In a double-blind randomized trial involving five Sydney hospitals and the city ambulance paramedical service, 145 patients with a first evolving myocardial infarction and with onset of pain less than 2.5 (mean 1.9 +/- 0.5 [SD]) hr previously were allocated to intravenous infusion of 100 mg recombinant tissue-type plasminogen activator (rt-PA) or placebo over 3 hr. The groups at entry were similar. At assessment 21 days later, left ventricular ejection fraction measured both by contrast and radionuclide ventriculography was higher in the rt-PA compared with the placebo group (61 +/- 13%, n = 64, vs 54 +/- 14%, n = 62, contrast, 2p = .006; 52 +/- 13%, n = 66, vs 48 +/- 13%, n = 62 isotope, 2p = .08). This indicates limitation of myocardial infarction by rt-PA.

The effects of antiarrhythmic drugs on electrograms have implications for arrhythmia-detection algorithms in implantable antitachycardia devices. Filtered and unfiltered intra-atrial electrograms were analyzed in eight patients who received procainamide (50 mg/min iv, up to 1000 mg) during 11 episodes of atrial fibrillation. Continuous recordings were made before, during, and after the infusion. The recordings were digitized, divided into 4.27 sec segments, and analyzed for atrial rate, median frequency and amplitude probability density function. Significant differences were noted before and after infusion of procainamide for atrial rate (498 +/- 97 vs 356 +/- 146 beats/min; p less than .005), median frequency (5.50 +/- 1.22 vs 4.24 +/- 0.99 Hz; p less than .0005), and density (58.3 +/- 13.9% vs 69.1 +/- 15.0%; p less than .005). Pre- and postprocainamide values were compared with published criteria for detection of atrial fibrillation. Before procainamide, only 2.3%, 5.7%, and 3.4% of the data segments failed to meet criteria for atrial fibrillation by rate, frequency content, and density, respectively. In contrast, after procainamide, 50%, 36.4%, and 28.4% of the data segments failed to meet these same criteria, despite electrograms still meeting morphologic criteria for atrial fibrillation. Thus procainamide resulted in changes sufficient to cause failure of published criteria for detection of atrial fibrillation. These findings have broad implications for the function of antitachycardia devices in patients receiving antiarrhythmic drug therapy.

To determine whether tissue-type plasminogen activator (t-PA) and urokinase (UK) act synergistically to achieve coronary thrombolysis, incremental doses of both drugs were infused intravenously over 60 min. In 146 consecutive patients treated 3.0 +/- 1.0 hr from symptom onset, coronary angiography was performed 90 min after the start of the infusion and at 7 days. The groups of patients treated by different dose regimen were as follows: group I, 14 patients treated with t-PA 25 mg and UK 0.5 million U; group II, 20 patients given t-PA 25 mg and UK 1.0 million U; group III, 24 patients given t-PA 1.0 mg/kg and UK 0.5 million U; group IV, 33 patients treated with t-PA 1.0 mg/kg and UK 1.0 million U; and group V, 55 patients given t-PA 1.0 mg/kg and UK 2.0 million U. In groups I and II, patency of the infarct-related vessel at 90 min was only 36% and 42%, respectively. With 1 mg/kg t-PA and increasing doses of UK (groups III to V), patency ranged from 72% to 75% (overall 73%). Repeat catheterization at 7 days demonstrated reocclusion in groups III to V in 10 of 110 (9%). The patency and reocclusion rates in groups III to V were not significantly different from those in our previous study of 386 patients treated with t-PA alone (150 mg over 6 to 8 hr). In that study the patency rate of the infarct-related vessel at 90 min was 75% (p = .66) and reocclusion occurred in 15% (p = .11).(ABSTRACT TRUNCATED AT 250 WORDS)

