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Transplantation of the Heart
Transplantation of the Heart* EUGENE DoNG, JR., EDWARD
J.
M.D.,
RICHARD R. LowER,
M.D., F.c.c.P.,
HURLEY, M .D. AND NORMAN E . SHUMWAY, M.D.
Palo Alto, California
T
HE
LOCALLY
DENERVATED BUT BID-
logically supported heart is a physiologic tool of great importance in the study of myocardial function and pharmacologic response. Additionally it provides hope that a natural replacement for an otherwise irreparably diseased heart may yet be realized. Therefore, successful experimental transplantation of the heart has important and exciting implications for clinical and physiologic investigation. We wish to review certain aspects of cardiac performance in short-term experiments with cardiac homografts and long-term experiments with cardiac autografts on 40 dags, of which 32 survived over five days. The technique of operation is that described by Lower and Shumway' in 1960 and by Hurley et al." in 1962. With the aid of cardiopulmonary bypass and peripheral venous cannulation, the heart is removed by transecting the atria and great vessels through a fourth left thoracotomy. The heart is removed from the chest, stored in 4•c. isotonic saline solution and replaced by suturing the right atrium, the atrial septum, the left atrium, the aorta and the pulmonary artery in that order. Digitalis and diuretics were not administered pre- or postoperatively. The homografts were studied awake when possible. Chloralose-urethane anesthesia was employed when necessa~· . Cardiac output was meac;ured by indocyanine green dilution using a Waters· X-300 densitometer. Arterial and venous pressures were measured by direct puncture. Cardiac •From the Department or Surgery, Stanrord University School or Medicine. Supported in part by United States Public Health Service Grant-in-Aid HE 08696, Santa Clara County Heart Association, Monterey Colnty Heart Association. Presented at the 30th Annual Meeting. American College or Chest Physicians, San Francisco. June 18-22, 1964. ·
455
catheterization in the cardiac autografts were carried out under chloralose-urethane anesthesia. The cardiac output in this instance was measured by Evans blue dilution; the vagi were stimulated at lO cycles per second using a I millisecond square wave stimulator. Acetylcholine, norepinephrine, tyramine, and epinephrine were infused either as single doses or by continuous infusion while monitoring electrocardiogram and blood pressure. CARDIAC RATE AND RHYTHM
After cardiac transplantation, the pacemaking cells are essentially free running influenced by physical and humoral factors, but not directly hy neurogenic factors. We would not have been surprised if severe disturbances in automaticity were present after operation considering the trauma inflicted during the operation such as myocardial ischemia, air embolism, a long atrial suture line, and prolonged artificial perfusion. Only occasionally, however, has this been a major problem. Indeed, a remarkable feature of the homograft has been the stability of the pacemaking system. The rate variability of the normal heart due to neutral influences is measured in terms of tenths of seconds. The standard deviation of the heart rate in transplanted animalc; after operation is measured in milliseconds. When a particular heart rate is established, it usually persists for several hours. Acute changes of heart rate are secondary to changes in pacemaker sites resulting in step changes in R-R intervals rather than smooth transitions. The most frequent rhythms noted after homotran~plantation are atrial in origin. They are generally established on the dav of operation. The P-wave is low and di·phasic, with a P-R interval of I 00 to 120
F.UGENE DONG, JR.,
( 1 ) the stability of the heart rate; ( 2) tachycardia with intravenous norepinephrine, and ( 3) absence of effect of tyramine and of direct vagal stimulation. Late in the postoperative course, at least three months after operation and some time before one year, there is both vagal and sympathetic reinnervation. Evidence for this lies in the reappearance of sinus arrhythmia correlated with respiration, cardiac arrest with direct vagal stimulation, atrial tachycardia with infusion of tyramine and dilute solutions of acetylcholine and no change in or slowing of the heart rate with norepinephrine infusion.
