Doxorubicin cardiotoxicity. Serial endomyocardial biopsies and systolic time intervals.

Doxorubicin, whose dose-limiting toxicity is cardiomyopathy, was given to four cancer patients. Endomyocardial biopsy specimens and test results of cardiac function were obtained before, during, and after treatment. The biopsy specimens were examined by light and electron microscopy and were graded blindly. Evidence of specific doxorubicin injury was found in 3/4 patients with as little as 180 mg/sq m of the drug and became progressively more severe with higher doses. All test results of cardiac function, including systolic time intervals, remained normal. These data suggest that a specific, progressive subclinical injury to the heart occurs with doxorubicin therapy, which cannot be reliably detected by routine tests. This potential risk must be taken into account with the use of doxorubicin, especially when combined with synergistic agents.

Recurrent tachyarrhythmia associated with a bifocal demand pacemaker.

A recurrent tachyarrhythmia complicated the course of a patient with a permanent atrioventricular sequential (bifocal) demand pacemaker. Investigation by intracardiac electrocardiographic studies revealed that the arrhythmia was associated with normally functioning bifocal pacemaker, whose atrioventricular sequential interval approximated the patient's conduction time from atrium to ventricle. The mechanism of initiation and conversion of the arrhythmia was elucidated. Appreciation of this arrhythmia is necessary for appropriate clinical use of a bifocal demand pacemaker.

The electrophysiologic effects of quinidine in the transplanted human heart.

Using His bundle recording techniques, we examined direct and autonomically mediated conduction system effects of quinidine in five cardiac transplant recipients who have anatomically denervated hearts. We made control conduction interval and refractory period measurements, and then infused 10 mg/kg quinidine gluconate over a 20-min period. At 30 min, we determined the electrophysiologic changes induced by quinidine. Quinidine significantly increased the atrial-His (AH) interval (from 97+/-9 [SEM] to 108+/-7 ms, P less than 0.001), the His-ventricular (HV) inteval (from 43.9 +/- 1 to 52.8 +/- 3 ms, P less than 0.01), the donor heart sinus cycle length (from 599 +/- 38 to 630 +/- 56 ms, P less than 0.08), and the atrial effective refractory period (from 214 +/- 14 to 241 +/- 11 ms, P less than 0.01). Quinidine significantly decreased the innervated, remnant atrial sinus cycle length (from 847 +/- 104 to 660 +/- 96 ms, P less than 0.01) and the blood pressure. The mean plasma concentration of quinidine at the time that electrophysiologic measurements were repeated was 4.37 +/- 0.449 micrograms/ml. We conclude that quinidine's predominant sinus nodal and atrioventricular nodal effects in man are autonomically mediated and opposite to its direct actions upon these structures. On the other hand, quinidine's prevailing effect on atrial refractoriness and His-Purkinje conduction in man is direct.

Does cardiac transplantation prolong life and improve its quality? An updated report.

The current status of the human cardiac transplant experience at Stanford University Medical Center is presented in order to reassess its role in the treatment of end-stage cardiac disease. Of 109 patients undergoing transplantation at Stanford between January 1968 and August 1976, 44 were still alive as of August 1, 1976. The overall 1- and 2-year survival rates for the series are 52% and 43%, respectively. Sixty-nine patients have survived more than 3 months, and their overall 1- and 2-year survival rates are 80% and 66%, respectively. Of the 3-month survivors, 62 (90%) returned to functional Class I New York Heart Association cardiac status and most of these returned to their pre-illness activities. Of 40 patients selected for transplantation for whom a donor did not become available, 38 were dead in less than 6 months. Complications related to immunosuppression with steroids are currently the major barrier to longer survival and improved rehabilitation postransplantation. On the basis of these data we conclude that cardiac transplantation not only prolongs survival, but can return carefully selected recipients to an active life.

Infections after cardiac transplantation: relation to rejection therapy.

We have analyzed the relation of the treatment of 76 acute graft rejection episodes in 45 late postoperative cardiac transplant patients to the 56 infections occurring in these patients. Intensification of immunosuppressive therapy for acute rejection greatly increased the occurrence of infection from a control incidence of 1.3 infections per 1000 patient-days to a posttreatment incidence of 3.6. Two modes of treatment, increased oral prednisone and high-dose methylprednisolone plus antithymocyte globulin, were further analyzed. Actuarial analysis of infections after these two treatment modes showed that the treatment-related increase in infection was nearly exclusively due to the latter form of therapy. Invasive cardiac procedures did not appear to be causally related to infections in these immunocompromised patients.

Cardiac transplantation: review of seven years' experience.

