Paul R. Conlin

Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet

Background The effect of dietary composition on blood pressure is a subject of public health importance. We studied the effect of different levels of dietary sodium, in conjunction with the Dietary Approaches to Stop Hypertension (DASH) diet, which is rich in vegetables, fruits, and low-fat dairy products, in persons with and in those without hypertension. Methods A total of 412 participants were randomly assigned to eat either a control diet typical of intake in the United States or the DASH diet. Within the assigned diet, participants ate foods with high, intermediate, and low levels of sodium for 30 consecutive days each, in random order. Results Reducing the sodium intake from the high to the intermediate level reduced the systolic blood pressure by 2.1 mm Hg (P<0.001) during the control diet and by 1.3 mm Hg (P=0.03) during the DASH diet. Reducing the sodium intake from the intermediate to the low level caused additional reductions of 4.6 mm Hg during the control diet (P<0.001) and 1.7 mm Hg during t...

Effects of Diet and Sodium Intake on Blood Pressure: Subgroup Analysis of the DASH-Sodium Trial

Although epidemiologic data show a direct relation between dietary sodium intake and blood pressure at the population level (1, 2), some experts question the universality of the findings and oppose public health recommendations to decrease sodium intake in the general population (3). Certainly, results from reports on the relationship between sodium and blood pressure among major subgroups vary considerably. Several studies suggest that African Americans and older adults have heightened salt sensitivity (greater blood pressure response to sodium intake) (4-6). Some evidence also indicates increased salt sensitivity in women (7), although other studies do not support this claim (4, 5). The association of sodium intake with cardiovascular morbidity and mortality varies by overweight status (8), perhaps reflecting a differential effect of sodium on blood pressure in overweight persons. Finally, higher dietary intakes of potassium and calcium have been shown to blunt the pressor effects of dietary sodium (9, 10). Dietary factors other than sodium also directly affect blood pressure, and these effects also appear to vary across subgroups. In the Dietary Approaches to Stop Hypertension (DASH) Trial, for example, a diet that had reduced total and saturated fat and was rich in fruits, vegetables, and low-fat dairy foods (the DASH diet) substantially decreased blood pressure compared with a more typical U.S. diet, in the absence of weight change and at sodium intakes approximating current U.S. consumption (11, 12). These effects persisted across all subgroups and were especially pronounced among hypertensive persons, African Americans, and persons who did not drink alcohol (13). The DASH-Sodium Trial examined the effects of reduced sodium intake in the context of the DASH diet and a more typical U.S. diet (14). In that study, highly significant decreases in blood pressure were observed with decreased sodium intake in participants following either diet, and the DASH diet decreased blood pressure at sodium intakes well below the current U.S. average. These results were observed overall and in subgroups defined by ethnicity, sex, and hypertension status (15). We report on more detailed subgroup analyses from the DASH-Sodium Trial, including results for subgroups defined by age, obesity, waist circumference, alcohol intake, and baseline sodium intake. We also report the results of multivariate analyses that demonstrate how these effects vary across subgroups defined jointly by age, ethnicity, sex, and hypertension status. Methods Study Design The DASH-Sodium Trial was a multicenter, randomized feeding trial comparing the effects on blood pressure of three levels of sodium intake and two dietary patterns. The 412 participants were 22 years of age or older and had systolic blood pressures of 120 to 159 mm Hg and diastolic blood pressures of 80 to 95 mm Hg (15). The three levels of sodium intake (lower, intermediate, and higher) varied according to energy intake in a ratio of 1:2:3; target intakes were 50, 100, and 150 mmol/d, respectively, for a 2100-kcal diet. The dietary patterns were a control diet, typical of what many Americans eat, and the DASH diet, which emphasizes fruits, vegetables, and low-fat dairy foods; includes whole grains, poultry, fish, and nuts; and is reduced in fats, red meat, sweets, and sugar-containing beverages (11, 14). Participants were recruited in four separate feeding cohorts and were randomly assigned to one of the two dietary patterns by using a parallel-group design. They then ate their assigned diet for three consecutive 30-day intervention feeding periods, during which sodium intake varied among the three levels by a randomly assigned sequence (Figure). Participants ate the control diet at the higher sodium intake during a 2-week run-in period. During the three intervention periods, participants received all their food in the context of the study and were asked not to eat any nonstudy food. Individual energy intake was adjusted to keep body weight stable. Figure. Design of the Dietary Approaches to Stop Hypertension (DASH)-Sodium Trial. Exclusion criteria were heart disease, renal insufficiency, poorly controlled hyperlipidemia or diabetes mellitus, diabetes requiring insulin, special dietary requirements, intake of more than 14 alcoholic drinks/wk, or use of antihypertensive drugs or other medications that would affect blood pressure