To examine the outcome of patients with persistent coronary artery occlusion despite treatment with intravenous tissue-type plasminogen activator (t-PA), the clinical course of 96 patients with persistent occlusion after 90 min of therapy was evaluated. All patients underwent cardiac catheterization 90 min after initiation of intravenous t-PA. Immediate coronary angioplasty (PTCA) was attempted when the infarct-related artery failed to reperfuse unless the vessel was technically unsuitable or the infarct was thought to be small. No baseline differences could be found between these 96 patients and 288 patients who achieved perfusion with the same protocol. Although patients with and without successful perfusion after t-PA had similar clinical courses before cardiac catheterization, those without perfusion had more complications (ventricular fibrillation, severe bradycardia, hypotension) during catheterization. PTCA achieved reperfusion with less than 50% residual stenosis in 73% of the 86 patients in whom it was attempted, while 16% were left with a high-grade (greater than 50%) residual stenosis and PTCA failed in 11%. Mortality was highest in the nine patients with complete PTCA failure (44%), compared with a 6% mortality in the 63 patients with an insignificant residual stenosis after PTCA and a 14% mortality in the 14 patients with reperfusion, but a greater than 50% residual stenosis after PTCA. In 10 patients with small infarcts (six), unsuitable anatomy (two), or "spontaneous" drug induced (but later) opening before contemplated PTCA (two), PTCA was not attempted and no mortality occurred. The in-hospital reocclusion rate after successful PTCA was 29%, despite the use of heparin and antiplatelet agents.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of the study was to examine whether the prolonged administration of the beta 1-adrenoceptor partial agonist xamoterol could improve left ventricular diastolic function and affect the global remodeling process of the left ventricle after anterior myocardial infarction. In 22 patients with anterior myocardial infarction and single-vessel disease, left ventricular angiography (+ Millar) was performed under basal conditions 1 to 2 months after the acute myocardial infarction. Eight patients were then treated for 3 months with placebo and 14 were treated with xamoterol (200 mg bid) and a second left ventricular angiographic study was performed. Angiograms were digitized frame by frame to derive the diastolic pressure-volume relationship and to compute wall stress. An index of elastic myocardial stiffness was computed at a constant stress of 30 kdynes/cm2 before and after treatment. To evaluate changes in left ventricular shape, segmental areas in anterior and inferior segments were computed and compared at end-diastole and end-systole. After xamoterol, left ventricular end-diastolic pressure and mean diastolic wall stress decreased (from 24 +/- 5 to 15 +/- 5 mm Hg and from 57 +/- 32 to 38 +/- 22 kdynes/cm2, respectively; both p less than .01 vs baseline and vs placebo). These changes were accompanied by a downward shift in the diastolic pressure-volume relationship and by a decrease in the index of myocardial stiffness from 526 +/- 270 to 371 +/- 194 kdynes/cm2 (p less than .02).(ABSTRACT TRUNCATED AT 250 WORDS)

It has been demonstrated in animal experiments that heparin accelerates the coronary collateral development induced by repeated coronary occlusion. We used this effect of heparin for the treatment of patients with stable effort angina. In 10 patients, treadmill exercise was performed according to standard Bruce protocol twice a day for 10 days. A single intravenous dose of heparin (5000 IU) was given 10 to 20 min before each exercise period. Exercise with heparin pretreatment increased the total exercise duration from 6.3 +/- 1.9 (SD) to 9.1 +/- 2.2 min (p less than .001) and the maximal double product (DP) from 18,900 +/- 5100 to 25,500 +/- 6800 mm Hg.beats/min (p less than .001). The DP at the onset of angina was also increased by 35% (p less than .01) and the DP at which ST depression (0.1 mV) first appeared was 19% (p less than .05) greater after treatment. Repeat coronary cineangiography revealed an increase in the extent of opacification of collaterals to the jeopardized myocardium. In an additional six patients, treadmill exercise was performed with no medication twice a day for 10 days. All of the above-mentioned variables of treadmill capacity remained unchanged, despite 20 exercise periods without heparin pretreatment. Thus, heparin accelerates exercise-induced coronary collateral development by promoting angiogenesis. The development of such a therapeutic modality will open a new field for the treatment of patients with ischemia.