milliseconds. The rate is usually above 90 beat<> per minute. The second most frequent rhythms are nodal in origin, often with observable retrograde atrial conduction, and intraventricular conduction delays. This rhythm persists no longer than the fourth postoperative day. Ventricular ectopic beats are decidedly rare after the first and second days postoperatively. Sinus arrest with nodal rhythm and absent atrial conduction is not uncommon. Periods of arrest up to ten seconds have been noted and may recur up to several months after surgery. Only in the case of sinus arrest with slow nodal rhythm has it been necessary to treat arrhythmias. Electronic pacemakers have been implanted with good effect. In the autotransplant, one year and a half to two years after operation a sinus arrh)thmia may be noted. P-waves are still small. An interesting anomaly arises because of the transatrial method of excision. Some atrial wall is left behind. On routine electrocardiography, its activity can be seen as an independent P-wave marching through the donor P-wave and QRS complex. This phenomenon is of diagnostic interest when there is absence of the donor P-wave. Is there, for example, third degree block, or is the atrial complex buried in the QRS? Resolution of this problem lies in intracardiac electrocardiography which demonstrated in all cases separate atrial pacemakers. Besides the intuitive argument that the heart is denervated after transplantation, the evidence for denervation is as follows :
MYOCARDIAL FUNCTION
The clinical status of these animals is remarkably good. Immediately after transplantation there is a depression of cardiac output with a slight elevation of venous pressure. The peripheral resistance is high. There is a rapid recovery of function with time after operation reflecting the probability that the major depressing factor is sustained at the time of surgery. It is not our experience that frank clinical congestive heart failure is a prominent feature in the early postoperative course. Pulmonary edema, peripheral edema, or ascites is unusual. We find that the small incidence of water retention has been related to known causative factors such as mitral insufficiency due to bacterial endocarditis or aorticpulmonary artery fistula:. Other investigators have noted severe failure leading to death despite treatment. Since this phenomenon is real, the reasons for the difference in results may lay in a smaller popula-
TABLE I-RESTING CARDIAC OuTPUT
Dog :'\lumber
t• 2 3 4
5 6 7
0 51 57 33 53 73 79 38
2 69
3 81
(mi./Kg. )
Postoperative Day 6 4 8 149
95 127
DiKasrt$ of th< Ch
et aJ.
9
153
144 122 102 !50 !09
•died 6th postoperative day with acute rejection ••duplicate detenninations on each day.
124
15
22
327••
263••
Volume 48, Nu. '\
TRANSPLAXTATIOX OF THE HEART
November 19M
tion sample on our part or due to differing surgical techniques or postoperative management between the several groups of investigators. Our objective data, however, reveal that there is an absence of weight gain, edema, or tachypnea, that there is an adequate cardiac output and normal venous pres..,ure and that there is a progres..,ive decline in circulation time. We do not have cause to feel, therefore, that there is a physiologic objection to cardiac transplantation. The cardiac output is well maintained six months after transplantation and also 18 months to two years after operation. At two years, the heart rate, the rhythm, the cardiac output, the venous pressure, and the left atrial wedge pressure are in the normal range and responses to exercise are normal." It has been reported that dogs with denervated heart" increase their cardiac output in response to exercise primarily by increa'ling stroke volume.• In the long-term autograft'!, as in normal dogs, the increase in cardiac output is proportional to the increase in heart rate and the stroke volume is essentially unchanged. SUMMARY
The performance of the heart has been examined after cardiac homa- and autOtransplantation. In the early postoperative period, measurements of cardiova'ICular responses reaffirm the good clinical condition of these preparations. In the late postoperative period the evidence suggest" that both sympathetic and parasympathetic reinnervation occur and that cardiac performance closely approaches normal levels. REst.'~IES
Este estudio se hasa en el exanwn del funcionamiento dt> transplantes cardiacos homo y UPPER LOBE FIBROSIS ASSOCIATED Six patients with severe ankyloslng spondylitis have been observed to have characterlstk pulmonarr tlbrosls. In five or the SIX patients, the condition began radiologically as spotty lrn!gular opacities In the upper halves or the lungs. There was progressl\·e Increase In the size and extent or the opacities together with contraction ot lung substance. Cysts. sometimes large. then appeared. At this stage. producth·e rough and repeated hemoptysis developed. Pathologic examination has been limIted. but biopsy or the lung In the Initial phaS<• revealed patchy pneumonia with round C<'ll and
