- Email: [email protected]
Heterotopic heart transplantation and recipient heart operation in ischemic heart disease
Heterotopic Heart Transplantation and Recipient Heart Operation in Ischemic Heart Disease Paul D. Ridley, FRCS, Asghar Khaghani, FRCS, Francesco Musumeci, MD, Roberto Favaloro, MD, El-Sayed Akl, MD, Nick R. Banner, MRCP, Andrew G. Mitchell, MRCP, and Magdi H. Yacoub, FRCS Departments of Cardiothoracic Surgery and Cardiology, Harefield Hospital, Harefield, Middlesex, England
The role of heterotopic heart transplantation in coronary heart disease has not been defined. Between 1983 and 1988, 28 patients with end-stage ischemic heart disease were managed by heterotopic heart transplantation and adjunctive operation on the recipient heart: coronary artery bypass grafts and aneurysmectomy, 20; coronary artery bypass grafts, 5; and aneurysmectomy, 3. Indications were feasibility of operative procedures to the recipient heart and small donor size (61% of the donors were <15 years). The 1-year and 5-year actuarial survival was 79% and 63%. Of the 22 patients who survived to 2-year follow-up, all of whom had been severely limited
(New York Heart Association grade III/IV) preoperatively, 20 were in grades I or I1 at 2-year follow-up ( p < 0.001). In 14 of 22 patients (64%), the recipient heart augmented the donor cardiac output substantially, and in 4 the recipient heart supported the patient when the donor heart failed to eject. In conclusion, this series demonstrates the efficacy of heterotopic transplantation combined with operation to the recipient heart in the management of patients with end-stage ischemic heart disease.
A
llograft transplantation in the orthotopic position is now well established as the most common method of heart transplantation, and good short-term and medium-term results are described in many centers [l].By contrast, the role of heterotopic heart transplantation remains controversial [2, 31. We have employed the technique of heterotopic heart transplantation in a minority of heart transplantation patients with specific indications, including possible useful postoperative recipient heart function. It is the purpose of this article to describe a group of patients with end-stage ischemic heart disease who were managed by heterotopic heart transplantation combined with adjunctive operation to improve recipient function.
procedures were carried out between 1983 and 1988, providing a minimum follow-up period of 2 years. In all patients the primary symptom was severely limiting dyspnea. All patients had hearts that were technically amenable to operation with an absence of mitral incompetence. All had very poor left ventricular function (ejection fractions less than 0.25) and were considered unsuitable for conventional operation without transplantation. Elevation of pulmonary vascular resistance (PVR) was a minor indication for heterotopic transplantation in this series. The mean preoperative PVR was 3.2 Wood units (standard error of the mean [SEMI, 0.48), and only 4 patients had moderately elevated PVR (4 to 6 Wood units).
Patients and Methods
The operative technique was similar to previous descriptions [4, 51 as follows.
(Ann Thorac Surg 1992;54:333-7)
Operative Techniques Patient Population Of the 890 patients who have undergone heart transplantation in our institution since 1980,48 received an allograft in the heterotopic position; 18 did not have an ischemic etiology and 2 had ischemic heart disease but had heterotopic transplantation without adjunctive operation. In this article we consider a subgroup of 28 patients (26 male) with end-stage ischemic heart disease who received an allograft in the heterotopic position combined with adjunctive operation to improve recipient function. Their mean age was 49 years (range, 33 to 60 years). The Accepted for publication Jan 23, 1992. Address reprint requests to Mr Ridley, 19 Allander Rd, Milngavie, Glasgow, Scotland G62 8PN.
0 1992 by The Society of Thoracic Surgeons
The orifice of the inferior vena cava was sutured closed. Long segments of aorta, pulmonary artery, and superior vena cava were preserved for anastomosis to the recipient. The posterior wall of the left atrium was prepared by joining the orifices of the four pulmonary veins. PREPARATION OF THE DONOR HEART.
Left ventricular assistance was performed in 23 cases. After cardiopulmonary bypass was established, with venous cannulas in the superior vena cava and inferior vena cava and the arterial cannula in the ascending aorta, the right pleural cavity was opened widely and the pericardium reflected posteriorly to form a pleuropericardial flap based on the ANASTOMOSIS OF DONOR HEART TO RECIPIENT.
0003-4975/92/$5.00
334
RIDLEY ET AL HETEROTOPIC HEART TRANSPLANTATION
phrenic nerve, which was carefully preserved. The recipient heart was electrically fibrillated. A vent was inserted into the apex of the recipient’s left ventricle. The donor left atrium was anastomosed to a long incision in the recipient’s left atrium, which extended from a point posterior to the interatrial groove, just behind the inferior vena cava, to the roof of the recipient’s left atrium. The donor superior vena cava was then incised posteriorly, and the stoma created was anastomosed to a large T-shaped incision in the recipient’s superior vena cava (this connection is important as it provides access to the donor right ventricle for endomyocardial biopsies). The donor left ventricle was vented at the apex, and the donor aorta was then anastomosed to the side of the recipient’s ascending aorta. Finally the donor pulmonary artery was anastomosed to the recipient’s right atrium. We prefer not to introduce foreign material such as Dacron [4, 61 in these immunosuppressed patients, and therefore tube prostheses to extend the pulmonary artery were not used. The donor pulmonary artery was usually too short to reach the recipient pulmonary artery; right atrial anastomosis was therefore technically easier and was employed in 23 cases. Biventricular assistance was performed in 5 cases. The donor pulmonary artery was anastomosed to the recipient pulmonary artery in 5 cases when there was poor recipient right ventricular function and sufficient length could be obtained from the donor pulmonary artery without distortion. In 3 patients in whom extra length was required, a section of donor aorta was used to bridge the donor and recipient pulmonary arteries. ADJUNCTIVE PROCEDURES TO RECIPIENT HEART. After completion of the transplant procedure, adjunctive operation on the recipient heart was performed as follows: left ventricular aneurysmectomy and coronary artery bypass graft in 20 patients, coronary artery bypass graft alone in 5 patients, and left ventricular aneurysmectomy alone in 3 patients. A total of 45 coronary artery bypass grafts were performed in 25 patients, for a mean of 1.8 grafts per patient (range, 1 to 4).
