasizing fruits, vegetables, and low fat dairy products significantly lowers
blood pressure (BP) in individuals with diastolic BP (DBP) between 80 and 95 mm Hg and systolic BP (SBP) ⬍160 mm Hg. The DASH diet was particularly effective in participants with stage 1 systolic or diastolic hypertension.2,3 The importance of these findings was acknowledged by the Sixth Report of the Joint National Committee (JNC-VI), which recommended the DASH diet for prevention and treatment of hypertension.4 The DASH study did not enroll patients with higher levels of BP. Most of these patients, who are currently treated with antihypertensive medication, might achieve additional BP lowering with concomitant use of the DASH diet. The present study was designed to test the hypothesis that the DASH diet enhances the BP response to antihy-
Received September 18, 2002. First decision November 13, 2002. Accepted December 19, 2002. From the Division of Endocrinology, Diabetes and Hypertension (PRC), Brigham and Women’s Hospital, Boston, Massachusetts; Veterans Affairs Boston Healthcare System and Harvard Medical School (PRC), Boston, Massachusetts; Johns Hopkins School of Medicine (TPE, ERM, LJA), Baltimore, Maryland; Duke Hypertension Center (AB, LPS), Duke University Medical Center and the Sarah W. Stedman Center for Nutritional Studies, Durham, North Carolina; and Boston University Medical Center (TJM), Boston, Massachusetts. This project was supported by an unrestricted grant from Merck and
Company, Inc. The authors also acknowledge grant support from the National Heart, Lung and Blood Institute (DK63214, HL57173, HL57114, HL57139, and HL03857) and the General Clinical Research Center Program of the National Center for Research Resources, National Institutes of Health to Brigham and Women’s Hospital (M01-RR02635) and Johns Hopkins University (M01-RR00722).
© 2003 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
Address correspondence and reprint requests to Dr. Paul R. Conlin, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, MA 02115; e-mail: [email protected] 0895-7061/03/$30.00 doi:10.1016/S0895-7061(03)00056-6
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Table 1. Nutrient composition of diets 2100 kcal/day Fat (%) Sat. Fat (%) Protein (%) CHO (%) Fiber (g) Potassium (mg) Magnesium (mg) Calcium (mg) Sodium (g)
Control Diet
DASH Diet
37 16 15 48 9 1700 165 450 3
27 6 18 55 31 4700 500 1240 3
DASH ⫽ Dietary Approaches to Stop Hypertension; CHO ⫽ carbohydrate.
pertensive medication in patients with stages 1 and 2 hypertension. Based on observations (unpublished) that the DASH diet was associated with a small but significant increase in plasma renin activity (PRA) and a significant association between the BP response to the DASH diet and the presence of the G-6A angiotensinogen gene polymorphism,5 we hypothesized that using an agent that interrupts the renin angiotensin system would be effective in conjunction with the DASH diet. The angiotensin receptor blocker losartan was used to explore this question.
Methods Study Population This multicenter feeding study was conducted in a double blind, randomized, placebo controlled manner. Study participants were adults with essential hypertension. The protocol excluded individuals with significant concomitant medical conditions that would interfere with or be affected by participation in the study. Those taking antihypertensive medication were withdrawn from medication before completing two screening visits at least 1 week apart. To be eligible, participants were required to have measurements of mean DBP 90 to 109 mm Hg and mean SBP ⬍180 mm Hg (JNC-VI stages 1 and 2 systolic and diastolic hypertension)4 at each screening visit. Human research committees approved the study at each of the participating centers and all individuals provided written informed consent before entering the study. Study Diets The study diets, outlined in Table 1, have been previously described.1,6 The control diet is typical of what many Americans eat in terms of macronutrient and micronutrient composition. The DASH diet emphasizes fruits, vegetables, and low–fat dairy products; it includes whole grains, poultry, fish, and nuts; and it is reduced in fat, red meat, sweets, and sugar containing beverages. Compared to the control diet, the DASH diet was designed to contain higher amounts of potassium, magnesium, calcium, fiber, and
FIG. 1. Study design. ABP ⫽ ambulatory blood pressure; DASH ⫽ Dietary Approaches to Stop Hypertension.
