Between 1972 and 1974, 121 patients with chronic stable angina pectoris and operative coronary artery disease, excluding significant left main coronary obstruction, were randomized to either medical therapy (60 patients) or surgical therapy (61 patients) as part of a larger Veterans Administration Cooperative Study of Surgery for Coronary Arterial Occlusive Disease. At the time of randomization, medical and surgical groups were similar with regard to clinical and hemodynamic features as well as degree of left ventricular impairment and extent of coronary disease. Follow-up to June 1, 1978, reveals significantly improved survival in surgical patients from 3 through 6 years after randomization. Sixteen cross-over patients (13 medical to surgery, and 3 surgical without surgery) do not appear to influence results. Results of this randomized study from a single hospital differ from the preliminary results of the larger cooperative study, primarily because of a higher mortality in the medical group. The medical mortality in our group is in keeping with other reports of the natural history of patients with angina pectoris, and we propose that the population of patients we randomized closely simulates the usual type of patient with chronic angina being considered for surgical treatment. Our good surgical results thus contrast significantly with the survival of medically treated patients, and this separates our study from the body of the Veterans Administration Cooperative Study.

Rate-pressure product (RPP) is a sensitive index of myocardial oxygen consumption (mVO2) in awake people. We wished to determine whether this relationship persisted under anesthesia and in the face of concurrent large changes in myocardial contractility and left ventricular filling pressures. In 16 patients scheduled for coronary artery bypass surgery, we inserted coronary sinus and Swan-Ganz catheters, and a central aortic catheter via the brachial artery, before induction of anesthesia with either morphine (2 mg/kg) or halothane, chosen in random order. We measured aortic, pulmonary, and venous pressures, cardiac output, systolic time intervals, and thermodilution coronary sinus flow. We calculated mVO2 as coronary sinus flow times myocardial arteriovenous oxygen content difference. We found significant correlations between mVO2 and heart rate (r = 0.57), systolic blood pressure (r = 0.52), the index delta /delta T (r = 0.53, and RPP (r = 0.78). Multiple regression of RPP and delta P/delta T against mVO2 increased their correlation (r = 0.86), while multiple regression of RPP and pulmonary wedge pressure against mVo2 did not significantly improve the correlation of RPP alone (r = 0.75). We conclude that hemodynamic changes anesthesia and surgery do not decrease the sensitivity of RPP as an index of mVO2.

The effect of exercise on the development of intercoronary collaterals and on left ventricular function is controversial. Twenty male patients (mean age 48 years, range 36-54 years) who had suffered an acute myocardial infarction were randomly allocated to an exercise group (10 patients) and a control group (10 patients). Both groups underwent coronary angiography, left ventricular function studies and myocardial perfusion studies with labeled microspheres, before and after the 7-month experimental period. Both groups had similar extent of disease as measured angiographically and both had mild progression of disease. Neither group showed changes in extent of callateralization, myocardial perfusion or left ventricular function. The exercise group had a significant increase in anginal threshold and a significant (p less than 0.01) decrease in heart rate at a given work load. Exercise, therefore, does not appear to affect progression of disease, myocardial perfusion, extent of collateralization, or left ventricular function in patients with coronary artery disease.

Diastolic time (DT) is calculated as the cycle length (RR) minus electromechanical systole (QS2). The ratio of DT (RR-QS2) to RR interval times 100, or the percent diastole (%D), varies nonlinearly with heart rate (HR), increasing rapidly with decreasing HR. The effect of commonly used cardioactive agents on %D was studied in five groups of normal subjects. In group 1 (n = 12), propranolol (160 mg daily) increased %D from 55.9 +/- 1.7 to 64.7 +/- 1.3 (p less than 0.001) by slowing HR. In group 2 (n = 12), dobutamine (2.5 micrograms/kg/min) increased %D from 56.4 +/- 1.4 to 61.8 +/- 1.3 (p less than 0.005) by shortening the QS2. In group 3 (n = 10), Cedilanid-D (1.6 mg i.v.) increased %D from 55.5 +/- 1 to 63.2 +/- 0.7 (p less than 0.001), both by slowing the HR and shortening the QS2. In group 4 (n = 12), isoproterenol (2 micrograms/min) increased HR and shortened the QS2 significantly. The net result was a significant reduction of %D from 56.1 +/- 1.4 to 53.5 +/- 1.1, (p less than 0.05). In group 5 (n = 15), a 100-mg bolus of i.v. lidocaine did not have a significant effect on %D. This study indicates that cardiovascular drugs may have significant effects on the relative duration of diastole either by affecting HR or the duration of systole. This may have clinical implications for patients with coronary artery disease and patients with left ventricular hypertrophy, since in both cases coronary flow in mostly diastolic.

