Coronary heart disease morbidity and mortality in hypercholesterolemic men predicted from an exercise test: the Lipid Research Clinics Coronary Primary Prevention Trial.

A positive exercise electrocardiogram (ECG) has been proved to predict cardiovascular events in asymptomatic normolipidemic men. To study whether it is also predictive for hypercholesterolemic men, data from 3,806 asymptomatic hypercholesterolemic men in the Lipid Research Clinics Coronary Primary Prevention Trial were analyzed. All the men had performed a submaximal treadmill exercise test at baseline, before they were assigned to the cholestyramine or placebo treatment group. Because of missing or inconclusive data, 31 men were excluded from the analyses. A test was positive if the ST segment was displaced by greater than or equal to 1 mm (visual code) or there was greater than or equal to 10 microV-s change in the ST integral (computer code), or both. The prevalence of a positive test was 8.3%. During the 7 to 10 year (mean 7.4) follow-up period, the mortality rate from coronary heart disease was 6.7% (21 of 315) in men with a positive test and 1.3% (46 of 3,460) in men with a negative test (placebo and cholestyramine groups combined). The age-adjusted rate ratio for a positive test, compared with a negative test, was 6.7 in the placebo group and 4.8 in the cholestyramine group. With use of Cox's proportional hazards models, it was found that the risk of death from coronary heart disease associated with a positive test was 5.7 times higher in the placebo group and 4.9 times higher in the cholestyramine group after adjustment for age, smoking history, systolic blood pressure, high density lipoprotein cholesterol and low density lipoprotein cholesterol. A positive test was not significantly associated with nonfatal myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Sensitivity of exercise electrocardiography for acute cardiac events during moderate and strenuous physical activity. The Lipid Research Clinics Coronary Primary Prevention Trial.

We determined whether the exercise electrocardiogram predicted acute cardiac events during moderate or strenuous physical activity among 3617 asymptomatic, hypercholesterolemic men (age range, 35 to 59 years) who were followed up in the Coronary Primary Prevention Trial. Submaximal exercise test results were obtained at entry and at annual follow-up visits in years 2 through 7. ST-segment depression or elevation (greater than or equal to 1 mm or 10 microV-sec) was considered to be a positive test result. The circumstances that surrounded each nonfatal myocardial infarction and coronary heart disease death were determined through a record review. The cumulative incidence of activity-related acute cardiac events was 2% during a mean follow-up period of 7.4 years. The risk was increased 2.6-fold in the presence of clinically silent, exercise-induced, ST-segment changes at entry (95% confidence interval [Cl], 1.3 to 5.2) after adjustment for 11 other potential risk factors. Of 62 men who experienced an activity-related event, 11 had a positive test result at entry (sensitivity, 18%; 95% Cl, 8 to 27). The specificity of the entry exercise test was 92% (95% Cl, 91 to 93). The sensitivity and specificity were similar when the length of follow-up was restricted to 1 year after testing. For a newly positive test result on a follow-up visit, the sensitivity was 24% (95% Cl, 12 to 36), and the specificity was 85% (95% Cl, 84 to 86); for any positive test result during the study (mean number of tests per subject, 6.2), the sensitivity was 37% (95% Cl, 25 to 49), and the specificity was 79% (95% Cl, 77 to 80). Our findings suggested that the presence of clinically silent, exercise-induced, ischemic ST-segment changes on a submaximal test was associated with an increased risk of activity-related acute cardiac events. However, this test was not sensitive when used to predict the occurrence of activity-related events among asymptomatic, hypercholesterolemic men. For this reason, the utility of the submaximal exercise test to assess the safety of physical activity among asymptomatic men at risk of coronary heart disease is likely to be limited.

Effects of beta-blockade and exercise on cardiovascular and cognitive functioning.