Over the past 7 years, the feasibility of human cardiac transplantation has been documented and proved to prolong useful human life. Ideal candidates are characterized by the relatively young vigorous patient who is otherwise healthy and optimistic about his long-term chances of survival. Survival statistics indicate over a 75% 1-year survival if the patient survived the first 3 months following transplantation, at which time the most severe rejection episodes occur. Allograft rejection in both acute and chronic form remain the single most challenging problem limiting the success of the transplant program. Despite this, there has been gradual improvement in survival statistics characterized by a 57% 1-year survival for the past 1 year. The early diagnosis of cardiac rejection has been facilitated by routine serial percutaneous transvenous endomyocardial biopsies of the right ventricle to confirm clinical evidence of rejection. Over 88% of patients have been vocationally and actively rehabilitated and the remaining 12% are not limited by cardiovascular function but by complications of immunosuppresive therapy. In conclusion, it appears that human cardiac transplantation has been successful and can be used to treat selected patients with end-stage cardiac disease.

The effect of cycle length on cardiac refractory periods in the denervated human heart.

We have previously demonstrated that the transplanted human heart is functionally denervated. With the use of the extra stimulus technique during His bundle electrocardiography, refractory periods of the arterioventricular (A-V) conduction system were determined at several heart rates after pacing-induced changes in cycle length in eight patients who had previously undergone cardiac transplantation. Shortening of the cycle length was accompanied by a decrease in both the effective and functional refractory periods of the atrium. No consistent change in A-V nodal effective refractory period or functional refractory period could be demonstrated. Because A-V conduction was limited at shorter cycle lengths by the functional refractory periods of the atrium and A-V node, bundle branch refractory periods could be determined in three patients only at the longest cycle length studied. In four of the eight patients, atrial arrhythmias were produced at short cycle lengths with the introduction of early atrial extra stimuli. This may be due to a lack of vagal innervation of the atrium. These results contribute to our understanding of atrial arrhythmias.

Electrophysiologic studies in the denervated transplanted human heart. II. Response to norepinephrine, isoproterenol and propranolol.

Five patients who had received a transplanted human heart 1 to 3 years previously were studied to determine the effects of norepinephrine, isoproterenol and propranolol on the atrioventricular (A-V) conduction system. Using the His bundle technique, atrial, His bundle and ventricular electrograms were recorded, and central aortic pressure was monitored during the administration of these drugs. Norepinephrine was given by continuous infusion to four patients in doses ranging from 4 to 8 mug/min, with the systolic arterial pressure increasing by an average of 72 mm Hg. Concomitantly, there was an average increase in the rate of the donor atrium of 32 beats/min, and a reflex slowing of the recipient atrium of 23 beats/min. The A-H interval shortened by an average of 27 msec. Isoproterenol dose-response curves were performed in three patients, with the maximal dose being 5.2 mug by intravenous bolus infusion. The rate of the donor atrium increased by an average of 40 beats/min, and that of the recipient atrium by 18 beats/min. The A-H time shortened by an average of 25 msec, with a drop in systolic blood pressure averaging 23 mm Hg. Propranolol (7 mg intravenously) was given to three patients and the peak doses of norepinephrine and isoproterenol were again infused. Beta adrenergic blockade was achieved at this dose of propranolol since there was only a minimal increase in the donor atrial rate after infusion of the drug. The A-H interval was not altered by catecholamine infusion after achievement of beta blockade. However, the levels of systolic hypertension noted after infusion of norepinephrine was not altered by propranolol. The denervated transplanted human heart appears to respond normally to norepinephrine and isoproterenol, and the electrophysiologic effects of these agents are blocked by propranolol. Extensive investigative work in the denervated canine model has demonstrated the presence of the alpha and beta cardiovascular receptors. Although the automonic nervous system is important in cardiac performance, this work is the first validation in man that (1) the functional integrity of the beta receptor is maintained even when the autonomic nerves are absent, and (2) the intrinsic properties of the sinus and atrioventricular nodes are the keystone in stabilizing cardiac electrophysiology after denervation.

The status of cardiac transplantation, 1975.

Since December 1967, 263 human cardiac transplant operations have been performed throughout the world. Eighty-two of these were performed at Stanford University Medical Center, In 1974, 27 such operations were performed, 15 at Stanford Survival rates for the entire Standford series are 48% at one year and 25% at three years; survival rates at one and three years for patients surviving the first three critical months after transplantation are 77% and 42%, respectively. Recipients under the age of 55 years, with New York Heart Association Class IV cardiac disability, are selected for transplant procedures according to criteria dictated by experience over the past seven years. A routine immunsuppressive regimen for organ transplantation, incorporating prednisone, azathioprine, and antithymocyte globulin is employed early postoperatively, and prednisone and azathioprine are used for indefinite maintenance therapy. Acute cardiac graft rejection in nearly all recipients is diagnosed by clinical signs, electrocardiographic changes, and percutaneous transvenous endomyocardial biopsy. Ninety-five percent of acute rejection episodes are reversible with appropriate immunosuppressive treatment, but infectious complications are common and have accounted for 56% of all postoperative deaths. The Stanford experience in cardiac transplantation has demonstrated the potential therapeutic value of this procedure. Maximum survival now extends beyond five years. Satisfactory graft function has been documented in long-term surviving patients, the majority of whom have enjoyed a high degree of social and physical rehabilitation.

