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Nifedipine gastrointestinal therapeutic system (GITS) is a once-daily formulation of nifedipine that provides stable plasma concentrations over the entire 24 h dosing interval. Two-hundred and one patients with Canadian Cardiovascular Society class II to III angina who were on 50 mg of atenolol yet still experiencing angina symptoms were randomized to receive either placebo or nifedipine GITS 30, 60 or 90 mg/day. After four weeks of treatment, the changes in time from baseline to onset of 1 mm ST segment depression in the 183 eligible patients were 26.7+/-10.2 s, 40.9+/-11.3 s, 63.2+/-12.9 s and 70.3+/-12.6 for the placebo, and 30, 60 and 90 mg/day groups, respectively. These differences were significant (P0.05) for the 60 and 90 mg/day groups compared with placebo and for the 60 mg/day group compared with the 30 mg/day group. The times to onset of pain and termination of exercise showed similar prolongation but did not achieve statistical significance. During the one-year open label phase of the study, patients exhibited statistically significant improvements in the time to onset of ST segment depression, time to anginal pain and time to termination of exercise at a mean dose of 52.3 mg/day of nifedipine GITS. Adverse events were primarily vasodilatory in nature. This study supports the use of nifedipine GITS in patients with chronic stable angina inadequately controlled on beta-blocker alone.

This study compared exercise and pharmacologic stress testing using arbutamine delivered by a closed-loop device for the detection of coronary artery disease.Arbutamine, an agent designed to simulate exercise, has been developed in conjunction with a closed-loop delivery device that modulates the rate of administration on the basis of physiologic feedback.Two hundred ten patients (180 men, 30 women) with symptoms and angiographic evidence of coronary artery disease were studied. Ischemia was categorized in three ways: 1) the presence of angina; 2) the occurrence ofor = 0.1-mV horizontal or downsloping ST segment depression or elevation at 60 ms after the J point; or 3) the presence of either condition 1 or 2.In the 210 patients, the mean increase in heart rate and systolic blood pressure evoked by arbutamine and exercise was 51 and 53 beats/min (p = NS) and 36 and 44 mm Hg (p0.0001), respectively. Arbutamine detected ischemia more often than exercise with each of the three ischemic end points. Sensitivity for detecting ischemia by either angina or ST segment change was 84% (95% confidence interval ¿ change was 84% (95% confidence interval [CI] 79% to 89%) for arbutamine and 75% (95% CI 69% to 81%) for exercise testing (p = 0.014). For angina alone, sensitivity was 73% (95% CI 67% to 79%) for arbutamine and 64% (95% CI 57% to 71%) for exercise (p = 0.026). For ST segment change alone, sensitivity was 47% (95% CI 40% to 54%) for arbutamine and 44% (95% CI 37% to 51%) for exercise (p = 0.426). Cardiac events occurred in five patients (1.8%) within 24 h of the arbutamine test.In detecting documented coronary artery disease, the sensitivity of arbutamine testing was equal to that of exercise for the electrocardiographic end point of ST segment change alone. Arbutamine testing was significantly superior to exercise testing for either ST change or angina or for angina alone.

Myocardial rejection is most apt to occur in the first 90 days after heart transplantation. Nevertheless, surveillance endomyocardial biopsies are often performed on a regular basis, indefinitely. The benefit of this approach to patient management is uncertain. Our objective was to determine the frequency of abnormalities and the influence of a routine annual endomyocardial biopsy on patient management.In a consecutive series of 235 transplant recipients who survived 1 year or more, the results of 1123 routine endomyocardial biopsies performed 1 year or more after transplantation were reviewed. The incidence of late rejection, presence of Quilty effect (focal endocardial or myocardial lymphocytic aggregates), and therapeutic reaction to the biopsy result were analyzed.Of 1123 biopsy specimens in 235 patients (1 to 12 years after transplantation), 1115 (99.3%) showed no evidence of significant rejection (grade 0 or 1). Only seven (0.6%) had evidence of rejection grade 2 or worse. Of the seven abnormal biopsy specimens in seven patients, two occurred at 1 year, two at 2 years, and one each at 4, 7, and 8 years. Of these, six were treated for rejection with an increase in the immunosuppressive therapy. One patient was identified as having a symptomatic condition at the time of biopsy. A focal endocardial or myocardial accumulation of lymphocytes (Quilty effect) was present in 311 biopsy specimens (27.6%). Beyond 1 year, 33 patients died, 14 because of graft vascular disease with or without rejection and 19 because of other causes. No deaths were predicted on the basis of a routine surveillance biopsy.Myocardial rejection is rare beyond 1 year after transplantation. The routine endomyocardial biopsy does not significantly impact patient management beyond 1 year. A selective approach to myocardial biopsies, on the basis of a change in clinical status or immunosuppressive medications, is justified.

To evaluate the physiologic basis for the suboptimal peak oxygen uptake observed after heart transplantation, we calculated the functional aerobic impairment ([(peak predicted oxygen uptake-peak observed oxygen uptake)/peak predicted oxygen uptake] x 100) and related it to donor/recipient, operative, and maximal exercise variables. Fifty-seven heart transplant recipients (mean age 50 +/- 10 years, 1 to 9 years after transplantation) underwent maximal upright cycle exercise testing. Concomitant exercise central hemodynamic measurements were obtained in 36 patients (63%).The mean peak oxygen uptake was 21.7 +/- 6.5 ml/kg/min and functional aerobic impairment was 34% +/- 17%. Functional aerobic impairment correlated positively (p0.01) with peak systemic vascular resistance (r = 0.55) and negatively with peak cardiac index (r = -0.62) and peak systemic arteriovenous oxygen difference (r = -0.66). A weak correlation was found between functional aerobic impairment and the duration of cardiac disease (r = 0.35, p0.01) but not the origin of heart failure. No correlation was seen between functional aerobic impairment and donor age, total ischemic time, time since transplantation, recipient age, and resting and exercise right and left ventricular filling pressures.These results suggest that the decreased exercise capacity observed in heart transplant recipients is in part due to increased peripheral vascular resistance and decreased oxygen extraction possibly due to skeletal muscle atrophy. These factors may be the result of irreversible changes from long-standing heart disease, deconditioning, or the effect of cyclosporine and prednisone.

