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A fatal early acute rejection occurred in a heart allograft recipient immunosuppressed with Cyclosporine. This failure to prevent rejection in spite of satisfactory plasma levels of Cyclosporine was associated with total absence of renal impairment. The latter has always been present in our experience. The absence of immune and nephrotoxic effects raises the question of a biological defect in this patient, possibly a lack of specific receptors for Cyclosporine.

The function of both the denervated donor and innervated recipient sinus nodes of 14 asymptomatic cardiac transplant recipients was assessed. Tests of sinoatrial function were performed in 14 donor and 10 recipient atria. The mean spontaneous cycle length of the recipient atria was significantly longer than that of the donor atria (944 +/- 246 versus 663 +/- 158 ms, p less than 0.01). Donor sinus node recovery time was prolonged in four patients (greater than 2,500 ms in two) and recipient recovery time was prolonged in six patients. In those patients with normal sinus node function tests, the recovery time of the recipient sinus node was longer than that of the donor sinus node (1,170 +/- 207 versus 864 +/- 175 ms, p less than 0.02). The pattern of response of recovery times to increasing pacing rate was predictable and organized in the donor but chaotic in the recipient, and the longest sinus node recovery time occurred at the shortest pacing cycle length used in 12 of the 14 donor atria but in only 1 of the 10 recipient atria (p less than 0.001). Secondary pauses occurred in none of the normal donor atria and in all of the abnormal donor atria (p less than 0.001); however, they occurred in both normal and abnormal recipient atria. The recipient and donor atria were paced alone and synchronously in the same patients. Synchronous pacing had no effect on the recovery times of the donor sinus node but significantly lengthened those of the recipient (sinus node recovery time: 1,266 +/- 218 to 1,547 +/- 332 ms, p less than 0.02; corrected recovery time: 322 +/- 102 to 686 +/- 188 ms, p less than 0.01). In the donor atria, abnormal recovery time was invariably associated with abnormal sinoatrial conduction time. There was a strong correlation between sinoatrial conduction time measured by the methods of Strauss and Narula and their coworkers in the donor atria (r = 0.98, p less than 0.001) but not in the recipient atria (r = 0.72). In the absence of autonomic influences, tests of sinus node function of the donor atria produce predictable and consistent results and, therefore, may be more clinically reliable than in intact human subjects. There is a high incidence of recipient sinus node dysfunction in asymptomatic long-term survivors of cardiac transplantation.

Donor sinus node function was studied in 10 patients from day 4 to day 24 after cardiac transplantation. Cycle length, atrial arrhythmias, corrected sinus node recovery time, and estimated sinoatrial conduction time were recorded daily. Five patients had at least two sets of results suggesting sinus node dysfunction (group A) while five patients had no such abnormalities (group B). The prognosis in group A was poor, with four of the five patients dying within four months of the operation; one unexpected death from arrhythmias was recorded by ambulatory electrocardiographic monitoring. All five patients in group B survived for at least eight months. In nine patients sinus node function varied from day to day, with corrected sinus node recovery time reaching a peak at 11 to 18 days after operation. The longest corrected sinus node recovery time was 11 160 ms. Neither the differences between the patients, nor the day to day variation, could be explained solely by the degree of rejection as assessed by biopsy or by the ischaemia time of the heart during procurement. Sinus node dysfunction soon after transplantation is associated with a poorer prognosis and might be the terminal event in some cases.

It is usual to record independent activity from both the innervated recipient and the denervated donor atria in cardiac transplant recipients except for occasional, short-lived periods of entrainment that may occur during exercise. In this report a case is described in which, following orthotopic cardiac transplantation, the recipient and donor atria remained synchronized during a variety of physiological and non-physiological situations. Under no circumstances did the two sets of atria beat independently. The mechanisms that might be involved in this unique situation are discussed.