Resting hemodynamics improve during vasodilator administration in patients, with congestive heart failure (CHF), but the effects of these agents on exercise is unknown. Twenty-two patients with class II or III CHF performed bicycle exercise to symptomatic maximum before and 90 minutes after random double-blind administration of oral hydralazine (100 mg) and isosorbide dinitrate (40 mg) (11 patients, group 1) or placebo (11 patients, group 2). Exercise duration was unchanged after treatment in either group. Maximal oxygen consumption changed insignificantly in both groups, from 12.6 +/- 1.2 (SEM) to 13.6 +/- 1.6 ml/kg/min in group 1, and from 11.7 +/- 1.4 to 13.4 +/- 1.7 ml/kg/min in group 2. Maximal cardiac index was unchanged in both group 1 (4.00 +/- 0.33 to 4.41 +/- 0.29 l/min/m2) and group 2 (4.11 +/- 0.43 to 4.14 +/- 0.42 l/min/m2). Systemic vascular resistance at peak exercise was also unchanged in both group 1 (14.1 +/- 1.6 to 11.8 +/- 1.0 units) and group 2 (14.7 +/- 1.6 to 13.5 +/- 1.6 units). at submaximal exercise (300 kilopond-meters/min), however, cardiac index after treatment increased in group 1 (0.51 +/- 0.18 l/min/m2, p less than 0.05) and systemic vascular resistance decreased (-3.3 +/- 1.3 units, p less than 0.05), but were unchanged in group 2. Thus, although vasodilators do not improve maximal exercise capacity acutely, they can improve hemodynamics at lower work loads which may, therefore, be better tolerated in patients with CHF.

The relationship of serum dopamine-beta-hydroxylase (DBH), plasma renin activity (PRA) and urinary catecholamines (IU catechols) in various forms of essential hypertension (EHT) (low, normal and high renin) was evaluated. Eighty-four predominantly white, young (37 +/ 8 years (SD)), mildly hypertensive patients (diastolic pressure 93 +/- 4 mm Hg (SD)) continued their regular diet and received no medications. Thirteen patients had low-renin, 64 had normal-renin, and seven had high-renin EHT. DBH, total IU catechols and urinary norepinephrine were not different between these renin subgroups. DBH was significantly lower in all hypertensives (55.6 +/- 36 IU) and in the low-renin subgroup (46 +/- 30 IU) compared with normal subjects (68 +/- 35 IU) (p less than 0.01). However, the DBH range was so broad that an individual DBH value did not distinguish EHT from normals. After a baseline period, patients were randomly assigned to receive chlorthali done 50 mg q.a.m. or placebo in a double-blind study. In the chlorthalidone group 1 month after therapy, the diastolic pressure decreased, PRA increased, and total IU catechols and urinary norepinephrine increased. Serum DBH did not change during diuretic therapy. A significant correlation could not be shown between pretreatment DBH and the changes in PRA and IU catechols before and after diuretics for all treated EHT patients. However, within the normal PRA EHT subgroup receiving chlorthalidone, the one-third of patients with lowest pretreatment DBH levels (n = 10) were compared with the one-third of patients with the highest pretreatment DBH values (n = 10). The lower DBH patients showed significantly less change in PRA (delta PRA = 2.9 +/- 1.8 ng/ml/hr) compared with the higher DBH patients (delta PRA = 8.2 +/- 1.6; P less than 0.05). In some EHT patients, DBH levels may be related to PRA response to diuretic therapy.

