Candidate Selection for Cardiac Transplantation

Daniel S. Yip, M.D., Mayo Clinic, Jacksonville, FL
Medical Director, Heart Failure and Transplantation

 
Epidemiologic studies indicate that over 4.8 million Americans (approximately 1.5% of the population) carry the diagnosis of congestive heart failure. Some studies suggest that one-third of these patients have New York Heart Association (NYHA) Class III or IV heart failure. It is estimated that there are 400,000 to 700,000 new cases of heart failure each year. It is the most frequent cause of hospitalization in the elderly and accounts for 5-10% of all hospital discharges. The number of heart failure cases continues to increase due to the significant reduction in mortality associated with advancement in treatment of acute ischemic syndromes with anti-platelet agents (e.g. Glycoprotein IIb-IIIa inhibitors), thrombolytic therapy, and primary angioplasty with stenting, improvements in cardiac surgical techniques, and use of implantable cardioverter defibrillators (ICD) for the treatment of sudden cardiac death.

There has been great progress made in the treatment of congestive heart failure over the past several years with the use of angiotensin converting enzyme (ACE) inhibitors, beta blockers, and spironolactone. However, the improvement in survival has been largely in patients with NYHA Class II and III heart failure who are not sick enough to warrant transplantation. In contrast, the survival and functional capacity associated with transplantation are significantly better than that reported for patients with NYHA Class IV heart failure who are medically managed. Although the majority of heart failure patients are over the age of 65, many patients meet age and heart failure severity criteria to be considered candidates for heart transplantation. There have been more than 55,000 heart transplants performed since 1967, when the procedure was first introduced clinically as a therapeutic alternative in the management of end stage congestive heart failure.1 Enormous progress has taken place over the past thirty years in the field of cardiac transplantation. Survival has increased from less than 30% at one year in 1967, to current estimates of 85% at one year, and 65% at five years, despite a continual evolution toward transplanting patients that have more advanced heart failure and using organs from older donors (Table 1).

The improved survival is due to improvements in candidate selection, immunosupression, and surgical and medical management after transplantation. The most common indication for heart transplantation is advanced heart failure symptoms refractory to maximal medical treatment. Cardiogenic shock or low cardiac output requiring mechanical circulatory support and/or inotropic support is another common indication to consider heart transplantation. Other less common indications include debilitating angina or recurrent life-threatening arrhythmias refractory to medical management, and primary cardiac tumors.

The most recent United Network for Organ Sharing (UNOS) statistics for 1999 show that approximately 4,200 people are currently awaiting heart transplant with 3,600 people added each year. The number of heart transplants performed each year has decreased to approximately 2,300 per year, thus the heart transplant waiting list continues to grow each year (Table 2).

 

 

 

Approximately 11% of those listed are considered critically ill and are placed at the highest priority. The average waiting time for these recipients is three to six months. Whereas, depending upon the blood type of the recipient, those waiting at a lower priority may wait for more than one year. The most common age group undergoing transplant are in the 50-64 year-old range (Table 3).

Functional Assessment

The primary criterion for considering a patient for heart transplant is significant functional impairment despite maximal medical therapy. The choice of the most effective medical regimen will differ from patient to patient depending on the response to therapy. It is generally recognized that use of digoxin, diuretics, angiotensin converting enzyme (ACE) inhibitors, beta blockers, and spironolactone should be attempted in all transplant candidates, as tolerated.

Cardiopulmonary exercise testing has proven to be an effective modality for assessing functional status and predicting mortality in patients with congestive heart failiure.8 Cardiopulmonary testing has also shown utility in selecting patients for heart transplantation. Peak oxygen consumption (VO2) is measured during maximal exercise testing and provides an objective assessment of functional capacity in patients with heart failure and is an indirect assessment of cardiovascular reserve. Mancini, et al demonstrated that patients who were able to achieve a peak VO2 of >14 ml/kg/min had a survival rate of 94% at 1 year and 84% at 2 years. Patients who achieved a peak VO2 of < 10 ml/kg/min had a markedly reduced 1 year survival of approximately 30%.2 Peak oxygen uptake is influenced by age, gender and body weight. The use of an exercise variable that adjusts for these factors may further improve the predictive accuracy of the peak VO2 variable in the risk stratification process. Stelken, et al used the percent achieved of predicted VO2, which accounts for age, gender and weight, to enhance the risk stratification of ambulatory patients evaluated for heart transplantation.3 In this study, patients who achieved predicted peak VO2 of >50% had a two year survival of 90%. In contrast, patients who were only able to achieve a predicted peak VO2 of <50% had a 2 year survival of less than 40%.