The major factors contributing to the recommencement of clinical heart transplantation in the United Kingdom last year were the steadily improving results from Stanford University, the clarification of the diagnosis of brain death, and advances in preserving donor hearts. Twelve men aged 16 to 52 years received heart transplants at Papworth Hospital from January 1979 to July 1980. Six had cardiomyopathies and six ischaemic heart disease. The donors were aged 16 to 35 (mean 21) years. A combination of road and air transport was used to transport the heart to Papworth in seven cases. The total donor heart ischaemic time ranged from 108 to 171 minutes (mean 151), and early graft function was satisfactory in all cases. Postoperative management was directed towards preventing rejection and infection. Equine antihuman thymocyte globulin, prednisolone, and azathioprine were used for immunosuppression. Endomyocardial biopsy was performed every 10 to 14 days during the early postoperative period. There were three deaths: one at 17 days from brain damage and two at 59 and 76 days from rejection. Of the remaining nine patients six left hospital and three returned to work. The number of patients who might benefit from heart transplantation is large, but the cost is high. The cost would fall if an effective non-toxic immunosuppressive agent were developed. Meanwhile, a careful evaluation of the benefits of heart transplantation should continue.

To evaluate the direct electrophysiologic effects of i.v. disopyramide phosphate and to differentiate these effects from its autonomically mediated actions, we administered the drug (2 mg/kg over 5 minutes) during electrophysiologic study to eight cardiac transplant recipients who had documented functional cardiac denervation. After disopyramide, the cycle length of the denervated donor right atrium increased from 626 +/- 129 to 716 +/- 148 msec (mean +/- SD, p less than 0.001), whereas that of the innervated recipient atrium decreased from 846 +/- 195 to 659 +/- 99 msec (p less than 0.02). There were small increases in both the sinus node recovery time (1128 +/- 616 to 1198 +/- 592 msec, p less than 0.05) and corrected sinus node recovery time (440 +/- 418 to 489 +/- 409 msec, p less than 0.02) of the donor atrium, whereas the recovery times of the recipient atrium shortened (sinus node recovery time, 1298 +/- 218 to 1218 +/- 196 msec; corrected sinus node recovery time, 464 +/- 108 to 410 +/- 115 msec). Disopyramide markedly prolonged all conduction intervals. The PA interval increased from 47 +/- 16 to 54 +/- 17 msec (p less than 0.01), the AH interval from 55 +/- 12 to 78 +/- 12 msec (p less than 0.001), the HV interval from 38 +/- 9 to 58 +/- 13 msec (p less than 0.001), the QRS duration from 93 +/- 18 to 129 +/- 34 msec (p less than 0.001) and the QT interval from 339 +/- 23 to 403 +/- 39 msec (p less than 0.001). There was no significant change in the effective refractory period of the atrium, ventricular or atrioventricular node. The functional refractory period of the atrioventricular node increased from 369 +/- 34 to 395 +/- 31 msec (p less than 0.001). The electrophysiologic effects of disopyramide in the denervated heart are markedly depressant. In the innervated normal heart, the majority of these effects are counteracted by the drug's autonomically mediated anticholinergic actions.

The success of orthotopic heart transplantation depends wholly on satisfactory function of the new heart on completion of the operation. This in turn depends on the quality of the donor heart before its removal, the effectiveness of the methods used to preserve it during transport from the donor to the recipient hospital, and the accuracy of the operative procedure. From January 1979 to December 1983, 62 donor hearts were transplanted into 61 recipients at Papworth Hospital. These hearts were selected from 250 offered for consideration. The most common reasons for not proceeding with an initial inquiry were failure of the donor to meet the medical criteria for selection (77 cases) and lack of intensive care facilities or staff shortages such that a transplant could not be accommodated at the time of inquiry (80). Eight early deaths occurred, of which three were due to primary failure of the donor heart. Actual one and three year survivals for the whole programme were 58% and 50% respectively, the current actual one year survival being 70%. Forty per cent of patients selected for transplantation died while waiting for a heart to become available. Their average survival time was 46 days. The number of donor hearts referred for transplantation depends on public attitudes towards organ transplantation, the willingness of doctors looking after brain dead patients to seek permission from relatives for the heart to be donated, and the cooperation of local kidney transplant surgeons. A larger number of suitable donor hearts to choose from would enable more patients to be treated, as transplant operations could be arranged so that existing facilities were used to their maximum capacity.