Emergency Procedures Two patients had emergency heterotopic transplantation. Both had maximal inotropic support for 2 days and 5 days, respectively, and were mechanically supported preoperatively; one with an intraaortic balloon pump for 36 hours and the other with supportive bypass using a conventional roller pump for 18 hours.
Ann Thorac Surg 1992;54:333-7
60
L
3 u)
40 20
-
1 0
20
40
60
80
Months
Fig 1. Actuarial survival of all patients undergoing heterotopic heart transplantation with adjunctive operation on the recipient heart.
tect arrhythmias together with echocardiographic determination of indices of systolic and diastolic function. The reference method for diagnosing acute rejection remained endomyocardial biopsy, which was performed routinely at regular intervals postoperatively. Additional biopsies were performed if rejection was suspected [5]. Cardiac catheterization and exercise testing according to the Bruce protocol [7] was performed annually.
Immunosuppressive Therapy The immunosuppression protocol consisted of cyclosporine A and azathioprine with no, or minimal, oral steroids ~51.
Anticoagulation Anticoagulation was not used routinely in all patients but was introduced in 11patients with intracardiac thrombus, severely impaired function of one or both hearts, or a thromboembolic event.
Statistics
Standard 2 and paired t tests were employed. Actuarial survival was calculated using the Kaplan-Meier productlimit method calculated using BMDP statistical software
PI.
Results Survival
The mean donor age was 17.6 years (SEM, 1.8) and the median age was 14 years. The donor age range was 7 to 40 years. Seventeen of 28 (61%) were aged 14 years or younger. Mean donor ischemic time was 166 minutes (SEM, 11 minutes), and median time was 160 minutes with a range of 90 to 275 minutes.
Early death (within 6 months of operation) occurred in 6 of 28 patients (21%);3 patients died of acute rejection and 3 died of infective complications associated with multiple system failure. Early death was not related to the number of coronary artery bypass grafts performed. All the remaining patients survived for more than 2 years. The longest survivor is alive and well at 8 years. Actuarial 1-year survival was 79%, and actuarial 5-year survival was 63% (Fig 1).
Follow-tlp
Symptomatic Status
All patients were monitored postoperatively for signs of cardiac failure and noninvasively with serial electrocardiograms to determine electrocardiographic voltage and de-
Preoperatively all patients were in New York Heart Association functional grade III/IV. Of the 22 patients surviving to 2-year follow-up, 20 were in grade 1/11 ( p < 0.001)
Donors
RIDLEY ET AL HETEROTOPIC HEART TRANSPLANTATION
Ann Thorac Surg 1992:54:333-7
and 2 showed some improvement in function, having gone from grade IV to grade I11 (Fig 2a). Of the 12 patients surviving to 5-year follow-up, 10 were in grade YII ( p < 0.001). The remaining 2 patients showed some functional improvement from grade IV to I11 (Fig 2b). Angina was experienced in 1 of the 22 patients surviving to 2-year follow-up compared with 15 preoperatively ( p < 0.001) and 2 of the 12 patients surviving to 5-year follow-up experienced angina compared with 9 preoperatively ( p < 0.01). Residual angina postoperatively was mild in 2 cases, only occurring with moderate or severe exercise and did not limit the patients' lifestyle. Annual exercise testing according to the Bruce protocol resulted in a mean exercise tolerance of 9.3 minutes (SEM, 0.6 minutes) at 2 years and 8.0 minutes (SEM, 0.8 minutes) at 5 years. Fourteen of the 22 patients (63%) surviving 2 years were able to return to some form of gainful employment. Postoperatively 2 patients suffered transient ischemic cerebral episodes and were fully anticoagulated. A further 9 patients required anticoagulation commencing between 6 months and 5 years postoperatively when thrombus was identified in the recipient heart ventricle or very poor left ventricular function occurred in the donor or recipient heart. There were no complications related to the use of anticoagulants.
Recipient Heart Function Of the 22 patients followed up for 2 years, 14 (64%) showed a substantial recipient contribution (defined as echocardiographic, Doppler and cardiac catheterization evidence of aortic ejection from the recipient heart) to cardiac output (Fig 3); only 1 of these patients showed evidence of thrombus in the recipient heart ventricle. The 20 c
5
._ 15 c
ma
10
E
5
J2
z
0
lGradt
Fig 3. Satisfactoy recipient heart function. From below upward are shown a complex arterial pressure trace (carotid ultrasound), a complex electrocardiogram, and an M-mode echocardiogram demonstrating regular opening of the aortic valve in the recipient heart. Both hearts contribute to the carotid pulse. The carotid pulse wave varies according to whether the two QRS complexes occur sequentially or synchronously. (D = donor heart QRS complex; R = recipient heart QRS complex.)
other 8 patients showed some evidence of ventricular contraction but minimal or no effective ejection, and the aortic valve remained closed throughout in 4 patients; 6 of these patients had thrombus in the recipient ventricle. Of the 12 patients followed up for 5 years, 9 patients (75%) showed a substantial recipient heart contribution to cardiac output. Left ventricular thrombus was present in all 3 hearts with minimal or no ejection and in 2 of the hearts with substantial contribution. In 4 patients the recipient heart supported the patient when the donor heart failed. Standardized angiographically determined ejection fractions of the contractile portion of the left ventricle were obtained preoperatively in 10 of the patients surviving to 2-year follow-up, and in these patients the mean ejection fraction in the recipient heart was 0.18 (SEM, 0.02) preoperatively and 0.25 (SEM, 0.02) at 2 years.
Coronary Artery Bypass Graft Function
v)
pa,
335
Bb
c
Of the 25 patients in this series who had coronary artery bypass grafts, the 20 surviving to 2-year follow-up received a total of 34 grafts. The mean number of grafts per patient was 1.8 (range, 1 to 3). The distribution of the grafts was as follows: circumflex, 19; right coronary, 10; left anterior descending, 4; diagonal of left anterior descending, 1. Endarterectomy to the right coronary artery was performed in 2 patients, and the internal mammary artery was used in 2 patients. The graft patency at 2-year catheterization was 79% (27/34). Both internal mammary artery grafts were patent. Eleven patients who underwent coronary artery bypass grafting survived to 5-year followup. A total of 16 grafts were performed in this group of patients, with a 5-year graft patency of 50% (8/16).
0
Donor Function
Fig 2 . New York Heart Association functional classification preoperatively and postoperatively in patients surviving to (a) 2 years and (b) 5 years.