protein, and lower amounts of saturated fat, total fat, and cholesterol. Both diets contained the same sodium content (approximately 3 g sodium/2100 kcal intake). Study Design Eligible participants began a 2-week run-in period of controlled feeding eating the control diet. This study period was used to determine caloric requirements and participant adherence to the feeding protocol. After the run-in period, participants were randomized in block format (accounting for ethnicity) to continue the control diet (n ⫽ 28) or begin the DASH diet (n ⫽ 27). The diet assignment was continued for 8 weeks and was subdivided into two 4-week treatment periods during which participants were given either losartan 50 mg daily or matching placebo in double blind, randomized, crossover fashion (Fig. 1). For the full 10 weeks of controlled feeding (2 weeks of run-in and 8 weeks of randomized diet feeding), all meals were prepared in metabolic kitchens and supplied to study participants. Compliance with the dietary intervention was assessed by participants’ daily attendance (Monday through Friday) for one on-site meal, attendance at study visits for BP measurement, and self-report of adherence. Caloric intake was adjusted during the study to maintain entry-level weight. All participants were asked to continue with any exercise or physical activities in which they had participated before entry into the study. Study Measurements The primary outcome measurements were 24-h SBP and DBP measured with ambulatory BP monitors (model 90207, SpaceLabs, Redmond, WA). The devices were placed on the nondominant arm and programmed to take readings automatically every 30 min over a 24-h period. Recordings were considered complete if at least 14 acceptable readings were recorded between 6:00 AM and 12:00 AM. Participants who failed to complete this number
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Table 2. Baseline characteristics of study participants Characteristic Number Blood pressure (mm Hg) SBP DBP Age (y) Ethnicity, n (%) African American Non–African American BMI (kg/m2) Female sex (%)
Control Diet
DASH Diet
28
27
150 ⫾ 12 95 ⫾ 4 52 ⫾ 8
151 ⫾ 12 95 ⫾ 6 52 ⫾ 11
18 (64) 10 (36) 30 ⫾ 5 54
17 (63) 10 (37) 32 ⫾ 18 56
SBP ⫽ systolic blood pressure; DBP ⫽ diastolic blood pressure; BMI ⫽ body mass index; other abbreviation as in Table 1. Data are given as mean ⫾ SD.
of acceptable readings were asked to wear the device for an additional 24-h period. Blood pressure was also measured with a standard mercury sphygmomanometer at baseline and weekly during the protocol. Duplicate seated measurements were obtained in the right arm after 5 min of undisturbed sitting. The mean of duplicate measurements taken on 2 successive days, at the time of ambulatory BP monitor placement and removal, were used for baseline and end of treatment period measurements. Twenty-four-hour urine collections were obtained at the end of each treatment period for measurement of creatinine, sodium, and potassium excretion. Plasma renin activity (PRA) was measured at baseline and after each treatment period, with participants in the sitting position after at least 90 min of upright posture. Statistical Analyses Data were analyzed based on all randomized participants (intent-to-treat) and are expressed as mean ⫾ SE. Changes in ambulatory BP from the end of the run-in period (baseline) to the end of each 4-week treatment period were the primary outcome measures. The study was designed with 80% power to detect a between group difference of 4 mm Hg for DBP and 6 mm Hg for SBP as significant. Analyses used an ANOVA model for repeated measures with adjustment for site, ethnicity, sex, treatment period, and carry-over effects. A value of P ⬍ .05 was considered significant. For analyses by diet and ethicity, corrections for multiple comparisons were applied. The association of PRA and change in BP was assessed by multiple linear regression.
Results A total of 183 individuals were screened for the study; 66 were eligible and started the run-in period. Of these, 55 participants were randomized. All randomized participants
FIG. 2. Twenty-four-hour ambulatory systolic (A) and diastolic (B) blood pressures at baseline and during placebo and losartan treatment. *P ⬍ .05 v baseline; †P ⬍ .05 v placebo. BP ⫽ blood pressure; other abbreviation as in Fig. 1.
completed the study. Baseline demographic characteristics of the 55 randomized participants are shown in Table 2. During the placebo period there was no significant change from baseline in 24-h ambulatory SBP or DBP on the control diet (⌬ BP, ⫺2.3 ⫾ 1.5/⫺1.6 ⫾ 1.0 mm Hg) but there was a significant reduction from baseline in ambulatory SBP (⫺5.3 ⫾ 1.5 mm Hg, P ⬍ .05) and no change in DBP (⫺2.5 ⫾ 1.0 mm Hg) on the DASH diet (Fig. 2). Losartan significantly reduced both SBP and DBP from baseline on the control diet (⌬ BP, ⫺6.7 ⫾ 1.5/⫺3.7 ⫾ 1.0 mm Hg, P ⬍ .05) and on the DASH diet (⌬ BP, ⫺11.7 ⫾ 1.5/⫺6.9 ⫾ 1.0 mm Hg, P ⬍ .05). The SBP and DBP changes from baseline with losartan were significantly greater (P ⬍ .05) on the DASH diet than on the control diet. Clinic BP changed in parallel with ambulatory BP (Table 3). Both SBP (P ⬍ .05) and DBP (P ⫽ .07) were lower in participants on the DASH diet versus the control diet. The DASH diet had greater effects in hypertensive African Americans than in non–African Americans, consistent with prior observations.1 There was a significant interaction of losartan treatment with ethnicity (P ⬍ .001) for both SBP and DBP. Overall, non–African Americans had a greater response to losartan than African Americans. However, the DASH diet substantially augmented the BP response to losartan in African Americans, (Table 4), in whom the interventions were more than additive. In non– African Americans the BP response to losartan did not differ on the DASH or control diets.