Hemodynamic monitoring after a single dose (10 mg) of nifedipine in 27 primary hypertensive subjects (diastolic pressure greater than 110 mm Hg) documented that this calcium antagonistic agent exerts a potent arteriolar vasodilating action, which results in prompt (-21% of control at 30 minutes) and persistent (-16% of control at 120 minutes) fall in mean arterial pressure associated with a rise in cardiac output and pulse rate. The same patients received oral treatment for 3 weeks. Hourly pressure readings showed that 1) the antihypertensive response to each dose lasts 8--12 hours; and 2) nifedipine every 6 hours significantly reduced blood pressure throughout the 24 hours, without postural hypotension. Side effect were short-lasting (headache in five patients, palpitation without arrhythmias in eight patients, burning sensation in the face and legs in five patients and sporadic extrasystoles in five patients) and tended to disappear with continued treatment. Development of drug resistance, sodium retention, plasma volume expansion, renin release or angina pectoris were not observed during the study. Although these findings seem to differentiate nifedipine from other vasodilators currently used in the treatment of hypertension, broader experience and more prolonged trials with nifedipine as an antihypertensive agent will be needed before conclusions can be drawn on these particular aspects.

The influence of a 6-week intervention on factors thought to be related to ectopic cardiac rhythms was tested in normal men with frequent ventricular premature contractions (VPCs), using a randomized, controlled and partial crossover design. The VPC intervention trial experimental regimen included total abstinence from caffeine and smoking, reduction of alcohol intake, and a physical conditioning program. Effects were studied in detail among 81 healthy men with persistent VPCs. VPCs were measured during standard states of rest, dynamic and isometric exercise and other stresses, and 24-hour ambulatory monitoring. Adherence to the treatment was excellent. The experimental group achieved more than 80% of activities asked of them, and little "contamination" occurred in the control group. VPCs were analyzed according to VPC/min, VPC/man and VPC/total number of heart beats. Moderate changes in VPC rates occurred in both experimental and control groups but no significant group differences were found at rest or during any induction test. This 6-week, multiple-factor "hygienic" intervention program had no significant influence on the frequency or occurrence of VPCs in apparently normal men with persistent and frequent VPCs. Because the mechanisms and the significance of VPCs are different in patients with ischemic heart disease, our approach and methods may be useful for similar trials among cardiac patients of adjunct or non-drug therapy for ectopic rhythms.

A 1-year, randomized study was conducted to test the possibility of improving compliance with therapeutic regimens in hypertensives by means of certain simple arrangements. Patients were given written treatment instructions concerning hypertension, a personal blood-pressure follow-up card, and, for those who failed to attend their blood-pressure check-up, an invitation for a new check-up. Using matched pairs, 202 Finnish hypertensives were randomly allocated either to an ordinary or a reorganized treatment group. By means of the latter system, patient compliance could be significantly (p less than 0.01) improved: Only 4% of the patients in this group dropped out of treatment, compared with 19% in the ordinary treatment group. By the end of the year, blood pressure had been lowered by at least 10% in 95% of the patients in the reorganized group and in 78% of those in the ordinary group (p less than 0.01). This was achieved in approximately 60% of cases using chlorthalidone alone.

The effect of the vasodilator prazosin vs placebo on exercise duration until marked dyspnea, and on left ventricular function measured by echocardiography, was evaluated in a double-blind, randomized study in 24 patients with chronic left ventricular failure despite digitalis and diuretic therapy. Compared with the double-blind placebo, prazosin reduced resting systolic and diastolic blood pressure and systolic blood pressure times heart rate, improved clinical symptoms, decreased cardiothoracic ratio measured by chest roentgenography, decreased left ventricular and left atrial dimensions, improved ejection fraction and Vcf measured by echocardiography, and improved treadmill exercise duration. All 12 patients taking prazosin had greater than or equal to 20% improved treadmill exercise duration; none of 12 receiving placebo improved. In six of 12 patients taking prazosin, roentgenographic evidence of pulmonary venous congestion disappeared compared with none of the patients on placebo. These data suggest that prazosin may be effective in treating chronic left ventricular failure.

