The effect on hypertension of hydrochlorothiazide 100 mg daily plus timolol 20-60 mg daily versus hydrochlorothiazide plus placebo and of hydrochlorothiazide plus timolol plus hydralazine 40-200 mg daily versus hydrochlorothiazide plus placebo plus hydralazine was evaluated in a double-blind, randomized, crossover study in 38 patients with hypertension. Hydrochlorothiazide plus timolol was more effective than hydrochlorothiazide plus placebo in lowering both supine and standing systolic and diastolic blood pressures. Hydrochlorothiazide plus timolol plus hydralazine was a very effective regimen in lowering both supine and standing systolic and diastolic blood pressure. The patients tolerated this regimen well with greater hypotensive activity and a lower incidence of side effects than on hydrochlorothiazide plus placebo plus hydralazine.

In a previous clinical study we demonstrated that tocainide is effective in the suppression of ventricular ectopic depolarizations (VEDs) after single oral doses. This information provided the basis for evaluating this drug's antiarrhythmic efficacy after multiple dose administration according to a loading-maintenance regimen. Twelve patients with stable VEDs were given loading doses of tocainide (400-600 mg) with maintenance doses every 12 hours. Every 48 hours the dose was increased until either arrhythmia suppression to less than 25% of VED frequency during placebo administration or side effects occurred. Computer analysis of 12-hr telemetric ECGs taken 24-36 hr after each dosage increment documented effective suppression (76-95%) in 8 of 12 patients. Those subjects demonstrating suppression were randomly assigned to a cross-over study of placebo or active drug at the dosage found effective in the dose-ranging phase. Dosages for the cross-over stage ranged from 400 to 1100 mg every 12 hours. Comparison of the two five-day periods documented suppression in these patients (mean +/- SE = 83.3 +/- 4%). No serious side effects or undue drug accumulation occurred during the study. The data indicate that tocainide can effectively suppress VEDs for 8-12 hours in many patients and that continuous suppression could be possible on an 8-12 hr dosage regimen.

Controversy persists as regards the efficacy of aortocoronary saphenous vein bypass graft (SVBG) compared to direct internal mammary artery (IMA) anastomosis. In general, the IMA graft (IMAG) is considered to be superior as regards postoperative patency. To avoid preselection bias, 74 consecutive, unselected patients with bypassable lesions of the left anterior descending artery (LAD) were randomized to undergo either SVBG or IMAG to the LAD in 1972-1974. The majority of patients had, in addition, SVBGs to other vessels. Postoperative angiograms, an average of 6 months after surgery, were obtained in two-thirds of the patients. The following observations were made: (formula: see text). In this series there is no clear advantage of the IMAG over the SVBG. The preparation of the internal mammary artery for grafting is tedious and the anastomosis more difficult to perform. The resultant flow in the internal mammary artery graft is less overall than in the SVBG. In over 400 unselected SVBGs to the LAD that have been restudied thus far in our practice, an 86% patency rate has been achieved.

In a randomized, double-blind, crossover study, 19 patients with angina were exercised 2 min after 0.4 mg sublingual nitroglycerin and after sublingual placebo and before and 1, 3, and 5 hours after oral isosorbide dinitrate (ISDN) and oral placebo. After initial testing, patients took the dose of ISDN they had had during the study (mean dose 29 mg) for a mean period of 5.6 months before retesting using the same protocol. Compared to placebo, exercise time after sublingual nitroglycerin increased 56% (P less than 0.001) initially and 51% (P less than 0.001) at retest. Compared to placebo, exercise time increased 58% (P less than 0.05) initially and 58% (P less than 0.005) at retest 1 hour after ISDN, 38% (P less than 0.05) initially and 27% (P less than 0.005) at retest 3 hours after ISDN, and 13% (NS) initially and 21% (P less than 0.02) at retest five hours after ISDN. The mean exericse times initially and at retest were not significantly different. Hemodynamic changes (decrease in systolic blood pressure and increase in heart rate) at 15 min persisted through 300 min after ISDN during both initial testing and during retesting. However, these changes were significantly less during retesting. We conclude that a partial tolerance to the hemodynamic effects of the drug develops after chronic use of high dose oral ISDN but that the antianginal efficacy of both sublingual nitroglycerin and oral ISDN is unimpaired.

The effect of acetyl strophanthanin on the rate of creatine phosphokinase (CPK) efflux was evaluated in 59 predominantly class I and II patients randomly allocated between treated and control. Therapy (0.5 mg) was begun 11-15 hours after the onset of symptoms and repeated four hours later (0.25 mg). Accumulated CPK activity (ACA) was determined from serial serum CPK changes sampled every two hours and compared to predicted CPK activity (PCA) determined from the first seven hours of CPK changes. In the control group, ACA was not significantly different from PCA. Digitalis consistently resulted in an augmentation of CPK efflux into serum which was temporally related to drug administration and resulted in a corresponding increase in ACA (P less than 0.001). Thus acetyl strophanthanin appears to increase apparent CPK activity in serum in class I and II patients.