or nutrient metabolism. The study was approved by the human subjects committees of the clinical centers and coordinating center, and participants gave informed consent. Measurement Protocol Trained staff measured blood pressure at each of three screening visits, on 2 days during the run-in period, and on 5 of the last 9 days of each intervention feeding period. Interim blood pressures were assessed once during each of the first 3 weeks of each intervention feeding period. During screening and the last week of each intervention feeding period, a 24-hour urine collection was obtained. Height and weight were measured, and body mass index was calculated. Baseline physical activity was measured by using a 7-day physical activity recall interview (16). Information on education level, income, alcohol consumption, and family history was obtained by using a questionnaire. Baseline blood pressure was defined as the average of the five preintervention blood pressures. End-of-feeding blood pressures were defined as the average of the five blood pressures at the end of each 30-day intervention feeding period. If no end-of-feeding blood pressure values were available (49 of 1236 possible cases), interim (n = 9) or screening (n = 40) blood pressures were used to impute end-of-feeding blood pressures. Definitions of Subgroups Ethnicity was categorized as African American versus other (primarily non-Hispanic white). Participants were considered hypertensive if their untreated baseline systolic blood pressure was 140 mm Hg or greater and their diastolic blood pressure was 90 mm Hg or greater. (Use of antihypertensive agents was an exclusion criterion [17].) Obesity was defined as body mass index of 30 kg/m2 or greater, and high-risk waist circumference was defined as greater than 102 cm in men and greater than 88 cm in women (18). Age, physical activity, baseline alcohol intake, baseline 24-hour urinary sodium level, and family income were dichotomized at the approximate median. Level of education was dichotomized as high school or less versus more than high school. Statistical Analysis The data were analyzed on an intention-to-treat basis. Given the differential effects of sodium on blood pressure observed in previous analyses among participants eating the DASH diet versus the control diet (15) and because power for subgroup analyses is more limited than for overall analysis, we focused our comparisons on the maximum contrasts (higher versus lower sodium intake with the control diet, DASH diet versus control diet at the higher sodium intake, and the combined effect of DASH diet and lower sodium intake versus control diet and higher sodium intake). We used generalized estimating equations (19) to fit linear models that predicted baseline and end-of-feeding blood pressures as a function of diet (DASH vs. control), sodium level, and subgroup indicators. Different ways of modeling the dietsodium effects and their interactions with the subgroup indicators were used to test specific hypotheses. In particular, two-way interactions of the various dietsodium effects with ethnicity, sex, hypertension status, and age were analyzed to determine the incremental effect on blood pressure in each of these subgroups while controlling for the main and incremental effects of the other subgroups. This model allowed us to estimate various diet-sodium contrasts for each of the 16 subgroups defined by hypertension status, ethnicity, sex, and age. A second set of models examined subgroup variables in a bivariate manner and did not assume simple additivity of subgroup effects. Finally, unadjusted subgroup analyses included main effects and interactions for a single subgroup indicator. All analyses were performed by using the xtgee procedure in Stata software, version 5 (Stata Corp., College Station, Texas) (20) and included adjustment for baseline blood pressure, site, feeding cohort, and carryover effects. An exchangeable covariance matrix was assumed for the repeated measurements for each participant. Unless otherwise stated, a P value less than 0.05 was significant, and all confidence intervals are 95% confidence intervals. Because subgroup analyses were planned to interpret and elucidate the overall study results, they are not adjusted for multiple comparisons. Results Of the 412 participants who underwent randomization, 390 (95%) completed the 12-week intervention feeding period. Adherence to the study diets seemed excellent, and body weight remained stable over time (15). Table 1 shows baseline characteristics of the 412 participants. Mean urinary sodium excretion at screening was 155 mmol/d, a value higher than that found while participants ate higher-sodium diets (142 mmol/d). Table 1. Characteristics of Study Sample Several key subgroups were highly interrelated. Women made up 70% of African-American participants but only 39% of non-African-American participants. Women were more likely to be hypertensive than were men. The percentage of both men and women with hypertension increased sharply with age among non-African-American participants (21% of those 45 years of age vs. 47% of those >45 years of age) but was equally high among older and younger African Americans (43% of those 45 years of age vs. 45% of those >45 years of age). These correlations highlight the potential for confounding in our results and, hence, the importance of the multivariate-adjusted analyses. Effects of the DASH Diet Table 2 shows the effect on systolic blood pressure of the DASH diet compared with the control diet du

Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function.