In all patients except 4, who survived past the initial postoperative period, the donor heart made the major contribution to cardiac output and was augmented to a greater or lesser extent by the recipient heart. In 4 patients the donor heart failed and the patient was supported by the recipient heart alone. In 1 patient severe acute rejection of the donor heart caused ventricular fibrillation 3 months postoperatively. The episode of acute rejection
336
RIDLEY ET AL HETEROTOPIC HEART TRANSPLANTATION
was successfully treated and the heart was cardioverted to sinus rhythm after 3 days. In a second patient, acute rejection caused intractable ventricular fibrillation, which did not respond to cardioversion. This was managed by removal of the donor heart, and because of the presence of antimyocardial antibodies [9], repeat transplantation was not undertaken. The patient remains alive but limited (New York Heart Association grade 111), supported only by the native recipient heart 6 years after his initial heart transplantation. In 2 patients the donor heart failed with advanced coronary artery disease. One was managed by a second heterotopic transplantion after 4 years and remains alive 2 years after the second transplantation. The other patient had, in addition to the typical distal diffuse coronary artery disease seen in the transplanted heart, a proximal localized lesion in an epicardial vessel, which was successfully dilated at angioplasty but which has not resulted in an increase in ejection from the donor heart. The incidence of coronary artery disease (defined as a narrowing in coronary artery diameter of greater than 33%) of the donor organ was 2 of 22 patients (9%) surviving to 2-year follow-up and 4 of 11 patients (36%) surviving, with their initial heterotopic heart, to 5-year follow-up. In 2 patients the disease was sufficiently severe to cause failure of the donor heart as described above. The lesions had a distal diffuse distribution, similar to those seen in orthotopic heart transplantation.
Effect on Pulmonary Artery Pressure and Pulmonary Vascular Resistance At first postoperative cardiac catheterization 1 year postoperatively, mean systolic pulmonary artery pressure fell from a preoperative value of 47.5 mm Hg (SEM, 2.9 mm Hg) to 28 mm Hg (SEM, 1.6 mm Hg) ( p < 0.05), and mean diastolic pulmonary artery pressure fell from 22.4 mm Hg (SEM, 3.1 mm Hg) to 14.9 mm Hg (SEM, 1.2 mm Hg). The mean PVR fell from 3.2 Wood units (SEM, 0.5 Wood units) to 1.8 Wood units (SEM, 0.5 Wood units) ( p < 0.05). Postoperatively all patients had a PVR of less than 4.5 Wood units.
Comment The role of heterotopic heart transplantation with or without adjunctive operation on the recipient heart remains controversial [2, 3, 6, 10, 111. The theoretical value of heterotopic heart transplantation is the possibility of augmenting the cardiac output of the donor heart with some useful function from the recipient heart. This is especially advantageous when the donor heart is small, particularly if a pediatric heart is used in an adult recipient, or at times of donor rejection. However, many potentially serious disadvantages have been attributed to heterotopic transplantation. Traditionally, these include recipient heart arrhythmias, thromboembolism, persistent angina [4], and compression of the right lower lobe of the lung by the donor heart. Postoperative follow-up and diagnosis of rejection are also technically more difficult as electrocardiogram analysis, echocardiography, and myocardial biopsy are all more challenging. The actuarial survival and symptomatic improvement
Ann Thorac Surg 1992;54:333-7
in this series compare favorably with those of other series employing heterotopic transplantation without adjunctive operation in the management of end-stage ischemic heart disease [3,6]. Poor outcome of conventional operation for ischemic heart disease is associated with poor ventricular function; ejection fraction less than 0.35, congestive heart failure, New York Heart Association functional classes I11 and IV, large diuretic requirement, and dyspnea as the primary symptom [12]. All patients in this series had these risk factors and were considered unlikely to have survived conventional surgical approaches without heart transplantation. In most patients the donor heart made the major contribution to cardiac output; the exceptions were the 4 patients in whom the donor heart failed to eject and the recipient heart supported the patient. However, in all 4 cases the patient would have been unlikely to have survived the immediate postoperative period without the donor heart. Recovery of recipient function has been described in patients with acute viral myocarditis [lo] but is not expected in patients with end-stage ischemic heart disease. The donor hearts in this series, as expected [lo], provided the major contribution to cardiac output. However unlike in other series [3], donor performance was augmented substantially in most cases by the recipient heart that had undergone adjunctive operation. In 4 cases the recipient heart supported the patient when the donor heart failed to eject; these patients would presumably have succumbed had they undergone orthotopic heart transplantation. Although not conclusive evidence, the fact that 64% showed substantial recipient contribution to cardiac output at 2 years supports the idea that recipient function was improved by adjunctive operation in this series [13, 141. There was a trend toward improvement in measured ejection fractions of the contractile portion of the left ventricle after operation on the recipient heart. However, measurements of ejection fractions were technically more difficult after heterotopic heart transplantation and, as most patients had ventricular aneurysmectomy, comparison of preoperative and postoperative recipient ejection fraction should be treated with caution. Previous studies have found ejection fraction to have a poor correlation with improved cardiac output after aneurysmectomy [ 121. The patency of the coronary artery bypass grafts was comparable with that obtained in routine coronary artery bypass grafting [15]. Internal mammary artery grafts remain patent longer than vein grafts in standard coronary artery bypass graft operations [16], and the internal mammary artery grafts performed in this series have remained patent in both patients until time of death (3 years in both cases). The low number of left anterior descending artery grafts reflects the fact that this artery was frequently obliterated and excised by left ventricular aneurysmectomy. Several factors may contribute to the relief of angina; coronary artery bypass grafting revascularized the heart and aneurysmectomy reduced the cavity size with a resultant reduction in wall stress and oxygen requirement. The donor heart further reduced the work of the recipient heart as its greater compliance meant that it received a greater proportion of the venous return in most cases.