One hundred and eight patients with initial diastolic blood pressure in the range of 100-124 mm Hg while taking hydrochlorothiazide were assigned randomly and double-blind to hydrochlorothiazide plus either bethanidine or guanethidine. The average reduction of the fifth and sixth months' diastolic blood pressure was 18.4 mm Hg for guanethidine and 13.6 mm Hg for bethanidine (P less than 0.01). The distribution of the individual values was such that 68.8% of guanethidine treated patients achieved a diastolic level below 90 mm Hg, compared to only 45.5% of the bethanidine treated group (P less than 0.025). The degree of orthostatic fall in blood pressure was greater with bethanidine than with guanethidine (P less than 0.05). The diurnal variation of blood pressure was slightly greater with bethanidine than with guanethidine. The results significantly favor guanethidine. This study failed to demonstrate that the shorter action of bethanidine confers significantly better control of blood pressure than the longer action of guanethidine.

This study examines whether the beneficial effects of molsydomine, a recently introduced antianginal agent, on exercise performance of patients with angina pectoris are long lasting. The hemodynamic effects are known to persist for several hours. The effects of molsydomine on the duration of exercise and the time to the onset of ST depression were compared to those of placebo during two hours after oral administration. Molsydomine prolonged the duration of exercise in all eight patients (average 2.8 min, P less than 0.001) and delayed the onset of ST depression (average 2.2 min, P less than 0.001), while the placebo failed to alter these measurements. The increment of the duration of exercise produced by 2 mg of molsydomine in two hours following oral administration was comparable to the increment produced in a few minutes after 0.3 mg of nitroglycerin given sublingually. The results indicate that molsydomine offers prophylasis for angina pectoris that lasts at least two hours after oral administration.

Twenty-one patients with documented coronary atherosclerotic heart disease were studied to determine the effect of high dose oral isosorbide dinitrate (ISDN) on heart rate, blood pressure, and exercise time until angina pectoris. Patients were tested in two phases, initially with 0.4 mg of sublingual nitroglycerin and with sublingual placebo, and then with oral ISDN, mean dose 29 mg, and oral placebo. Both phases of the study were conducted in a randomized, double-blind, crossover manner. After ISDN was compared to oral placebo, heart rate increased at 30 to 300 min (P less than 0.01) (peak increase 18 beats/min at 60 min), and systolic blood pressure decreased from 45 to 300 min (P less than 0.005) (peak decrease 18 mm Hg at 60 min). Exercise time at 2 min after sublingual nitroglycerin increased 51% as compared to oral placebo, exercise time increased 54% at 1 hr (P less than 0.005), 37% at 3 hr (P less than 0.01), and 12% at 5 hr (NS). Twelve of 21 patients (57%) improved their exercise time until angina larger than or equal to 25% at 1 hr after oral ISDN. The exercise response to sublingual nitroglycerin was a good predictor of this response to oral ISDN.

Dobutamine is a newly developed catecholamine reported to have minimal direct vascular effects relative to its inotropic activity and to have less chronotropic and arrhythmogenic properties than other catecholamines used in the treatment of low output states. In this study, the acute hemodynamic effects of dobutamine were compared to those of dopamine in 13 patients with chronic low output cardiac failure. At dosages adjusted to achieve similar increments in cardiac output, dobutamine reduced left ventricular filling pressure (LVEP) from 24 +/- 2 mm Hg (SEM) to 17+/- 2 mm Hg, while dopamine increased LVEP to 30 +/- 3 mm Hg and in six patients caused arterial O2 saturation to fall below 90%. This poor response to dopamine was probably the result of its vasoconstrictive effects and illustrates the potential advantages of using a cardioselective agent such as dobutamine when the desired goal of therapy is to improve ventricular function by direct inotropic stimulation.

Labetalol was administered to six hypertensive subjects in increasing doses for seven days. A decrease in both supine and standing arterial pressure and heart rate was observed with no change in cardiac output and few side effects. Exercise tolerance was unaltered by the drug, but the heart rate and arterial pressure response to exercise were significantly blunted. The infusion rate of isoproterenol required to produce tachycardia was increased sevenfold by 800 mg/day labetalol and tenfold by 1600 mg/day. More than twice the control dose of phenylephrine was required during labetalol therapy to produce a rise in diastolic arterial pressure reflex tachycardia to amyl nitrite-induced hypotension was attenuated. These studies indingina pectoris.

