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Background: Thiazide-type diuretics are associated with an increased incidence of diabetes compared with other antihypertensive medications. In this study, we determined the long-term cardiovascular disease (CVD) consequences of incident diuretic-associated diabetes compared with the effects of incident diabetes associated with calcium channel blocker and angiotensin-converting enzyme inhibitor use.Methods and Results: A total of 22 418 participants from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with baseline diabetes, incident diabetes (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril), or no diabetes at 2 years of in-trial follow-up were followed for a mean total of 6.9 years (2.9 years in-trial and 4 additional years posttrial) through the use of national databases. The primary outcome was CVD mortality (death from coronary heart disease [CHD], stroke, heart failure, or other CVD). Among other outcomes were all-cause mortality, non-CVD mortality, and CHD (nonfatal myocardial infarction or fatal CHD). Participants on chlorthalidone with incident diabetes versus no diabetes had consistently lower, nonsignificant risk for CVD mortality (hazard ratio [HR], 1.04; 95% CI, 0.74-1.47), all-cause mortality (HR, 1.04; 95% CI, 0.82-1.30), and non-CVD mortality (HR, 1.05; 95% CI, 0.77-1.42) than participants on amlodipine or lisinopril with incident diabetes (HR range, 1.22-1.53). Participants with incident diabetes had elevated CHD risk compared with those with no diabetes (HR, 1.46; 95% CI, 1.09-1.96), but those on chlorthalidone had significantly lower risk than those on lisinopril (HR, 1.18 versus 2.57; P=0.04 for interaction).Conclusions: The findings suggest that thiazide-related incident diabetes has less adverse long-term CVD impact than incident diabetes that develops while on other antihypertensive medications. [ABSTRACT FROM AUTHOR]

A nested case-control study was undertaken involving men participating in the Multiple Risk Factor Intervention Trial (MRFIT). Serum samples from 712 men, stored for up to 20 years, were analyzed for homocyst(e)ine. Cases involved nonfatal myocardial infarctions (MIs), identified through the active phase of the study, which ended on February 28, 1982, and deaths due to coronary heart disease (CHD), monitored through 1990. The nonfatal MIs occurred within 7 years of sample collection, whereas the majority of CHD deaths occurred more than 11 years after sample collection. Mean homocyst(e)ine concentrations were in the expected range and did not differ significantly between case patients and control subjects: MI cases, 12.6 mumol/L; MI controls, 13.1 mumol/L; CHD death cases, 12.8 mumol/L; and CHD controls, 12.7 mumol/L. Odds ratios versus quartile 1 for CHD deaths and MIs combined were as follows: quartile 2, 1.03; quartile 3, 0.84; and quartile 4, 0.92. Thus, in this prospective study, no association of homocyst(e)ine concentration with heart disease was detected. Homocyst(e)ine levels were weakly associated with the acute-phase protein (C-reactive protein). These results are discussed with respect to the suggestion that homocyst(e)ine is an independent risk factor for heart disease.

The highlights of each generation of hypertension trials have been varied, but interrelated. The initial hypertension trials focused on middle-aged hypertensive individuals and later on the elderly, with emphasis on diastolic blood pressure and subsequently on systolic blood pressure. Past generations of trials elucidated whether and whom to treat. The current explosion of morbidity and mortality trials in hypertension largely seeks to learn what drugs should be used and to delineate what blood pressure goals should be targeted.

Background: Findings from numerous epidemiologic and clinical studies worldwide attest to a strong, graded, consistent relationship between blood pressure level and cardiovascular-renal diseases, subclinical and clinical, nonfatal and fatal., Objective: This review summarizes results from selected prospective observational studies, primarily from US populations, and from randomized clinical trials. Review Analyses from the Multiple Risk Factor Intervention Trial (MRFIT) subjects (middle-aged men) and the Framingham Heart Study (middle-aged and elderly men and women) clearly establish that systolic blood pressure is a more powerful predictor of cardiovascular events than diastolic pressure. Wherever the full range of blood pressure has been examined, for example for systolic pressure in the MRFIT subjects and for diastolic pressure in pooled data from nine epidemiologic studies, the associations for coronary heart disease and stroke are seen to extend over the whole range, including 'normotensive' levels. In MRFIT, this continuous relationship has also recently been shown for end-stage renal disease and both systolic and diastolic pressure. Data from Framingham document further associations with peripheral vascular disease, congestive heart failure, and both electrocardiographic and echocardiographic left ventricular hypertrophy. Several studies are row available demonstrating a relationship between hypertension and carotid wall intimal-medial thickness. Finally, the causal nature of the relationships with major cardiovascular events is supported by the results of 17 large-scale randomized trials of blood-pressure-lowering using primarily diuretic- and beta-blocker-based drug regimens., Conclusions: These trials have demonstrated highly significant reductions in fatal and nonfatal stroke and major coronary heart disease. There are few trial data, however, on health benefits from further reducing blood pressure among normotensive persons.

