To examine which factors affect the reproducibility of ejection fraction (EF), pulmonary transit time (PTT) and segmental wall motion assessed from first-pass radionuclide angiograms (FPRA), 32 patients who had FPRA were randomized for site of injection of isotope (right or left arm) and projection (right or left anterior oblique [RAO or LAO]). The quality of injected bolus was measured from the full width at half maximum (FWHM) of the bolus time-activity curve in the superior vena cava. All patients had two sequential studies on each of two consecutive days, and each study was analyzed independently by two observers. For EF, inter- and intraobserver correlations ranged from 0.94-0.98. EF was higher in the RAO than the LAO projection (mean 47.4% vs 40.3%, p less than 0.001), but neither injection site nor bolus FWHM affected the results. For PTT, interobserver correlations ranged from 0.75-0.93 and intraobserver correlations from 0.61-0.85. Variability in PTT was large, and inter- and intraobserver variabilities were directly related to bolus FWHM (mean 0.60 +/- 0.21 second for interobserver differences in PTT of less than 2.0 seconds, mean 1.55 +/- 0.86 seconds for interobserver differences in PTT of greater than 2 seconds [p less than 0.005]). Differences in FWHM between sequential studies were 0.28 +/- 0.29 second when intraobserver differences in PTT were less than 2 seconds and 1.04 +/- 0.67 seconds when differences in PTT were greater than 2.0 seconds (p less than 0.005). Variations in PTT were not related to differences in projection or injection site. Wall motion was highly reproducible for both projections. In the RAO projection, one of 116 anterior segments (0.9%), one of 116 apical segments (0.9%), and four of 116 inferior segments (3%) were judged normal from one observer's images and abnormal from another. In the LAO view, discrepancies occurred in one of 126 septal segments (0.8%), two of 126 apical segments (1.6%) and four of 126 posterolateral segments (3%). This study shows that EF and wall motion are highly reproducible in any projection, but the choice of projection significantly affects the values for EF from FPRA. PTT measurements are less reliable, highly bolus dependent, and their use in clinical practice depends on quality control of the bolus of injected radionuclide.

Using a double-blind protocol, we investigated the use of propranolol in patients with coronary artery spasm as assessed by subjective and objective variables. Both low-dose (40 mg every 6 hours) and high-dose (160 mg every 6 hours) propranolol were administered. At both doses, the duration of angina attacks was significantly prolonged but the frequency was not. We conclude that propranolol at doses up to 160 mg every 6 hours as single therapy is frequently detrimental in angina pectoris due to coronary artery spasm and should not be used as the sole treatment of this disorder.

We studied the association between the outcome of antihypertensive care and three items of that care among 230 hypertensive steelworkers who were referred to 83 physicians. The first item was the decision to treat some patients but not others: 63% of the patients were prescribed antihypertensive drugs and the mean decrease in their diastolic blood pressure (DBP) was greater than that among untreated patients (12.2 +/- 0.84 vs 7.8 +/- 0.83 mm Hg [+/- SEM], p less than 0.001). The second item was the vigor of prescribed medication: Patients prescribed more vigorous treatments had lower DBP (p less than 0.005). Third, patient compliance was related to achieving a goal DBP of less than 90 mm Hg (p less than 0.05) and the product of prescribed vigor and compliance was highly associated with DBP response (p less than 0.0001). These results stand in contrast to those of previous studies that failed to detect associations between various other items of the care process and the outcome of antihypertensive care.

Although serious hemorrhage during therapeutic coadministration of sulfinpyrazone and racemic warfarin occurs, no prospective studies have been done. In this study, single oral doses of racemic warfarin, 1.5 mg/kg, were administered to six normal subjects with and without oral sulfinpyrazone, 400 mg daily. Both the hypoprothrombinemia (p less than 0.001) and the plasma warfarin concentrations (p less than 0.05) were significantly augmented. To determine if this interaction was stereoselective, the experiments were repeated in the same subjects with R-and S-warfarin enantiomorphs. S-warfarin with sulfinpyrazone caused a highly significant augmentation of both the hypoprothrombinemia (p less than 0.001) and the plasma warfarin concentrations (p less than 0.001). R-warfarin with sulfinpyrazone did not significantly change the hypoprothrombinemia but significantly (p less than 0.05) reduced warfarin concentrations. Thus, sulfinpyrazone augmented the hypoprothrombinemia of racemic warfarin stereoselectively by reduced metabolic clearance of S-warfarin. Sulfinpyrazone and racemic warfarin are most dangerous when either drug is added to a stabilized regimen of the other drug.