BackgroundRecent clinical trial data indicate that the use of angiotensin converting enzyme (ACE) inhibitors among patients with left ventricular dysfunction results in reduced rates of coronary thrombosis, a provocative finding that suggests a potential interaction between the renin-angiotensin system and fibrinolytic function Methods and ResultsIn four normotensive subjects and six hypertensive patients, we investigated whether infusion of angiotensin II (Ang II) affected circulating levels of plasminogen activator inhibitor-i (PAI-1), the most important physiological inhibitor of tissue-type plasminogen activator (t-PA). Overall, mean levels of PAI-1 antigen increased significantly from 20.1 ng/mL before Ang H infusion to 36.0 ng/mL at the end of Ang II infusion (p=0.008), whereas no change in PAI-1 was observed for control subjects infused with 5% dextrose (p=0.46). Among the normotensive subjects for whom graded doses of Ang II were infused at 0, 1, 3, and 10 ng · kg-1 · min-1, mean PAI-1 levels increased sequentially from 14.7 ng/mL to 23.0, 26.8, and 33.5 ng/mL, a dose-response relation that, compared with controls, was highly significant (p<0.001). Among the hypertensive patients for whom a single 45-minute infusion of Ang II was given at a dose of 3 ng · kg-1 · min-1, PAI-1 levels increased from 23.7 to 37.7 ng/mL, whereas PAI-1 levels among control subjects infused with 5% dextrose decreased from 16.9 to 10.8 ng/mL (p=0.04). Finally, when compared with infusion of 5% dextrose solution, infusion of Ang II appeared to have little effect on circulating levels of t-PA antigen. ConclusionThese in vivo data suggest that infusion of Ang H results in a rapid increase in circulating levels of PAI-1, a finding that may help to explain clinical observations linking the renin-angiotensin system and thrombotic risk. (Circulation 1993;87:1969-1973)

The effect of dietary patterns on blood pressure control in hypertensive patients: results from the Dietary Approaches to Stop Hypertension (DASH) trial.

To determine the impact of dietary patterns on the control of hypertension we studied the subgroup of 133 participants with systolic blood pressure (BP) of 140 to 159 mm Hg and/or diastolic BP of 90 to 95 mm Hg enrolled in the Dietary Approaches to Stop Hypertension (DASH) study. Participants were fed a control diet for a 3-week period and were then randomized to receive for 8 weeks either the control diet; a diet rich in fruits and vegetables, but otherwise similar to control; or a combination diet rich in fruits, vegetables, and low-fat dairy products, including whole grains, fish, poultry, and nuts, and reduced in fats, red meats, sweets, and sugar-containing beverages. Sodium intake and body weight were held constant throughout the study. The combination diet significantly reduced systolic BP (-11.4 mm Hg, P < .001) and diastolic BP (-5.5 mm Hg, P < .001). The fruits-and-vegetables diet also significantly reduced systolic BP (-7.2 mm Hg, P < .001) and diastolic BP (-2.8 mm Hg, P = .013). The combination diet produced significantly greater BP effects (P < .05) than the fruits-and-vegetables diet. Blood pressure changes were evident within 2 weeks of starting the intervention feeding. After the 8-week intervention period, 70% of participants eating the combination diet had a normal BP (systolic BP < 140 and diastolic BP < 90 mm Hg) compared with 45% on the fruits-and-vegetables diet and 23% on the control diet. In patients with hypertension, the DASH combination diet effectively lowers BP and may be useful in achieving control of Stage 1 hypertension.

Four-year persistence patterns among patients initiating therapy with the angiotensin II receptor antagonist losartan versus other antihypertensive drug classes☆

BACKGROUND It has been reported that a statistically greater percentage of patients initially treated with losartan, an angiotensin II receptor antagonist (AIIA), stayed on therapy at 1 year compared with patients treated with antihypertensive drugs from other classes. OBJECTIVE The purpose of this study was to determine whether the stay-on-therapy (persistence) patterns observed in the previous analysis were maintained over a 4-year period. METHODS We investigated a subgroup of 15,175 hypertensive patients from an earlier studied cohort who were continuously eligible for benefits over a 4-year follow-up period. A linear regression model was developed to test the statistical significance of differences in the percentage of patients staying on therapy from 12 months to 48 months for the different antihypertensive classes. RESULTS From 12 to 48 months, there was a slow continuous decline in persistence that was similar across all classes of antihypertensive medications. A greater percentage of patients treated with an AIIA (losartan) stayed on therapy from 12 to 48 months compared with patients treated with angiotensin-converting enzyme inhibitors (67.4% vs 60.7% at 12 months, P < 0.01; 50.9% vs 46.5% at 48 months, P = 0.095), calcium antagonists (67.4% vs 54.1% at 12 months, P < 0.01; 50.9% vs 40.7% at 48 months, P < 0.03), beta-blockers (67.4% vs 45.6% at 12 months, P < 0.01; 50.9% vs 34.7% at 48 months, P < 0.03), or thiazide diuretics (67.4% vs 20.8% at 12 months, P < 0.01; 50.9% vs 16.4% at 48 months, P < 0.03). The percentage of patients staying on AIIA therapy from 12 months to 48 months was statistically greater (P < 0.001) than the percentage of patients staying on therapy with other antihypertensive drug classes. CONCLUSIONS This analysis supports the observation that initiation of antihylertensive therapy with an AIIA such as losartan results in a greater persistence rate over a 4-year period than does therapy with any other antihypertensive class. These findings may have important implications for blood pressure control, reduction of cardiovascular risks, and health care resource utilization.