The incidence of keloid and hypertrophic change and of scar stretching in the presternal region were studied in a fair-skinned population following open heart surgery through a median sternotomy incision. No patient in this study developed keloid change although scar hypertrophy and stretching were frequent. These changes were unrelated to the material used in subcuticular suture of the skin in a comparison of catgut, prolene and polyglycolic acid. Hitherto, unrecognised differences of scar maturation between different areas of the presternal skin were noted to be statistically significant. Scar hypertrophy is most likely in that part of the scar overlying the body of the sternum and particularly in the female. Scar stretching occurs most frequently in the lower third of the scar overlying the xiphisternum and extending onto the abdomen.

A 13 year old girl with Ebstein's anomaly was investigated for refractory paroxysmal tachycardias and ventricular pre-excitation. Intracardiac electrophysiological studies demonstrated that ventricular pre-excitation was due to conduction in an anomalous nodo-ventricular pathway. Tachycardia occurred as a result of re-entry within the A-V node with pre-excitation during tachycardia due to conduction in the nodo-ventricular pathway. These tachycardias were controlled initially by medical therapy but because of increasing frequency of attacks, occasionally requiring D.C. conversion, further electrophysiological studies and epicardial mapping were undertaken. The epicardial surface of the right ventricle and right atrium were mapped during tachycardia. The results of the studies confirmed that a direct anomalous atrio-ventricular pathway was not present and that re-entrant tachycardia did not involve an accessory pathway of this type. A rapid atrial pacing system was implanted and paroxysmal tachycardias have been successfully controlled.

A raised hemidiaphragm has been reported as an uncommon complication of cardiopulmonary bypass, possibly resulting from cold injury to the phrenic nerve. At Papworth Hospital myocardial protection during cardiac arrest relies in part on irrigation of the pericardial cavity with large volumes of Hartmann's solution at 4 degrees C. Retrospective review of the chest radiographs of 100 consecutive patients undergoing cardiopulmonary bypass showed that 31 had a raised left hemidiaphragm soon after operation. The only significant correlation was with aortic cross clamp time (p less than 0.03). A prospective study of 36 consecutive patients undergoing cardiopulmonary bypass was then undertaken with diaphragmatic screening and chest radiography. Preoperative screening gave normal results in all patients. In the early postoperative period 16 (44%) had left diaphragmatic weakness or paralysis, two (5.5%) right sided weakness, and two (5.5%) bilateral weakness. Repeat screening of these patients showed resolution in all but four cases (80%) at six months and in all but two (90%) at one year. The greater number of left sided lesions than of right (8:1) is probably due to the fact that the cold jet of irrigating fluid is directed towards the left phrenic nerve. These findings have implications with regard to the optimum temperature of the irrigant fluid for myocardial protection during cardiopulmonary bypass.

Between April 1984 and July 1986, 14 patients underwent heart-lung transplantation at Papworth Hospital, Cambridge, England. The donors for the first five operations were brought to our hospital and the organs removed in the operating theater adjacent to that in which the recipients were prepared. Subsequently, organs have been procured from distant centers. The total ischemic time ranged from 48 to 51 minutes (mean 49.6) for the near procurement group and from 70 to 186 minutes (mean 123.6) for the distant procurement group. Our method of preservation consists of cold cardioplegic arrest of the heart with St. Thomas' Hospital solution followed by a single cold (4 degrees C) pulmonary artery flush with a solution containing 500 ml donors blood, 700 ml Ringer's solution, 200 ml 20% salt-poor albumin, 100 ml 20% mannitol, 20 micrograms prostacyclin, and 10,000 units heparin. Function of the lungs after implantation was assessed by measuring the alveolar-arterial oxygen gradient. The median alveolar-arterial oxygen gradient measured shortly after discontinuation of bypass (point 1), just before extubation (point 2), and at 1 week (point 3) were 96.0, 62.3, and 18.8 mm Hg, respectively, for the near procurement group and 91.5, 60.0, and 11.3 mm Hg, respectively, for the distant procurement group. Comparison of the two groups at the three measurement points by the nonparametric Wilcoxon test showed no significant difference (p = 0.44, 0.52, and 0.11, respectively). The two groups showed significant decline of the alveolar arterial oxygen gradient differences over the first week (p = 0.004, nonparametric Friedman test). We conclude that our method of preservation provides a satisfactory function after implantation. The alveolar-arterial oxygen gradient differences were high immediately after implantation but decreased significantly afterward.