Verapamil and placebo were compared in patients with stable, effort-induced angina. Single-blind dose titration (240, 360 and 480 mg/day) preceded a double-blind crossover. Among the 18 patients who completed graded exercise stress tests with reproducible pretreatment effort-limiting angina, exercise duration increased from 348 +/- 127 seconds (SD) before treatment to 494 +/- 182 seconds after verapamil (p less than 0.001), but did not change after placebo. Compared with placebo, verapamil reduced the weekly number of anginal episodes from 4.54 +/- 5.03 to 2.44 +/- 3.30 (p less than 0.05) and reduced nitroglycerin consumption from 3.46 +/- 5.30 to 1.55 +/- 2.89 tablets per week (p less than 0.05). Of 26 patients who completed the single-blind dose titration, 16 were improved (greater than 1 minute) at a dosage of 240 or 360 mg/day. No patient improved (greater than 1 minute) on 480 mg/day who had not already improved on a lower dose, but side effects requiring reduction in dosage occurred in seven patients receiving 480 mg of verapamil per day. Verapamil is an effective antianginal drug that appears most efficacious at a dose of 360 mg/day, but side effects are common at a dose of 480 mg/day.

Diseases that cause symptoms incompletely relieved by available modes of treatment stimulate search for new therapies. Chronic disease processes, in which interventions are palliative rather than curative provide a particular challenge in determining the value of therapeutic intervention. Management of patients with angina pectoris is an example of this challenge.

Lidoflazine is a synthetic drug with calcium-channel blocking effects. In a 7-month study, 36 patients with stable angina pectoris were tested during a 3-month single-blind placebo phase. Nineteen were then randomized by double-blind methods to lidoflazine and 17 to placebo therapy. The lidoflazine group had a significant (p less than 0.01) reduction in anginal attacks; the placebo group did not. Exercise testing demonstrated that lidoflazine therapy was associated with a 34% increase in total work performance and a 15.6% increase in peak calculated oxygen uptake during double-blind treatment (both p less than 0.004 compared with the placebo group). Heart rate was significantly reduced at submaximal levels of exercise during lidoflazine therapy (p less than 0.04). Nitroglycerin consumption and electrocardiographic changes at the end of exercise did not change during the double-blind phase. In a second study of six similar patients, single-blind administration of lidoflazine was associated with improved myocardial perfusion during exercise as determined by thallium-201 stress scintigraphy. These studies demonstrate that lidoflazine therapy is associated with relief of angina, an increased physical work capacity, and improved regional myocardial perfusion during exercise.

Twenty sodium-replete patients with hypertension were allocated either to a placebo or to a captopril treatment group. Each patient was investigated in rest-recumbent (RR) and rest-sitting (RS) positions and during an uninterrupted, graded, submaximal exercise test (up to the anaerobic threshold) before treatment, and with a similar protocol 75 minutes after treatment with captopril or placebo on the same morning. Captopril decreased brachial intraarterial pressure by 7/4 mm Hg at RR, by 16/10 mm Hg at RS, and by 19/10 mm Hg during exercise (p less than 0.001), based on a decrease of systemic vascular resistance (p less than 0.001). Slight increases of cardiac output and of heart rate were noted at rest; cardiac output was not significantly affected during exercise, but the increase of heart rate of 2.4 beats/min was significant (p less than 0.01). Captopril decreased pulmonary artery (p less than 0.05) and capillary wedge pressures (p less than 0.001), with unchanged pulmonary vascular resistance. The data indicate that the action of captopril is characterized by arteriolar and possibly venous dilatation both at rest and during exercise. Pulmonary vascular resistance, however, is not affected.

