Morbidity and mortality on combination versus monotherapy: a posthoc analysis of the Systolic Hypertension in Europe trial.

BACKGROUND: The current literature supports the immediate use of combinations of antihypertensive drugs in terms of ease of use and adherence, but the key issue whether combination therapy is more effective than monotherapy in the prevention of cardiovascular complications remains unproven. METHODS: We analysed the double-blind (median follow-up 2.0 years) and open follow-up (6.0 years) phases of the Systolic Hypertension in Europe trial. Patients were 60 years or more with an entry systolic/diastolic blood pressure (BP) of 160-219/less than 95 mmHg. Antihypertensive treatment started immediately after randomization in the active-treatment group, but only after completion of the double-blind trial in control patients. Treatment consisted of nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day). We adjusted our analyses for sex, age, history of cardiovascular complications, baseline systolic BP and previous antihypertensive treatment. RESULTS: During the double-blind trial, adding enalapril to nitrendipine (n = 515), compared with the equivalent combination of placebos (n = 559), decreased systolic BP by a further 9.5 mmHg and reduced all cardiovascular events by 51% (P = 0.0035) and heart failure by 66% (P = 0.032), with similar trends for stroke (-51%; P = 0.066) and cardiac events (-44%; P = 0.075). Over the whole duration of follow-up, combination therapy (n = 871), compared with nitrendipine monotherapy (n = 1552), decreased systolic BP by 3.1 mmHg and reduced total mortality (-32%; P = 0.023), with similar trends for all cardiovascular events (-23%; P = 0.081) and stroke (-42%; P = 0.054). CONCLUSION: Despite the limitations of a posthoc analysis, but congruent with the stronger BP reduction, our results suggest that combination therapy with nitrendipine plus enalapril might improve outcome over and beyond the benefits seen with nitrendipine monotherapy.

Inhibition of superoxide dismutase induces collagen production in cardiac fibroblasts.

BACKGROUND: The aim of this study was to determine whether inhibition of superoxide dismutase (SOD) with diethyldithiocarbamic acid (DETC) could affect the collagen production, the mRNA and protein expression of collagen types I and III, and fibronectin in control and angiotensin II (ANG II)-treated cardiac fibroblasts. Its effect was compared with the SOD mimetics tempol and EUK-8 and with polyethyleneglycol (PEG)-SOD. METHODS: Cardiac fibroblasts were cultured to confluence, incubated in serum-free Dulbecco's modified Eagle's medium for 24 h, preincubated with(out) the tested inhibitors for 1 h and further incubated with(out) ANG II (1 micromol/l) for 24 h. RESULTS: DETC dose-dependently inhibited the activity of CuZn-SOD in cardiac fibroblasts. Superoxide anion production was increased by DETC and decreased by tempol in control and ANG II-treated fibroblasts. DETC also reduced the intracellular generation of reactive oxygen species (ROS) (such as H2O2, hydroxyl radicals, hydroperoxides) in control and ANG II-treated fibroblasts, whereas tempol reduced the ROS production only in ANG II-treated fibroblasts. ANG II and DETC stimulated the collagen production and the collagen I and fibronectin content in fibroblasts. The SOD mimetics tempol and EUK-8 as well as PEG-SOD reduced the collagen production. ANG II and DETC stimulated the tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 levels, whereas tempol decreased the TIMP-2 content in control and ANG II-treated fibroblasts. Matrix metalloproteinase (MMP)-1 level was reduced by ANG II and DETC and increased by tempol. CONCLUSION: These data suggest a vital role of SOD and the formed ROS in the accumulation of collagen in cardiac fibroblasts.

Blood pressure and blood selenium: a cross-sectional and longitudinal population study.

AIMS: Western Europeans have low blood levels of selenium (BSe), an antioxidant trace element. In a Flemish population, we investigated the cross-sectional and longitudinal association of blood pressure (BP) with BSe. METHODS AND RESULTS: We randomly recruited 710 subjects (mean age 48.8 years; 51.8% women). We measured BP and BSe and kept participants in follow-up for BP. At baseline, systolic/diastolic BP averaged (SD) 130/77 (17.3/9.2) mmHg. BSe was 97.0 (19.0) microg/L. Of 385 participants with normal baseline BP (<130 and <85 mmHg), over 5.2 years (range 3.4-8.4 years), 139 developed high-normal BP (130-139/85-90 mmHg) or hypertension (>or=140/90 mmHg). In multivariate-adjusted cross-sectional analyses of men, a 20 microg/L ( approximately 1 SD) higher BSe was associated with lower BP with effect sizes of 2.2 mmHg systolic (95% CI -0.57 to -5.05; P = 0.009) and 1.5 mmHg diastolic (95% CI -0.56 to -2.44; P = 0.017). In prospective analyses of men, a 20 microg/L higher baseline BSe was associated with a 37% (95% CI -52 to -17; P = 0.001) lower risk of developing high-normal BP or hypertension. None of these associations was significant in women. CONCLUSION: Deficiency of selenium might be an underestimated risk factor for the development of high BP in European men.