Cardiac amyloidosis. Diagnosis by transvenous endomyocardial biopsy.

Endomyocardial tissue, obtained from two patients presenting with restrictive cardiomyopathies, demonstrated amyloid infiltration. The percutaneous transvenous cardiac biopsy technic, using a modified Konno-Sakakibara cardiac bioptome, was safe and quick. Physical examination and catheterization data may not provide a definite differential diagnosis between restrictive and constrictive myocardial disease. Confirmation by biopsy of the cardiac amyloidosis assisted in providing optimum diagnostic and therapeutic care for these patients.

Sinus node function in the denervated human heart. Effect of digitalis.

Evaluation of sinus node function was performed in 5 patients with an intact cardiac autonomic nervous system (group I), and in 8 patients with a transplantated, denervated heart (group 2). After baseline data were recorded, the electrophysiological studies were repeated in all group I patients and in 6 of the 8 group 2 patients, 45 to 60 minutes after the administration of digoxin 1.25 mg intravenously. Baseline cycle length, sinus node recovery time, and sinoatrial conduction time were significantly shorter in the transplanted heart than in those with intact autonomic innervation, but correction of the sinus node recovery time and sinoatrial conduction time for heart rate abolished these differences. Digoxin produced a small increase in cycle length, sinus node recovery time, and sinoatrial conduction time which did not reach statistical significance in this small study group of patients with innervated hearts. In the denervated, transplanted patients, no change in cycle length occurred after digoxin in any patient. The sinus node recovery time was unaffected by glycoside administration in 3 of 6 patients, while the sinoatrial conduction time was unchanged in 4 of 6. In one group 2 patient, digoxin produced first degree sinoatrial node exit block, and in a second patient, 2:1 sinoatrial nodal exit block developed. The mechanisms responsible for these effects in the denervated heart are not clear.

Effect of digoxin on atioventricular conduction. Studies in patients with and without cardiac autonomic innervation.

The effect of digoxin on atrioventricular (a-v) conduction was compared in five patients with an intact cardiac autonomic nervous system (Group I) and seven patients who had undergone cardiac transplantation (Group II), in whom we have previously shown the transplanted heart to be completely denervated. Small decreases in the atrial effective refractory period (ERP) (from 262 plus or minus 12 to 254 plus or minus 11 msec) and atrial functional refractory period (FRP) (from 304 plus or minus 12 msec) were observed in Group I patients after digoxin, but these changes were not significant. However, significant increases in the A-V nodal ERP (from 315 plus or minus 18 msec to 351 plus or minus 17 msec, P less than 0.05), and A-V nodal FRP (from 426 plus or minus 42 to 460 plus or minus 46 msec, P less than 0.01) were produced by digoxin and were unrelated to changes in cycle length. In Group II patients with denervated hearts, changes in atrial ERP (from 246 plus or minus 4 to 243 plus or minus 6 during spontaneous sinus rhythm; from 204 plus or minus 10 to 216 plus or minus 8 msec during atrial pacing) and atrial FRP (from 311 plus or minus 12 to 316 plus or minus 11 msec during spontaneous sinus rhythm; from 254 plus or minus 12 to 260 plus or minus 10 msec during atrial pacing) were not significant. However, in contrast to the Group I patients, the digoxin-induced changes in A-V nodal ERP (from 280 plus or minus 22 to 297 plus or minus 18 msec during atrial pacing) and FRP (from 368 plus or minus 18 to 377 plus or minus 18 msec during spontaneous sinus rhythm; from 334 plus or minus 13 to 346 plus or minus 16 msec during atrial pacing) were also statistically insignificant. Our results demonstrate that the electrophysiologic effects of digoxin on atrioventricular conduction in man are most marked in the atrioventricular node and are dependent on cardiac innervation

Hemodynamic observations in the early period after human heart transplantation.

Serial hemodynamic measurements, including determination of cardiac output by the Fick technique, were obtained in 10 human cardiac recipients for intervals up to 38 days after transplantation. Immediately postoperatively, donor cardiac output was severely depressed because of limitation of stroke volume. Spontaneous recovery of cardiac output and stroke volume then occurred gradually over the first 4 postoperative days to normal or nearly normal levels. Rate augmentation by arterial and/or ventricular pacing early after transplantation had little effect on donor heart performance, but isoproterenol caused significant enhancement of graft function and is now used routinely in postoperative management. Serial hemodynamic monitoring proved to be of little use in the prediction or confirmation of acute graft rejection episodes.