457
heterologos. En las etapas tempranas del periodo postoperatorio Ia medida de las reaccion~ cardio\'asculares confirman el buen estado dinico de estas preparaciones. En period05 mas tardios las observaciones existentes parecen indicar el restablecimiento de Ia inervacion simpatica y parasimpatica con normalizacion aproximada del rendimiento cardiaco. RESUMi. Le tra\'ail du coeur a ete etudie apres homoet auto-transplantation du coeur. Dans Ia ~riode post-o~ratoire precose, des mesures des reponses cardio-vasculaires confirment Ia bonne efficacite clinique de ces preparations. Dam Ia )Xriode powt-o)Xratoire tardive, les ~suhats sugg!rent qu'il se produit une reinervation a Ia fois sympathique et parasympathique et que le travail du couer aproche de pres les niveaux normaux. ZusAMMENFAssusc. Die Herzleistung nach cardialer Homo- und Autotransplantation wurde einer Priifung unterzogen. Messungen der cardiovasculliren Reaktiont>n in der ersten postoperati\'en Phase bestatigen die guten klinischen Verhaltnisse dieser Praparate. In der spateren postoperativen Periode laf3t der Augenschein vermuten, daj3 sowohl eine sympathische als auch parasyrnpathische Reinnet>·ation eintritt, und daf3 die Herzleistung sich weitgehend Normawerten nahert. R£F£RENCES Lowr.a, R. R. AND SHUMWAY, N. E. : "Studies on Orthotopic Homotransplantation of the Canine Heart," s.. ,,. For.,m, II: 18, 1960. 2 HuRLr.Y, E. J., DoNo, E., Ja., STOr.FR, R. C. AND SHUMWAY, N. E.: "Isotopic Replacement of the Totally Excised Canine Heart," J. s.. rg., Rn, 2:90, 1962. 3 Doso, E., Ja., Fowxr.s, W. C., HuaLr.Y, E. J ., HANCOCK, E. w. AND PILLSBURY, R. C.: "Hemodynamic Effects of Cardia<" Autotransplantation." Circ.,ldtion (supplement), 29 : 77. 1964. 4 DosALn. D. E. AND SHEPHERD, J. T .: "Response to Exercise in Dogs with Cardiac Dt>· nt>t>•ation," Am. J. Ph)•riol., 205: 393, 1963. For reprints, please write: Dr. Dong. Division uf Cardiovascular Surgery, Stanford Medical Center, Palo Alto, California. WITH ANKYLOSING SPONDYLITIS fibroblastic Infiltration. A lobe trom a patient with more advanced disease showed dense pleural and Intrapulmonary fibrosis with contraction or lung substanC<' and the development or many cysts. The Involvement resembles the ftbrostng Inflammation which may Involve the 110rta In spondylitis ankylopoletlca and Is possibly part or the pathologic process ot that condition. CAWPBllL .
A. H.
AND MACDoNALD,
C. B.: "Upper Lobe
Fibrosis Associated with Ankylosin& Spondylitis," Brit. Di1. Chw. ~9:90, 196,.
J.
J.
M.D.,
RICHARD R. LowER,
M.D., F.c.c.P.,
HURLEY, M .D. AND NORMAN E . SHUMWAY, M.D.
Palo Alto, California
T
HE
LOCALLY
DENERVATED BUT BID-
logically supported heart is a physiologic tool of great importance in the study of myocardial function and pharmacologic response. Additionally it provides hope that a natural replacement for an otherwise irreparably diseased heart may yet be realized. Therefore, successful experimental transplantation of the heart has important and exciting implications for clinical and physiologic investigation. We wish to review certain aspects of cardiac performance in short-term experiments with cardiac homografts and long-term experiments with cardiac autografts on 40 dags, of which 32 survived over five days. The technique of operation is that described by Lower and Shumway' in 1960 and by Hurley et al." in 1962. With the aid of cardiopulmonary bypass and peripheral venous cannulation, the heart is removed by transecting the atria and great vessels through a fourth left thoracotomy. The heart is removed from the chest, stored in 4•c. isotonic saline solution and replaced by suturing the right atrium, the atrial septum, the left atrium, the aorta and the pulmonary artery in that order. Digitalis and diuretics were not administered pre- or postoperatively. The homografts were studied awake when possible. Chloralose-urethane anesthesia was employed when necessa~· . Cardiac output was meac;ured by indocyanine green dilution using a Waters· X-300 densitometer. Arterial and venous pressures were measured by direct puncture. Cardiac •From the Department or Surgery, Stanrord University School or Medicine. Supported in part by United States Public Health Service Grant-in-Aid HE 08696, Santa Clara County Heart Association, Monterey Colnty Heart Association. Presented at the 30th Annual Meeting. American College or Chest Physicians, San Francisco. June 18-22, 1964. ·
455