Once an individual has been shown to have significant functional limitation despite maximal medical therapy, they are generally referred for definitive transplant evaluation, which consists of a careful review of potential co-morbidities and contraindications. The following is a review of some of the controversial aspects of the evaluation process.

Age

Age limit is perhaps the most controversial aspect of candidate selection for heart transplantation. The age of 55 years has traditionally been the accepted upper limit beyond which heart transplantation should not be considered.4 However, with advances in surgical and immunosupression techniques, older patients are often considered for transplantation. Heart transplantation in patients as old as 72 years of age have been reported.5 However, a study comparing carefully selected heart transplant recipients greater than 65 years of age to those between the ages of 55 and 64, show that although survival is similar, the number of hospital days and infections during post-transplant year one is significantly greater for the older group. In addition, patients greater than 65 years of age had more severe functional limitations after transplantation and had difficulty returning to full functional capacity. Patients between the ages of 60 and 65 should be carefully scrutinized, because the incidence of co-morbidities that would limited life expectancy or quality of life increases with age. These co-morbidities include cerebrovascular disease, peripheral vascular disease, renal disease, hepatic disease, pulmonary disease, osteoporosis, malignancy, benign prostatic hypertrophy, diverticulosis, obesity, loss of mental acuity and deceased rehabilitation potential.

Pulmonary Vascular Hypertension

Pulmonary vascular hypertension is a common complication of severe long-standing heart failure. This is due to chronic elevation of the left ventricular end-diastolic pressure from left ventricular systolic dysfunction, increased levels of circulating catecholamines due to neurohormonal activation, and pulmonary vasoconstriction due to chronic hypoxemia. Untreated, pulmonary vascular hypertension can lead to acute right ventricular failure and death soon after the donor heart is implanted. Because the donor right heart has not previously been exposed to this level of elevation in pulmonary vascular resistance, it is unable to adequately handle the sudden increase in workload.

Studies have documented that baseline pulmonary vascular hypertension correlates with increased mortality from right ventricular failure and pulmonary infections. Thus, careful measurements of pulmonary vascular pressures are made in potential heart transplant candidates with right heart catheterization. One study found that pulmonary vascular resistance (PVR) <2.5 Wood units, systolic pulmonary artery pressure <50 mmHg, transpulmonary gradient <15 mmHg, and pulmonary vascular resistance index <5 predicted the best prognosis of survival after transplantation.7 Frequently, because of long standing congestive heart failure, pulmonary vascular pressures and resistance are above the ideal parameters. 100% oxygen, inhaled nitric oxide, vasodilators and inotropes are used in an attempt to reduce the PVR. If the PVR is >2.5 Wood units and can be reduced to <2.5 Wood units with intravenous nitroprusside, while maintaining a systolic blood pressure >85 mmHg, outcome of transplant success is equal to those whose resting PVR is <2.5 Wood units. However, if the PVR is >2.5 Wood units and cannot be reduced to <2.5 Wood units, with intravenous nitroprusside, or is reduced to <2.5 Wood units with concomitant reduction of systolic blood pressure to <85 mmHg, the incidence of right ventricular failure and death due to pulmonary vascular hypertension is much higher. The responsiveness of PVR to nitroprusside cannot be predicted based on resting hemodynamic parameters.8

Because PVR is dependent upon cardiac output, and the cardiac output measurement by thermodilution may be inaccurate with tricuspid regurgitation, some centers have advocated use of the transpulmonary gradient (TPG) as the preferred measurement of pulmonary vascular hypertension. A TPG <12mm Hg has been shown to be a strong marker of improved survival.9

Pulmonary Disease

Severe chronic obstructive pulmonary disease, including severe emphysema and severe chronic bronchitis, predisposes patients to pulmonary infections and respiratory failure requiring prolonged ventilatory support after transplantation.4 It has generally been accepted that patients with severe obstructive lung disease, as manifested by forced vital capacity (FVC) <50% predicted, forced expiratory volume in one second (FEV1) <50% predicted, and FEV1/FVC <40-50% predicted, are poor candidates for heart transplantation.