Six cardiac transplant recipients underwent maximal exercise testing before and after the administration of intravenous propranolol to assess the effect of beta blockade on their exercise heart rate response and exercise capacity. Before propranolol the patients were capable of a mean of 6.8 minutes of exercise and heart rate increased from a resting value of 102 +/- 25 a minute to 138 +/- 34 at peak exercise--a mean increase of 35%. All tests were terminated because of tiredness or muscle weakness. After one hour's rest, intravenous propranolol (0.2 mg/kg over 10 minutes) was administered with a reduction in resting heart rate from 109 +/- 28 a minute to 83 +/- 16. During the repeat exercise test the patients were capable of a mean of 4.5 minutes of exercise and all tests were terminated by extreme exhaustion and/or unsteadiness requiring immediate cessation of the treadmill. Heart rate increased from a resting value of 83 +/- 16 a minute to 96 +/- 18 at peak exercise. The exercise capability of the denervated heart is conspicuously reduced by beta blockade, presumably because of its reliance on circulating catecholamines.

Thirteen heart transplant patients receiving heterologous antithymocyte globulin were examined serially for the presence of circulating immune complexes, activation of complement, and antibodies to antithymocyte globulin. Using three independent assays, all patients were found to develop immune complexes at some time following transplantation, mostly as a consequence of antithymocyte globulin administration and infection. Simultaneous analysis of endogenous complement levels revealed C3 and C4 hypocomplementaemia in 28 and 44% of the samples, respectively. However, no correlation was evident between immune complex or complement levels and cardiac rejection assessed histologically in 64 endomyocardial biopsies. Serial analysis of antibodies to equine and rabbit antithymocyte globulin by solid-phase radioimmunoassay showed that 8 of 10 patients had significantly elevated values. Evidence was also obtained which indicated a substantial degree of cross-reactivity between the antibodies to these heterologous proteins. The results demonstrate a complex interplay of immune reactants relating to transplantation, infection, and immunosuppression therapy.

The aim of the study was to evaluate myocardial protection during the transportation of human donor hearts stored at 4 degrees C in crystalloid cardioplegic solution. Biopsies were performed on 50 donor hearts before excision and at four subsequent time intervals during transplantation. Quantitative birefringence measurements on cryostat sections of the left ventricular biopsy specimens were used to assess myocardial function. Fifteen donor hearts had poor birefringence assessments before excision, and 67% received inotropic support after implantation; 22 deteriorated during transportation, and 50% received inotropic support; 13 were unchanged throughout the procedure, and none required inotropic support. This study demonstrates the need for improved protection of donor hearts during transportation and recommends the use of rigorous criteria in the selection of these hearts.

Infectious complications constitute a major cause of morbidity and mortality after heart transplantation. Those infections transmitted with the transplanted heart are potentially avoidable. Cytomegalovirus infections and toxoplasmosis occupy a prominent position in this category. The outcome of transplanting hearts from donors previously exposed to these infections depends largely on the existing immune status of the recipient. This paper is a retrospective study on the incidence of Toxoplasma gondii and cytomegalovirus infections in patients undergoing heart and heart-lung transplantation at Papworth Hospital, Cambridge.