Hypercholesterolemia, a common problem after heart transplantation, may be important in the genesis and progression of allograft coronary artery disease. The current study was performed to compare the efficacy of gemfibrozil, simvastatin, and cholestyramine for cholesterol lowering in heart transplant recipients.In this prospective 1-year study, 48 heart transplant recipients with moderate hypercholesterolemia were randomized to therapy with gemfibrozil 600 mg twice daily (n = 17), simvastatin 10 mg daily (n = 13), and cholestyramine 4 gm twice daily (n = 18). Detailed lipoprotein analysis was performed at baseline and after 3, 6, and 12 months of treatment.Total cholesterol and low-density lipoprotein cholesterol were reduced 19% and 29%, respectively, after 3 months of simvastatin therapy (p0.0001) with a sustained reduction in total cholesterol (25%) and low-density lipoprotein cholesterol (39%) at 1 year. Gemfibrozil and cholestyramine treatment did not result in a reduction in cholesterol levels. Apolipoprotein B levels were reduced by 29% at the end of 1 year with simvastatin but not with the other treatments. Serum triglyceride levels were reduced significantly by treatment with gemfibrozil (up to 36%, p0.01) but not by the other treatments. High-density lipoprotein cholesterol initially rose in patients treated with simvastatin and gemfibrozil; however, this effect did not persist to 12 months. However, the ratio of low-density lipoprotein/high-density lipoprotein was favorably affected by simvastatin, with a 38% reduction by 12 months (p0.0001) but not by the other treatments. Over the course of 1 year, 14 patients dropped out of the study: four from the gemfibrozil arm and ten from the cholestyramine arm. Gastrointestinal intolerance was the most common reason for study termination (8 of 14). All patients in the simvastatin treatment arm completed 12 months of therapy. No biochemical abnormalities resulted from any therapy, and no therapy caused significant alteration in cyclosporine blood levels.Of the three therapies studied, simvastatin was found to be the most efficacious and well tolerated for cholesterol lowering in patients after heart transplantation.

A case control study was performed to determine whether previous implantable cardioverter-defibrillator (ICD) insertion adversely affects outcome after heart transplantation. Six male heart transplant recipients who had undergone ICD insertion 12 +/- 5 months before heart transplantation were compared to a cohort of six heart transplant recipients who were matched according to age, preoperative status and hemodynamics, date of transplantation, graft ischemic time, history of a previous cardiac operation, and duration of follow-up. There were no significant differences in operating room time, chest tube drainage, time to extubation, and the duration of intensive care unit or hospital stay between the two groups. Furthermore, there were no significant differences in the number of units of packed cells, fresh frozen plasma, platelets and cryoprecipitate transfused. The number of treated rejection episodes and the number of patients requiring intravenous antibiotics for infection in the first 90 days was identical between groups. It was concluded that heart transplantation after ICD implantation did not appear to carry more risk than heart transplantation after a previous cardiac operation. Our limited experience supports the potential use of the ICD in patients with life-threatening ventricular dysrhythmias who are awaiting transplantation.

Thirty-nine heart transplant recipients were randomized prospectively to receive OKT3 or antilymphoblast globulin (ALG) for 7 days, having otherwise identical protocols (group 1: OKT3, n = 20 patients; group 2: ALG, n = 19 patients). No preoperative immunosuppression was given. The protocol consisted of methylprednisolone, 500 mg intraoperatively, followed by 1 mg/kg/day, intravenously or orally, tapering to 0.2 mg/kg/day at 1 month; oral cyclosporine starting 3 to 5 days after transplantation; selective use of azathioprine, 1 to 4 mg/kg/day; and either OKT3, 5 mg/day for 7 days, or ALG, 15 mg/kg/day for 7 days. Of the 39 patients in the study, 34 are alive 6 months to 2 years after transplantation. The actuarial survival at 2 years for the OKT3 and ALG groups was 92% (+/- 0.07%) and 83% (+/- 0.09%), respectively (not significant [NS]). The time to first rejection for group 1 was 5.6 weeks and for group 2 was 5.3 weeks (NS). The mean number of rejections for group 1 and group 2 was 2.1 episodes per patient and 1.4 per patient, respectively (NS). Three patients in each group were free of rejection at 6 months. The total number of infections at 6 months was 1.05 per patient in group 1, 0.74 per patient in group 2 (NS), with 35% of patients receiving OKT3 and 52% of patients receiving ALG actuarially free of infection by 6 months after surgery (NS). During the first 24 hours after surgery, no significant differences were noted in mean blood pressure, central venous pressure, or Po2 between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Central hemodynamic responses during upright exercise were studied at 1 year in 40 orthotopic cardiac transplant recipients. Hemodynamic responses were characterized by slow rise in heart rate and blunted peak exercise heart rate response, a significant early increase in stroke index followed by a plateau phase, and a steady increase in ventricular filling pressures and pulmonary artery pressure. In spite of exclusive utilization of the Frank-Starling mechanism to augment cardiac output during early exercise, the pressure responses were comparable to those reported in normal subjects. Our observations also indicate that similarly to normal subjects, the heart rate response plays an important role in the cardiac output achieved at maximum exercise. Although patients with younger donor hearts achieved a more favorable maximum heart rate, the other hemodynamic parameters showed no correlation with the donor heart age. Thus, no hemodynamic disadvantage of older donor hearts could be demonstrated. These data provide further enlightenment regarding the mechanisms of the well-preserved functional capacity noted in these patients.