Diabetes Mellitus

Diabetes mellitus, especially Type I, had been considered a contraindication to heart transplantation. It was felt that end organ damage from diabetes decreased life expectancy and increased morbidity due to infection, blindness, renal failure and amputation. However, studies have shown that carefully selected diabetics with no evidence of end organ damage (i.e. retinopathy, nephropathy and peripheral vascular disease), had survival and rejection rates similar to those of non-diabetics. This was done without worsening of renal function due to immunosupression drugs.10,11

One study showed no increase in infections after heart transplantation.10 Another study showed that there was no increase in bacterial infections, but an increase in opportunistic infections.11 Both studies showed that the use of corticosteroids caused worsening glucose tolerance resulting in an increase in the dosage of insulin needed for insulin-requiring diabetics, and caused some diabetics, formerly controlled with oral hypoglycemics, to require insulin for maintenance of normal blood glucose levels. This was most pronounced in the first few months after transplantation, and improved as the dosage of corticosteroids decreased over time.

Renal Disease

Severe left ventricular systolic dysfunction frequently leads to prerenal azotemia with mild to moderate abnormalities in serum urea nitrogen and creatinine. It is often difficult to differentiate between renal insufficiency due to poor cardiac output, and renal insufficiency due to intrinsic renal disease. Frequently, renal insufficiency due to poor cardiac output will improve if intravenous inotropes are instituted to improve renal perfusion by increasing cardiac output. Renal ultrasound showing the presence of normal-sized kidneys and improvement in creatinine with inotropes, favors pre-renal azotemia which typically improves after heart transplantation. Pre-transplant renal insufficiency is an important issue because use of immunosupression drugs such as cyclosporin and tacrolimus may worsen renal function.12 If severe, this will predispose patients to post-transplant morbidity such as uremia and infection.

Hepatic Dysfunction

As with renal dysfunction, hepatic dysfunction often accompanies severe heart failure. Immunosupression regimens can cause liver dysfunction. Transaminase elevation two to three times above normal, as well as, coagulopathy, should be considered contraindications to transplantation. As with prerenal azotemia, transaminase elevation may improve or resolve, if cardiac output is improved with inotropic support, and the volume status improved. If suspected, the absence of cirrhosis or other hepatic disorders should be confirmed by liver biopsy, since these conditions increase post-transplant mortality due to hepatic failure.4 In addition, presence of biliary tree disease should be considered prior to transplantation, as cholecystitis is often encountered after transplantation.

Cerebrovascular and Peripheral Vascular Disease

Significant cerebrovascular or peripheral vascular disease may be a contraindication to heart transplantation, especially if it inhibits rehabilitation after transplantation.4 Significant cerebrovascular and peripheral vascular disease has an adverse effect on mortality, morbidity and infection. Cerebrovascular accidents from thrombotic and embolic events are of great concern. Asymptomatic carotid disease should not be intervened upon prior to surgery, but symptomatic carotid disease should be surgically resolved prior to transplantation. Severe symptomatic peripheral vascular disease is considered a contraindication to heart transplantation in many centers.13 One needs to consider the difficulty and associated consequences of instituting intra-aortic balloon pump support in patients with peripheral vascular disease, if graft function is poor immediately post-operatively. In addition, symptoms due to peripheral vascular disease make rehabilitation more difficult and predisposes patients to lower extremity infections, and adversely effect post-transplant mortality and morbidity.

Malignancy

Active malignancy is generally considered a contraindication to heart transplantation, because active ongoing malignancy is a risk for premature mortality. In addition, there is concern that post-transplant immunosupression may lead to recurrent or de novo tumors. However, transplantation in patients deemed to be "cured" of their malignancy has become controversial due to publications which report successful solid organ transplantation in carefully selected candidates.14,15 Heart transplantation has been successfully performed in patients with primary cardiac tumors restricted to the heart.16

Screening for malignancy should be performed in all candidates. Screening should at least include: rectal examination, serial stool occult blood examination, prostate specific antigen measurement, pelvic examination, Pap smear and mammography.