From the Coronary Artery Surgery Study Registry, all patients undergoing initial bypass surgery procedures with independent vein grafts were identified. The 950 patients receiving an internal mammary artery bypass graft were compared with the 6027 patients receiving vein graft alone. Improved survival rates with internal mammary artery grafts were noted at hospitals in which these grafts were performed infrequently as well as those in which the internal mammary artery graft was used frequently. The improved survival was noted in patients with normal (p = .004) as well as impaired (p = .004) ventricular function, in men (p = .0001) as well as women (p = .005), in patients over age 65 (p = .01) as well as younger patients (p less than .0001), and in those with (p = .05) or without (p less than .0001) critical stenosis of the left main coronary artery. The internal mammary artery bypass graft was an independent predictor of survival (p = .0004) and reduced the risk of dying by a factor of 0.64. It was concluded that the internal mammary artery graft is the bypass vessel of choice and should not be denied any subgroup.

The efficacy and safety of oral nifedipine and diltiazem were compared in 20 patients with stable angina pectoris with use of a placebo run-in, randomized, double-blind titration to maximal effect crossover protocol. The effects of treatment withdrawal were also analyzed. All patients received placebo for 2 weeks and were then randomly assigned to receive either diltiazem or nifedipine. A 2 week drug titration phase in which patients received either diltiazem (180 to 360 mg/day) or nifedipine (30 to 120 mg/day) in three divided doses was followed by a 1 week maintenance phase. Patients then received placebo for 1 to 2 weeks, followed by crossover to the other treatment regimen and a second placebo washout period of 1 week. Patients (n = 13) who remained symptomatic on both diltiazem and nifedipine during the monotherapy periods entered a 3 week combination treatment phase, followed by a final 1 week placebo washout period. Frequency of angina, nitroglycerin consumption, exercise tolerance (Naughton protocol), and frequency of daily episodes of ST segment deviations on the electrocardiogram (1 mm of ST segment depression persisting for at least 1 min with and without chest pain) on an ambulatory electrocardiographic monitor were assessed during the baseline placebo, active monotherapy, placebo withdrawal, and combination treatment phases. Plasma drug levels were also measured. Compared with initial placebo values, the frequency of angina and the amount of nitroglycerin treatment were reduced by both diltiazem (p less than .001) and nifedipine (p less than .02). Diltiazem was more effective than nifedipine in reducing angina (p less than .02). Exercise duration increased with both drugs (p less than .0001). Diltiazem was significantly better than nifedipine in reducing the episodes of ST segment depression on the ambulatory monitor (p less than .01). Diltiazem reduced the resting heart rate (p less than .01); both drugs reduced the resting blood pressure and rate-pressure product. Overall, combination therapy was more effective in patients who did not maximally respond to diltiazem or nifedipine alone with respect to anginal and exercise variables and in reducing blood pressure at rest and during exercise. Plasma drug levels could not predict an individual patient's treatment response. Diltiazem may increase nifedipine drug levels when the drugs are combined. Fewer side effects were observed with diltiazem than nifedipine; the most side effects were seen with combination treatment. There were no apparent withdrawal effects observed with either treatment regimen.(ABSTRACT TRUNCATED AT 400 WORDS)

A double-blind, cross-over study was designed to evaluate the effects of L-carnitine in patients with peripheral vascular disease. After drug washout, 20 patients were randomly assigned to receive placebo or L-carnitine (2 g bid, orally) for a period of 3 weeks and were then crossed over to the other treatment for an additional 3 weeks. The effect on walking distance at the end of each treatment period was measured by treadmill test. Absolute walking distance rose from 174 +/- 63 m with placebo to 306 +/- 122 m (p less than .01) with carnitine. Biopsy of the ischemic muscle, carried out before and after 15 days of L-carnitine administration in four additional patients, showed that treatment significantly increased total carnitine levels. An additional goal of this study was to ascertain the effects of L-carnitine on the metabolic changes induced by exercise in the affected limb. In six patients under control conditions, arterial and popliteal venous lactate and pyruvate concentrations were determined at rest, when the maximal walking distance was reached, and 5 min after the walking test. Twenty-four hours later, L-carnitine was administered intravenously (3 g as a bolus followed by an infusion of 2 mg/kg/min for 30 min) and metabolic assessments were repeated. Five minutes after the walking test, popliteal venous lactate concentration increased by 107 +/- 16% before treatment and by only 54 +/- 32% (p less than .01) after carnitine. Furthermore, carnitine induced a more rapid recovery to the resting value of the lactate/pyruvate ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