Angiotensin II antagonists for hypertension: are there differences in efficacy?

We compared the antihypertensive efficacy of available drugs in the new angiotensin-II-antagonist (AIIA) class. The antihypertensive efficacy of losartan, valsartan, irbesartan, and candesartan was evaluated from randomized controlled trials (RCT) by performing a metaanalysis of 43 published RCT. These trials involved AIIA compared with placebo, other antihypertensive classes, and direct comparisons between AIIA. A weighted-average for diastolic and systolic blood pressure reduction with AIIA monotherapy, dose titration, and with addition of low-dose hydrochlorothiazide (HCTZ) were calculated. Weighted-average responder rates were also determined. The metaanalysis assessed a total of 11,281 patients. The absolute weighted-average reductions in diastolic (8.2 to 8.9 mm Hg) and systolic (10.4 to 11.8 mm Hg) blood pressure reductions (not placebo-corrected) for AIIA monotherapy were comparable for all AIIA. Responder rates for AIIA monotherapy were 48% to 55%. Dose titration resulted in slightly greater blood pressure reduction and an increase in responder rates to 53% to 63%. AIIA/hydrochlorothiazide combinations produced substantially greater reduction in systolic (16.1 to 20.6 mm Hg) and diastolic (9.9 to 13.6 mm Hg) blood pressure reductions than AIIA monotherapy and responder rates for AIIA/HCTZ combinations were 56% to 70%. This comprehensive analysis shows comparable antihypertensive efficacy within the AIIA class, a near-flat AIIA-dose response when titrating from starting to maximum recommended dose, and substantial potentiation of the antihypertensive effect with addition of HCTZ.

Aortic Diameter, Wall Stiffness, and Wave Reflection in Systolic Hypertension

Systolic hypertension is associated with increased pulse pressure (PP) and increased risk for adverse cardiovascular outcomes. However the pathogenesis of increased PP remains controversial. One hypothesis suggests that aortic dilatation, wall stiffening and increased pulse wave velocity result from elastin fragmentation, leading to a premature reflected pressure wave that contributes to elevated PP. An alternative hypothesis suggests that increased proximal aortic stiffness and reduced aortic diameter leads to mismatch between pressure and flow, giving rise to an increased forward pressure wave and increased PP. To evaluate these two hypotheses, we measured pulsatile hemodynamics and proximal aortic diameter directly using tonometry, ultrasound imaging, and Doppler in 167 individuals with systolic hypertension. Antihypertensive medications were withdrawn for at least 1 week before study. Patients with PP above the median (75 mm Hg) had lower aortic diameter (2.94±0.36 versus 3.13±0.28 cm, P<0.001) and higher aortic wall stiffness (elastance-wall stiffness product: 16.1±0.7 versus 15.7±0.7 ln[dyne/cm], P<0.001) with no difference in augmentation index (19.9±10.4 versus 17.5±10.0%, P=0.12). Aortic diameter and wall stiffness both increased with advancing age (P<0.001). However, an inverse relation between PP and aortic diameter remained significant (P<0.001) in models that adjusted for age, sex, height, and weight and then further adjusted for aortic wall stiffness, augmentation index, and mean arterial pressure. Among individuals with systolic hypertension, increased PP is primarily attributable to increased wall stiffness and reduced aortic diameter rather than premature wave reflection.