Twenty-four men with mild essential hypertension were assigned randomly to receive propranolol (n = 9), atenolol (n = 7), or a placebo (n = 8). All subjects participated in a 12-week study and provided physiological and behavioral data four times during the study: after a medication-free baseline period (Session 1); after 2 weeks of medication, without exercise (Session 2); after 8 weeks of continued medication while participating in a program of aerobic exercise (Session 3); and after 2 weeks of maintenance exercise without medication (Session 4). Subjects' maximal oxygen uptake increased significantly between Sessions 2 and 3, and the magnitude of this increase did not vary across the drug groups. Subjects' resting heart rates varied as a function of the presence of beta-blocking medication, but there was in addition a reduction attributable to exercise training that did not vary across the drug groups. The decrease in blood pressure associated with beta-blockade (Session 2) was not decreased any further by exercise training (Session 3). Despite an increase in blood pressure following the withdrawal of active medication (Session 4), blood pressure remained significantly lower compared with the Session 1 baseline level. Performance in a reaction-time test of short-term memory functioning improved slightly for all three groups between Sessions 1 and 2 and remained constant thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)

Quality of life among hypertensive patients with a diuretic background who are taking atenolol and enalapril.

The cardioselective beta-blocker atenolol and the angiotensin-converting enzyme inhibitor enalapril were compared for efficacy, safety, and quality-of-life factors in 30 patients with hypertension whose hypertension was inadequately controlled with diuretic alone. Atenolol (50 to 100 mg once a day) and enalapril (2.5 to 40 mg once a day), combined with hydrochlorothiazide (25 mg once a day), had similar levels of efficacy and safety. A comprehensive battery of psychologic assessments for quality of life was administered, including measures of anxiety, depression, psychiatric symptoms, memory, and psychomotor function. These five conceptually based clusters were first analyzed by multivariate analysis of variance procedures, followed by univariate analyses of the individual variables composing each domain. In general, neither atenolol nor enalapril was associated with major changes in psychologic functioning. The only data cluster with a statistically significant change was memory function, primarily as a result of lower scores of the digit span (backward) test, for atenolol relative to enalapril. These preliminary findings suggest that atenolol and enalapril have comparable degrees of efficacy and safety, with no major disparities in quality-of-life effects, for hypertensive patients with a history of taking diuretics and this sort of quality-of-life assessment can be performed during trials of antihypertensive drugs.

Short-term behavioral effects of beta-adrenergic medications in men with mild hypertension.

beta-Adrenergic-inhibiting drugs are widely prescribed for the treatment of hypertension. These drugs have previously been found to influence a variety of psychologic and behavioral functions and have, in some cases, been associated with serious psychiatric side effects. The present study examined psychologic changes associated with beta-blockade therapy. Twenty-six men with mild hypertension (diastolic blood pressure 90 to 110 mm Hg) were randomly assigned to receive either a selective beta 1-antagonist (atenolol), a nonselective beta 1- and beta 2-antagonist (propranolol), or a placebo. Both before and after a 2-week period of drug administration, subjects completed a comprehensive assessment of quality of life including measures of mood, memory performance, and side effects. In general, beta-blocker therapy was associated with relatively few adverse symptoms, particularly when compared with control subjects taking placebo. Reductions in negative emotional states (tension and anger) were observed for subjects receiving atenolol, and the largest improvements in memory performance were observed for subjects receiving propranolol. These results suggest that beta-blocker therapy is not invariably associated with negative side effects and that some behavioral functions may actually be improved.

Interval cancers and cancers in non-attenders in the Ostergötland Mammographic Screening Programme. Duration between screening and diagnosis, S-phase fraction and distant recurrence.

The study was based on a population mammographic screening programme for women aged 40-74 years. Metastatic potential was analysed in 843 invasive breast cancers with regard to mode of detection and a number of prognostic factors. There was a higher metastatic capacity in clinically detected cases, but multivariate analyses showed that neither the mode of detection (hazard rate ratio of distant recurrence RR = 1.39, 95% CI 0.78-2.46 interval cancers and RR = 1.6, 95% CI 0.76-3.36 non-attenders) nor the duration between screening and diagnosis for true interval cancers (RR = 0.47, 95% CI 0.16-1.35 in tumours detected later than one year after screening) were independent prognostic factors. A correlation was found between metastatic potential and the SPF (RR = 2.94, 95% CI 1.57-5.50 in tumours with a high SPF), the oestrogen receptor status and the tumour stage. In conclusion, interval cancers intrinsically are not different from other breast cancers with equivalent characteristics; the duration between screening and diagnosis in interval cancers was not clearly correlated to the prognosis, but the S-phase fraction was a powerful predictor of prognosis.