RIDLEY ET AL HETEROTOPIC HEART TRANSPLANTATION
Ann Thorac Surg 1992:54:33.3-7
The h i g h incidence of intraventricular thrombus i n poorly functioning recipient ventricles was not associated w i t h a large incidence (2 transient cases) of thromboembolic phenomena. This is probably due t o t h e failure of t h e aortic valve t o open i n m a n y of these patients a s well as t h e introduction of full anticoagulation with warfarin if thrombus was detected. Avoidance of routine anticoagulation a n d steroid therapy meant that patients w i t h a history of peptic ulceration w e r e n o t excluded from consideration for heterotopic transplantation. The presence of intraventricular thrombus preoperatively is usually considered t o be a contraindication t o heterotopic heart transplantation, b u t t h e use of adjunctive operation including, or consisting of, aneurysmectomy allowed organized t h r o m b u s t o be removed a t operation i n 5 patients i n this series. Early coronary artery disease was identified i n t h e donor h e a r t i n t h e heterotopic position, which did n o t differ substantially i n incidence o r distribution from t h a t seen i n orthotopic heart transplantations [17]. A s recently e m p h a s i z e d by Kotliar and associates [18], there continues to be an inadequate supply of d o n o r hearts for all potential recipients [19], and patients with end-stage ischemic h e a r t disease continue t o die on t h e waiting list [20]. T h e use of small hearts i n t h e heterotopic position c a n t h u s be justified a s making best use of a limited resource i n an a t t e m p t to reduce transplant waiting times. Small donor size, particularly pediatric donors for a d u l t recipients, w a s t h e major indication for leaving t h e recipient heart i n situ i n this series. Elevated preoperative PVR was n o t a major indication for heterotopic heart transplantation i n this series. O t h e r m o d e s of transplantation m a n a g e m e n t a r e available for patients w i t h elevated PVR. Recipients w i t h moderately elevated PVR (4to 8 W o o d units) were considered for orthotopic heart transplantation using a large donor, o r a preconditioned heart from a heart-lung recipient w i t h secondary right ventricular hypertrophy (the "domino" operation) [17]. Severe p u l m o n a r y hypertension (>8 Wood units) was managed b y heart-lung transplantation. Elevated PVR has been emphasized as a n indication for heterotopic heart transplantation [2, 211 b u t remains controversial; experience from Paris suggests that, although pulmonary hemodynamics a r e improved, heterotopic h e a r t transplantation i n patients w i t h elevated PVR is associated with frequent p u l m o n a r y complications a n d fails t o improve t h e prognosis i n patients w i t h preoperative pulmonary hypertension [6, 221. In conclusion, this series demonstrates that heterotopic transplantation w i t h adjunctive operation on t h e recipient heart is a satisfactory m e t h o d of managing selected patients w i t h end-stage ischemic heart disease a n d should be considered i n t h o s e cases where t h e only available o r g a n is small and adjunctive operation on t h e recipient h e a r t is technically possible.
337
References 1. Kreitt J, Kaye M. The Registry of the International Society for Heart Transplantation: seventh official report-1990. J Heart Transplant 1990;9:32%30. 2. Reichenspurner H, Hildebrant A, Boehm D, et al. Heterotopic heart transplantation in 1988-recent selective indications and outcomes. J Heart Transplant 1989;8:381-6. 3. Cooper D, Novitzky D, Becerra E, Reichart B. Are there indications for heterotopic heart transplantations in 1986? A 2- to 11-year follow-up of 49 consecutive patients undergoing heterotopic heart transplantation. Thorac Cardiovasc Surg 1986;34:30&4. 4. Novitzky D, Cooper D, Barnard C. The surgical technique of heterotopic heart transplantation. Ann Thorac Surg 1983;36: 476-82. 5. Banner N, Fitzgerald M, Khaghani A, et al. Cardiac transplantation at Harefield hospital. In: Terasaki P, ed. Clinical transplants 1987. Los Angeles: UCLA Tissue Typing Laboratory, 198717-26. 6. Desruennes M, Muneretto C, Gandjbakhch I, et al. Heterotopic heart transplantation: current status in 1988. J Heart Transplant 1989;8:479-85. 7. Bruce R. Exercise testing for ventricular function. N Engl J Med 1977;296:671-5. 8. Dixon W. In: BMDP statistical software. Berkeley: University of California Press, 1985. 9. Lanza R, Campbell E, Cooper D, DuToit E, Barnard C. The problem of the presensitized heart transplant recipient. Heart Transplant 1983;2:1514. 10. Hassoulas J, Barnard C. Heterotopic cardiac transplantation: a 7-year experience at the Groote Schuur hospital, Cape Town. S Afr Med J 1984;65:675-82. 11. Nakatani T, Frazier 0, Lammermeier D, Macris M, Radovancevic B. Heterotopic heart transplantation: a reliable option for a select group of high risk patients. J Heart Transplant 1989;8:4&7. 12. Vauthey J, Berry D, Snyder D, et al. Left ventricular aneurysm repair with myocardial revascularization: an analysis of 246 consecutive patients over 15 years. Ann Thorac Surg 1988;46:29-35. 13. Olearchyk A, Lemole G, Spagna P. Left ventricular aneurysm. Ten years experience in surgical treatment of 244 cases; improved clinical status, hernodynamics and long-term longevity. J Thorac Cardiovasc Surg 1984;88:54&53. 14. Dilsizian V, Bonow R, Cannon R 111, et al. The effect of coronary artery bypass grafting on left ventricular function at rest: evidence for preoperative subclinical myocardial ischemia. Am J Cardiol 1988;61:124%54. 15. Fuster V, Chesebro J. Role of platelet inhibitors in aortocoronary artery vein-graft disease. Circulation 1986;73:227-38. 16. Lytle B, Loop F, DM C, Ratcliff N, Easley K, Taylor P. Long term (5 to 12 years) serial studies of internal mammary artery and saphenous vein coronary bypass grafts. J Thorac Cardiovasc Surg 1985;89:24&58. 17. Banner N, Khaghani A, Fitzgerald M, Mitchell A, RadleySmith R, Yacoub M. The expanding role of cardiac transplantation. In: Unger F, ed. Assisted circulation. Berlin: SpringerVerlag, 1989:448-67. 18. Kotliar C, Smart F, Sekela M, et al. Heterotopic heart transplantation and native heart ventricular arrhythmias. Ann Thorac Surg 1991;51:987-91. 19. Copeland J, Emery P, Levinson M, et al. Selection of patients for cardiac transplantation. Circulation 1987;75:2-9. 20. Fowler M, Schroeder J. Current status of cardiac transplantation. Mod Concepts Cardiovasc Dis 1986;55:3741. 21. Shumway S, Baugham K, Trail1T, et al. Persistent pulmonary hypertension after heterotopic heart transplantation: a case report. J Heart Transplant 1989;8:387-90. 22. Kawaguchi A, Gandjbakhch I, Pavie A, et al. Factors affecting survival after heterotopic heart transplantation. J Thorac Cardiovasc Surg 1989;98:928-34.