Left ventricular wall motion was assessed in 105 consecutive patients both invasively, using biplane cineangiography, and noninvasively, by a real-time, phased-array, two-dimensional echocardiography system. Ventricular wall motion in five anatomic areas of the ventricle (anterolateral, posterolateral, apical, septal, and inferior) was analyzed by both methods in a double-blind manner. Two-dimensional echocardiographic images were deemed adequate for analysis in 82% of the regions (430 of 525). Fifty-five discrepancies were noted in the comparison of the remaining 430 regions. The reasons for discrepancies in interpretation between the two methods were established for 54 during retrospective review: 33 were due to echocardiography (inadequate target visualization, observer error, or tangential echo views). Fifteen were related to angiography (overlay of silhouettes or observer error), and six were due to other reasons including definition problems or spatial orientation difficulties. Both real-time, two-dimensional echocardiography and cineangiography have advantages and disadvantages. The techniques used together could provide more complete information concerning ventricular wall movement than is now currently available.

From a large cooperative prospective randomized study, data relating to a subgroup of 113 patients with angina pectoris and a significant lesion of the left main coronary artery were analyzed. Of these patients, 53 had been randomly allocated to a medical treatment group and 60 to a surgical treatment group. The former group received conventional medical treatment, while the surgical treatment group received one or more aortocoronary saphenous vein bypass grafts. Important risk factors were approximately uniformly distributed between the two groups. Both are being followed up to 60 months (average follow-up, 30 months). To date, 12 of 60 surgical patients (20%) and 19 of 53 medical patients (36%) died (P less than 0.06). The operative (30-day) mortality declined from a rate of 25% for the first 2 years of the study to 7% for the last 3 years. Of patients randomized in the latter 3 years of the study, 12 of 41 medical patients (29%) and three of 42 surgical patients (7%) died (P less than 0.01). The average follow-up period in this group was 24 months. The proportion surviving 24 months was clearly larger in the surgically treated group (P less than 0.02). The difference in the proportion of patients surviving after surgery as compared with medical treatment was greatest in patients with additional significant disease involving the right coronary artery, with or without left ventricular dysfunction. Relief of angina as assessed by an "anginal score" was also better in surgical patients to a significant degree. Graft-patency rates correlated well with relief of angina, but objective studies including treadmill testing are not yet available.

Tocainide, a new oral antiarrhythmic agent, was studied in man in a short-term protocol designed to evaluate the efficacy, kinetics, and toxicity of this compound. Premature ventricular contractions (PVCs) were suppressed by less than 70% in 11 of 15 patients compared with pre-drug placebo controls. For these 11 responders, there was an average PVC reduction of 91% +/- 10 (range 70 to 100%) at tocainide doses not associated with side effects. Mild transient central nervous system toxicity was observed in some patients near the time of peak concentrations during the highest dose administered. The drug was found to have linear kinetics over the dose range studied and a plasma half-life of 13.5 +/- 2 hours. Plasma concentration-response curves indicate antiarrhythmic activity over all plasma concentrations, with 70% PVC reduction above 6.0 mug/ml. This study suggests that tocainide is a safe and effective antiarrhythmic agent during short-term administration and is worthy of further clinical trials.

Heart rate, blood pressure, physical working capacity, and electrocardiographic changes were evaluated during upright bicycle exercise in 43 asymptomatic patients, aged seven to 41 years, one to 14 years after total surgical correction of tetralogy of Fallot (TF). One hundred and nine normal subjects between the ages of five and 42 years served as controls. The patient and control groups, subdivided by sex and body surface area (BSA), were similar in height and weight. When comparing males to males and females to females with BSA greater than or equal to 1.2 m2, maximal heart rates and working capacities were lower in the patient groups than in the control groups. An inverse relationship was observed between maximal working capacity and age at surgery in both male and female patient groups. By contrast, especially in the males with BSA less than 1.2 m2, the mean maximal heart rates and working capacities did not differ significantly between the patient and control groups. Premature atrial or ventricular contractions were recorded in ten of 43 patients (23%) after exercise. Five of these ten patients had multifocal premature ventricular contractions (PVC) and four had unifocal PVC. In the five patients with multifocal PVC, a short burst of ventricular tachycardia occurred in two, coupling in one, and bigeminal rhythm in two. Cardiac arrhythmia was not observed in the control group. Although our current surgical results are excellent, this study suggests that impaired cardiovascular function persists after corrective surgery and that early surgical treatment may be more desirable. Furthermore, additional data suggest that the exercise procedure may be useful in detecting and managing patients who may develop life-threatening arrhythmias following intraventricular surgery.

