91 HEART TRANSPLANTATION
Daniel R. Meldrum M.D., Azad Raiesdana M.D., Jeffrey A. Breall M.D., John W. Brown M.D.

1. Who performed the first experimental heart-lung transplant?

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Alexis Carrel, a French-born American surgeon, developed the vascular techniques required for heart-lung transplantation and performed the first experimental heart-lung transplant in 1907. He transplanted the lungs, heart, aorta, and vena cava of a 1-week-old cat into the neck of a large adult cat. For devising the technique of vascular anastomosis and other outstanding accomplishments, Carrel received the Nobel Prize in 1912 (the first Nobel Prize awarded to a scientist working in an American laboratory).

2. Who performed the first successful experimental heart-lung transplant?

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V.P. Demikhov performed the first successful heart-lung transplant in a dog in 1962.

3. Who developed the surgical strategy required for human heart transplantation?

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Norman Shumway.

4. Who performed the first human heart transplant? When?

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C.N. Bernard performed the first human heart transplant in December, 1967 (in Capetown, South Africa, after visiting Dr. Shumway), although Dr. Shumway set the stage by developing the technique in animals. Shumway and the Stanford group performed the first heart transplant in the United States and accomplished the first successful clinical series.

5. Who performed the first successful heart-lung transplant? When?

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Dr. Bruce Reitz at Stanford in 1981 on a 21-year-old woman with pulmonary hypertension secondary to an atrial septal defect.

6. How many heart transplants are performed annually? Is the number increasing or decreasing?

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In 1983 approximately 300 heart transplants were performed worldwide. By 1988, the number had rapidly increased to approximately 3000 and remains relatively stable between 3500 and 4000.

7. What anastomoses (surgical connections) must be performed for a combined heart and lungs transplant?

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The operation requires only a right atrial-to-cava (inflow) anastomosis and an aortic (outflow) anastomosis with a connection at the trachea. Heart-lung transplant is less complicated (fewer anastomoses) than heart transplant alone, which may explain why heart-lung transplant was attempted first.
8. What anastomoses must be performed for a heart transplant? Show answer
Left atrial, right atrial, aortic, and pulmonary arterial.

9. Who is an acceptable cardiac donor?

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Acceptable cardiac donors meet the following criteria:

1. Requirements for brain death
2. Consent from next of kin
3. ABO blood group compatibility with recipient
4. Within 20% of the same size as recipient
5. Absence of history of cardiac disease
6. Normal echocardiogram (ventricular wall motion)
7. Normal heart by inspection during organ recovery

10. Who is an acceptable cardiac recipient?

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Although selection criteria are evolving as a result of improved techniques and outcomes, the following criteria are standard: age between newborn and 65 years; irremediable New York Heart Association Functional Class IV cardiac disease; normal renal, hepatic, pulmonary, and central nervous system function; pulmonary vascular resistance < 6-8 Wood units; and absence of malignancy, infection, recent pulmonary infarction, and severe peripheral vascular or cerebrovascular disease. Diabetes is a relative contraindication; the steroids used in posttransplant immunosuppression make diabetes difficult to manage. Also, normal psychological status has proven to be important.

11. What are the most common indications for heart transplant in adults and in children?

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In adults, coronary artery disease (ischemic cardiomyopathy) and idiopathic cardiomyopathy each account for approximately 45% of transplants.
In children, congenital heart disease and cardiomyopathy are most common, with hypoplastic left heart being the most common congenital malformation requiring heart transplantation.

12. What percentage of potential recipients (on the transplant list) die while waiting for a heart transplant?

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20%.

13. At what point does donor heart ischemic time influence mortality?

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Donor heart ischemic time > 6 hours definitely increases mortality. Ischemic times between 4 and 6 hours stun the donor heart. Most transplant teams try to keep ischemic times (from donor harvest to perfusion in the recipient) to < 4 hours.

14. Who pioneered hypothermic myocardial preservation?

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Henry Swan at the University of Colorado. He submerged anesthetized children in a bathtub of ice water before cardiac procedures.

15. How is cardiac allograft rejection prevented?

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Pharmacologically induced immunosuppression is performed by using one of two protocols. The first is triple therapy, which combines cyclosporine, azathioprine, and prednisone. The second major protocol incorporates the monoclonal antibody OKT3 into the triple therapy protocol. OKT3 is substituted for cyclosporine for the first 2 weeks after transplant.

16. What is OKT3?

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OKT3 is a mouse monoclonal antibody that binds to and blocks the T-cell CD3 receptor. A monoclonal antibody is an antibody generated from the clones of a single cell. For instance, a single B cell, which recognizes the CD3 receptor as an antigen (foreign), is immortalized in cell culture and produces the monoclonal antibody in limitless supply. The CD3 receptor, which is common to all T cells, is important for antigen recognition and T-cell activation; therefore, OKT3 is highly immunosuppressive.
KEY POINTS: CRITERIA FOR ACCEPTABLE HEART DONORS

1. Donors must meet the criteria for brain death.
2. Consent from donor’s next of kin.
3. ABO blood group compatibility with recipient.
4. Donor must be within 20% of same size as recipient.
5. Donor must have no history of cardiac disease and a normal echocardiogram.
6. Donor heart must appear normal by inspection during organ recovery.