Reduction of exercise-induced ST segment depressions following long-term serum lipid lowering by drugs in hyperlipoproteinaemia.

The effect of serum lipid-lowering drug treatment for a mean time of more than 5 years on the development of ischaemic ECG response to exercise has been studied in 34 asymptomatic subjects with hyperlipoproteinaemia. Seventy percent of the subjects had ischaemic exercise response at a first test. After treatment 10 subjects had improved and 9 deteriorated. Improvement of the ischaemic response was related to a decrease in low density lipoprotein (LDL) cholesterol as the only parameter significantly differing from those who developed a more marked ischaemia. For confirmation, controlled study of the influence of serum lipid lowering on the ischaemic exercise ECG response are necessary. The present finding indicates that marked lowering of LDL cholesterol might decrease the ischaemic response seen in hyperlipidaemia.

Blood pressure and heart rate response during exercise in men and women in the USA and Russia lipid research clinics prevalence study.

Examination of blood pressure (BP) and heart rate (HR) measurements at rest and during exercise in samples of USA and Russian middle-aged men and women show significant differences between countries for both genders. Russian men had higher resting systolic blood pressure (SBP) than USA men but lower SBP at both stages of exercise. Russian women had significantly higher resting SBP than USA women at rest and also during exercise. Russian men and women had significantly lower HR at rest and during exercise than USA men and women. Differences between countries were also noted for mean body weight, height, lipid levels, percentages of smokers and several other variables, and it was postulated that differences in these factors might be responsible in part for differences in SBP and HR during exercise. After adjustment for these variables, differences in SBP during exercise between USA and Russian men remained, but differences between USA and Russian women disappeared. For both genders, differences in HR during exercise remained after adjustment. Mortality analyses in USA and Russian men indicated that stage 2 SBP response during exercise was generally not a significant mortality risk factor after adjustment for age, BMI, TC, smoking and resting SBP. In a similar model, stage 2 HR response during exercise was also a non-significant risk factor in mortality.

Nifedipine in combination therapy for chronic hypertension. A review.

Results are presented from a study conducted in twelve male patients with hypertension who were treated during alternating one-month periods with a calcium channel blocker, a beta blocker, or a combination of both drugs. After one month of placebo therapy, the patients received 10 mg of nifedipine three times daily, 100 mg of metoprolol twice daily plus 10 mg of nifedipine three times daily, or 100 mg of metoprolol twice daily during successive periods. Nifedipine monotherapy resulted in a significant decrease in both systolic and diastolic blood pressures at rest and in systolic blood pressure during exercise. Monotherapy with metoprolol also significantly reduced systolic blood pressure during exercise. Combination therapy with the calcium channel blocker and the beta blocker produced a significantly greater decrease in both resting and exercise blood pressures than with either drug alone, with achievement of adequate blood pressure control in all patients.

Effects of cedilanid-D in combination with metoprolol on exercise tolerance and systolic time intervals in angina pectoris.

The interaction between cedilanid-D and metoprolol, a selective beta receptor blocking agent, on exercise tolerance and systolic intervals was studied in 15 patients with angina pectoris. The patients had been treated with metoprolol for several months in a dose of 50 mg, three times daily (one patient received 25 mg three times daily). Each patient participated in two studies separated by at least 1 week. After arriving at the laboratory each received 50 mg of metoprolol orally; thereafter, either cedilanid-D or placebo was infused intravenously in a double-blind study performed in randomized order. When the effect of the drugs was maximal, the systolic intervals and the heart volume were recorded at rest, and the exercise tolerance was tested with a bicycle ergometer. The mean maximal value of plasma concentrations of metoprolol assessed during the study was about 50 ng/ml but the variation among subjects was great (20 to 187 ng/ml). After administration of cedilanid-D there was a shortening of the pre-ejection period and left ventricular ejection time compared with results after placebo; the reduction was similar to that found after administration of cedilanid-D without beta blocking drugs. The total heart volume decreased by an average of 55 ml, but the individual variation was great. The patients' average work capacity, expressed as total work, was not altered by cedilanid-D when compared with results after placebo. No relation was found between initial heart size and the effect of cedilanid-D on capacity for physical work. It therefore appears that there is no indication for the routine use of digitalis during beta blocking therapy in patients with angina pectoris who do not have cardiac failure.