The vasodilator effects of nitroglycerin (NTG) are mediated via activation of guanylate cyclase; this process is believed to require the availability of free sulfhydryl groups. Previous studies in man have shown that the sulfhydryl donor N-acetylcysteine (NAC) potentiates the systemic and coronary vasodilator effects of NTG. Furthermore, interaction of NTG and NAC may lead to the formation of S-nitroso-NAC, which strongly inhibits platelet aggregation. The effects of intravenous NTG combined with intravenous NAC (5 g 6 hourly) were compared with those of intravenous NTG alone in a double-blind trial in 46 patients with severe unstable angina pectoris unresponsive to conventional treatment, which included calcium antagonists and cutaneous nitrates in all but one patient. Treatment with NTG/NAC (24 patients) and that with NTG alone (22 patients) was associated with a similar frequency of episodes of chest pain and of increments in NTG infusion rate for pain control (10 vs 17; p = NS). The NTG/NAC group had a significantly lower incidence of acute myocardial infarction than the NTG/placebo group (three vs 10 patients; p = .013). Symptomatic hypotension occurred frequently in the NTG/NAC group (seven vs 0 patients; p = .006). Lactate-pyruvate ratios and venous NTG concentrations were not significantly affected by NAC. Subsequently, another 20 consecutive patients were treated with intravenous NTG and continuously infused NAC (10 g/day). Seven remained pain free during the first 24 hr of NTG infusion; 11 required increments in NTG infusion rate for pain control. Acute myocardial infarction occurred in one patient, while none developed symptomatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

The large cohort of white men (317,871) 35 to 57 years old at initial screening for possible enrollment into the Multiple Risk Factor Intervention Trial (MRFIT) was examined with regard to initial blood pressure levels and subsequent coronary heart disease (CHD), stroke, and all-cause mortality. The overall prevalence of isolated systolic hypertension (ISH), defined as systolic blood pressure (SBP) greater than or equal to 160 mm Hg and diastolic blood pressure (DBP) less than 90 mm Hg, was 0.67% among white men screened for MRFIT and increased with age (0.31% among 35- to 39-year-olds to 1.7% among 55- to 57-year-olds). The 6 year CHD and all-cause mortality rates in men over 50 were highest in those with ISH compared with both subjects with diastolic hypertension and those with normal pressure. The relative risk of death from stroke in those with ISH, compared with that in those with SBP less than 160 mm Hg and those with DBP less than 90 mm Hg, was 3.0 (95% confidence interval 1.3 to 6.8). In addition, at any level of DBP, the level of SBP appeared to be the major determinant of all-cause and CHD mortality. The determinants of ISH in individuals under 60 years of age as well as the possible efficacy of its treatment should be evaluated further.

Three hundred sixty-eight patients were randomly assigned to receive intravenous streptokinase (IVSK) (n = 191) or standard therapy (n = 177) to determine the efficacy of IVSK in the treatment of acute myocardial infarction. The mean time to treatment was 3.5 hr. At 14 days there were 12 deaths in the treatment group (6.3%) and 17 deaths in the control group (9.6%) (p = .23). Early mortality was related to infarct location. Fourteen day mortality for anterior infarctions was 10.4% for treatment with IVSK and 22.4% for control patients (p = .06) and was similar for IVSK-treated patients with inferior infarctions, 4.0% vs 1.8% (p = .32). For those randomized under 3 hr, 14 day mortality tends to be lower in treated patients, 5.2% vs 11.5% (p = .11). There was significant improvement in long-term survival for patients with anterior infarction; 2 year survival was 81% for IVSK-treated patients and 65% for control patients (p = .05). There was no improvement in survival for patients with inferior myocardial infarction (p = .27). We conclude that patients with anterior myocardial infarction have improved survival when treated within the first 6 hr of symptoms. Patients with inferior infarction do not appear to have improved survival with thrombolytic therapy. Some of this improvement in survival in patients with anterior infarction may be due to a higher frequency of revascularization procedures in the treatment group.

