(Circulation. 1995;92:3593-3612.)
© 1995 American Heart Association, Inc.
Articles |
Selection and Treatment of Candidates for Heart Transplantation
A Statement for Health Professionals From the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association
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Abstract |
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 Top Abstract IntroductionPrognostic Factors in Patients...Coronary Artery Disease and...Recommendations for Evaluation...Conclusion References |
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Improved outcome of heart failure in response to medical therapy, coupled with a critical shortage of donor organs, makes it imperative to restrict heart transplantation to patients who are most disabled by heart failure and who are likely to derive the maximum benefit from transplantation. Hemodynamic and functional indexes of prognosis are helpful in identifying these patients.
Stratification of ambulatory heart failure patients by objective criteria, such as peak exercise oxygen consumption, has improved ability to select appropriate adult patients for heart transplantation. Such patients will have a poor prognosis despite optimal medical therapy. When determining the impact of individual comorbid conditions on a patient's candidacy for heart transplantation, the detrimental effects of each condition on posttransplantation outcome should be weighed.
Evaluation of patients with severe heart failure should be done by a multidisciplinary team that is expert in management of heart failure, performance of cardiac surgery in patients with low left ventricular ejection fraction, and transplantation. Potential heart transplant candidates should be reevaluated on a regular basis to assess continued need for transplantation.
Long-term management of heart failure should include continuity of care by an experienced physician, optimal dosing in conventional therapy, and periodic reevaluation of left ventricular function and exercise capacity. The outcome of high-risk conventional cardiovascular surgery should be weighed against that of transplantation in patients with ischemic and valvular heart disease.
Establishment of regional specialized heart failure centers may improve access to optimal medical therapy and new promising medical and surgical treatments for these patients as well as stimulate investigative efforts to accelerate progress in this critical area.
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Introduction |
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TopAbstractIntroductionPrognostic Factors in Patients...Coronary Artery Disease and...Recommendations for Evaluation...Conclusion References |
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Over the past decade heart transplantation has evolved from a rarely performed experimental procedure to an accepted therapy for patients with end-stage congestive heart failure.1 Improved immunosuppression has resulted in an excellent outcome after heart transplantation in terms of quality of life and survival.2 During the same time period the incidence of heart failure has dramatically increased. It is estimated that at least 400 000 new cases of heart failure are diagnosed each year.3 In the United States more than $34 billion is spent each year for care of persons with heart failure.4 Increasingly complex medical therapy has decreased morbidity and mortality associated with heart failure. Despite these advances, heart failure is the principal cause of 40 000 deaths and a contributing cause of another 250 000 deaths each year.3 The donor shortage, which limits heart transplants in the United States to 2500 procedures per year, underscores the alarming discrepancy between the number of patients with heart failure who might benefit from transplantation (approximately 25 000) and those fortunate enough to receive a suitable donor organ.1 These facts make it imperative to restrict the option of transplantation to those patients with the greatest need and who are likely to derive the maximum benefit from transplantation. In the absence of contraindications to transplantation, the choice of recipients from a pool of critically ill patients who require frequent hospitalization for parenteral medical therapy or mechanical circulatory support or who have refractory ventricular arrhythmias is not controversial. By contrast, expansion of the list of recipients beyond these seriously ill patients requires greater selectivity. Guidelines regarding criteria for selection of heart transplantation candidates have been published, including the American Heart Association scientific statement on cardiac transplantation5 and proceedings of the American College of Cardiology Twenty-fourth Bethesda Conference on Cardiac Transplantation.6 Contraindications for heart transplantation were reviewed in the AHA statement and policies of donor organ allocation in the ACC proceedings.
The specific objectives of this report are to (1) analyze the factors that determine prognosis in patients with severe heart failure, (2) discuss therapeutic options for patients with heart failure who have comorbid conditions, (3) evaluate data from recent clinical trials of medical therapies that may improve the prognosis of patients with severe heart failure, and (4) provide guidelines for referral, evaluation, follow-up, and optimal therapy of potential heart transplant candidates. The audience for this paper includes practicing cardiologists, specialists in internal medicine, and primary care providers, because all three groups may become involved in the evaluation, treatment, and referral of patients with heart failure for heart transplantation.