Prognostic significance of electrocardiographic voltages and their serial changes in elderly with systolic hypertension.

The aim of the present study was to assess the prognostic value of ECG voltages at baseline and their serial changes during follow-up in a large prospective study with standardized follow-up and strictly defined end points. Patients who were 60 years old or older, with systolic blood pressure of 160 to 219 mm Hg and diastolic pressure <95 mm Hg, were randomized into the double-blind placebo-controlled Systolic Hypertension in Europe trial. Active treatment consisted of nitrendipine, which could be combined with or replaced by enalapril, hydrochlorothiazide, or both. At the end of the double-blind part of the trial (median follow-up, 2.0 years), follow-up was extended and all patients received active study drugs (median total follow-up, 6.1 years). Electrocardiography was performed at baseline and yearly thereafter. Electrocardiographic left ventricular mass was prospectively defined as the sum of 3 voltages (RaVL+SV1+RV5), which averaged 3.1+/-1.0 mV. The adjusted relative hazard rate, associated with a 1 mV higher sum at baseline, amounted to 1.10 and 1.15 for all-cause and cardiovascular mortality and to 1.21 and 1.18 for strokes and cardiac events, respectively (P< or =0.01 for all). A 1-mV decrease in electrocardiographic voltages during follow-up independently predicted a lower incidence of cardiac events (relative hazard rate: 0.86; P< or =0.05), but not of stroke or mortality. In conclusion, electrocardiographic voltages at baseline and their serial changes during follow-up predict subsequent events in older patients with systolic hypertension.

Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial.

BACKGROUND: To assess the impact of immediate versus delayed antihypertensive treatment on the outcome of older patients with isolated systolic hypertension, we extended the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial by an open-label follow-up study lasting 4 years. METHODS: The Syst-Eur trial included 4695 randomized patients with minimum age of 60 years and an untreated blood pressure of 160-219 mmHg systolic and below 95 mmHg diastolic. The double-blind trial ended after a median follow-up of 2.0 years (range 1-97 months). Of 4409 patients still alive, 3517 received open-label treatment consisting of nitrendipine (10-40 mg daily) with the possible addition of enalapril (5-20 mg daily), hydrochlorothiazide (12.5-25 mg daily), or both add-on drugs. Non-participants (n = 892) were also followed up. RESULTS: Median follow-up increased to 6.1 years. Systolic pressure decreased to below 150 mmHg (target level) in 2628 participants (75.0%). During the 4-year open-label follow-up, stroke and cardiovascular complications occurred at similar frequencies in patients formerly randomized to placebo and those continuing active treatment. These rates were similar to those previously observed in the active-treatment group during the double-blind trial. Considering the total follow-up of 4695 randomized patients, immediate compared with delayed antihypertensive treatment reduced the occurrence of stroke and cardiovascular complications by 28% (P = 0.01) and 15% (P = 0.03), respectively, with a similar tendency for total mortality (13%, P = 0.09). In 492 diabetic patients, the corresponding estimates of long-term benefit (P < 0.02) were 60, 51 and 38%, respectively. CONCLUSIONS: Antihypertensive treatment can achieve blood pressure control in most older patients with isolated systolic hypertension. Immediate compared with delayed treatment prevented 17 strokes or 25 major cardiovascular events per 1000 patients followed up for 6 years. These findings underscore the necessity of early treatment of isolated systolic hypertension.

American College of Sports Medicine position stand. Exercise and hypertension.