Although encainide is an effective antiarrhythmic agent, plasma concentrations and pharmacologic effects are not well correlated. One explanation is the generation of active metabolites: while in most patients (extensive metabolizers; EMs) concentrations of the metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (3MODE) are higher than those of encainide, a small subset (poor metabolizers; PMs) lack the ability to extensively biotransform encainide. Considerable data from studies in vitro and animal studies, as well as indirect evidence in patients, indicate that ODE and 3MODE produce the effects seen during long-term encainide therapy in EMs. We now report the initial direct evaluation of the pharmacologic actions of these metabolites of encainide in man. Nine patients with ventricular arrhythmias, seven of the EM phenotype and two of the PM phenotype, were studied. Chronic high-frequency ventricular arrhythmias were suppressed by encainide therapy in seven of nine; monitoring arrhythmia frequency during withdrawal of encainide allowed definition of plasma concentrations of encainide and metabolites associated with arrhythmia suppression. Intravenous infusions of both ODE and 3MODE suppressed chronic ventricular arrhythmias, while infusions of placebo had no effect. ODE clearance was a function of metabolizer phenotype, with higher clearance (mean 914 ml/min; range 554 to 1,314) in EMs than in PMs (434, 298 ml/min); moreover, 3MODE was detected during ODE infusions in all seven EMs but in neither PM. 3MODE clearance was more uniform (mean 289 ml/min in EMs [range 180-410] vs 300 and 78 ml/min in the two PMs) and ODE was not detected in any subject during 3MODE infusion. Encainide itself was not detected after any infusion of ODE or 3MODE. During withdrawal of encainide therapy, ODE plasma concentration at the time of arrhythmia recurrence was 55 +/- 40 ng/ml (mean +/- SD), while ODE by infusion was effective at a concentration of 37 +/- 15 ng/ml. Similarly, plasma concentration of 3MODE at the time of arrhythmia recurrence after withdrawal of chronic encainide was 116 +/- 35 ng/ml and that during 3MODE infusion was 105 +/- 50 ng/ml. While both compounds prolonged QRS duration, ODE was the more potent, increasing QRS by 9.2 +/- 1.6% per 100 ng/ml vs 1.2 +/- 0.5% per 100 ng/ml for 3MODE. On the other hand, 3MODE prolonged the corrected JT interval by 1.9 +/- 0.6% per 100 ng/ml, while ODE shortened it by 2.7 +/- 1.9% per 100 ng/ml.(ABSTRACT TRUNCATED AT 400 WORDS)

Eight centers participated in a study in which intrapulmonary and intravenous administration of recombinant tissue-type plasminogen activator (rt-PA) were compared in 34 patients with acute massive pulmonary embolism. All patients received intravenous heparin in a bolus of 5,000 IU followed by 1,000 IU/hr. After 50 mg rt-PA given over 2 hr the severity of embolism, determined from pulmonary angiograms, declined by 12% in the intrapulmonary drug group (p less than .005) and 15% in the intravenous drug group (p less than .005); mean pulmonary arterial pressure fell from 31 +/- 7 to 22 +/- 6 mm Hg (p less than .005) and from 31 +/- 12 to 21 +/- 9 mm Hg (p less than .005) in the respective groups. After a further 50 mg given over 5 hr (22 patients), the angiographically determined severity of embolism had decreased by 38% from baseline in the intrapulmonary drug group and by 38% in the intravenous drug group. The mean pulmonary arterial pressure further declined to 18 +/- 7 and 12 +/- 5 mm Hg in the respective groups. Fibrinogen levels dropped to 48% of baseline after 50 mg and to 36% of baseline after 100 mg rt-PA. Some degree of bleeding at puncture and/or operation sites was noted in 16 patients, including four who required a transfusion of two or more units of blood and had been operated on an average of 7.5 days (range 2 to 13) before thrombolytic treatment was started.(ABSTRACT TRUNCATED AT 250 WORDS)