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Prognostic Factors in Patients With Advanced Heart Disease |
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TopAbstractIntroductionPrognostic Factors in Patients...Coronary Artery Disease and...Recommendations for Evaluation...Conclusion References |
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Recent studies have identified clinical, biochemical, hemodynamic, and electrophysiological variables that correlate with prognosis in patients with heart failure (Table 1
).7 The studies are retrospective and include
small numbers of patients. Variable criteria were used for the
diagnosis of heart failure, and patient populations were not
homogeneous in etiology of heart disease,
hemodynamics, functional status, and duration of
follow-up. Few studies tested the prognostic value of individual
factors using multivariable analyses. Moreover, the
indexes of outcome varied from study to study. Most studies did not
specify the clinical and hemodynamic status of patients
at the time the prognostic variables were analyzed. This is
an important limitation because the prognostic importance of individual
factors may be altered by therapeutic interventions.
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Moreover, the results of prognostic studies cannot easily be compared because those published before routine use of angiotensin converting enzyme (ACE) inhibitors are not applicable to those reported today.8 9 While these limitations cannot be overlooked, some helpful information can be extracted from studies evaluating the prognosis of patients with heart failure.
Etiology of Heart Disease
With the exception of one report in
which
nonischemic heart disease predicted a poorer
outcome,10 patients with heart failure due to
coronary artery disease (CAD) generally have a higher mortality
than those with congestive heart failure without ischemic heart
disease.9 11 12 13 When
considered in selection of candidates
for heart transplantation, this information supports the concept that
when all other clinical and hemodynamic variables
are similar, patients with CAD should be actively listed for heart
transplantation before patients without CAD, provided
revascularization is not feasible.
When evaluating candidacy for heart transplantation in patients with cardiomyopathy who have neither ischemic nor valvular heart disease, it is important to consider that prognosis may differ, depending on the etiology of the cardiomyopathy. Spontaneous remission of cardiac dysfunction has been reported in patients with active lymphocytic myocarditis and peripartum cardiomyopathy.14 15 The cardiac function of patients with dilated cardiomyopathy associated with excessive consumption of alcohol may improve with abstinence. Caution should be exercised when judging prognosis in these patient subgroups, and a period of observation and intense pharmacological therapy should be undertaken before heart transplantation is considered. The heterogeneity of idiopathic dilated cardiomyopathy must be taken into account when attempting to predict outcome of patients with this condition. One study showed that survival was dramatically better in a population-based idiopathic dilated cardiomyopathy cohort than in a referral-based idiopathic dilated cardiomyopathy cohort both at 1 year (95% versus 69%, respectively) and at 5 years (80% versus 36%, respectively) (P<.001).16 Furthermore, 1- and 5-year survival of 137 patients with idiopathic dilated cardiomyopathy who were referred for heart transplantation between 1982 and 1987 were significantly better than that of 85 patients with idiopathic dilated cardiomyopathy referred in the preceding 22 years.17 These findings suggest that both referral bias and improvement in diagnosis and treatment affect the natural history of idiopathic dilated cardiomyopathy.
Effect of Gender
Multicenter randomized trials of new
therapies for heart failure
have been conducted primarily in Caucasian males. Prognostic
variables and therapeutic responses have not been adequately
evaluated in female and non-Caucasian patients. Recently reported data
from the Studies in Left Ventricular Dysfunction (SOLVD)
Registry and the Survival and Ventricular Enlargement
(SAVE) and Cooperative New Scandinavian Enalapril Survival Study
(CONSENSUS) II
trials18 19 20 21 22
suggest that the benefits of
ACE inhibitor therapy are fewer in females than in males.
Because the effects of gender and race on heart failure prognosis are
ill defined at best, it is not known whether gender and
race-related differences in heart failure outcome should influence
the timing of heart transplantation. Clearer guidelines will be
provided by clinical trials planned to evaluate the effects of gender
and race on response to heart failure therapy.
Duration of Illness
A short duration of heart failure
symptoms appears to be
associated with a greater likelihood of spontaneous improvement. In one
study heart failure symptoms improved in 6 of 11 patients (51%) with
heart failure duration of less than 7 months and in none of 17 patients
(0%) with duration more than 7 months.23 In another
study, 16 of 55 patients (29%) with a heart failure duration of less
than 12 months improved, compared with 17 of 114 patients (15%) with
heart failure duration greater than 12 months
(P<.02).24 However, patients with recent onset
cardiomyopathy require close clinical surveillance
and aggressive medical therapy because mortality rates are highest
early after referral in patients with severe heart
failure.25 26 If the condition of patients with
recent
onset cardiomyopathy deteriorates, such patients
should be listed for heart transplantation.