Verapamil, a calcium antagonist, has been used extensively for treatment of cardiac arrhythmias. Concern persists, however, that it may seriously depress myocardial function in cardiac patients. To investigate this possibility, 20 patients with coronary artery disease (CAD) but no heart failure were given intravenous verapamil (0.1 mg/kg bolus, followed by 0.005 mg/kg/min infusion), and studied hemodynamically and angiographically. Verapamil markedly lowered mean aortic pressure (94 +/- 17 to 82 +/- 13 mm Hg, p less than 0.0005) and systemic vascular resistance (1413 +/- 429 to 1069 +/- 235 dyn-sec-cm5, p less than 0.0005). Simultaneously, all indices of left ventricular (LV) performance greatly improved: cardiac index rose from 2.8 +/- 0.6 to 3.1 +/- 0.7 1/min/m2 (p less than 0.0005), mean velocity of circumferential fiber shortening increased from 0.85 +/- 0.39 to 0.97 +/- 0.46 circ/sec (p less than 0.01), and ejection fraction improved from 55 +/- 16 to 61 +/- 18% (p less than 0.01). No significant changes were noted in the heart rate before and after verapamil administration, and verapamil did not worsen the extent of LV asynergy in the majority of patients. In patients with CAD, the intrinsic negative inotropic effect of verapamil is of negligible importance because its potent vasodilatory properties more than compensate for any intrinsic decrease in LV contractility, and thereby improve the overall cardiac function.

Long-term effects of diet and colestipol (a bile acid sequestrant) were studied in 25 patients with familial type II hyperlipoproteinemia. Serum lipids and body weights of an initial group of 30 patients were stabilized by low cholesterol-saturated fat-refined carbohydrate diet and the patients were then randomized into placebo and drug-treatment groups. After explaining that the drug is nontoxic and effective in lowering serum lipids, total cholesterol (C) and low-density lipoprotein cholesterol (LDL-C), colestipol (30 g/day) and diet were given to the 25 patients who remained in the long-term follow-up program. The treatment resulted in highly significant lowering of serum lipids (mg/dl, mean +/- SEM): C and LDL-C from 412.7 +/- 24.4 and 331.1 +/- 22.8 to 270 +/- 11.0 and 188.1 +/- 13.8, respectively (p less than 0.001 in each instance) over 7--7 1/2 years. Although we observed no absolute increase in high density lipoprotein (HDL), the HDL/LDL ratio was elevated. Long-term colestipol and diet treatment reduced the xanthoma size and stabilized serially angiographically visualized atherosclerotic lesions in 21 of the 25 patients who showed a satisfactory hypolipemic response. It did not cause nutritional or metabolic disturbances.

We assessed the effects of ethanol and autonomic blockade on left ventricular function in nine normal subjects, age 20--35 years, using M-mode echocardiography and systolic time intervals. On day 1, measurements were made of heart rate, mean velocity of circumferential fiber shortening, and left ventricular pre-ejection period and left ventricular ejection time ratio (PEP/LVET), during a control period and after autonomic blockade. Autonomic blockade was produced with intravenous propranolol (0.2 mg/kg body weight) and atropine (0.04 mg/kg body weight). On day two, measurements were again made during a control period, then with ethanol alone, followed by addition of autonomic blockade to ethanol. One hundred eighty milliliters of ethanol were ingested over 60 minutes, resulting in a mean blood ethanol level of 110 mg/dl (range 77--135 mg/dl) at 60 minutes post-ingestion. There were no significant differences between the control data on days 1 and 2. Blood pressure was unchanged throughout the study. study. On day 1, autonomic blockade alone resulted in the expected increase in heart rate (p less than 0.001), with a proportional increase in mean velocity of circumferential fibr shortening (p less than 0.01), and an increase in PEP/LVET (p less than 0.01). On day 2, ethanol alone resulted in no significant changes except for a slight increase in PEP/LVET (p less than 0.02). Ethanol plus autonomic blockade, (day 2), compared with autonomic blockade alone (day 1), revealed a decrease in mean velocity of circumferential fiber shortening (p less than 0.05), and an increase in PEP/LVET (p less than 0.01), with a decrease in intrinsic heart rate (p less than 0.001). We conclude that in normal subjects: 1) autonomic blockade does not directly affect contractility; 2) acute ethanol ingestion alone does not produce important changes in cardiac function; and, 3) ethanol in the autonomic blockaded heart causes a significant decrease in contractility. Thus, we infer that ethanol has a negative inotropic effect which is masked by catecholamines and/or autonomic nervous system discharge.