The first case of disseminated toxoplasmosis following cardiac transplantation in the UK is described, with details of Toxoplasma antibody tests made on other cardiac transplant patients. Sixteen of 40 (39%) of recipients had Toxoplasma antibody before operation. Eleven of 30 (37%) of donors had Toxoplasma antibody. The were four occasions when a negative recipient received a heart from a positive donor. Three survived the immediate postoperative period and two became infected with toxoplasmosis. The implications of this are discussed. Disseminated toxoplasmosis appears much more often when heart muscle from a dye test positive donor is given to a dye test negative recipient. Antibiotic therapy is limited by the fact that the antitoxoplasma drugs available are static in their effect, and need to be given for prolonged periods postoperatively.

The electrophysiologic characteristics of the denervated human heart were assessed in 14 cardiac transplant recipients. Conduction intervals and refractory periods were measured at pacing cycle lengths of 500 msec and 400 msec. The faster pacing rate caused lengthening of the AH interval (83 +/- 23 msec to 116 +/- 41 msec, p less than 0.01) and shortening of the QT (338 +/- 27 msec to 313 +/- 22 msec, p less than 0.001) and JT (249 +/- 21 msec to 229 +/- 19 msec, p less than 0.001) intervals. There was no change in the SA, HV, or QRS durations. Wenckebach periodicity occurred at a longer cycle length in the retrograde than in the anterograde direction (409 +/- 96 msec vs 318 +/- 46 msec, p less than 0.01) and anterograde conduction was better than retrograde conduction in 13 of the 14 patients (93%). Increasing pacing cycle length resulted in shortening of the atrial effective (203 +/- 28 msec to 190 +/- 25 msec, p less than 0.001), ventricular effective (224 +/- 18 msec to 211 +/- 17 msec, p less than 0.01), and AV nodal functional (367 +/- 38 msec to 357 +/- 36 msec, NS) refractory periods. The AV nodal effective refractory period lengthened (294 +/- 31 msec to 314 +/- 52 msec, p less than 0.05). There was a close correlation between AV Wenckebach cycle length and the functional refractory period of the AV node (r = 0.853, p less than 0.001). These results are qualitatively and quantitatively similar to those reported in the innervated heart. The autonomic nervous system appears to have little influence on the resting electrophysiologic characteristics of the atrioventricular conduction system in the innervated heart.

A 74 year old woman with mixed mitral valve disease presented with episodes of loss of consciousness and fainting. The attacks were noted to be closely related to posture, especially crouching, and this, with the clinical finding that the radial pulse disappeared before she lost consciousness, suggested the diagnosis of a ball valve thrombus. Cardiac catheterisation confirmed the diagnosis but was followed by a fall in blood pressure necessitating emergency surgery. The only position in which the circulation could be maintained was the right lateral, with steep head down tilt, and left femoro-femoral cardiopulmonary bypass had to be established in this position. Operation confirmed the presence of a ball valve thrombus and the patient recovered uneventfully.

Fourteen relatively long term survivors of cardiac transplantation underwent systematic electrophysiological evaluation and ambulatory electrocardiographic monitoring. Six patients had prolonged conduction intervals during sinus rhythm. Sinus node function could be assessed in all donor atria and in 10 recipient atria. Sinus node recovery times were prolonged in four of the donor atria and in six recipient atria. In the donor atria abnormalities of sinus node automaticity were invariably associated with abnormalities of sinoatrial conduction. Four patients showed functional duality of atrioventricular nodal conduction during programmed extrastimulation, but no patient developed re-entrant arrhythmia. During ambulatory electrocardiographic monitoring no pronounced tachyarrhythmias were recorded. Three patients showed abnormalities of sinus node impulse formation. All three patients had abnormal sinus node recovery times during their electrophysiological study. Long term survivors of cardiac transplantation have a high incidence of electrophysiological abnormalities. Abnormalities of donor sinus node function are probably of clinical significance. The clinical significance of abnormalities detected within the atrioventricular conduction system of the denervated heart remains to be elucidated.