The evolution of resting hemodynamics was studied at 1 week and 1 year in 40 patients following orthotopic cardiac transplantation. Abnormal hemodynamics after transplantation, characterized by elevated ventricular filling pressures (indicating diastolic dysfunction) and also by pulmonary hypertension, showed normalization by 1 year. In the absence of innervation, the resting heart rate of heart transplant recipients should theoretically be close to the intrinsic heart rate predicted by the age of the donor heart. In this study, a high incidence of relative sinus bradycardia (an indicator of sinus node dysfunction) was noted in the first post-operative week, although again there was a tendency to normalization by 1 year. These beneficial changes help to explain the dramatic and sustained improvement in the functional capacity of these patients late after transplantation.

BACKGROUND Although progressive chronic congestive heart failure (CHF) is associated with elevated systemic vascular resistance and increased impedance to ventricular outflow, the contribution of changes in large artery function has not been well documented in humans. METHODS AND RESULTS We studied 45 patients with a broad range of clinical severity of CHF and compared noninvasive measurements of brachial artery diameter, flow, and pulse wave velocity with 22 normal controls of similar age. In CHF, mean arterial pressure was lower than in controls (85 +/- 1 versus 93 +/- 2 mm Hg, p less than 0.001), as were brachial artery diameter (4.07 +/- 0.10 versus 4.53 +/- 0.09 mm, p less than 0.001), flow (40.9 +/- 4.1 versus 70.9 +/- 11.5 ml.min-1, p less than 0.02), compliance (1.29 +/- 0.12 versus 2.00 +/- 0.18 cm4.dyne-1.10(-7), p less than 0.002), and conductance (0.49 +/- 0.05 versus 0.76 +/- 0.13 units, p = 0.06). Limb vascular resistance (40.2 +/- 5.0 versus 20.5 +/- 3.1 units, p less than 0.001) and pulse wave velocity (10.6 +/- 0.5 versus 9.2 +/- 0.4 m.sec-1, p less than 0.03) were higher than in controls. Brachial artery diameter was progressively lower than in controls as severity of CHF increased (New York Heart Association class II, 4.47 +/- 0.23 mm, p = NS; class III, 4.05 +/- 0.10 mm, p less than 0.05; class IV, 3.71 +/- 0.28 mm, p less than 0.05). Similar changes were observed for arterial compliance (class II, 1.76 +/- 0.32 cm4.dyne-1.10(-7), p = NS; class III, 1.21 +/- 0.13 cm4.dyne-1.10(-7), p less than 0.05; class IV, 0.95 +/- 0.10 cm4.dyne-1.10(-7), p less than 0.05). While the lower arterial pressure and flow might be expected to passively reduce arterial diameter, this would be associated with a reduced pulse wave velocity and improved arterial compliance, yet the opposite was observed. Differences in large artery function were not likely caused by underlying atherosclerosis alone, because patients with dilated cardiomyopathy and patients with ischemic heart disease of the same sex, age, left ventricular ejection fraction, and exercise treadmill duration had similar changes in large artery function. CONCLUSIONS We conclude that alterations in brachial artery function are present in patients with moderate and severe CHF. The observed reduction in arterial compliance, if present diffusely throughout the arterial tree, could increase left ventricular end-systolic stress directly and through increased velocity of reflected pressure waves from the periphery.

Of 219 heart transplant patients with follow up for at least 3 months after transplantation, cardiac allograft ischemic time was more than 4 hours in 28% and more than 5 hours in 10%. In 1988 and 1989 grafts with ischemic times longer than 4 hours were used in 44% and 45% of cases, respectively. Overall, donor age has been 35 or more years in 22% and 45 or more in 9%. In 1989 donor age was 35 or more years in 39% of cases and 45 or more in 18%. Fifteen of 20 grafts from donors 45 years or older were used for patients aged 50 or older. There was no relationship between donor age or ischemic time and 90-day graft loss. At 3 and 12 months, cardiac function, assessed by treadmill exercise duration, radionuclide angiography, and rest and peak supine exercise hemodynamics, was also unrelated to donor age or ischemic time. Therefore by careful selection of appropriate donors, extending both graft ischemic time and donor age has increased the potential donor pool and has not to date been associated with increased graft loss or adverse effects on cardiac function 3 months and 1 year after heart transplantation.

The results of heart-lung transplantation are improving with increasing experience in postoperative management, but obliterative bronchiolitis may still develop late postoperatively. We have performed 19 heart-lung transplants, with 1-month, 1-year, and 2-year actuarial survival rates of 95% +/- 5%, 84% +/- 8%, and 69% +/- 16%, respectively. Three early recipients died of bronchiolitis, and four patients who were operated on more than 2 years ago are currently being followed up with bronchiolitis. Since August 1988, 13 surviving recipients have undergone serial postoperative bronchoscopies and transbronchial biopsies with topical analgesia. Diffuse bronchomalacia, involving the main bronchi down to the fifth-order bronchi bilaterally, has developed in four patients with bronchiolitis 9 +/- 2 months after the diagnosis of bronchiolitis was confirmed. Pulmonary function tests have revealed a lower ratio of forced expiratory volume in 1 second to forced vital capacity, lower specific airway conductance, and higher airway resistance in heart-lung recipients with bronchomalacia than in patients with bronchiolitis alone. We conclude that diffuse bronchomalacia occurs frequently in heart-lung transplant recipients who have obliterative bronchiolitis. Bronchomalacia worsens the functional airflow obstruction caused by bronchiolitis and may play an important role clinically in the declining respiratory status of heart-lung transplant recipients.