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Table 3. Clinic blood pressures Control Diet (n ⴝ 28) Baseline Placebo Losartan
DASH Diet (n ⴝ 27)
SBP
DBP
SBP
DBP
148.7 ⫾ 2.7 147.0 ⫾ 3.2 138.6 ⫾ 3.5*
94.0 ⫾ 0.9 93.2 ⫾ 1.7 87.5 ⫾ 1.6
150.1 ⫾ 3.0 142.0 ⫾ 2.6* 132.2 ⫾ 2.5*†
94.2 ⫾ 1.6 89.2 ⫾ 1.3 85.6 ⫾ 1.7*
Abbreviations as in Tables 1 and 2. Data are given as mean ⫾ SD. * P ⬍ .05 v baseline; † P ⬍ .05 v control diet.
A greater number of losartan treated participants on the DASH diet had clinic BP ⬍140/90 mm Hg than did those on the control diet. In all, 46% (13/28) of those on the control diet with losartan had BP ⬍140/90 mm Hg, whereas 63% (17/27) on the DASH diet with losartan achieved BP ⬍140/90 mm Hg. African Americans showed similar trends: 33% (6/18) on the control diet with losartan and 53% (9/17) on the DASH diet with losartan had BP ⬍140/90 mm Hg. Twenty-four-hour urine potassium excretion showed clear separation between diets, with participants on the DASH diet having significantly higher urine potassium, reflecting the increased fruit and vegetable intake (Table 5). There was no difference in urinary potassium excretion within diets during the placebo and losartan treatment periods. The PRA did not change from baseline after the placebo period on either diet, but it increased significantly (P ⬍ .05) during losartan treatment, similarly on both diets (Table 5). In participants on the DASH diet, the losartan induced change in SBP was significantly but inversely related to baseline PRA (r ⫽ ⫺0.53, P ⫽ .004) (Fig. 3). Those with higher PRA at baseline had a greater fall in SBP in response to the combined DASH diet–losartan interventions. Multiple linear regression, including terms for baseline BP, ethnicity, and intervention period, showed
that this relationship remained significant (P ⬍ .01). The relationship between change in DBP from baseline and baseline PRA was also inverse (P ⫽ .08). No similar relationships were present in individuals on the control diet.
Discussion In this study, the DASH diet with losartan significantly reduced BP in patients with stages 1 and 2 hypertension in comparison to losartan treatment on a control diet background. These results have important implications for the treatment of patients with essential hypertension. Dietary modifications are frequently advocated as an adjunct to antihypertensive therapy, with a focus on sodium restriction.4 Fewer data are available on the effects of dietary patterns such as the DASH diet. Two prior studies assessed the impact of low fat/high fiber diets with or without sodium restriction on BP in treated hypertensive subjects. Significant antihypertensive effects were achieved only with the addition of sodium restriction.7,8 The DASH diet combined with multiple lifestyle changes— exercise, moderate sodium restriction, and weight loss—when compared with a control diet without lifestyle changes is associated with significantly lower BP in treated hypertensive patients.9 Our data show that the
Table 4. Changes in 24-h ambulatory blood pressure from baseline in African Americans and non–African Americans African Americans
Placebo ⌬ SBP Losartan ⌬ SBP Placebo ⌬ DBP Losartan ⌬ DBP
Non–African Americans
Control (n ⴝ 18)
DASH (n ⴝ 17)
Control (n ⴝ 10)
DASH (n ⴝ 10)
⫺2.3 ⫾ 1.9
⫺6.4 ⫾ 1.9
⫺2.2 ⫾ 2.1
⫺3.3 ⫾ 2.2
⫺11.0 ⫾ 1.9*†
⫺11.0 ⫾ 2.2*
⫺12.7 ⫾ 2.2*
⫺1.5 ⫾ 1.4
⫺2.8 ⫾ 1.4
⫺1.8 ⫾ 1.5
⫺2.0 ⫾ 1.5
⫺2.0 ⫾ 1.4
⫺6.1 ⫾ 1.4*†
⫺6.7 ⫾ 1.5*
⫺8.3 ⫾ 1.5*
⫺4.3 ⫾ 1.9*
Abbreviations as in Tables 1–3. Data are given as mean ⫾ SD. * P ⬍ .01 v placebo; † P ⬍ .05 v control diet.