The safety and end points of graded symptom-limited bicycle exercise were assessed in 607 patients before they were randomized to vasodilator or placebo in the Veterans Administration Cooperative Study-Vasodilator Heart Failure Trial. Their mean age was 58 years and left ventricular ejection fraction averaged 30%. The peak exercise responses were as follows: oxygen consumption, 14.5 +/- 3.9 ml/kg/min; heart rate, 132 +/- 24 beats/min; systolic blood pressure, 154 +/- 29 mm Hg. No major complications occurred with the baseline tests. The initial baseline test was stopped in only 10 patients (1.6%) for arrhythmias and in one patient for hypotension. Ventricular tachycardia assessed by ambulatory electrocardiographic monitoring during the second exercise test (before exercise, during exercise, and 4 hr after the test) revealed a prevalence of 5.7% during exercise and 28.8% during the rest of the monitoring period. This study has demonstrated that stable male patients with congestive heart failure can safely exercise on a bicycle ergometer to their peak effort in a well-supervised setting. In addition, we have demonstrated that ambulatory electrocardiographic monitoring is a better method than exercise testing to evaluate presence and extent of ventricular arrhythmias in patients with congestive heart failure.

A prospective alternate-day controlled trial of prehospital transcutaneous cardiac pacing (PACE) of hemodynamically significant bradycardia and asystole was undertaken. All patients had a Glasgow coma scale score of 12 or less. Patients in the control group (n = 101) received standard advanced cardiac life support (ACLS) care. Patients in the pacing group (n = 101) were to receive PACE in addition to standard ACLS treatment; 89 patients were actually paced. The two groups were comparable in terms of age, sex, presenting rhythm, and mean times to cardiopulmonary resuscitation (CPR) and ACLS. For the 144 patients in whom the time of arrest could be estimated, the mean times to CPR and ACLS were 5.3 +/- 4.0 and 10.9 +/- 7.1 min, respectively. For the 65 paced patients in whom the time of arrest could be estimated, the mean time from arrest to pacing was 21.8 +/- 8.8 min (range 2 to 43). Multivariate analysis of outcome variables (presentation to emergency department with a pulse, admission to the hospital, and discharge from the hospital) revealed that an initial rhythm of ventricular tachycardia or fibrillation and a short time to ACLS were correlated with a favorable outcome (p less than .05; logistic regression analysis). A short time to PACE was associated with admission to the hospital (p = .20; logistic regression analysis). The use of a stand-alone transcutaneous pacing device in the prehospital arrest setting was associated with generally long times until pacing and did not appreciably improve outcome. Use of PACE in patients demonstrating prehospital bradycardia without neurologic impairment remains to be evaluated.

Seasonal variation of plasma cholesterol levels was studied in 1446 hypercholesterolemic 35- to 59-year-old male participants in the Lipid Research Clinics Coronary Primary Prevention Trial placebo group. Each man's serial cholesterol data, obtained at bimonthly intervals for 2.0 to 6.5 years, were analyzed as a separate periodic time series, and distributions of cycle zeniths and amplitudes were calculated. A highly significant (chi 2= 706, 2 degrees of freedom) seasonal effect, 7.4 mg/dl higher on December 30 than on June 30, was found. This effect was similar among the 12 LRC centers, including such disparate climates as those of Minneapolis and San Diego, and tended to be larger in the southern centers. Its magnitude was independent of baseline levels of plasma cholesterol and other baseline characteristics. Observed seasonal differences in weight and diet explained less than one-third of the seasonal variation in plasma cholesterol levels. Plasma low- and high-density lipoprotein cholesterol levels, analyzed similarly, also showed significant synchronous seasonal cycles. Plasma triglyceride levels showed a weaker irregular seasonal pattern, highest in midsummer and late autumn and lowest in spring. The etiologies and mechanisms for these seasonal patterns remain largely unknown.