The possibility of beta-adrenoreceptor hypersensitivity after abrupt withdrawal of long-term therapy (8-18 months) with the slow-release (SR) formulation of oxprenolol (160-320 mg/day) was assessed in six patients with uncomplicated essential hypertension. The chronotropic dose 25 of isoproterenol (the dose that increases the resting heart rate by 25 beats/min), plasma concentration of catecholamines, triiodothyronin and thyroxin, plasma renin activity and aldosterone, hemoglobin, hematocrit and oxyhemoglobin dissociation were measured on the last day of oxprenolol SR intake and 1, 2, 3, 6 and 13 days after abrupt replacement by identical placebo tablets. The chronotropic dose 25 of isoproterenol (microgram/m2), which was greater than 25.6 in all patients on the last day of oxprenolol SR, fell to 4.83 +/- 2.03 on the second day and to 3.50 on the third day after its abrupt withdrawal and reached a minimal value on the thirteenth day (2.78 +/- 0.30). Throughout the study, plasma concentrations of catecholamines, triiodothyronin and thyroxin and oxyhemoglobin dissociation remained unchanged. Plasma renin activity and plasma aldosterone, which were suppressed during oxprenolol administration, rose significantly during placebo, coinciding with a significant fall in hematocrit and hemoglobin. No major subjective symptoms were reported by the patients. Thus, hypersensitivity of beta-adrenoreceptor-mediated responses was not demonstrated after sudden withdrawal of oxprenolol SR.

The purpose of this study was to assess noninvasively the effects of intense aerobic training on cardiac structure and function in a group of healthy, college-age men (25 experimental and 11 control, mean age 22 years). Echocardiographic, electrocardiographic (ECG), and fitness measurements were obtained before and after a 3-month endurance training program and compared with similar measurements obtained in nonexercising subjects. The supervised training program consisted of 50-minute jogging sessions 5 days a week at 85% of maximal heart rate. Compared with the control group, echocardiography after training showed an increase in left ventricular (LV) end-diastolic dimension (p less than 0.05). LV posterobasal wall thickness, septal wall thickness and ejection fraction did not change significantly. ECG measurements revealed a decrease in resting heart rate (p less than 0.05) and an increase in R-wave voltage in leads V5 and V6 (p less than 0.01). The measured maximal oxygen consumption increased by 16% (p less than 0.001). These data indicate that intense aerobic training in college-age men results in a significant increase in resting LV end-diastolic dimension and volume. The increase in maximal stroke volume associated with exercise training may be partially explained by these changes in cardiac dimensions.

The antihypertensive efficacy and the incidence of side effects of prazosin and hydralazine were compared in a randomized, double-blind trial in 232 adult male hypertensives who could not be controlled with hydrochlorothiazide alone. There were no significant differences between regimens in the percentage of patients who attained goal blood pressure (reduction of diastolic blood pressure to below 90 mm Hg and at least 5 mm less than the baseline randomization pressure), effect on pulse rate or the incidence or reasons for terminations. Absolute reduction of blood pressure was similar for both drugs except for sitting systolic pressure at 3 and 6 months, when prazosin effected a 3.7- and 3.6-mm Hg greater response (p less than 0.05). Orthostatic dizziness (p less than 0.005), sexual dysfunction (p less than 0.02), and nightmares (p less than 0.02) were more frequent with prazosin than with hydralazine; nevertheless, patient compliance was similar for both drugs. An unexpected finding was the lack of pulse rate increase associated with hydralazine, particularly in older patients.

The realization that bias in patient selection may influence the results of clinical studies has helped to establish the randomized controlled clinical trial in medical research. However, bias can be equally important at other stages of a trial, especially at the time of analysis. Withdrawing patients from consideration in the analysis because of ineligibility on account of study entry criteria, lack of compliance to the protocol, or data of poor quality may be a source of systematic error. Examples to illustrate the possible consequences are taken from trials in the cardiovascular field. We recommended that reported study results should include outcome data from all subjects randomized in the group to which they were originally assigned.

Randomized clinical trials constitute the formal experiments in therapeutics. Many such trials in coronary heart disease have terminated inconclusively or in controversy. In this editorial, we analyze some of the methodologic issues that may lead to controversy; the main reason for the low success rate may lie in insufficient understanding of the complex biology of the disease and in failure to select the appropriate models for therapy. We argue that these difficulties only strengthen the need for the rigorous experimental approach to the evaluation of therapies for coronary heart disease.