Frame-by-frame analysis of angiograms in 16 patients revealed that hemodynamic interventions are capable of producing substantial shifts in the diastolic pressure-volume curve. Angiotensin raises blood pressure and shifts the entire pressure-volume curve up, and nitroprusside lowers blood pressure and shifts the curve down. Indirect measurements of pleural pressure in seven patients (via esophageal pressure) showed that pleural pressure changes were too small to account for these shifts. Analyzing our results in terms of a theoretical pressure-volume equation previously validated in dog studies did not show the observed shifts to be the product of acute changes in the elasticity of the myocardium itself. This same analysis suggested that indirect changes in the external mechanical constraints acting on the left ventricle such as the right ventricular pressure, the pericardium, and perhaps viscoelastic effects related to changes in filling rate account for the pressure-volume curve shifts with intervention. The fact that one cannot in general relate a specific volume to a given pressure in the face of hemodynamic interventions calls into question the use of end-diastolic pressure interchangeably with end-diastolic fiber length when interpreting systolic events in terms of the Frank-Starling mechanism.

Instantaneous aortic arch blood velocity was recorded transcutaneously from the suprasternal notch, using a 2.2 MHz Doppler ultrasound unit, in 18 normals and 16 patients undergoing cardiac catheterization who had murmurs of mitral regurgitation. In normals aortic blood velocity rose rapidly in early systole to a midsystolic peak then fell to zero velocity. These roughly parabolic patterns had area ratios beneath the first and second halves of the curves measuring 52:48 +/- 3 (SD). With increasingly severe mitral regurgitation the pattern became skewed leftward such that the percent in the first half of systole ranged from 53-79%. From the angiograms of our sixteen patients an estimate of true percent regurgitation was made using the Fick cardiac output and ventricular volume measurements. When compared with the area under the first half of the velocity curve a strong correlation was found (r = 0.84) indicating that this Doppler technique can be used to evaluate mitral insufficiency.

Conduction of the sino-atrial impulse from the high right atrium to the ventricles was studied by intracardiac electrography in 21 unoperated patients, age 3 months to 11 years, with endocardial cushion defects (ECD). The high right atrium-to-low right atrium conduction time was prolonged in 15 of 18 subjects (mean 57 +/- 20 msec). The low right atrium-to-His bundle conduction time (LRA-H) was normal in 16 of 17 subjects (mean 82 +/- 30 msec), prolonged in one. The His-to-ventricle conduction time (H-V) was normal in 16 of 17 subjects (mean 37 +/- 8 msec), equivocally short in one. Nine patients with ECD, age 3 to 21 years, were studied postoperatively. One had an acquired complete atrioventricular block in the His bundle. Two had prolonged LRA-H and two prolonged LRA-H and two prolonged H-V. The surface ECG failed to identify accurately either prolonged atrioventricular conduction or the site of prolongation.

Echocardiograms of 52 patients with the Wolff-Parkinson-White (WPW) syndrome were investigated. Abnormal patterns of motion were observed in the left ventricular posterior wall (LVPW) and the interventricular septum (IVS). The abnormal LVPW motion was presumably specific for the syndrome and included early onset of the anterior motion which preceded the first heart sound (S1) and a premature peak formation of the anterior displacement which occurred before the second heart sound. The latter was usually followed by a second lower peak. These findings seem to suggest that both contraction and relaxation of LVPW begin earlier than normal due to ventricular pre-excitation initiated at or near the LVPW. The IVS abnormality characteristic of the syndrome was a posterior protrusion, the onset of which preceded S1. Subsequent motion of IVS was either paradoxical or hypokinetic during ejection. These IVS abnormalities were quite similar to those observed in left bundle branch block. The abnormal LVPW motion was observed in all 20 Type A patients and 10 of the 32 Type B patients. The abnormal IVS motion was observed in 10 Type B patients. We feel that echocardiography could be used as an auxiliary noninvasive means of locating the pre-excitation site in patients with WPW.

A comparison of electrocardiographic manifestations of left atrial enlargement (LAE) and left atrial size by echocardiography was made in 307 patients in sinus rhythm. Electrocardiographic criteria used were L:P wave duration in lead II equal to or greater than 0.12 sec; Va: the ratio of the duration of negative terminal P in V1 to the P-R segment equal to or greater than 1.0; Vb: a negative P terminal force in V1 less than -0.03 mm sec. The echocardiographic diagnosis of left atrial enlargement was based on 1) transverse dimension greater than 4.0 cm; or 2) a ratio of transverse atrial to transverse aortic root dimension greater than 1.17. In the presence of left atrial enlargement, a combination of criteria occurred more often than a single criterion. The overall predictive index of the electrocardiogram for left atrial enlargement was 63% (excluding criterion Vb raised probability to 80%); and that for absence of left atrial enlargement was 78%. The index of coarse versus fine fibrillary waves was unreliable in predicting left atrial enlargement. Changes in P wave morphology may be used as a reasonably specific but less sensitive indicator of left atrial enlargement.