DASH (Dietary Approaches to Stop Hypertension) Diet Is Effective Treatment for Stage 1 Isolated Systolic Hypertension

Use of the DASH (Dietary Approaches to Stop Hypertension) diet, which is rich in fruits, vegetables, and low-fat dairy foods, significantly lowers blood pressure. Among the 459 participants in the DASH Trial, 72 had stage 1 isolated systolic hypertension (ISH) (systolic blood pressure, 140 to 159 mm Hg; diastolic blood pressure, <90 mm Hg). We examined the blood pressure response in these 72 participants to determine whether the DASH diet is an effective treatment for stage 1 ISH. After a 3-week run-in period on a typical American (control) diet, participants were randomly assigned for 8 weeks to 1 of 3 diets: a continuation of the control diet (n=25), a diet rich in fruits and vegetables (n=24), or the DASH diet (n=23). Sodium content was the same in the 3 diets, and caloric intake was adjusted during the trial to prevent weight change. Blood pressure was measured at baseline and at the end of the 8-week intervention period with standard sphygmomanometry. Use of the DASH diet significantly lowered systolic blood pressure compared with the control diet (−11.2 mm Hg; 95% confidence interval, −6.1 to −16.2 mm Hg;P <0.001) and the fruits/vegetables diet (−8.0 mm Hg; 95% confidence interval, −2.5 to −13.4 mm Hg;P <0.01). Overall, blood pressure in the DASH group fell from 146/85 to 134/82 mm Hg. Similar results were observed with 24-hour ambulatory blood pressure measurements. In the DASH diet group, 18 of 23 participants (78%) reduced their systolic blood pressure to <140 mm Hg, compared with 24% and 50% in the control and fruits/vegetables groups, respectively. Our results indicate that the DASH diet, which is rich in fruits, vegetables, and low-fat dairy foods, is effective as first-line therapy in stage 1 ISH.

Effect of Dietary Sodium Intake on Blood Lipids: Results From the DASH–Sodium Trial

Abstract—We evaluated the effect on serum lipids of sodium intake in 2 diets. Participants were randomly assigned to a typical American control diet or the Dietary Approaches to Stop Hypertension (DASH) diet, each prepared with 3 levels of sodium (targeted at 50, 100, and 150 mmol/d per 2100 kcal). The DASH diet is increased in fruits, vegetables, and low-fat dairy products and is reduced in saturated and total fat. Within assigned diet, participants ate each sodium level for 30 days. The order of sodium intake was random. Participants were 390 adults, age 22 years or older, with blood pressure of 120 to 159 mm Hg systolic and 80 to 95 mm Hg diastolic. Serum lipids were measured at baseline and at the end of each sodium period. Within each diet, sodium intake did not significantly affect serum total cholesterol, LDL cholesterol, HDL cholesterol, or triglycerides. On the control diet, the ratio of total cholesterol-to-HDL cholesterol increased by 2% from 4.53 on higher sodium to 4.63 on lower sodium intake (P =0.04). On the DASH diet, sodium intake did not affect this ratio. There was no dose-response of sodium intake on serum lipids or the cholesterol ratio in either diet. At each sodium level, total cholesterol, LDL cholesterol, and HDL cholesterol were lower on the DASH diet versus the typical American diet. There were no significant interactions between the effects of sodium and the DASH diet on serum lipids. In conclusion, changes in dietary sodium intake over the range of 50 to 150 mmol/d did not affect blood lipid concentrations.

Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients

NSAIDs are known to attenuate the effects of some antihypertensive medications. It is not known whether the new class of angiotensin II receptor antagonists is similarly affected. We conducted a multicenter study assessing the effect of indomethacin on the antihypertensive effects of losartan and captopril. After 4 weeks of placebo washout, hypertensive patients received 6 weeks of active antihypertensive therapy with either 50 mg losartan once daily (n=111) or 25 mg captopril twice daily for 1 week, which was increased to 50 mg twice daily for 5 weeks (n=105). This was followed by 1 week of concomitant therapy with indomethacin (75 mg daily). The primary outcome measure was the change in mean 24-hour ambulatory diastolic blood pressure after the addition of indomethacin. Both captopril and losartan significantly lowered ambulatory diastolic blood pressure (losartan −5.3 mm Hg, P <0.001; captopril −5.6 mm Hg, P <0.001) after 6 weeks of therapy. Indomethacin significantly attenuated the 24-hour ambulatory diastolic blood pressure for both losartan (2.2 mm Hg, P <0.05) and captopril (2.7 mm Hg, P <0.001) and also attenuated the effect of captopril on trough sitting diastolic blood pressure. Changes in daytime diastolic blood pressure (7:00 am to 11:00 pm) were similar to the 24-hour response in both groups. Nighttime diastolic blood pressure (11:01 pm to 6:59 am) was significantly attenuated in captopril-treated patients (2.0 mm Hg, P <0.05), but losartan was unaffected (0.4 mm Hg). Thus, concurrent treatment with indomethacin similarly attenuates the 24-hour antihypertensive response to losartan and captopril.