catheterization in the cardiac autografts were carried out under chloralose-urethane anesthesia. The cardiac output in this instance was measured by Evans blue dilution; the vagi were stimulated at lO cycles per second using a I millisecond square wave stimulator. Acetylcholine, norepinephrine, tyramine, and epinephrine were infused either as single doses or by continuous infusion while monitoring electrocardiogram and blood pressure. CARDIAC RATE AND RHYTHM
After cardiac transplantation, the pacemaking cells are essentially free running influenced by physical and humoral factors, but not directly hy neurogenic factors. We would not have been surprised if severe disturbances in automaticity were present after operation considering the trauma inflicted during the operation such as myocardial ischemia, air embolism, a long atrial suture line, and prolonged artificial perfusion. Only occasionally, however, has this been a major problem. Indeed, a remarkable feature of the homograft has been the stability of the pacemaking system. The rate variability of the normal heart due to neutral influences is measured in terms of tenths of seconds. The standard deviation of the heart rate in transplanted animalc; after operation is measured in milliseconds. When a particular heart rate is established, it usually persists for several hours. Acute changes of heart rate are secondary to changes in pacemaker sites resulting in step changes in R-R intervals rather than smooth transitions. The most frequent rhythms noted after homotran~plantation are atrial in origin. They are generally established on the dav of operation. The P-wave is low and di·phasic, with a P-R interval of I 00 to 120
F.UGENE DONG, JR.,
( 1 ) the stability of the heart rate; ( 2) tachycardia with intravenous norepinephrine, and ( 3) absence of effect of tyramine and of direct vagal stimulation. Late in the postoperative course, at least three months after operation and some time before one year, there is both vagal and sympathetic reinnervation. Evidence for this lies in the reappearance of sinus arrhythmia correlated with respiration, cardiac arrest with direct vagal stimulation, atrial tachycardia with infusion of tyramine and dilute solutions of acetylcholine and no change in or slowing of the heart rate with norepinephrine infusion.
milliseconds. The rate is usually above 90 beat<> per minute. The second most frequent rhythms are nodal in origin, often with observable retrograde atrial conduction, and intraventricular conduction delays. This rhythm persists no longer than the fourth postoperative day. Ventricular ectopic beats are decidedly rare after the first and second days postoperatively. Sinus arrest with nodal rhythm and absent atrial conduction is not uncommon. Periods of arrest up to ten seconds have been noted and may recur up to several months after surgery. Only in the case of sinus arrest with slow nodal rhythm has it been necessary to treat arrhythmias. Electronic pacemakers have been implanted with good effect. In the autotransplant, one year and a half to two years after operation a sinus arrh)thmia may be noted. P-waves are still small. An interesting anomaly arises because of the transatrial method of excision. Some atrial wall is left behind. On routine electrocardiography, its activity can be seen as an independent P-wave marching through the donor P-wave and QRS complex. This phenomenon is of diagnostic interest when there is absence of the donor P-wave. Is there, for example, third degree block, or is the atrial complex buried in the QRS? Resolution of this problem lies in intracardiac electrocardiography which demonstrated in all cases separate atrial pacemakers. Besides the intuitive argument that the heart is denervated after transplantation, the evidence for denervation is as follows :
MYOCARDIAL FUNCTION
The clinical status of these animals is remarkably good. Immediately after transplantation there is a depression of cardiac output with a slight elevation of venous pressure. The peripheral resistance is high. There is a rapid recovery of function with time after operation reflecting the probability that the major depressing factor is sustained at the time of surgery. It is not our experience that frank clinical congestive heart failure is a prominent feature in the early postoperative course. Pulmonary edema, peripheral edema, or ascites is unusual. We find that the small incidence of water retention has been related to known causative factors such as mitral insufficiency due to bacterial endocarditis or aorticpulmonary artery fistula:. Other investigators have noted severe failure leading to death despite treatment. Since this phenomenon is real, the reasons for the difference in results may lay in a smaller popula-
TABLE I-RESTING CARDIAC OuTPUT
Dog :'\lumber
t• 2 3 4
5 6 7
0 51 57 33 53 73 79 38
2 69
3 81
(mi./Kg. )
Postoperative Day 6 4 8 149
95 127
DiKasrt$ of th< Ch
et aJ.
9
153
144 122 102 !50 !09
•died 6th postoperative day with acute rejection ••duplicate detenninations on each day.