Background: Elevated blood pressure remains a widespread major impediment to health. Obesity and specific dietary factors such as high salt and alcohol intake and low potassium intake adversely affect blood pressure. It is a reasonable hypothesis that additional dietary constituents, particularly macronutrients, may also influence blood pressure., Methods and Results: Participants were 11,342 middle-aged men from the Multiple Risk Factor Intervention Trial (MRFIT). Data from repeat 24-hour dietary recalls (four to five per person) and blood pressure measurements at six annual visits were used to assess relationships, singly and in combination, of dietary macronutrients to blood pressure, adjusted for multiple possible confounders (demographic, dietary, and biomedical). Multiple linear regression was used to assess diet-blood pressure relations in two MRFIT treatment groups (special intervention and usual care), with adjustment for confounders, pooling of coefficients from the two groups (weighted by inverse of variance), and correction of coefficients for regression-dilution bias. In multivariate regression models, dietary cholesterol (milligrams per 1000 kilocalories), saturated fatty acids (percent of kilocalories), and starch (percent of kilocalories) were positively related to blood pressure; protein and the ratio of dietary polyunsaturated to saturated fatty acids were inversely related to blood pressure. These macronutrient-blood pressure findings were obtained in analyses that controlled for body mass, dietary sodium and ratio of sodium to potassium, and alcohol intake, each positively related to blood pressure, and intake of potassium and caffeine, both inversely related to blood pressure., Conclusions: These data support the concept that multiple dietary factors influence blood pressure; hence, broad improvements in nutrition can be important in preventing and controlling high-normal and high blood pressure.

Objective: To study the effects of moderate doses of fish oil on blood pressure and high-density lipoprotein (HDL)-cholesterol., Methods: The participants were 350 normotensive men and women aged 30-54 years who were enrolled from seven academic medical centers in phase I of the Trials of Hypertension Prevention. They were randomly assigned to receive placebo or 6 g purified fish oil once a day, which supplied 3 g n-3 polyunsaturated fatty acids for 6 months., Results: Baseline blood pressure was (mean +/- SD) 123 +/- 9/81 +/- 5 mmHg. The mean differences in the blood pressure changes between the fish oil and placebo groups were not statistically significant. There was no tendency for fish oil to reduce blood pressure more in subjects with baseline blood pressures in the upper versus the lower quartile (132/87 versus 114/75 mmHg), low habitual fish consumption (0.4 versus 2.9 times a week) or low baseline plasma levels of n-3 fatty acids. Fish oil increased HDL2-cholesterol significantly compared with the placebo group. Subgroup analysis showed this effect to be significant in the women but not in the men. Increases in serum phospholipid n-3 fatty acids were significantly correlated with increases in HDL2-cholesterol and decreases in systolic blood pressure., Conclusion: Moderate amounts of fish oil (6 g/day) are unlikely to lower blood pressure in normotensive persons, but may increase HDL2-cholesterol, particularly in women.

This review summarizes papers and reports published during the past year that contribute important knowledge or perspectives about prevention of elevated arterial blood pressure. Emphasis is on controlled intervention trials, particularly the large, multicenter Trials of Hypertension Prevention-Phase I, but all relevant randomized trials known to the author are included. Observational epidemiologic studies that are cross-sectional, eg, the INTERSALT study and the US Pitt County Study, or longitudinal, eg, the large Health Professionals Followup Study and the National Health and Nutrition Examination Survey (I) Epidemiologic Followup Study, are also discussed. The recent evidence, when viewed in the context of the previously accumulated literature, supports the recommendations of two recent expert reports to the effect that 1) much knowledge is available to help avoid the rise of blood pressure with age that is the hallmark of the epidemic of hypertension in industrialized societies, and 2) efforts should be particularly directed toward control of obesity, increased physical activity, reduced salt intake, and moderation of alcohol use.