Systemic Diseases

Systemic diseases such as connective tissue diseases, neuromuscular diseases, amyloidosis, scleroderma, sarcoidosis, and hemochromatosis are associated with decreased life expectancy and are considered relative contraindications to heart transplantation in many transplant centers. Although considered a relative contraindication, some centers have successfully transplanted patients with some of these systemic diseases. Some centers have successfully performed combined heart and liver transplantation for hemochromatosis. Although patients with amyloidosis have been successfully transplanted, it often reoccurs in the transplanted graft and progresses to other organs.17 In addition, patients with sarcoid granulomas confined to the heart have undergone successful transplantation, although reoccurrence in the graft has been reported.10

Obesity

Obesity is associated with a number of co-morbidities which can complicate heart transplantation before and after surgery. Weight gain is frequently noted after transplantation, and the need for corticosteroids compounds the problems of pre-operative obesity.4 Obesity before transplantation may cause difficulty identifying a donor heart that is appropriately sized. Severe obesity is associated with restrictive pulmonary disease, obesity hypoventitation syndrome with its associated hypoxemia, hypercarbia and pulmonary hypertension, and abnormal hepatic function with steatosis, all of which complicates heart transplantation surgery.18 In addition, obesity is associated with gout, gall bladder disease, diabetes and degenerative joint disease, all of which occur with increased frequency in the post-heart transplant population. Furthermore, obesity decreases the patients ability to adequately rehabilitate post-operatively and may prevent the patient from returning to full function. Lastly, obesity may be a sign of non-compliance, which is catastrophic to the survival of the graft after transplantation.

Psychosocial

All potential heart transplantation candidates should undergo psychosocial screening for substance abuse, noncompliance and psychiatric disorders. Underlying mental illness or personality disorder may lead to inability or unwillingness to comply with post-transplant care, and thus leads to excess mortality and morbidity. There is great consensus that current alcoholism, tobacco or cocaine use, current incarceration, and noncompliance are absolute contraindications to heart transplantation. In addition, many transplant centers believe that Axis II psychiatric disorders, mental retardation with an IQ less than 50, substance abuse within six months, and previous felony conviction are relative contraindications. Lack of permanent address or telephone, lack of social support system, and language barrier places patients at high risk for graft failure.13

Non-compliance has been studied in the renal transplant population.19,20 Noncompliance leads to increased morbidity, graft failure and mortality. In a majority of the time, there is no clear reason for non-compliance. However, when a reason is found, it is typically related to psychiatric disorders or substance abuse. Health care professionals are usually poor at predicting which patients will be non-compliant. But pre-transplant compliance is the most important predictor of post-transplant compliance. Risk factors for noncompliance include race (minorities are at highest risk), complexity of treatment, duration of therapy, and belief in efficacy of the treatment. By providing the patient with a supportive environment of friends, family and health care professionals, and simplifying the treatment regimen, the risk of noncompliance decreases.

Substance abuse is a sign of noncompliance and will increase morbidity and mortality after transplantation. Many centers advocate abstinence of four to six months prior to transplantation and completion of substance abuse treatment programs. In addition, some centers believe that illicit drug usage is an absolute contraindication to heart transplantation.21

The most common psychiatric disorders which caused candidates to be rejected for transplantation were substance abuse, antisocial personality, and borderline intellectually functioning.22 Patients with antisocial personality disorder before transplantation had significant post-operative psychiatry complications including adjustment difficulty, conflicts with staff, and noncompliance with medications, rehabilitation and other restrictions.

Conclusion

Cardiac Transplantation is an effective treatment for severe heart failure in selected groups. Cardiopulmonary stress testing is an effective means of identifying patients who are at increased risk of death and therefore, would most benefit from cardiac transplantation. In addition, favorable results on cardiopulmonary stress testing would allow for the safe delay of cardiac transplantation.