17. What complications are associated with the use of OKT3?

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OKT3 may have severe side effects, including pulmonary edema and high fevers, that result from transient cytokine release, which may occur when OKT3 binds to the T-cell activation site. Because OKT3 is an antigen (an antibody from a different species [i.e., a mouse]), patients develop anti-OKT3 antibodies fairly quickly; the result is that OKT3 can only be used to treat one rejection episode. Severe side effects occur in < 5% of patients.

18. Does HLA mismatch influence the incidence of rejection after heart transplantation? Is HLA typing routinely performed before heart transplantation?

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Yes and no. In a multi-institutional, multivariate analysis of 1719 cardiac transplant recipients by Jarcho et al., HLA mismatch increased the incidence of rejection. However, HLA typing is not routinely done before heart transplantation because it takes too long. In addition, with three of six mismatches, there was still only a trend toward increased rejection-related deaths (P = 0.14). If longer organ preservation times can be achieved, donor/recipient HLA matching will become feasible and should improve survival rates. Again, ABO blood group compatibility does influence graft survival.

19. What are the major complications of heart transplantation?

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* Allograft rejection (days to weeks)
* Infection (months)
* Transplant coronary artery disease (years)

20. What is the incidence of transplant coronary artery disease? What are the risk factors?

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Nearly 50% of patients have angiographic evidence of coronary artery disease by 5 years after transplant. However, only approximately 10% develop at least 70% stenosis (hemodynamically significant stenosis). Severe stenosis is highly predictive of the need for retransplantation. Risk factors for transplant coronary artery disease include male gender of the donor or recipient, older donor age, and donor hypertension.

21. How is cardiac allograft rejection diagnosed?

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Clinical suspicion is raised by new-onset cardiac arrhythmia, fever, or hypotension. Diagnosis depends on endomyocardial biopsy, which is performed at regular intervals to detect histologic evidence of rejection before signs or symptoms occur. Radionuclide ventriculography and echocardiography are useful adjuncts in following the hemodynamic manifestations of rejection. Electrocardiography itself is not very sensitive in the diagnosis of rejection.

22. Are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (”statin” drugs) generally recommended for post-cardiac transplant patients?

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Yes. Hypercholesterolemia is common after transplantation, and HMG-CoA reductase inhibitors reduce the development of the diffuse atherosclerosis that tends to occur in transplanted hearts. In addition, statins have an early effect on mortality, which suggests that these drugs may also have immunosuppressive effects.

23. What are ventricular assist devices (VADs)?

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These devices are designed to unload either the right (RVAD) or left (LVAD) ventricle while supporting the pulmonary or systemic circulation. Patients with these VADs may be ambulatory, and the devices may be worn for weeks to months. VADs may be used as a bridge to transplant (when the patient is listed for transplantation) or as destination therapy (when no transplant is planned).

24. What is the most serious complication of transvenous endomyocardial biopsy?

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Cardiac perforation occurs in 0.5% of cases. This can rapidly lead to tamponade and circulatory collapse.

25. What is the typical infection pattern for a posttransplant patient?

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* First postoperative month: conventional bacterial pathogens encountered in surgical patients
* 1-4 months: opportunistic pathogens, especially cytomegalovirus
* >4 months: both conventional and opportunistic infections

26. Is the transplanted heart denervated?

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Initially, yes, but it is believed that partial reinnervation begins within 1 year. Because of this, the heart’s anatomically mediated reflexes are blunted (e.g., higher resting heart rate because of decreased or absent vagal tone).

27. Can one heart be successfully transplanted twice?

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Yes. Meiser et al. transplanted the same heart a second time on March 19, 1991, 42 hours after the initial transplantation. Second transplant of the same heart has since been reported by others.

28. What is “domino heart transplant”?

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The good heart from a heart-lung recipient is transplanted into a patient requiring a heart transplant. Some patients with primary lung dysfunction have secondary irreversible cardiac dysfunction (i.e., Eisenmenger’s syndrome); others, however, such as patients with cystic fibrosis, have good cardiac function. Patients with good cardiac function may serve as donors and increase the donor pool.

29. Is the heart capable of making tumor necrosis factor (TNF)? What does TNF have to do with heart transplantation?

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TNF, typically described as a macrophage- or monocyte-derived inflammatory cytokine, is also produced in large quantities by the heart. TNF released by the heart after ischemia-reperfusion probably contributes to immediate injury (dysfunction) and possibly to later rejection. Anti-TNF strategies are intuitively promising (but undocumented) therapeutic strategies.

30. What is the overall 30-day mortality rate after heart transplant? What is the breakdown in mortality between adult and pediatric patients?

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The registry of the International Society for Heart and Lung Transplantation, which has data for approximately 45,000 heart transplants, has recorded a 30-day mortality rate of 10%. The 30-day mortality rate for adult recipients is about 8%; for pediatric recipients, it is slightly higher.

31. What are the 5- and 10-year actuarial survival rates for heart transplant recipients?

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75% and 50%, respectively (and the quality of life is dramatically improved).
32. What work remains to be done in heart transplantation?

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The future of heart transplantation is bright. Knowledge gained in experimental myocardial ischemia-reperfusion injury and protection is accelerating. New, exciting ways to manipulate myocardial immunology (e.g., signal transduction, gene therapy, chimerism) will further extend donor ischemic times and improve postoperative myocardial function and graft tolerance. Ultimately, genetic alteration of donor hearts will increase the donor pool.

References
WEB SITE
http://www.transplantation-soc.org
BIBLIOGRAPHY
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