The acute effects of the angiotensin converting-enzyme inhibitor captopril on regional blood flow, renal hemodynamics and sodium excretion were studied in 12 patients with severe congestive heart failure. Converting-enzyme inhibition decreased systemic vascular resistance by 27% and increased cardiac index by 16%. Estimated hepatic blood flow decreased 17%, but renal blood flow increased 60%. The ratio of renal-systemic blood flow increased from 0.10 +/- 0.01 to 0.14 +/- 0.02 (p = 0.031). Although renal plasma flow increased from 202.8 +/- 28.8 to 323.7 +/- 42.7 ml/min (p less than 0.008), the glomerular filtration rate did not change significantly from the mean pretreatment value of 82.1 +/- 12.3 ml/min. The filtration fraction decreased from 41.3 +/- 3.8% to 33.4 +/- 4.5% (p = 0.050), while urinary sodium excretion doubled, from 34.5 +/- 9.6 to 68.2 +/- 19.6 muEq/min. The plasma renin activity increased from 12.6 +/- 5.0 to 29.9 +/- 8.4 ng/ml/hr (p = 0.030) as plasma aldosterone concentration decreased from 30.5 +/- 6.5 to 11.3 4/- 1.2 ng/dl (p = 0.010) and norepinephrine concentrations decreased from 774 +/- 105 to 618 +/- 85 pg/ml (p = 0.020). We conclude that converting-enzyme inhibition reverses renal vasoconstriction in congestive heart failure and redistributes regional blood flow. The natriuresis may be mediated by one or more of the following: improved renal plasma flow, reduction in filtration fraction, suppression of hyperaldosteronism, and lowering of circulatory catecholamine concentrations.

Thirty-six of 42 consecutive patients who underwent corrective surgery for tetralogy of Fallot were operated upon without or with minimum right ventriculotomy and with repair of the pulmonary valve. The other six patients underwent conventional right ventriculotomy primarily because they required external valved conduits for repair. One of the 36 patients (2.8%) died 11 days postoperatively. Postoperative hemodynamic and angiocardiographic studies were performed randomly in eight patients. The results were compared with those obtained from 21 control patients who underwent conventional corrective surgery with right ventriculotomy and without repair of pulmonary valve. There were no differences in the degree of residual pulmonary stenosis. Moderate-to-severe pulmonary regurgitation occurred in none of the patients who underwent the new procedures and in 24% of the controls. Cardiac and stroke volume indexes at rest measured postoperatively did not differ significantly between the two series of patients. The cardiac index for both series of patients increased significantly during isoproterenol infusion, measuring 7.29 +/- 1.97 l/min/m2 for the present series of patients (p less than 0.005) and 5.76 +/- 1.64 l/min/m2 for the controls (p less than 0.001). These two values were significntly different (p less than 0.05). Stroke volume index in the present series of patients increased significantly during isoproterenol infusions., from 37 +/- 5 ml/m2 to 45 +/- 15 ml/m2 (p less than 0.05), whereas that for the controls decreased significantly, from 43 +/- 10 ml/m2 to 38 +/- 12 ml/m2 (p less than 0.01). These differences in the response to isoproterenol infusion in the two series of patients indicated that right ventricular function after corrective surgery for tetralogy of Fallot was well maintained in patients who underwent the new method of operation. The two series of patients did not differ with respect to the development of right bundle branch block.

We conducted a prospective, randomized study to evaluate the influence of oral anticoagulation on graft patency early after aortocoronary bypass surgery. Eighty-nine patients who received 251 distal venous anastomoses were treated with phenoprocoumon, a vitamin K antagonist, starting on the seventh postoperative day; 84 patients with 238 distal venous anastomoses received no anticoagulation. Both groups were comparable with respect to age, exercise hemodynamics, extent of coronary disease and left ventricular dysfunction. In each group, 2.8 distal anastomoses were constructed per patient. Graft patency after surgery was 90.4% in the treatment group and 84.6% in the control group (p less than 0.015). All anastomoses were patent in 81% and 67% of patients, respectively (p less than 0.02). Flow measurements in 279 grafts suggest that grafts with a flow of less than 90 ml/min benefit from oral anticoagulation. No graft with a flow of more than 90 ml/min was occluded.