Effects of felodipine versus nifedipine on exercise tolerance in stable angina pectoris.

The effects of single doses of felodipine (5 and 10 mg) and nifedipine (10 and 20 mg) on chronic stable effort angina pectoris were assessed in a placebo-controlled, double-blind, crossover study of 24 patients receiving beta blockers and short-acting nitroglycerin. The effects were measured by repeated bicycle ergometer tests. The total work, and time until 1 mm of ST depression increased significantly by 9 to 31% after both active drugs at both dose levels in comparison with placebo. The differences were not significant between drugs or doses. At rest, blood pressure decreased (10 to 15%) and heart rate increased (5 to 10%) significantly after both active drugs. During exercise at the highest comparable work load, systolic blood pressure decreased significantly (23 to 26%), whereas heart rate was not affected after felodipine and nifedipine compared with placebo. The 2 drugs were well tolerated, and side effects were mild. Therefore, single doses of 5 and 10 mg of felodipine, and 10 and 20 mg of nifedipine have similar antianginal and anti-ischemic properties. However, felodipine has a longer duration of action, which may improve compliance.

A comparison of amplitude-modulated and frequency-modulated ambulatory monitoring systems.

To compare the results of monitoring for ischemia with amplitude-modulated (AM) and frequency-modulated (FM) ambulatory recorders, 22 patients with coronary artery disease were monitored during exercise and during 24 to 48 hours of daily activities. Simultaneous recordings were obtained with Oxford Medilog 4000-II and Medilog MR-35 systems from the same 2 bipolar leads. Each potential ischemic episode was interpreted blindly by 2 investigators. Significant ST depression was strictly defined as greater than or equal to 1 mm of horizontal or down-sloping ST depression persisting for 0.06 second beyond the J point and lasting greater than or equal to 1 minute. Of 82 episodes reviewed, 63 (77%) were either positive (37) or negative (26) for ischemia by both systems. However, 17 episodes were interpreted as positive on AM tracings but negative on FM tracings; the converse was true for only 2 episodes (p less than 0.01). For episodes read as positive with both systems, there were close correlations between recorders for duration (r = 0.80) and magnitude (r = 0.90) of ST depression. Because of the greater number of positive AM events, however, the mean total duration of ST depression for patients with ischemia during daily activities was greater on AM than on FM recordings (74 +/- 77 vs 39 +/- 42 minutes, p less than 0.10). Discrepancies between AM and FM tracings were invariably due to small differences in ST-segment morphology or in the magnitude of ST-segment depression. In summary, AM monitors generate complexes similar in appearance to those produced by FM devices in most instances.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical characteristics of patients in studies of left ventricular dysfunction (SOLVD).