Background: Echocardiography provides a noninvasive means of assessing left ventricular (LV) structure and evidence of LV wall remodeling in hypertensive persons. The relation of demographic, biological, and other factors with LV structure can be assessed., Methods and Results: LV structure was assessed by M-mode echocardiograms for 511 men and 333 women with mild hypertension (average blood pressure, 140/91 mm Hg). Measurements of LV wall thicknesses and internal dimensions were made, and estimates of LV mass indexes and other derivations of structure were calculated. LV hypertrophy criteria were based on previously reported echocardiographic population studies of normal subjects. These measures were compared by age, sex, race, body mass index, systolic blood pressure, antihypertensive drug use, physical activity, alcohol intake, cigarette smoking, and urinary sodium excretion. Despite virtual absence of ECG-determined LV hypertrophy, 13% of men and 20% of women had echocardiographically determined LV hypertrophy indexed by body surface area (g/m2), and 24% of men and 45% of women had LV hypertrophy indexed by height (g/m). Black participants had slightly higher mean levels of wall thickness than nonblack participants but similar LV mass. Systolic blood pressure and urinary sodium excretion were significantly and independently associated with LV mass index and LV hypertrophy using both g/m2 and g/m. Body mass index was significantly related to LV mass index and LV hypertrophy using g/m. Smoking was significantly associated with LV mass index, i.e., using continuous measurement but not using the dichotomy for LV hypertrophy., Conclusions: This study of a large population of men and women with mild primary hypertension, largely without ECG evidence of LV hypertrophy, showed a substantial percentage of participants with echocardiographically determined LV hypertrophy. LV mass indexes correlated positively with systolic blood pressure, body mass index, urinary sodium excretion, and smoking.

The pilot study of the Systolic Hypertension in the Elderly Program was a randomized, double-blind, placebo-controlled trial of drug therapy for isolated systolic hypertension. It followed 551 elderly participants with untreated blood pressures of greater than 160/less than 90 mm Hg for an average of 34 months. Mean age of the participants was 72 years; 63% were women, and 82% were white. Pretreatment blood pressures averaged 172/75 mm Hg. Participants were randomly assigned to treatment with chlorthalidone or placebo as Step I medication. Blood pressures at annual visits averaged 141/68 and 157/73 mm Hg for the drug-treated and placebo-treated groups, respectively, with 60% and 33% of the survivors on blinded medication having systolic blood pressures of less than 160 mm Hg at their last annual visit. All-cause mortality rates for the drug-treated and placebo-treated groups were 25.4 and 22.7 deaths per 1,000 participant-years of risk, and rates for definite "first stroke" were 8.3 and 12.8 per 1,000 years of risk. Differences between groups were significant for systolic and diastolic blood pressure but not for death or stroke rates. A full-scale study has begun to determine the effects of drug therapy for isolated systolic hypertension on stroke and mortality rates.

We compared pooled mortality and morbidity results from nine randomized trials of antihypertensive drug treatment (total n = 43,139), in which diastolic blood pressure (DBP) was reduced by a mean of 5.8 mmHg, with mortality and morbidity differences associated with the same DBP difference in two large prospective, observational studies [the follow-up study of the Multiple Risk Factor Intervention Trial (MRFIT) screenees and the Framingham Study]. These results indicate that the effect on stroke of BP reduction in the trials (-36%, 95% confidence interval +/- 10%) was about 80% of that estimated from the epidemiological studies, suggesting that the effects of long-term BP elevation on the cerebral vasculature are mostly reversible over 5-6 years of BP reduction. For coronary heart disease (CHD), the effect of BP reduction in the trials (-9 +/- 10%) was about 36% of that estimated from the epidemiological studies. This difference may reflect chronic processes involved in the pathophysiological association of BP with CHD; however, selective treatment of control patients at high risk of CHD and an adverse effect of diuretics on serum cholesterol may have influenced the effect of treatment in the trials.

Ten randomized clinical trials of beta-blocking drugs in secondary prevention of coronary heart disease are reviewed. The six trials of long-term treatment involving three drugs have completed recruitment; the results should be reported during the next few years. In addition to the possibility of confirming the positive results from other trials, the findings may provide further information on the timing of treatment initiation and the mechanism of benefit. Three of the four trials concerned with the efficacy of beta blockers in the early acute phase of myocardial infarction are still recruiting. Two of these (the Prehospital Myocardial Infarction Study and the International Study of Infarct Survival) are large trials aiming to determine the effect on mortality from all causes. The third (Multicenter Investigation of the Limitation of Infarct Size) has infarct size as the primary end point, as does the one trial with completed follow-up (Belfast), whose preliminary findings indicate no effect on threatened infarction.

Preservation of thirty-eight consecutive renal allograft donors was studied in a prospective, randomized protocol. Procurement was in-situ cooled, en-bloc nephrectomy accomplished by a single program. Nine pairs were deleted because of nonutilization of one kidney or change in mode of preservation. The remaining twenty nine pairs were implanted by twenty two institutions through usual organ sharing policies. Results showed that posttransplantation dialysis was required in 17% of machine-perfused and 63% of cold-stored allografts, which reached statistical significance (P less than 0.01). This increased number of dialyses in patients receiving the cold-stored kidneys offsets cost savings achieved through transporting cold stored allografts. This study shows machine-perfused renal allografts to be superior to paired, cold-stored allografts when analyzed with respect to early graft function.