References

  1. Hosenpud JD, Bennett LE, Keck BM, et al. The Registry of the Internal Society for Heart and Lung Transplantation: Seventeenth Official Report-2000. J Heart Lung Transplant 2000;19:909-931
  2. Mancini DM, Eisen H, Kussmaul W, et al. Value of Peak Exercise Oxygen Consumption for Optimal Timing of Cardiac Transplantation in Ambulatory Patients with Heart Failure. Circulation 1991;83:778-786
  3. Stelken AM, Younis LT, Jennison SH, et al. Prognostic Value of Cardiopulmonary Exercise Testing Using Percent Achieved of Predicted Peak Oxygen Uptake for Patients with Ischemic and Dilated Cardiomyopathy. J Am Coll Cardiol 1996;27:345-52
  4. Costanzo MR, Augustine S, Bourge R, et al. Selection and Treatment of Cardidates for Heart Transplantation. Circulation 1995;92:3593-3612
  5. Young JB, Naftel DC, Bourge RC, et al. Matching the heart donor and heart transplant recipient. Clues for successful expansion of the donor pool: a multivariable, multiinstitutional report. J Heart Lung Transplant 1994;13:353-365
  6. Heroux AL, Costanzo-Nordin MR, O'Sullivan JE, et al. Heart transplantation as a treatment option for end-stage heart disease in patients older than 65 years of age. J Heart Lung Transplant 1993;12:573-579
  7. Costard-Jackle A, Hill I, Schroeder JS, et al. The influence of preoperative patient characteristics on early and late survival following cardiac transplantation. Circulation 1991;84(suppl III):III-329-III-337
  8. Costard-Jackle A, Fowler MB. Influence of preoperative pulmonary after pressure on mortality after heart transplantation: Testing of potential reversibility of pulmonary hypertension with nitroprusside is useful in defining a high risk group. J Am Coll Cardiol 1992;19:48-54
  9. Erickson KW, Costanzo-Nordin MR, O'Sullivan J, et al. Influence of preoperative transpulmonary gradient on late mortality after orthotopic heart transplantation. J Heart Transplant 1990;9:526-537
  10. Ladowski JS, Kormos RL, Uretsky BP, et al. Heart transplantation in diabetic recipients. Transplantation 1990;49:303-305
  11. Munoz E, Lonquist JL, Radovancevic B, et al. Long-term result in diabetic patients undergoing heart transplantation. J Heart Lung Transplant 1992;11:943-949
  12. McGriffin DC, Kirklin JK, Naftel DC, et al. Acute renal failure after heart transplantation and cyclosporin therapy. J Heart Transplant 1985;4:396-399
  13. Miller LW, Kubo SH, Young JB, et al. Report of the consensus conference on candidate selection for heart transplantation-1993. J Heart Lung Transplant 1995;14:562-571
  14. Edwards BS, Hunt SA, Fowler MB, et al. Cardiac transplantation in patients with preexisting neoplastic diseases. Am J Cardiol 1990;65:501-504
  15. Dillon TA, Sullivan M, Schatzlein MH, et al. Cardiac transplantation in patients with preexisting malignancies. Transplantation 1991;52:82-85
  16. Aravot DJ, Banner NR, Madden B, et al. Primary cardiac tumours: Is there a place for cardiac transplantation? Eur J Cardiothorac Surg 1989;3:521-524
  17. Hosenpud JD, Uretsky BF, Griffith BP, et al. Successful intermediate-term outcome for patients with cardiac amyloidosis undergoing heart transplantation: Results of a multicenter survey. J Heart Transplant 1990; 9:346-350
  18. Bray GA. Complications of obesity. Ann Intern Med 1985;103(6 pt 2):1052-1062
  19. Rovelli M, Palmeri D, Vossler E, et al. Noncompliance in organ transplant recipients. Transplant Proc 1989;21:833-834
  20. Rodriguez A, Diaz M, Colon A, et al. Psychosocial profile of noncompliant transplant patients. Transplant Proc 1991;23:1807-1809
  21. Kubo SH, Ormaza SM, Francis GS, et al. Trends in patient selection for heart transplantation. J Am Coll Cardiol 1993;21:975-981
  22. Frierson RL, Lippmann SB. Heart transplant candidates rejected on psychiatric indications. Psychosomatics 1987;28:347-355
Jacksonville Medicine / February, 2002

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