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Table 5. Plasma renin activity and 24-h urine potassium excretion Control Diet Plasma renin activity (ng/mL/h) Urine potassium (mmol/24 h)
DASH Diet
Baseline
Placebo
Losartan
Baseline
Placebo
Losartan
1.1 ⫾ 0.9
1.5 ⫾ 1.9
4.1 ⫾ 7.3*
0.7 ⫾ 0.7
0.8 ⫾ 0.7
3.4 ⫾ 4.3*
ND
38 ⫾ 19
ND
53 ⫾ 25†
58 ⫾ 28†
40 ⫾ 17
ND ⫽ not determined; other abbreviation as in Tables 1– 4. Data are given as mean ⫾ SD. * P ⬍ .05 v placebo and baseline; † P ⬍ .05 v control diet.
DASH diet alone lowers BP and augments the BP response to losartan in patients with stages 1 and 2 hypertension. This study showed effects of the DASH diet that were qualitatively similar to findings from the hypertensive subgroups (stage 1 systolic or diastolic hypertension) in the DASH study1–3,10 and the DASH-Sodium study.11 The changes that we observed in clinic BP were less than those observed in hypertensive patients in the DASH study2,3 but were greater than those observed in hypertensive subjects in the DASH-Sodium trial.11 However, the present study involved patients with higher levels of BP and also enrolled fewer participants than either the DASH study or DASH-Sodium study, potentially contributing to more variability in the BP responses. The BP response to losartan on the control diet differed by ethnicity. Non–African Americans experienced a greater effect than did African Americans. The lesser effect of losartan in African Americans on the control diet is consistent with prior observations showing lesser BP effects with agents that block the renin-angiotensin system in African Americans than in non–African Americans.12,13 These differences by ethnicity may be negated by concomitant administration of a diuretic14,15 or sodium restriction. In our study, the BP response to losartan with the DASH diet was similar in both ethnic subgroups. Thus, the DASH diet neutralizes ethnic differences in the BP response to losartan.
FIG. 3. Regression relationship between the change in systolic blood pressure (SBP) and baseline plasma renin activity (PRA).
Although this study was not designed to elucidate the mechanism(s) for an amplified effect of the DASH diet with losartan, an interaction with the renin-angiotensin system is suggested by the relationship between baseline PRA and the BP response to the DASH diet and losartan. Those participants with higher baseline PRA, regardless of ethnicity, had greater BP responses to the DASH diet and losartan. We recently reported an association between the BP response to the DASH diet and the G-6A angiotensinogen gene polymorphism,5 which is associated with increased angiotensinogen levels16,17 and enhanced BP responses to sodium restriction18 and ACE-inhibition.19 African Americans have a much higher prevalence of the G-6A polymorphism than nonminorities,20 and it is also this ethnic subgroup that had the greatest response to the DASH diet.1,11 The nutrients responsible for an interaction between the DASH diet and the renin-angiotensin system cannot be directly ascertained. Still, it is worthwhile to consider this issue in view of the evidence that certain dietary factors may affect renin-angiotensin system function. Two nutrients that may play a role are potassium and calcium. Studies have evaluated the effects of potassium intake on renin-angiotensin system activity and suggest that an interaction exists.21,22 Hollenberg et al.21 showed that a low potassium intake (40 mmol/day) reduced renal blood flow and blunted the vascular response to angiotensin II, consistent with an increase in renin-angiotensin system activity. Potassium supplementation significantly lowers BP23 and significantly increases PRA.23 Similarly, a relationship between dietary calcium, calcium regulating hormones, and the renin-angiotensin system has been known for some time.24 Oral calcium administration significantly increases PRA and suppresses calcium regulating hormones (ie, parathyroid hormone and 1,25 dihydroxyvitamin D).25 Despite these observations, the available evidence does not clarify the specific nutrients responsible for effects of the DASH diet on BP or renin-angiotensin system activity. As such, an interactive effect among nutrients is quite plausible, as has been suggested in other clinical trials of the effects of diet on BP.26 Our results show that the DASH diet with losartan significantly lowers BP in patients with stages 1 and 2 hypertension. This effect is particularly marked in African
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Americans. For hypertensive individuals, adopting the DASH diet may further lower BP and lead to better control rates.
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