The Studies of Left Ventricular Dysfunction (SOLVD) trials were designed to evaluate the effects of enalapril on long-term mortality in patients with severe left ventricular (LV) dysfunction. Patients with LV ejection fractions less than or equal to 0.35 and symptoms of congestive heart failure (CHF) were enrolled in the treatment trial, whereas those with no history of overt CHF and taking no treatment directed for LV dysfunction were enrolled in the prevention trial. The baseline clinical characteristics of SOLVD patients were compared to characterize differences between patients in these 2 separate but concurrent trials. From over 70,000 patients screened with LV dysfunction, 4,228 patients were enrolled in the prevention trial and 2,569 patients in the treatment trial. Ischemic heart disease was the primary cause of LV dysfunction in both prevention (83%) and treatment (71%) trial patients. Prior myocardial infarction was present in 80% of the prevention and 66% of the treatment trial patients (p less than 0.001). In the prevention trial, infarction was recent (less than or equal to 6 months) in 27% patients and remote (greater than 6 months) in 57% patients. Treatment trial patients had proportionately more women (20 vs 13%; p less than 0.001) and non-Caucasians (20 vs 14%; p less than 0.001), as well as the coexisting risk factors of hypertension (42 vs 37%; p less than 0.001) and diabetes (26 vs 15%; p less than 0.001) than did prevention trial patients. Clinical characteristics of patients in both trials were influenced by the gender and race of enrolled patients. Similarly, coronary artery bypass surgery was performed less often in women and non-Caucasians.(ABSTRACT TRUNCATED AT 250 WORDS)

Black-white differences in electrocardiographic left ventricular mass and its association with blood pressure (the ARIC study). Atherosclerosis Risk in Communities.

Black-white differences in the association between antihypertensive therapy, continuous measures of mean arterial and pulse pressures and left ventricular (LV) mass estimated from a multivariable electrocardiographic algorithm were examined in 6,020 men (23% black) and 7,970 women (29% black) participating in the Atherosclerosis Risk in Communities (ARIC) study. Mean arterial and pulse pressures, weight, the percentage of subjects taking antihypertensive medication, and LV mass were higher in black than in white men (98 vs 89 mm Hg, 47 vs 46 mm Hg, 188 vs 187 pounds, 30% vs 17%, and 243 vs 217 g, respectively). Results of similar direction but greater magnitude were observed in black versus white women (mean arterial pressure, 94 vs 85 mm Hg; pulse pressure, 50 vs 47 mm Hg; weight, 180 vs 153 pounds; percent treated, 42% vs 18%; and LV mass, 203 vs 169 g, respectively). In multivariable regression analyses, blacks had higher levels of LV mass, and LV mass increased more sharply with increasing mean arterial pressure in blacks than in whites after adjusting for age, pulse pressure, and weight. At equal mean arterial and pulse pressures, age, and weight, treated blacks had higher LV mass than treated whites. These data indicate that blacks have higher LV mass than whites, and a more pronounced blood pressure-LV mass relation after controlling for other risk factors and treatment status. Given the prognostic importance of LV hypertrophy,

Correlates of systolic and diastolic blood pressure in men 40 to 59 years of age sampled from United States of America and Union of Soviet Socialist Republics Lipid Research Clinics populations.

The correlates of blood pressure (BP) were investigated in 2 samples using common protocols, one from a Union of Soviet Socialist Republics study in 2 locations and one from a United States of America study in 9 locations. Age, heart rate, Quetelet index, high density lipoprotein cholesterol, natural logarithm of triglycerides and fasting glucose were positively related to systolic BP in both samples. In diastolic BP, alcohol consumption, heart rate, Quetelet index and natural logarithm of triglycerides were positively associated, and number of cigarettes smoked was negatively related in both samples.

Cyclic seasonal variation in plasma lipid and lipoprotein levels: the Lipid Research Clinics Coronary Primary Prevention Trial Placebo Group.

Seasonal plasma lipid and lipoprotein cycles were studied in 1446 hypercholesterolemic 35-59 year-old men followed for 7 years as the placebo group of the Lipid Research Clinics (LRC) Coronary Primary Prevention Trial (CPPT). Separate periodic time series were calculated for each study participant; mean parameter estimates were obtained by vector algebra. Highly significant (p less than 0.001) synchronous sinusoidal seasonal cycles, peaking in the first month of winter, were demonstrated for plasma levels of total (TOT-C), low-density lipoprotein (LDL-C), and high-density lipoprotein (HDL-C) cholesterol. Their mean seasonal changes (nadir to zenith) were 7.4, 6.4, and 0.8 mg/dl, respectively. An irregular but statistically significant seasonal pattern was also observed for plasma triglyceride (TG) levels, with peak levels in the autumn. The variation of these seasonal effects among subgroups and geographic locales and their correlation with seasonal weight and dietary patterns yielded few clues as to their underlying etiologic mechanisms.