Hemodynamics, Functional Capacity, and Neurohumoral
Activation
Four categories of variables have been shown to
independently predict the prognosis of patients with heart failure due
predominantly to systolic dysfunction. These are (1)
hemodynamic measures of cardiac pump
performance, (2) functional capacity, (3) indexes of
neurohumoral stimulation, and (4) spontaneous arrhythmias.
Left ventricular ejection fraction (LVEF) is a measure of global ventricular function that is among the most powerful predictors of survival in patients with cardiac disorders due to diverse causes. Left ventricular ejection fraction is widely used because it can be measured noninvasively by radionuclide ventriculography, echocardiography, or magnetic resonance imaging. In large populations of patients with a wide spectrum of symptoms, LVEF has a significant relation to mortality.7 10 27 28
In V-HeFT-I, which enrolled patients with mild to moderate heart failure, LVEF was dichotomized at the mean value of 28%. Patients with LVEF below this value had an annual mortality of 22%, compared with a rate of 13% in patients with LVEF above the mean.12 Preliminary results from a combined analysis of data from V-HeFT-I and II suggest that serial determinations of LVEF may enhance the prognostic value of this measure. Patients in whom LVEF decreased by more than 5% demonstrated nearly twice the number of deaths during the follow-up period than did patients in whom LVEF remained unchanged. Improvement of LVEF by more than 5% was a very favorable prognostic sign and identified a subgroup of patients with a mortality risk of less than 10% over a 1-year period.29
Studies confined to patients with advanced heart failure (New York Heart Association [NYHA] functional Classes III and IV) have failed to demonstrate a difference in LVEF between survivors and nonsurvivors.30 However, patients with low LVEF values (less than 20%) may be further stratified on the basis of peak exercise oxygen consumption (VO2max)31 and response to optimal preload and afterload reduction.13 32 Right ventricular ejection fraction (RVEF) may also influence survival in patients with heart failure. Of 34 patients with LVEF below 40%, those with RVEF less than 35% had a 71% mortality over a 2-year follow-up period, whereas those with an RVEF greater than 35% had mortality rates of only 23%.33
The relation between invasively obtained hemodynamic parameters and mortality in heart failure patients has also received considerable attention. In most studies nonsurvivors have a lower systolic blood pressure, higher left ventricular end-diastolic pressure, right atrial pressure, and pulmonary artery wedge pressure, and a lower cardiac output and stroke work index than survivors.34 Although individual studies have reported the superior prognostic value of one or the other parameters, in general, pulmonary artery wedge pressure and stroke work index appear to be the most useful of these prognostic indexes.13 31 A recent report pointed out that pulmonary artery wedge pressure achieved after optimal reduction in preload and afterload predicts survival better than pulmonary artery wedge pressure measured when patients are first referred as potential heart transplant candidates.13 According to the findings of this study, patients achieving pulmonary artery wedge pressure less than 16 mm Hg while maintaining adequate cardiac output and systemic arterial blood pressure had a 1-year survival rate that was significantly greater than those in whom these hemodynamic effects could not be achieved by maximally tolerated therapy (83% versus 38%, P=.0001).
Hemodynamics measured during exercise may have greater prognostic accuracy than values obtained at rest. In one study survivors had lower pulmonary artery wedge pressure and stroke work index at rest than nonsurvivors. The response of the stroke work index with exercise significantly enhanced ability to separate survivors from nonsurvivors: in patients with a stroke work index greater than 20 g/m2 at peak exercise, the mortality rate was 13%; in patients with peak exercise stroke work index below this value, the mortality rate was 67%.35
Clearly the severity of hemodynamic impairment is among the most powerful predictors of mortality in patients with heart failure. Of the available variables, LVEF is the most widely applicable and clinically useful measure. However, all hemodynamic variables, with the possible exception of those related to right ventricular function, lose predictive value in patients with symptoms of refractory heart failure.
Functional Capacity
The relation between
functional capacity (ability of individuals
to perform tasks requiring physical exertion) and survival in heart
failure is well established. The NYHA classification is a subjective
measure of functional capacity describing the amount of activity a
patient can do before onset of heart failure symptoms.