Twenty-four patients were randomized to a double-blind, triple placebo controlled, latin square protocol to examine the relative efficacy of propranolol or diltiazem given as monotherapy or in combination with isosorbide dinitrate. Treatment phases were preceded and followed by placebo control periods. At the end of each phase, symptom-limited treadmill exercise stress tests were performed, as well as rest and exercise radionuclide ventriculography. Both forms of monotherapy were effective in reducing episodes of angina and nitroglycerin use, and in improving exercise tolerance. Diltiazem monotherapy was associated with slightly higher treadmill times (509.9 +/- 123 s) compared to propranolol (462.7 +/- 131 s, P less than 0.05). The addition of isosorbide dinitrate to either form of monotherapy allowed no further improvement in any of the measured clinical responses. Radionuclide ventriculography showed no significant difference in resting left ventricular function. The addition of isosorbide dinitrate to propranolol showed a reduction in end diastolic volume in keeping with a reduction in preload. In response to exercise, stress-induced left ventricular dysfunction was equal in all groups except for the diltiazem-nitrate combination, which was associated with a higher ejection fraction (56.2 +/- 8.6%) compared to monotherapy (52.6 +/- 10.9%, P less than 0.01). A higher cardiac output could be achieved in the groups treated with diltiazem; this was related to increased heart rate and maintenance of stroke volume. It was concluded that diltiazem is equally effective as propranolol for the treatment of chronic stable angina and, in terms of exercise capacity and cardiac output, superior to beta-blockade. The addition of isosorbide dinitrate appears to impart no overt benefits, but some evidence suggests a reduction in left ventricular decompensation in the face of stress.

Milrinone is a nonglycoside, nonsympathomimetic bipyridine with positive inotropic and systemic vasodilator properties. In order to evaluate the efficacy and safety of a short term infusion of milrinone, 105 patients with stable New York Heart Association (NYHA) class III or IV heart failure received a loading dose (50 micrograms/kg) and a 48 h continuous infusion (0.5 micrograms/kg/min). Administration of the loading dose resulted in a 28% decrease in pulmonary capillary wedge pressure (PCWP) (P less than 0.001), a 38% increase in cardiac index (P less than 0.001), and a 34% increase in stroke volume index (P less than 0.001) within 15 mins. Milrinone infusion maintained an average 27% and 24% reduction in PCWP during the first and second days, respectively (P less than 0.001). Cardiac index was 32% and 34% above baseline during the same intervals (P less than 0.001). There were no clinically significant changes in heart rate or mean arterial blood pressure during the study period. In a subset of 47 patients who underwent Holter monitoring before and during infusion, a significant increase in ventricular arrhythmias (premature ventricular complexes per hour, ventricular couplets per hour and ventricular runs greater than or equal to three) was demonstrated (P less than 0.0001). In general, milrinone was well tolerated. Of the 105 patients entered, one died of an acute myocardial infarction after premature termination of the infusion, and the infusion rate was decreased in two others because of supraventricular arrhythmias. In patients with severe heart failure, intravenous milrinone has significant beneficial hemodynamic effects. ECG monitoring for arrhythmias is recommended during milrinone infusion.

To reduce perioperative hemorrhage following heart-lung transplantation, several technical modifications were introduced in June 1988 to secure better posterior mediastinal hemostasis. The intraoperative and postoperative use of blood and blood products, as well as the chest tube drainage in the first 24 hours postoperatively, were compared in the seven patients operated on since June 1988 with the nine patients operated on before that date. Significant (p less than 0.05) reductions were demonstrated in the intraoperative and postoperative transfusion of packed cells, in the postoperative administration of fresh frozen plasma, and in the chest tube drainage within the first 24 hours postoperatively. The one-month and total hospital mortality rates were 6 percent and 12.5 percent, respectively. It is concluded that newer techniques to obtain optimal posterior mediastinal hemostasis have significantly reduced blood loss following heart-lung transplantation in our experience and have contributed to our excellent early postoperative results.

Congenital heart disease as an indication for heart transplantation accounts for a small number of the total heart transplant experience--less than 3% in most centers. We have performed heart transplantation in eight such patients, accounting for 4% of our total experience. All these patients had specific anatomic anomalies relevant to transplantation. None had morbidity directly related to their anatomic defect and subsequent transplant. Six of the eight had undergone no prior palliative or corrective repairs. One child had a left Blalock-Taussig shunt, and one had bilateral Glenn shunts and a Fontan repair. Technical considerations for orthotopic heart transplantation are described for transposition of the great arteries, left superior vena cava with and without bridging innominate vein, common atrium, presence of Blalock-Taussig shunt, bilateral Glenn shunts, and Fontan repair. Anatomic congenital heart disease is becoming a more frequent indication in heart transplantation. Heart transplantation in the presence of structural congenital heart disease may be technically challenging. Nevertheless, transplantation offers an effective therapeutic alternative for patients with end-stage congestive heart failure and congenital heart disease.