Quality-adjusted meta-analysis of the hypertension/coronary dilemma.

Primary investigators of randomized drug trials in hypertension were invited to rate quality of such trials. The intention of the survey was to ask if antihypertensive drug therapy reduces incidence of coronary heart disease (CHD) in hypertensive patients. Response was obtained for 7 of the 11 invited investigators, covering 69% of patients and 75% of CHD cases. Principal component analysis was used to construct a quality score based on answers to 12 questions along visual analog scales. The score correlated well with the answer to a global question of overall quality given by the raters. No systematic tendency toward favoring one's own trial could be demonstrated, therefore, all raters have contributed to the rating. The trials with the highest rated quality to answer the research question were Systolic Hypertension in the Elderly Program (SHEP), Australian National Blood Pressure Study, Medical Research Council, Veterans Administration, and European Working Party of Hypertension in the Elderly. The large Heart Detection and Follow-up Program (HDFP) trial was rated at 11th place among the trials with a score of < 40% of the SHEP. The small trials performed in the 1960s were placed at the bottom of the ranking list. Because SHEP is the only trial without diastolic hypertension, results were given with and without SHEP results. When incorporating the quality score into a meta-analysis of CHD outcome, results were dependent on whether SHEP was included or not. For diastolic hypertension only, the effect of therapy was estimated to be about 8% for all higher quality studies, whereas inclusion of the lower quality HDFP changed it to 14%. When isolated systolic hypertension trial was pooled with the others, no major relation to quality rating was observed. A 14% CHD preventive efficacy was established when pooling the three top quality studies. This stayed unchanged until HDFP at rank 11 was included raising this estimate to 16%. Inclusion of the two latest published trials in the elderly, the Medical Research Council trial of treatment of hypertension in older adults and the Swedish Trial in Old Patients with hypertension, did not change this overall estimate of 16% (standard error = 3.8%). It is concluded that if all randomized drug trials in hypertension had the same treatment efficacy, the estimated CHD prevention would be in the range of 15%. Subgroup analyses revealed no relationship to age, but a difference in efficacy was shown depending on whether the trials were performed in the United States or elsewhere. Also, patients at higher risk levels showed better benefit than lower risk patients.

Memory performance by mild hypertensives following beta-adrenergic blockade.

Previous experiments have reported deficits in cognitive performance following the administration of beta-adrenoceptor antagonists. These deficits have not appeared consistently, however, and it is not clear from previous studies whether changes in the central nervous system, rather than end-organ functioning, are responsible. The present experiment investigated the effects of beta blockade in a memory-search paradigm that distinguished the relatively central process of memory comparison from the more peripheral processes of stimulus encoding and response selection. Twenty-six adult men with mild essential hypertension received either a placebo or a beta blocker (atenolol or propranolol) for 2 weeks. Although beta blockade did occur in the active drug groups, there were no significant effects of the drugs on memory-search performance.

Effect of glucocorticoids on fetal immunoglobulin production after premature rupture of membranes.

Cord blood IgA and IgM levels were measured in newborns of mothers with prematurely ruptured membranes (PRM) who had also received prenatal glucocorticoid treatment to accelerate fetal lung maturity. Previous data show that some newborns of mothers with PRM had elevated IgA and/or IgM levels. This increase was also found in the present glucocorticoid-treated group, indicating that glucocorticoid therapy did not appear to alter fetal humoral immune response at all.

Fetal immunoglobulin production following prenatal glucocorticoid treatment.

In order to accelerate fetal lung maturation 46 pregnant women were given either dexamethasone or betamethasone intramuscularly during 3 consecutive days during 29--36 weeks of gestation. At birth, the infants appeared to have intact humoral immune function in that they could produce normal amounts of immunoglobulins in utero, and 2 fetuses responded with increased synthesis of IgA or IgM following premature rupture of the membranes. The clinical course did not show any increased incidence of puerperal or neonatal illness attributable to intrauterine infection.