124
15
22
327••
263••
Volume 48, Nu. '\
TRANSPLAXTATIOX OF THE HEART
November 19M
tion sample on our part or due to differing surgical techniques or postoperative management between the several groups of investigators. Our objective data, however, reveal that there is an absence of weight gain, edema, or tachypnea, that there is an adequate cardiac output and normal venous pres..,ure and that there is a progres..,ive decline in circulation time. We do not have cause to feel, therefore, that there is a physiologic objection to cardiac transplantation. The cardiac output is well maintained six months after transplantation and also 18 months to two years after operation. At two years, the heart rate, the rhythm, the cardiac output, the venous pressure, and the left atrial wedge pressure are in the normal range and responses to exercise are normal." It has been reported that dogs with denervated heart" increase their cardiac output in response to exercise primarily by increa'ling stroke volume.• In the long-term autograft'!, as in normal dogs, the increase in cardiac output is proportional to the increase in heart rate and the stroke volume is essentially unchanged. SUMMARY
The performance of the heart has been examined after cardiac homa- and autOtransplantation. In the early postoperative period, measurements of cardiova'ICular responses reaffirm the good clinical condition of these preparations. In the late postoperative period the evidence suggest" that both sympathetic and parasympathetic reinnervation occur and that cardiac performance closely approaches normal levels. REst.'~IES
Este estudio se hasa en el exanwn del funcionamiento dt> transplantes cardiacos homo y UPPER LOBE FIBROSIS ASSOCIATED Six patients with severe ankyloslng spondylitis have been observed to have characterlstk pulmonarr tlbrosls. In five or the SIX patients, the condition began radiologically as spotty lrn!gular opacities In the upper halves or the lungs. There was progressl\·e Increase In the size and extent or the opacities together with contraction ot lung substance. Cysts. sometimes large. then appeared. At this stage. producth·e rough and repeated hemoptysis developed. Pathologic examination has been limIted. but biopsy or the lung In the Initial phaS<• revealed patchy pneumonia with round C<'ll and
457
heterologos. En las etapas tempranas del periodo postoperatorio Ia medida de las reaccion~ cardio\'asculares confirman el buen estado dinico de estas preparaciones. En period05 mas tardios las observaciones existentes parecen indicar el restablecimiento de Ia inervacion simpatica y parasimpatica con normalizacion aproximada del rendimiento cardiaco. RESUMi. Le tra\'ail du coeur a ete etudie apres homoet auto-transplantation du coeur. Dans Ia ~riode post-o~ratoire precose, des mesures des reponses cardio-vasculaires confirment Ia bonne efficacite clinique de ces preparations. Dam Ia )Xriode powt-o)Xratoire tardive, les ~suhats sugg!rent qu'il se produit une reinervation a Ia fois sympathique et parasympathique et que le travail du couer aproche de pres les niveaux normaux. ZusAMMENFAssusc. Die Herzleistung nach cardialer Homo- und Autotransplantation wurde einer Priifung unterzogen. Messungen der cardiovasculliren Reaktiont>n in der ersten postoperati\'en Phase bestatigen die guten klinischen Verhaltnisse dieser Praparate. In der spateren postoperativen Periode laf3t der Augenschein vermuten, daj3 sowohl eine sympathische als auch parasyrnpathische Reinnet>·ation eintritt, und daf3 die Herzleistung sich weitgehend Normawerten nahert. R£F£RENCES Lowr.a, R. R. AND SHUMWAY, N. E. : "Studies on Orthotopic Homotransplantation of the Canine Heart," s.. ,,. For.,m, II: 18, 1960. 2 HuRLr.Y, E. J., DoNo, E., Ja., STOr.FR, R. C. AND SHUMWAY, N. E.: "Isotopic Replacement of the Totally Excised Canine Heart," J. s.. rg., Rn, 2:90, 1962. 3 Doso, E., Ja., Fowxr.s, W. C., HuaLr.Y, E. J ., HANCOCK, E. w. AND PILLSBURY, R. C.: "Hemodynamic Effects of Cardia<" Autotransplantation." Circ.,ldtion (supplement), 29 : 77. 1964. 4 DosALn. D. E. AND SHEPHERD, J. T .: "Response to Exercise in Dogs with Cardiac Dt>· nt>t>•ation," Am. J. Ph)•riol., 205: 393, 1963. For reprints, please write: Dr. Dong. Division uf Cardiovascular Surgery, Stanford Medical Center, Palo Alto, California. WITH ANKYLOSING SPONDYLITIS fibroblastic Infiltration. A lobe trom a patient with more advanced disease showed dense pleural and Intrapulmonary fibrosis with contraction or lung substanC<' and the development or many cysts. The Involvement resembles the ftbrostng Inflammation which may Involve the 110rta In spondylitis ankylopoletlca and Is possibly part or the pathologic process ot that condition. CAWPBllL .
A. H.
AND MACDoNALD,
C. B.: "Upper Lobe
Fibrosis Associated with Ankylosin& Spondylitis," Brit. Di1. Chw. ~9:90, 196,.
J.