Cibenzoline is a new antiarrhythmic agent with predominant Vaughan-Williams type 1 properties. The safety, tolerance, and adverse effects of incremental single intravenous doses of this agent were investigated. A total of 28 patients received incremental doses of 0.25 mg/kg (four patients), 0.5 mg/kg (five patients), 0.75 mg/kg (seven patients), 1.0 mg/kg (six patients), or 1.2 mg/kg (six patients) cibenzoline. Another six patients received 2.0 mg/kg disopyramide. Left ventricular function by radionuclide ventriculography and plasma cibenzoline levels were measured at frequent intervals. In the patients who received 1.0 mg/kg and 1.2 mg/kg cibenzoline or patients who received 2.0 mg/kg disopyramide, right and left ventricular filling pressures and cardiac output were measured with a Swan-Ganz catheter. At low-dose cibenzoline (0.25 to 0.75 mg/kg) there was a modest drop in ejection fraction (60% ± 7% to 53% ± 7%). With the higher doses of cibenzoline (1.0 or 1.2 mg/kg) there was a more profound fall in ejection fraction (69% ± 8% to 49% ± 8%) that persisted for approximately 2 hours. This was associated with a rise in end diastolic volume index (74 ± 24 to 85 ± 27 ml/m2) and end systolic volume index (29 ± 15 to 43 ± 18 ml/m2) and a fall in cardiac index (2.65 ± 0.62 to 2.14 ± 0.24 L/min/m2). These hemodynamic changes were similar to those of disopyramide infused at a dose of 2.0 mg/kg: a fall in ejection fraction (57 ± 9 to 48 ± 8), rise in end-end diastolic index (81 ± 44 to 95 ± 55 ml/m2) and end systolic volume index (37 ± 22 to 49 ± 26 ml/m2), and a fall in cardiac index (2.51 ± 0.15 to 2.13 ± 0.16 L/min/m2) and stroke volume (39 ± 8 or 30 ±4 ml/m2). After intravenous infusion, cibenzoline results in significant dose-related negative inotropic effects. An infusion of 1.0 to 1.2 mg/kg results in a similar decline in left ventricular function as does disopyramide infused at a dose of 2.0 mg/kg. Clinical Pharmacology and Therapeutics (1987) 41, 537–545; doi:10.1038/clpt.1987.69

Spontaneous regression of a left anterior descending coronary artery lesion was diagnosed by noninvasive testing (stress electrocardiography and thallium-201 myocardial imaging) and confirmed on selective coronary angiography in a 46-year-old man. The patient's clinical improvement, normalization of stress ECG and thallium-201 imaging, together with the loss of collateral filling, confirm that the regression is genuine. This case provides evidence that regression of coronary atherosclerosis can occur in man.

To assess the hemodynamic influence of posture during radionuclide cardiac studies, rest and exercise electrocardiographically gated blood pool cardiac scintigraphy was performed in the supine and sitting positions in 22 normal subjects and in 20 patients with coronary artery disease (CAD). In normal subjects, left ventricular ejection fraction was higher in the sitting position both at rest (67 +/- 6% versus 64 +/- 5%, p less than 0.01) and during exercise (79 +/- 9% versus 76 +/- 6%, p less than 0.05). Left ventricular end-diastolic volume in the sitting position was smaller at rest (by 19 +/- 26%, p less than 0.001), but this variable was similar in both positions during exercise (p greater than 0.05). Left ventricular end-systolic volume was smaller in the sitting position both at rest, by 26 +/- 31 percent, and during exercise, by 14 +/- 20% (p less than 0.001). Left ventricular end-diastolic volume increased from rest to exercise, in the sitting position by 31 +/- 23% (p less than 0.001) and in the supine position by 6 +/- 22% (p greater than 0.05). In patients with CAD, similar left ventricular ejection fractions in both postures were found at rest and during exercise. Left ventricular end-diastolic volume in the sitting posture was smaller at rest by 16 +/- 22% (p less than 0.01) and during exercise by 8 +/- 18% (p less than 0.05). Sitting left ventricular end-systolic volume was smaller by 18 +/- 20% (p less than 0.001) at rest and by 14 +/- 21% (p less than 0.01) during exercise. Left ventricular end-diastolic volume increased from rest to exercise, in the sitting position by 45 +/- 36% (p less than 0.001) and in the supine position by 32 +/- 51% (p less than 0.01). Despite significant hemodynamic differences, the value of rest-exercise radionuclide cardiac studies to detect CAD was similar in the 2 positions.

To investigate the role of intrinsic sympathomimetic activity on left ventricular (LV) function during antianginal therapy with beta-adrenoreceptor antagonists, 23 patients with chronic, exercise-induced angina pectoris and normal or near normal LV function underwent radionuclide ventriculography at rest and during exercise, during 3 randomly allocated periods: (a) treatment with oral propranolol, a drug without intrinsic sympathomimetic activity, 40 to 80 mg 4 times a day; (2) treatment with pindolol, a drug with marked intrinsic sympathomimetic activity, 5 to 10 mg 2 times a day; and (3) a control period. During the control period, the LV ejection fraction decreased from rest (58.9 +/- 8.2%) to exercise (54.3 +/- 10.7%), and the wall motion score decreased from 0.57 +/- 1.08 at rest to 2.39 +/- 2.10 during exercise, p less than 0.001. After propranolol, the ejection fraction did not change significantly at rest (57.2 +/- 8.1%) but improved during exercise (56.8 +/- 11.8%), compared with control values. After pindolol, the ejection fraction did not change at rest (57.9 +/- 8.6%) but improved during exercise (56.9 +/- 8.1%), compared with control values. Similarly, the wall motion score after administration of both agents did not change significantly at rest, but improved during exercise (p less than 0.001). The number of anginal episodes, nitroglycerin tablets consumed, and magnitude of S-T segment depression decreased significantly with both pindolol and propranolol. With both drugs, a similar improvement in exercise tolerance and a similar decrease in exercise heart rate and blood pressure were obtained. It is concluded that pindolol and propranolol, beta-adrenoreceptor antagonists with and without intrinsic sympathomimetic activity, respectively, have similar effects on global and regional LV function in patients with angina pectoris, at doses producing equal suppression of exercise heart rate and similar antianginal effect.