Twenty-six patients with unstable angina pectoris had biplane left ventricular (LV) angiograms and coronary arteriograms (CAGs) initially and at a median of 1 year following randomization to medical (15 patients) or surgical 11 patients) therapy. Left ventricular segmental wall motion was analyzed by a digital computer yielding segmental ejection fraction for 10 zones along the LV perimeter. Baseline and follow-up CAGs were analyzed simultaneously by one observer, and changes in LV segmental coronary perfusion were estimated. Left ventricular angiograms were analyzed separately from CAGs and independently of knowledge of changes in estimated segmental coronary perfusion. Left ventricular segmental wall motion was more frequently improved in surgical patients than in medical patients. Furthermore, in surgical patients there was a significant correlation between changes in LV segmental wall motion and perfusion to LV segments supplied by the left anterior descending coronary artery, whereas no such correlation for any segment was found in the medical group. Thus, this prospective randomized study suggests that, in patients with unstable angina, coronary revascularization may significantly improve LV segmental wall motion compared to medically treated patients. In the surgical group, improvement in LV wall motion relates to improvement in coronary perfusion to the segments supplied by the left anterior descending artery.

The effect of propranolol (0.1 mg/kg intravenously followed by 320 mg given over 27 hour orally) on serum levels of creatine kinase enzyme was studied in a randomized trial involving 95 patients seen within 12 hours of onset of symptoms of uncomplicated myocardial infarction. In 15 patients who were treated with propranolol within 4 hours of onset, and who eventually developed pathological Q waves, peak measured enzyme levels were 27% (P less than 0.0125) lower than in 19 control patients who were also seen within 4 hours of the onset but had no specific treatment. Total calculated enzyme appearance was also lower in the treated patients (reduced 25%, P less than 0.05) as was the calculated rate of the appearance (33%, P less than 0.005). No significant difference was found for treated compared with control patients entering the trial more than 4 hours after the onset of chest pain. This evidence suggests that propranolol may reduce the size of uncomplicated infarctions if it is given intravenously within 4 hours of the onset.

Systolic time intervals, stroke volume, cardiac output and (dZ/dt)/RZ index were serially estimated in 51 normal healthy volunteers at sea level, for ten days after air induction to 3658 m altitude and on return to sea level. The subjects were divided into three groups and were administered a diuretic, beta methyldigoxin and placebo in a double blind protocol. The group on placebo showed an increase in heart rate, reduction in stroke index and cardiac index during high altitude exposure with normalization on return to sea level. A deterioration in left ventricular function as manifested by prolongation of pre-ejection period, increase in PEP/LVET ratio, reduction in (dZ/dt)/RZ index and left ventricular ejection time was also noted at high altitude. The subjects on digoxin maintained normal stroke/cardiac index and did not show any significant changes in the parameters of myocardial function. The diuretic group showed more deterioration in the parameters than the placebo group. No significant side effects were noted. Left ventricular dysfunction and reduction of stroke index at high altitudes may be causually related; digoxin administration may prevent them from occurring.

In Part I of this study, the in-hospital course of 219 patients who had undergone a cardiac operation is analyzed. Fever (greater than or equal to 37.8 degrees C, rectal) was present after postoperative day 6 in 159 patients (73%) and was of unexplained cause in 118. Fever decay in the population of unexplained fever patients was exponential. All patients with unexplained postoperative fever were afebrile by postoperative day 19. In-hospital pericardial rub and pleuritic chest pain, widening of the mediastinum on chest film, and pleural effusion were not specifically associated with unexplained postoperative fever. In Part II, 67 patients with unexplained postoperative fever were given indomethacin (100 mg per day) or placebo for 7 days by a randomized, double-blind protocol. Indomethacin resulted in a shorter duration of fever (2.4 vs 3.5 days, P is less than 0.01) and in a shorter duration of chest pain, malaise, and myalgias compared to placebo. Sixty-seven percent of the patients in Part I and all of the patients in Part II were contacted 2-8 months following hospital discharge. Five percent had experienced an illness that we considered to be acute pericarditis, but its occurrence was unrelated to whether the patient had had in-hospital unexplained postoperative fever, in-hospital rub or chest pain, or in-hospital administration of indomethacin.