Hypertension (HTN), one of the most common medical disorders, is associated with an increased incidence of all-cause and cardiovascular disease (CVD) mortality. Lifestyle modifications are advocated for the prevention, treatment, and control of HTN, with exercise being an integral component. Exercise programs that primarily involve endurance activities prevent the development of HTN and lower blood pressure (BP) in adults with normal BP and those with HTN. The BP lowering effects of exercise are most pronounced in people with HTN who engage in endurance exercise with BP decreasing approximately 5-7 mm HG after an isolated exercise session (acute) or following exercise training (chronic). Moreover, BP is reduced for up to 22 h after an endurance exercise bout (e.g.postexercise hypotension), with greatest decreases among those with highest baseline BP. The proposed mechanisms for the BP lowering effects of exercise include neurohumoral, vascular, and structural adaptations. Decreases in catecholamines and total peripheral resistance, improved insulin sensitivity, and alterations in vasodilators and vasoconstrictors are some of the postulated explanations for the antihypertensive effects of exercise. Emerging data suggest genetic links to the BP reductions associated with acute and chronic exercise. Nonetheless, definitive conclusions regarding the mechanisms for the BP reductions following endurance exercise cannot be made at this time. Individuals with controlled HTN and no CVD or renal complications may participated in an exercise program or competitive athletics, but should be evaluated, treated and monitored closely. Preliminary peak or symptom-limited exercise testing may be warranted, especially for men over 45 and women over 55 yr planning a vigorous exercise program (i.e. > or = 60% VO2R, oxygen uptake reserve). In the interim, while formal evaluation and management are taking place, it is reasonable for the majority of patients to begin moderate intensity exercise (40-<60% VO2R) such as walking. When pharmacological therapy is indicated in physically active people it should be, ideally: a) lower BP at rest and during exertion; b) decrease total peripheral resistance; and, c) not adversely affect exercise capacity. For these reasons, angiotensin converting enzyme (ACE) inhibitors (or angiotensin II receptor blockers in case of ACE inhibitor intolerance) and calcium channel blockers are currently the drugs of choice for recreational exercisers and athletes who have HTN. Exercise remains a cornerstone therapy for the primary prevention, treatment, and control of HTN. The optimal training frequency, intensity, time, and type (FITT) need to be better defined to optimize the BP lowering capacities of exercise, particularly in children, women, older adults, and certain ethnic groups. based upon the current evidence, the following exercise prescription is recommended for those with high BP: Frequency: on most, preferably all, days of the week. Intensity: moderate-intensity (40-<60% VO2R). Time: > or = 30 min of continuous or accumulated physical activity per day. Type: primarily endurance physical activity supplemented by resistance exercise.

Are low dehydroepiandrosterone sulphate levels predictive for cardiovascular diseases? A review of prospective and retrospective studies.

STUDY OBJECTIVE: It has been suggested that low levels of dehydroepiandrosterone sulphate (DHEAS) are predictive for cardiovascular diseases in men. We aimed to review the available evidence from prospective cohort studies and retrospective case-control studies. METHODS: We extracted summary statistics from 4 case-control studies and 8 cohort studies, and calculated the pooled relative risk associated with a 2 micromol/l increase in DHEAS. MAIN RESULTS: The number of subjects included in each of the individual studies ranged from 94 to 2134, mean age from 48 to 83 years and mean DHEAS levels from 1.2 to 7.3 pmol/l. In men, coronary mortality was available as outcome in 3 cohort studies and 1 case-control study. Combining data from these 4 studies showed a 15% (95% CI: 4%-28%, p = 0.008) increase in fatal coronary heart disease associated with a 2 micromol/l decrease in DHEAS. However, statistical significance was lost when the retrospective study causing significant heterogeneity (p = 0.02) was excluded. Fatal and non-fatal coronary events were reported in 1 cohort study and 3 case-control studies. The average increase in fatal plus non-fatal coronary heart disease associated with a 2 micromol/l decrease in DHEAS amounted to 13% (2%-26%, p = 0.02). The available data did not allow drawing any conclusions on the prognostic value of DHEAS in women, nor on the relationship between DHEAS and total or cardiovascular mortality or stroke in men. CONCLUSIONS: The present findings suggest that, in men, low serum levels of DHEAS may be associated with coronary heart disease. However, whether DHEA supplementation has any cardiovascular benefit is not clear. Data from prospective randomised trials are needed.

The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study.

BACKGROUND: After the double-blind, placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial ended in February 1997, randomized patients were offered active study medication for a further period of observation. OBJECTIVE: To refine the estimates of the long-term effects of antihypertensive therapy on the incidence of dementia. METHODS: Eligible patients had no dementia and were at least 60 years old. Their systolic blood pressure at entry was 160 to 219 mm Hg, with diastolic blood pressure below 95 mm Hg. Antihypertensive therapy was started immediately after randomization in the active treatment group, but only after termination of the double-blind trial in the control patients. Treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d), hydrochlorothiazide (12.5-25 mg/d), or both add-on drugs. RESULTS: Median follow-up increased from 2.0 years in the double-blind trial to 3.9 years overall. The incidence of dementia doubled from 32 to 64 cases, 41 of whom had Alzheimer disease. Throughout follow-up, systolic/diastolic blood pressure was 7.0/3.2 mm Hg higher in the 1417 control patients than in the 1485 subjects randomized to active treatment. At the last examination, the blood pressure difference was still 4.2/2.9 mm Hg; 48.1%, 26.4%, and 11.4% of the control patients were taking nitrendipine, enalapril, and/or hydrochlorothiazide, whereas in the active treatment group these proportions were 70.2%, 35.4%, and 18.4%, respectively. Compared with the controls, long-term antihypertensive therapy reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1000 patient-years (43 vs 21 cases, P<.001). After adjustment for sex, age, education, and entry blood pressure, the relative hazard rate associated with the use of nitrendipine was 0.38 (95% confidence interval, 0.23-0.64; P<.001). Treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% confidence interval, 7-33). CONCLUSION: The extended follow-up of Syst-Eur patients reinforces the evidence that blood pressure-lowering therapy initiated with a long-acting dihydropyridine protects against dementia in older patients with systolic hypertension.