The role of heterotopic heart transplantation in coronary heart disease has not been defined. Between 1983 and 1988, 28 patients with end-stage ischemic heart disease were managed by heterotopic heart transplantation and adjunctive operation on the recipient heart: coronary artery bypass grafts and aneurysmectomy, 20; coronary artery bypass grafts, 5; and aneurysmectomy, 3. Indications were feasibility of operative procedures to the recipient heart and small donor size (61% of the donors were <15 years). The 1-year and 5-year actuarial survival was 79% and 63%. Of the 22 patients who survived to 2-year follow-up, all of whom had been severely limited
(New York Heart Association grade III/IV) preoperatively, 20 were in grades I or I1 at 2-year follow-up ( p < 0.001). In 14 of 22 patients (64%), the recipient heart augmented the donor cardiac output substantially, and in 4 the recipient heart supported the patient when the donor heart failed to eject. In conclusion, this series demonstrates the efficacy of heterotopic transplantation combined with operation to the recipient heart in the management of patients with end-stage ischemic heart disease.
A
llograft transplantation in the orthotopic position is now well established as the most common method of heart transplantation, and good short-term and medium-term results are described in many centers [l].By contrast, the role of heterotopic heart transplantation remains controversial [2, 31. We have employed the technique of heterotopic heart transplantation in a minority of heart transplantation patients with specific indications, including possible useful postoperative recipient heart function. It is the purpose of this article to describe a group of patients with end-stage ischemic heart disease who were managed by heterotopic heart transplantation combined with adjunctive operation to improve recipient function.
procedures were carried out between 1983 and 1988, providing a minimum follow-up period of 2 years. In all patients the primary symptom was severely limiting dyspnea. All patients had hearts that were technically amenable to operation with an absence of mitral incompetence. All had very poor left ventricular function (ejection fractions less than 0.25) and were considered unsuitable for conventional operation without transplantation. Elevation of pulmonary vascular resistance (PVR) was a minor indication for heterotopic transplantation in this series. The mean preoperative PVR was 3.2 Wood units (standard error of the mean [SEMI, 0.48), and only 4 patients had moderately elevated PVR (4 to 6 Wood units).
Patients and Methods
The operative technique was similar to previous descriptions [4, 51 as follows.
(Ann Thorac Surg 1992;54:333-7)
Operative Techniques Patient Population Of the 890 patients who have undergone heart transplantation in our institution since 1980,48 received an allograft in the heterotopic position; 18 did not have an ischemic etiology and 2 had ischemic heart disease but had heterotopic transplantation without adjunctive operation. In this article we consider a subgroup of 28 patients (26 male) with end-stage ischemic heart disease who received an allograft in the heterotopic position combined with adjunctive operation to improve recipient function. Their mean age was 49 years (range, 33 to 60 years). The Accepted for publication Jan 23, 1992. Address reprint requests to Mr Ridley, 19 Allander Rd, Milngavie, Glasgow, Scotland G62 8PN.
0 1992 by The Society of Thoracic Surgeons
The orifice of the inferior vena cava was sutured closed. Long segments of aorta, pulmonary artery, and superior vena cava were preserved for anastomosis to the recipient. The posterior wall of the left atrium was prepared by joining the orifices of the four pulmonary veins. PREPARATION OF THE DONOR HEART.
Left ventricular assistance was performed in 23 cases. After cardiopulmonary bypass was established, with venous cannulas in the superior vena cava and inferior vena cava and the arterial cannula in the ascending aorta, the right pleural cavity was opened widely and the pericardium reflected posteriorly to form a pleuropericardial flap based on the ANASTOMOSIS OF DONOR HEART TO RECIPIENT.
0003-4975/92/$5.00
334
RIDLEY ET AL HETEROTOPIC HEART TRANSPLANTATION
phrenic nerve, which was carefully preserved. The recipient heart was electrically fibrillated. A vent was inserted into the apex of the recipient’s left ventricle. The donor left atrium was anastomosed to a long incision in the recipient’s left atrium, which extended from a point posterior to the interatrial groove, just behind the inferior vena cava, to the roof of the recipient’s left atrium. The donor superior vena cava was then incised posteriorly, and the stoma created was anastomosed to a large T-shaped incision in the recipient’s superior vena cava (this connection is important as it provides access to the donor right ventricle for endomyocardial biopsies). The donor left ventricle was vented at the apex, and the donor aorta was then anastomosed to the side of the recipient’s ascending aorta. Finally the donor pulmonary artery was anastomosed to the recipient’s right atrium. We prefer not to introduce foreign material such as Dacron [4, 61 in these immunosuppressed patients, and therefore tube prostheses to extend the pulmonary artery were not used. The donor pulmonary artery was usually too short to reach the recipient pulmonary artery; right atrial anastomosis was therefore technically easier and was employed in 23 cases. Biventricular assistance was performed in 5 cases. The donor pulmonary artery was anastomosed to the recipient pulmonary artery in 5 cases when there was poor recipient right ventricular function and sufficient length could be obtained from the donor pulmonary artery without distortion. In 3 patients in whom extra length was required, a section of donor aorta was used to bridge the donor and recipient pulmonary arteries. ADJUNCTIVE PROCEDURES TO RECIPIENT HEART. After completion of the transplant procedure, adjunctive operation on the recipient heart was performed as follows: left ventricular aneurysmectomy and coronary artery bypass graft in 20 patients, coronary artery bypass graft alone in 5 patients, and left ventricular aneurysmectomy alone in 3 patients. A total of 45 coronary artery bypass grafts were performed in 25 patients, for a mean of 1.8 grafts per patient (range, 1 to 4).
Emergency Procedures Two patients had emergency heterotopic transplantation. Both had maximal inotropic support for 2 days and 5 days, respectively, and were mechanically supported preoperatively; one with an intraaortic balloon pump for 36 hours and the other with supportive bypass using a conventional roller pump for 18 hours.