The effects of mitral valve replacement or commissurotomy on cardiac function were studied using radionuclide ventriculography in 13 patients with chronic mitral stenosis and in 8 with chronic mitral regurgitation, before and after mitral valve surgery. The stenosis resulted from rheumatic heart disease in all instances while regurgitation was due to mitral valve prolapse in three patients and rheumatic heart disease in five. Fourteen patients had a Carpentier-Edwards valve inserted and 4 a Lillehei-Kaster disc valve. Three patients with mitral stenosis had an open commissurotomy. All patients underwent supine-rest and symptom-limited exercise radionuclide ventriculography shortly before and 6 to 12 months after operation. The data obtained showed that left ventricular function remained unchanged postoperatively in patients with mitral stenosis but deteriorated in those with mitral regurgitation. Right ventricular function improved postoperatively in those with mitral stenosis but remained unchanged in patients who had regurgitation.

Six left atrial myxomas were detected at one hospital in a 15-month period. These tumours are not as rare as was once thought and they frequently cause systemic problems. The diagnosis may easily be missed, but echocardiography is a simple way of establishing the diagnosis. Excision of the tumour usually results in marked symptomatic improvement.

The authors have reviewed the literature in search of the coexistence of single coronary artery with significant coronary artery disease. Two cases of single right coronary artery are described. In both, the anomalies were unsuspected and diagnosed roentgenographically in life. Both patients had angina pectoris, positive graded-exercise stress tests, and hemodynamically significant obstruction or occlusion to the coronary arteries. In neither case was the stenosis proximal or amenable to bypass surgery. ImagesFIG. 1FIG. 2

In a 14-month period mitral leaflet prolapse was diagnosed in 85 patients by echocardiography or cineangiography. Chest pain alone was the presenting complaint in 30 patients and linked with palpitation, dyspnoea, or syncope in 9. Eleven presented with major neurological disturbances (9 had transient ischaemic attacks), 10 with palpitation, 4 with undue and persistent fatigue, 2 with dyspnoea, and 2 with dizziness. Seventeen were referred not because of symptoms but because of clicks and murmurs. Overall, chest pain affected 61 patients and unless associated with coronary artery disease was not anginal. Palpitation was admitted by 42 patients; dizziness, lightheadedness, or paraesthesiae by 15, and syncope by 12. Systolic auscultatory abnormalities were noted in 69: 25 had single clicks, 3 had multiple clicks, 19 had both click(s) and murmur, and 22 had a murmur alone. Electrocardiography revealed ST segments flat for greater than 0-10 s in 21, prolonged QTc in 18, and T wave flattening or inversion in inferior limb and lateral chest leads in 14. The exercise stress test was abnormal in 13 of 27 patients. Mitral valve echograms showed definite mitral leaflet prolapse in 61, 'possible' prolapse in 14, and were normal in 8 patients with angiographic proof of mitral leaflet prolapse. Cardiac catheterization with left ventriculography showed prolapse of posterior mitral leaflet in 36, of both leaflets in 2, and left ventricular wall motion abnormalities in 16 cases. Selective coronary arteriography in 31 cases showed major vessel narrowing of larger than or equal to 80 per cent lumen diameter in 4, all with angina. This consecutive series indicates that the physical event of mitral leaflet prolapse is more common than hitherto appreciated, is priminently associated with non-anginal chest pain, palpitation, and neurological disturbances, and in 90 per cent of cases could be shown echocardiographically.

Left ventricular function and volume changes during supine isotonic exercise were assessed in 32 patients with coronary artery disease (CAD) and 12 normal subjects by electrocardiographically gated blood pool cardiac scintigraphy. Ejection fraction (EF) in normal subjects was 49 +/- 10% at rest, 54 +/- 10% during intermediate exercise (P less than 0.05 vs. rest), and 62 +/- 14% during maximal exercise (P less than 0.01 vs. rest). In patients with CAD the resting EF was 42 +/- 14%, 43 +/- 23% at intermediate exercise (P = nonsignificant vs. rest) and 36 +/- 11% at maximal exercise (P less than 0.01 vs. rest). Changes of average and maximal ejection rates from rest to exercise were similar to those of EF but had a lesser degree of statistical significance. End-diastolic volume index (EDVI) in patients with CAD, at intermediate exercise was equal to that at rest, but it increased during maximal exercise (P less than 0.01). In normal subjects EDVI did not change with exercise. Thus, during supine exercise the Frank-Starling mechanism is apparent in patients with CAD but not in normal subjects. Analysis of EF response to exercise is a highly sensitive technique to detect CAD provided that adequate exercise is achieved.

Few studies have assessed the effect of severity of mitral stenosis (MS) on ventricular function. Using equilibrium radionuclide ventriculography to measure ejection fraction and volume changes, 63 patients were studied during supine, symptom-limited exercise. To more carefully assess the 12 patients with MS and impaired left ventricular function, 2 groups of patients were formed. Group I (n = 51) had a normal (less than 50%) resting left ventricular (LV) ejection fraction (EF) and group II (n = 12) had an abnormally low (less than 50%) resting LVEF. Both groups were divided into mild (greater than 1.4 cm2), moderate (1.1-1.4 cm2) and severe (less than 1.0 cm2) MS. There were no differences in mean rest or exercise LVEF for group I. Exercise LVEF increased significantly (p less than 0.05) from rest with mild MS, but not with moderate or severe MS. The decrease in exercise LVEF was due to a decrease in exercise end-diastolic volume of 9 +/- 23% and 15 +/- 18% for moderate and severe MS, respectively. Exercise end-systolic volume decreased normally for all degrees of MS severity. Exercise right ventricular (RV)EF did not increase for any degree of MS severity due to an increase in end-systolic volume. All patients in group II had an RVEF of less than 40%. For this group, severity of MS had no effect on resting LVEF and the response to exercise was similar to group I. We conclude that in patients with MS, resting LVEF is unaffected by MS severity whereas exercise LVEF decreases with increased severity of MS due to impaired diastolic filling.(ABSTRACT TRUNCATED AT 250 WORDS)