The efficacy of oral enoximone, a new positive inotropic and vasodilator agent, was assessed in 12 patients with chronic congestive heart failure (New York Heart Association [NYHA] class II or III) in a double-blind randomized crossover comparison with placebo. Duration of each treatment was 6 weeks and the dose of enoximone was 150 mg tid. Efficacy was assessed by exercise tolerance, symptoms, radionuclide angiography for ejection fraction at rest and during exercise, and Holter monitoring. Two patients were withdrawn before completion of the study, one with pulmonary edema after 1 week on placebo and the other for noncompliance with enoximone therapy. Symptom-limited exercise capacity improved with enoximone by 30% and 43% (p less than .01) compared with baseline after 2 and 6 weeks treatment, respectively. Ejection fraction improved at rest (p less than .02) with enoximone but not with placebo. No change was found during exercise. Heart rate and blood pressure remained unaltered. During treatment with enoximone symptoms of exertional dyspnea and fatigue were improved and NYHA class decreased by at least one class for every patient. Holter monitoring revealed an overall increase (NS) in ectopic activity during enoximone therapy. There were no serious adverse effects and laboratory values did not change significantly. The addition of enoximone to the existing therapy of patients with moderately severe congestive heart failure provided clear and sustained subjective and objective benefit when compared with placebo.

The long-term effect of percutaneous and oral estrogen replacement therapy on blood pressure, plasma renin substrate, and serum estrogens was examined in a 2 year placebo-controlled study with 110 early postmenopausal women. The women were allocated to four treatment groups: (1) oral cyclical combination of 2 mg estradiol valerate and cyproterone acetate, (2) oral placebo, (3) percutaneous 17 beta-estradiol, supplemented by 200 mg oral progesterone during the second year, or (4) percutaneous placebo cream. Systolic and diastolic blood pressure remained unchanged in both hormone treatment groups, whereas the diastolic blood pressure tended to increase in both placebo groups. Plasma renin substrate increased during oral treatment with estradiol, but remained unchanged with percutaneous estradiol. No correlation was found between blood pressure and plasma renin substrate. During percutaneous administration of estradiol, the serum concentrations of estrone and estradiol continued to rise after 3 months and reached a plateau at 6 months of therapy. Serum estrone but not estradiol showed the same pattern during oral estradiol therapy. No further changes in any of the measured variables were observed in the women treated with percutaneous estradiol after addition of cyclical oral progesterone. We conclude that both oral and percutaneous treatment with estradiol may provide protection against the age-related increase in diastolic blood pressure observed in early postmenopausal women, and that the metabolic steady state is not attained until after 3 months of estradiol therapy.

This investigation was undertaken to study the effects of beta-adrenergic blockade with timolol on infarct size and on the incidence of late ventricular tachycardia in patients with acute myocardial infarction of less than 6 hr of evolution. Patients were assigned randomly either to a placebo-treated group (98 patients) or to a timolol-treated group (102 patients). The patients were treated with 5.5 mg iv timolol (or matched placebo) as a bolus divided into four doses during the first 2 hr followed by 10 mg orally twice daily for 1 month. Cumulative total creatine kinase (CK) release, which reflects the amount of myocardial necrosis was 1677 +/- 132 IU/liter in the placebo group (n = 83) and 1274 +/- 73 IU/liter in the timolol group (n = 81, p less than .01), a 24% reduction. Cumulative release of CK-MB was 138 +/- 8 IU/liter in the placebo group and 106 +/- 8 IU/liter in the timolol group (p less than .01), a 23% reduction. Twenty-four hour Holter electrocardiograms were obtained on days 7, 14, 21, and 28 after the onset of the acute myocardial infarction in 80 patients in the placebo group and 82 patients in the timolol group. The incidence of ventricular tachycardia was lower in the timolol than in the placebo group (7 vs 16 patients, p = .05). We conclude that early administration of intravenous timolol followed by oral treatment in patients with acute myocardial infarction reduces infarct size as assessed by CK and CK-MB serum activity, and decreases the occurrence of late ventricular tachycardia.