Ann Thorac Surg 1992;54:333-7
60
L
3 u)
40 20
-
1 0
20
40
60
80
Months
Fig 1. Actuarial survival of all patients undergoing heterotopic heart transplantation with adjunctive operation on the recipient heart.
tect arrhythmias together with echocardiographic determination of indices of systolic and diastolic function. The reference method for diagnosing acute rejection remained endomyocardial biopsy, which was performed routinely at regular intervals postoperatively. Additional biopsies were performed if rejection was suspected [5]. Cardiac catheterization and exercise testing according to the Bruce protocol [7] was performed annually.
Immunosuppressive Therapy The immunosuppression protocol consisted of cyclosporine A and azathioprine with no, or minimal, oral steroids ~51.
Anticoagulation Anticoagulation was not used routinely in all patients but was introduced in 11patients with intracardiac thrombus, severely impaired function of one or both hearts, or a thromboembolic event.
Statistics
Standard 2 and paired t tests were employed. Actuarial survival was calculated using the Kaplan-Meier productlimit method calculated using BMDP statistical software
PI.
Results Survival
The mean donor age was 17.6 years (SEM, 1.8) and the median age was 14 years. The donor age range was 7 to 40 years. Seventeen of 28 (61%) were aged 14 years or younger. Mean donor ischemic time was 166 minutes (SEM, 11 minutes), and median time was 160 minutes with a range of 90 to 275 minutes.
Early death (within 6 months of operation) occurred in 6 of 28 patients (21%);3 patients died of acute rejection and 3 died of infective complications associated with multiple system failure. Early death was not related to the number of coronary artery bypass grafts performed. All the remaining patients survived for more than 2 years. The longest survivor is alive and well at 8 years. Actuarial 1-year survival was 79%, and actuarial 5-year survival was 63% (Fig 1).
Follow-tlp
Symptomatic Status
All patients were monitored postoperatively for signs of cardiac failure and noninvasively with serial electrocardiograms to determine electrocardiographic voltage and de-
Preoperatively all patients were in New York Heart Association functional grade III/IV. Of the 22 patients surviving to 2-year follow-up, 20 were in grade 1/11 ( p < 0.001)
Donors
RIDLEY ET AL HETEROTOPIC HEART TRANSPLANTATION
Ann Thorac Surg 1992:54:333-7
and 2 showed some improvement in function, having gone from grade IV to grade I11 (Fig 2a). Of the 12 patients surviving to 5-year follow-up, 10 were in grade YII ( p < 0.001). The remaining 2 patients showed some functional improvement from grade IV to I11 (Fig 2b). Angina was experienced in 1 of the 22 patients surviving to 2-year follow-up compared with 15 preoperatively ( p < 0.001) and 2 of the 12 patients surviving to 5-year follow-up experienced angina compared with 9 preoperatively ( p < 0.01). Residual angina postoperatively was mild in 2 cases, only occurring with moderate or severe exercise and did not limit the patients' lifestyle. Annual exercise testing according to the Bruce protocol resulted in a mean exercise tolerance of 9.3 minutes (SEM, 0.6 minutes) at 2 years and 8.0 minutes (SEM, 0.8 minutes) at 5 years. Fourteen of the 22 patients (63%) surviving 2 years were able to return to some form of gainful employment. Postoperatively 2 patients suffered transient ischemic cerebral episodes and were fully anticoagulated. A further 9 patients required anticoagulation commencing between 6 months and 5 years postoperatively when thrombus was identified in the recipient heart ventricle or very poor left ventricular function occurred in the donor or recipient heart. There were no complications related to the use of anticoagulants.
Recipient Heart Function Of the 22 patients followed up for 2 years, 14 (64%) showed a substantial recipient contribution (defined as echocardiographic, Doppler and cardiac catheterization evidence of aortic ejection from the recipient heart) to cardiac output (Fig 3); only 1 of these patients showed evidence of thrombus in the recipient heart ventricle. The 20 c
5
._ 15 c
ma
10
E
5
J2
z
0
lGradt
Fig 3. Satisfactoy recipient heart function. From below upward are shown a complex arterial pressure trace (carotid ultrasound), a complex electrocardiogram, and an M-mode echocardiogram demonstrating regular opening of the aortic valve in the recipient heart. Both hearts contribute to the carotid pulse. The carotid pulse wave varies according to whether the two QRS complexes occur sequentially or synchronously. (D = donor heart QRS complex; R = recipient heart QRS complex.)
other 8 patients showed some evidence of ventricular contraction but minimal or no effective ejection, and the aortic valve remained closed throughout in 4 patients; 6 of these patients had thrombus in the recipient ventricle. Of the 12 patients followed up for 5 years, 9 patients (75%) showed a substantial recipient heart contribution to cardiac output. Left ventricular thrombus was present in all 3 hearts with minimal or no ejection and in 2 of the hearts with substantial contribution. In 4 patients the recipient heart supported the patient when the donor heart failed. Standardized angiographically determined ejection fractions of the contractile portion of the left ventricle were obtained preoperatively in 10 of the patients surviving to 2-year follow-up, and in these patients the mean ejection fraction in the recipient heart was 0.18 (SEM, 0.02) preoperatively and 0.25 (SEM, 0.02) at 2 years.
Coronary Artery Bypass Graft Function
v)
pa,
335
Bb
c
Of the 25 patients in this series who had coronary artery bypass grafts, the 20 surviving to 2-year follow-up received a total of 34 grafts. The mean number of grafts per patient was 1.8 (range, 1 to 3). The distribution of the grafts was as follows: circumflex, 19; right coronary, 10; left anterior descending, 4; diagonal of left anterior descending, 1. Endarterectomy to the right coronary artery was performed in 2 patients, and the internal mammary artery was used in 2 patients. The graft patency at 2-year catheterization was 79% (27/34). Both internal mammary artery grafts were patent. Eleven patients who underwent coronary artery bypass grafting survived to 5-year followup. A total of 16 grafts were performed in this group of patients, with a 5-year graft patency of 50% (8/16).
0
Donor Function
Fig 2 . New York Heart Association functional classification preoperatively and postoperatively in patients surviving to (a) 2 years and (b) 5 years.