Serial electrocardiography, technetium-99m pyrophosphate scintigraphy and measurement of myocardial creatine kinase (CK2) and lactic dehydrogenase isoenzyme activity (specifically the LD1 to LD2 ratio) were evaluated prospectively in 26 patients who underwent aortocoronary bypass grafting and 11 patients who underwent valvular or other thoracic surgery, as methods of diagnosing perioperative myocardial infarction. Of the 26 patients who had aorto coronary bypass grafting, 7 (group 1) had myocardial infarction perioperatively; of these, only 2 had positive results from all four diagnostic tests. The other 19 patients (group 2) had no perioperative myocardial infarction and the only diagnostic method yielding positive results was the LD1 to LD2 ratio, in 7 of the 19. In the 11 patients who did not undergo aortocoronary bypass grafting (group 3), only 1 patient had myocardial infarction perioperatively; results from the measurement of CK2 isoenzyme activity and LD1 to LD2 ratio were positive while electrocardiography and 99mTc pyrophosphate scintigraphy yielded negative results. The respective sensitivity (%) and specificity (%) of the four diagnostic methods were as follows: electrocardiography: 38, 100; 99mTc pyrophosphate scintigraphy: 88, 100; LD1 to LD2 ratio: 100, 68; CK2: 38, 100. When the CK2 criterion was redefined, using patients in group 2 as controls, the sensitivity and specificity of this method became 100 and 90 respectively. The authors conclude that 99MTc pyrophosphate scintigraphy and measurement of myocardial creatine kinase isoenzyme are of comparable value and are the most reliable indicators of perioperative myocardial infarction.

The efficacy of two beta-receptor antagonists, propranolol and pindolol, was compared with that of a calcium antagonist, verapamil, in the treatment of exertional angina pectoris in 22 men (mean age 51 years). The clinical response and left ventricular function were evaluated with treadmill exercise and with radionuclide ventriculography performed while the patient was at rest or exercising supine with a bicycle ergometer. All the treatments significantly prolonged exercise duration (p less than 0.001) and reduced the number of patients terminating treadmill exercise because of angina (p less than 0.05). The resting heart rate was decreased markedly (p less than 0.001) by propranolol but only slightly (p less than 0.05) by pindolol and verapamil. The left ventricular ejection fraction during rest was unchanged by any treatment, but that during exercise was improved (p less than 0.05) by all the treatments. Patients who failed to gain relief from angina with one of the drugs often responded to another, and adverse reactions occurring with one drug did not necessarily occur with another. In summary, pindolol and verapamil were safe and effective alternatives to propranolol in the treatment of the exertional angina pectoris of these patients.

The possible value of myocardial imaging with 201thallium as a screening procedure for the detection of latent disease has not been previously shown. Fifty-eight asymptomatic men underwent exercise 201thallium imaging together with a risk score profile based on the Framingham criteria for predicting future coronary events. Six subjects (10%) developed perfusion defects compatible with myocardial ischemia. The risk score for the population with an abnormal test was 7.7 +/- 2.9%, compared to 2.0 +/- 2.2% (p less than 0.001) for those men with normal tests. Three of the subjects with abnormal scans underwent selective coronary arteriograms; all three had normal coronary arteries. During a 30-month follow-up, all individuals remained physically active and free of cardiac symptoms. Exercise myocardial imaging is not a cost-effective means of detecting coronary artery disease in an asymptomatic population and should not be used as a screening procedure.

Regular tachycardia with wide QRS complexes may be difficult to classify as supraventricular (SVT) or ventricular (VT) without electrophysiologic studies. We felt that hemodynamic differences between VT and SVT should allow their distinction by echocardiography. In this study, we utilized high speed M-mode echocardiography in the usual projections in eight patients during tachycardia. Two patients had spontaneous VT and three had spontaneous SVT with aberrant conduction. The remaining three were patients in sinus rhythm undergoing electrophysiologic studies in whom right ventricular (RV) pacing (induced VT), right atrial (RA) pacing (induced SVT) and sequential RV-RA pacing (induced VT with 1:1 retrograde conduction) were carried out. The echocardiographic parameters studied included: left ventricular internal dimensions, time during which the mitral valve remained open (MVOT), left ventricular ejection time (LVET) and pre-ejection period. We measured 20 consecutive beats and for each parameter defined its variability. During A-V dissociation (VT, RV pacing) there was always a striking beat-to-beat variability in the values of MVOT (68 percent to 129 percent) and in LVET (41 percent to 175 percent). In contrast, during A-V association (SVT, sequential RV-RA pacing, sinus rhythm) the maximal variability of MVOT and LVET was 22 percent and 12 percent, respectively. Variability during A-V dissociation could be explained by asynchronous timing of atrial systole. We conclude that echocardiography can readily identify atrioventricular dissociation, a feature heavily in favor of a diagnosis of VT.

Between May 1980 and April 1981 four patients were referred to one hospital with syncope or recurrent ventricular fibrillation while taking antiarrhythmic or phenothiazine drugs. In all the patients ventricular tachyarrhythmias with the characteristics of torsades de pointes were documented in association with prolonged QT intervals. With removal of the offending agent (in all the patients) supplemented by temporary overdrive pacing (in two patients) the tachyarrhythmias subsided. This study suggests that drug-induced torsades de pointes is an important clinical entity that occurs more frequently than has been suspected.