In all patients except 4, who survived past the initial postoperative period, the donor heart made the major contribution to cardiac output and was augmented to a greater or lesser extent by the recipient heart. In 4 patients the donor heart failed and the patient was supported by the recipient heart alone. In 1 patient severe acute rejection of the donor heart caused ventricular fibrillation 3 months postoperatively. The episode of acute rejection
336
RIDLEY ET AL HETEROTOPIC HEART TRANSPLANTATION
was successfully treated and the heart was cardioverted to sinus rhythm after 3 days. In a second patient, acute rejection caused intractable ventricular fibrillation, which did not respond to cardioversion. This was managed by removal of the donor heart, and because of the presence of antimyocardial antibodies [9], repeat transplantation was not undertaken. The patient remains alive but limited (New York Heart Association grade 111), supported only by the native recipient heart 6 years after his initial heart transplantation. In 2 patients the donor heart failed with advanced coronary artery disease. One was managed by a second heterotopic transplantion after 4 years and remains alive 2 years after the second transplantation. The other patient had, in addition to the typical distal diffuse coronary artery disease seen in the transplanted heart, a proximal localized lesion in an epicardial vessel, which was successfully dilated at angioplasty but which has not resulted in an increase in ejection from the donor heart. The incidence of coronary artery disease (defined as a narrowing in coronary artery diameter of greater than 33%) of the donor organ was 2 of 22 patients (9%) surviving to 2-year follow-up and 4 of 11 patients (36%) surviving, with their initial heterotopic heart, to 5-year follow-up. In 2 patients the disease was sufficiently severe to cause failure of the donor heart as described above. The lesions had a distal diffuse distribution, similar to those seen in orthotopic heart transplantation.
Effect on Pulmonary Artery Pressure and Pulmonary Vascular Resistance At first postoperative cardiac catheterization 1 year postoperatively, mean systolic pulmonary artery pressure fell from a preoperative value of 47.5 mm Hg (SEM, 2.9 mm Hg) to 28 mm Hg (SEM, 1.6 mm Hg) ( p < 0.05), and mean diastolic pulmonary artery pressure fell from 22.4 mm Hg (SEM, 3.1 mm Hg) to 14.9 mm Hg (SEM, 1.2 mm Hg). The mean PVR fell from 3.2 Wood units (SEM, 0.5 Wood units) to 1.8 Wood units (SEM, 0.5 Wood units) ( p < 0.05). Postoperatively all patients had a PVR of less than 4.5 Wood units.
Comment The role of heterotopic heart transplantation with or without adjunctive operation on the recipient heart remains controversial [2, 3, 6, 10, 111. The theoretical value of heterotopic heart transplantation is the possibility of augmenting the cardiac output of the donor heart with some useful function from the recipient heart. This is especially advantageous when the donor heart is small, particularly if a pediatric heart is used in an adult recipient, or at times of donor rejection. However, many potentially serious disadvantages have been attributed to heterotopic transplantation. Traditionally, these include recipient heart arrhythmias, thromboembolism, persistent angina [4], and compression of the right lower lobe of the lung by the donor heart. Postoperative follow-up and diagnosis of rejection are also technically more difficult as electrocardiogram analysis, echocardiography, and myocardial biopsy are all more challenging. The actuarial survival and symptomatic improvement
Ann Thorac Surg 1992;54:333-7
in this series compare favorably with those of other series employing heterotopic transplantation without adjunctive operation in the management of end-stage ischemic heart disease [3,6]. Poor outcome of conventional operation for ischemic heart disease is associated with poor ventricular function; ejection fraction less than 0.35, congestive heart failure, New York Heart Association functional classes I11 and IV, large diuretic requirement, and dyspnea as the primary symptom [12]. All patients in this series had these risk factors and were considered unlikely to have survived conventional surgical approaches without heart transplantation. In most patients the donor heart made the major contribution to cardiac output; the exceptions were the 4 patients in whom the donor heart failed to eject and the recipient heart supported the patient. However, in all 4 cases the patient would have been unlikely to have survived the immediate postoperative period without the donor heart. Recovery of recipient function has been described in patients with acute viral myocarditis [lo] but is not expected in patients with end-stage ischemic heart disease. The donor hearts in this series, as expected [lo], provided the major contribution to cardiac output. However unlike in other series [3], donor performance was augmented substantially in most cases by the recipient heart that had undergone adjunctive operation. In 4 cases the recipient heart supported the patient when the donor heart failed to eject; these patients would presumably have succumbed had they undergone orthotopic heart transplantation. Although not conclusive evidence, the fact that 64% showed substantial recipient contribution to cardiac output at 2 years supports the idea that recipient function was improved by adjunctive operation in this series [13, 141. There was a trend toward improvement in measured ejection fractions of the contractile portion of the left ventricle after operation on the recipient heart. However, measurements of ejection fractions were technically more difficult after heterotopic heart transplantation and, as most patients had ventricular aneurysmectomy, comparison of preoperative and postoperative recipient ejection fraction should be treated with caution. Previous studies have found ejection fraction to have a poor correlation with improved cardiac output after aneurysmectomy [ 121. The patency of the coronary artery bypass grafts was comparable with that obtained in routine coronary artery bypass grafting [15]. Internal mammary artery grafts remain patent longer than vein grafts in standard coronary artery bypass graft operations [16], and the internal mammary artery grafts performed in this series have remained patent in both patients until time of death (3 years in both cases). The low number of left anterior descending artery grafts reflects the fact that this artery was frequently obliterated and excised by left ventricular aneurysmectomy. Several factors may contribute to the relief of angina; coronary artery bypass grafting revascularized the heart and aneurysmectomy reduced the cavity size with a resultant reduction in wall stress and oxygen requirement. The donor heart further reduced the work of the recipient heart as its greater compliance meant that it received a greater proportion of the venous return in most cases.