In a previous report from our laboratory, visual assessment of wall motion in patients with coronary artery disease demonstrated no advantage for pindolol, a beta blocking agent with intrinsic sympathomimetic activity (ISA), over propranolol on impaired regional left ventricular (LV) function. In this study, we reanalyzed the radionuclide ventriculograms using a computer-assisted method of deriving regional ejection fraction. Use of normalized values allowed hypokinetic and normokinetic segments to be identified and examined separately. Pindolol (5-10 mg twice a day) was compared to propranolol (40-80 mg 4 times a day) in 23 patients using a randomized, crossover study design. Supine resting heart rate was reduced less (70 +/- 12 beats/min vs 63 +/- 10 beats/min, p less than 0.01) by pindolol; exercise heart rate was reduced equally by both agents. Derivation of normalized regional LV ejection fractions showed that 17 segments were hypokinetic at rest. Function of these segments increased (p less than 0.02) with pindolol. This improvement was not detected by visual assessment of regional wall motion. Thirty-seven segments were found to be hypokinetic during exercise and a significant (p less than 0.05) improvement in function occurred with pindolol and propranolol. In summary, derivation of normalized regional LV ejection fraction values allows the demonstration of significant improvement in resting LV function with pindolol, but not with propranolol in patients with regional dysfunction due to coronary artery disease. This advantage may provide a rationale for further evaluation of this agent in patients with more widespread ventricular dysfunction.

Short-term amrinone therapy has been shown to exert beneficial hemodynamic effects in patients with heart failure. To determine whether this improvement persists longer, the effects of maximally tolerated doses of amrinone on exercise duration, oxygen consumption, and left ventricular function and volumes were examined during maintenance therapy. After four weeks of amrinone therapy, 75 to 150 mg three times a day (mean 292 +/- 70 mg daily), treadmill exercise duration, maximal oxygen consumption, and functional class were unchanged from control values. Radionuclide-derived ejection fraction and end-diastolic and end-systolic volumes were not altered at rest or during maximal supine exercise. Similarly, significant changes in echocardiographic end-systolic and end-diastolic dimensions did not occur. This lack of clinical benefit on functional capacity and left ventricular function, together with frequent adverse reactions, will limit the application of amrinone in the treatment of heart failure. These findings are relevant to the investigation of amrinone-like derivations presently being studied for the treatment of heart failure. Before their release, these agents will require careful evaluation and demonstration of a therapeutic action during maintenance therapy, together with a low incidence of adverse reactions.

Over a 6-year period at the University Hospital in London, Ont., 101 patients underwent heart transplantation and 5 heart-lung transplantation. The authors review the general surgical problems identified from the charts of 13 of these patients. In the early postoperative period (within 30 days), laparotomy was required for pancreatitis (one), perforated peptic ulcer (two), cholecystectomy (one), pancreatic cyst (one) and appendicitis (one). In addition, a spontaneous colocutaneous fistula and spontaneous pneumoperitoneum occurred; both were managed conservatively. Later, three patients required cholecystectomy; one underwent a below-knee and a Symes amputation for dry gangrene and one surgical correction of a lymphocele. The incidence of surgical problems (13%) indicates an increased susceptibility in this group of patients. Four of the 13 patients died. Pancreatitis is a well-recognized complication of cardiac surgery; it is frequently associated with a normal or only slightly elevated serum amylase level, making a definitive diagnosis without laparotomy almost impossible. Persistence of abdominal signs should signal the need for exploratory surgery. During the early postoperative period and in the absence of multiorgan failure, immediate operation for an acute abdomen is usually successful. Despite the additional risk, cardiac transplantation does not preclude later surgery, but immunosuppression must be continued and carefully monitored.

The preoperative and postoperative chest radiographs of 44 patients undergoing 45 orthotopic cardiac allografts were evaluated retrospectively. Patients were followed from two months to four years postoperatively. Radiographic findings were correlated with echocardiograms and endocardial biopsies. The postoperative cardio-pericardial silhouette stabilized in size by six months. Contrary to previous reports, any marked increase in size of the cardiac silhouette in this series was due to pericardial effusion and not to cardiac rejection. Unusual postoperative features of the chest radiographs included calcification of the residual native left atrium, localized pericardial effusion simulating a left ventricular aneurysm, and a prominent left atrial appendage.

Insertion of transvenous permanent pacemaker leads through the subclavian vein is relatively safe and simple. This procedure was performed in 29 patients. The only serious complication was dislocation of the lead in eight patients. With this technique the endocardial lead can be positioned quite readily in the right ventricle. Use of the technique should be considered whenever the cephalic vein cannot be located readily or is too small to permit placement of an endocardial lead.

For monotherapy, beta-blockers and calcium-entry blockers are effective and safe antianginal medications. For prophylaxis of myocardial ischemia, a different mechanism of action for each class of drugs is reflected by the different heart rate and rate-pressure product during exercise. In patients who continue to have anginal symptoms despite adequate beta-blockade, further alleviation of symptoms together with an increase in exercise tolerance may be observed with the addition of a calcium-entry blocker. Of note is the individual patient response to the various calcium-entry blockers when combined with propranolol. Although of theoretic concern with combination therapy, no deleterious effect on left ventricular function or increased adverse clinical effects were noted in our studies. Combination therapy with beta-blockers and calcium-entry blockers is well tolerated, effective, and safe both over the short and long term in patients with exertional angina.

Angiographic-morphologic correlation was done on findings in 16 patients with proven prolapse of the posterior mitral leaflet and severe mitral regurgitation. A triscalloped bulge into the left atrium in the left ventriculogram taken in the right anterior oblique projection is caused by prolapse of all three scallops of the posterior mitral leaflet. The prolapsed middle scallop produces a central bulge, the prolapsed posteromedial commissural scallop a posteroinferior bulge ih tne area of the posteromedial commissure, and the prolapsed anterolateral commissural scallop an anterosuperior bulge in the anterolateral commissural area. The latter is often overlapped by the aortic root but if prominent, juts beyond it. Correlation proved that the diagnosis of individual scallop prolapse in this syndrome can be made accurately despite gross mitral regurgitation.