RIDLEY ET AL HETEROTOPIC HEART TRANSPLANTATION
Ann Thorac Surg 1992:54:33.3-7
The h i g h incidence of intraventricular thrombus i n poorly functioning recipient ventricles was not associated w i t h a large incidence (2 transient cases) of thromboembolic phenomena. This is probably due t o t h e failure of t h e aortic valve t o open i n m a n y of these patients a s well as t h e introduction of full anticoagulation with warfarin if thrombus was detected. Avoidance of routine anticoagulation a n d steroid therapy meant that patients w i t h a history of peptic ulceration w e r e n o t excluded from consideration for heterotopic transplantation. The presence of intraventricular thrombus preoperatively is usually considered t o be a contraindication t o heterotopic heart transplantation, b u t t h e use of adjunctive operation including, or consisting of, aneurysmectomy allowed organized t h r o m b u s t o be removed a t operation i n 5 patients i n this series. Early coronary artery disease was identified i n t h e donor h e a r t i n t h e heterotopic position, which did n o t differ substantially i n incidence o r distribution from t h a t seen i n orthotopic heart transplantations [17]. A s recently e m p h a s i z e d by Kotliar and associates [18], there continues to be an inadequate supply of d o n o r hearts for all potential recipients [19], and patients with end-stage ischemic h e a r t disease continue t o die on t h e waiting list [20]. T h e use of small hearts i n t h e heterotopic position c a n t h u s be justified a s making best use of a limited resource i n an a t t e m p t to reduce transplant waiting times. Small donor size, particularly pediatric donors for a d u l t recipients, w a s t h e major indication for leaving t h e recipient heart i n situ i n this series. Elevated preoperative PVR was n o t a major indication for heterotopic heart transplantation i n this series. O t h e r m o d e s of transplantation m a n a g e m e n t a r e available for patients w i t h elevated PVR. Recipients w i t h moderately elevated PVR (4to 8 W o o d units) were considered for orthotopic heart transplantation using a large donor, o r a preconditioned heart from a heart-lung recipient w i t h secondary right ventricular hypertrophy (the "domino" operation) [17]. Severe p u l m o n a r y hypertension (>8 Wood units) was managed b y heart-lung transplantation. Elevated PVR has been emphasized as a n indication for heterotopic heart transplantation [2, 211 b u t remains controversial; experience from Paris suggests that, although pulmonary hemodynamics a r e improved, heterotopic h e a r t transplantation i n patients w i t h elevated PVR is associated with frequent p u l m o n a r y complications a n d fails t o improve t h e prognosis i n patients w i t h preoperative pulmonary hypertension [6, 221. In conclusion, this series demonstrates that heterotopic transplantation w i t h adjunctive operation on t h e recipient heart is a satisfactory m e t h o d of managing selected patients w i t h end-stage ischemic heart disease a n d should be considered i n t h o s e cases where t h e only available o r g a n is small and adjunctive operation on t h e recipient h e a r t is technically possible.
337
References 1. Kreitt J, Kaye M. The Registry of the International Society for Heart Transplantation: seventh official report-1990. J Heart Transplant 1990;9:32%30. 2. Reichenspurner H, Hildebrant A, Boehm D, et al. Heterotopic heart transplantation in 1988-recent selective indications and outcomes. J Heart Transplant 1989;8:381-6. 3. Cooper D, Novitzky D, Becerra E, Reichart B. Are there indications for heterotopic heart transplantations in 1986? A 2- to 11-year follow-up of 49 consecutive patients undergoing heterotopic heart transplantation. Thorac Cardiovasc Surg 1986;34:30&4. 4. Novitzky D, Cooper D, Barnard C. The surgical technique of heterotopic heart transplantation. Ann Thorac Surg 1983;36: 476-82. 5. Banner N, Fitzgerald M, Khaghani A, et al. Cardiac transplantation at Harefield hospital. In: Terasaki P, ed. Clinical transplants 1987. Los Angeles: UCLA Tissue Typing Laboratory, 198717-26. 6. Desruennes M, Muneretto C, Gandjbakhch I, et al. Heterotopic heart transplantation: current status in 1988. J Heart Transplant 1989;8:479-85. 7. Bruce R. Exercise testing for ventricular function. N Engl J Med 1977;296:671-5. 8. Dixon W. In: BMDP statistical software. Berkeley: University of California Press, 1985. 9. Lanza R, Campbell E, Cooper D, DuToit E, Barnard C. The problem of the presensitized heart transplant recipient. Heart Transplant 1983;2:1514. 10. Hassoulas J, Barnard C. Heterotopic cardiac transplantation: a 7-year experience at the Groote Schuur hospital, Cape Town. S Afr Med J 1984;65:675-82. 11. Nakatani T, Frazier 0, Lammermeier D, Macris M, Radovancevic B. Heterotopic heart transplantation: a reliable option for a select group of high risk patients. J Heart Transplant 1989;8:4&7. 12. Vauthey J, Berry D, Snyder D, et al. Left ventricular aneurysm repair with myocardial revascularization: an analysis of 246 consecutive patients over 15 years. Ann Thorac Surg 1988;46:29-35. 13. Olearchyk A, Lemole G, Spagna P. Left ventricular aneurysm. Ten years experience in surgical treatment of 244 cases; improved clinical status, hernodynamics and long-term longevity. J Thorac Cardiovasc Surg 1984;88:54&53. 14. Dilsizian V, Bonow R, Cannon R 111, et al. The effect of coronary artery bypass grafting on left ventricular function at rest: evidence for preoperative subclinical myocardial ischemia. Am J Cardiol 1988;61:124%54. 15. Fuster V, Chesebro J. Role of platelet inhibitors in aortocoronary artery vein-graft disease. Circulation 1986;73:227-38. 16. Lytle B, Loop F, DM C, Ratcliff N, Easley K, Taylor P. Long term (5 to 12 years) serial studies of internal mammary artery and saphenous vein coronary bypass grafts. J Thorac Cardiovasc Surg 1985;89:24&58. 17. Banner N, Khaghani A, Fitzgerald M, Mitchell A, RadleySmith R, Yacoub M. The expanding role of cardiac transplantation. In: Unger F, ed. Assisted circulation. Berlin: SpringerVerlag, 1989:448-67. 18. Kotliar C, Smart F, Sekela M, et al. Heterotopic heart transplantation and native heart ventricular arrhythmias. Ann Thorac Surg 1991;51:987-91. 19. Copeland J, Emery P, Levinson M, et al. Selection of patients for cardiac transplantation. Circulation 1987;75:2-9. 20. Fowler M, Schroeder J. Current status of cardiac transplantation. Mod Concepts Cardiovasc Dis 1986;55:3741. 21. Shumway S, Baugham K, Trail1T, et al. Persistent pulmonary hypertension after heterotopic heart transplantation: a case report. J Heart Transplant 1989;8:387-90. 22. Kawaguchi A, Gandjbakhch I, Pavie A, et al. Factors affecting survival after heterotopic heart transplantation. J Thorac Cardiovasc Surg 1989;98:928-34.