The NYHA criteria are most valuable in predicting prognosis of patients with Class IV heart failure (symptoms at rest or with any physical activity). In most published series the yearly mortality of Class IV heart failure exceeds 50% and may be as high as 77%.30 In patients with less severe heart failure symptoms there is a considerable overlap in mortality rates between Class II (range, 3% to 25% per year) and Class III patients (range, 10% to 45% per year). This overlap is due to differences in classification from center to center, because in individual studies mortality rates are almost invariably higher in Class III patients than in Class II heart failure patients.34
Standardized methods of exercise testing, with and without analysis of respiratory gas exchange, are performed to derive objective measurements of functional capacity. The most commonly used technique is to have patients exercise on a treadmill or stationary bicycle to the point of exhaustion. Total exercise duration in seconds is the primary measure of functional capacity. Most, but not all, studies have reported an inverse relation between total exercise duration and mortality.34 Because exercise performance varies among individuals and in the same individual on repeat testing, total exercise duration is a highly variable measurement. Exercise testing with respiratory gas analysis has been used to eliminate this source of variability and provide a more standardized approach to selection of patients for heart transplantation. Measurement of oxygen uptake and the anaerobic threshold during exercise has proved to be an objective, reproducible, safe, and noninvasive method for characterizing cardiac reserve.9 31 Because maximal oxygen uptake is the product of maximal cardiac output and maximal arterial-venous oxygen difference, oxygen extraction in tissues of patients with heart failure is always maximal at completion of symptom-limited exercise, irrespective of the degree of functional impairment.36 Thus, maximal oxygen uptake primarily reflects the level of cardiac output during exercise. The measurement of anaerobic threshold, calculated by analysis of expired gases, correlates with the onset of lactate production in the exercising patient, as oxygen delivery becomes inadequate to sustain aerobic metabolism. Peak exercise oxygen consumption measured during maximal exercise testing (VO2max) provides a measure of functional capacity and cardiovascular reserve in patients with heart failure once maximal therapy has been instituted and maintained.31 Several studies have suggested that in patients with heart failure, VO2max is a good short-term predictor of mortality and that its deterioration frequently precedes clinical decompensation.9 37 38 39 Studies in patients with CAD and low LVEF suggest that VO2max measurements also provide long-term prognostic information.39 In a recent study VO2max was used to evaluate ambulatory patients awaiting heart transplantation. Three groups were identified.31 The 1-year survival rate for the group with VO2max greater than 14 mL/kg per minute was 94%. Survival was lower for the two groups with VO2max less than 14 mL/kg per minute—70% for those accepted for heart transplantation and 47% for those rejected for it. The three groups had comparable NYHA functional classes, LVEFs, and cardiac indexes. Patients in the low-risk group with preserved exercise capacity (VO2max greater than 14 mL/kg per minute) despite severe hemodynamic impairment at rest had survival rates equal to that afforded by heart transplantation.31 Thus, patients with preserved exercise capacity can be treated safely with medical therapy until exercise capacity deteriorates. For patients with VO2max less than 14 mL/kg per minute, it is important to prove that exercise testing was truly maximal by documenting achievement of anaerobic threshold at approximately 50% to 70% of VO2max. Ischemia and ventricular arrhythmias may cause termination of exercise testing before achievement of the anaerobic threshold, and thus VO2max should not be considered an inflexible guideline. Hormonal changes, age, conditioning status, and motivation also affect VO2max. For example, a VO2max of 14 mL/kg per minute represents approximately 60% of predicted maximal exercise capacity in an active 60-year-old man but only 30% of predicted capacity for a 20-year-old man. This level of activity may provide an unacceptable quality of life for a young adult. Thus, other variables, such as age and ventricular arrhythmias, should be considered together with VO2max when evaluating a patient's candidacy for heart transplantation. Ventricular arrhythmias may be associated with an increased risk of sudden death despite preserved exercise capacity.6 Although the prognostic value of VO2max may be limited in patients with ventricular arrhythmias, stratification of ambulatory heart failure patients by objective criteria such as VO2max has improved ability to identify adult patients with the poorest prognoses who should be selected for heart transplantation.
The 6-minute walk test was developed to assess patients' day-to-day efforts at submaximal exertion. It measures the distance an individual can traverse over a 6-minute test period. Data obtained in patients with asymptomatic or mild to moderate heart failure enrolled in the SOLVD study show that compared with patients able to cover the longest distance, those who could walk only the shortest distance had a greater chance of being hospitalized for any reason, of being hospitalized for heart failure, and of dying.21 There are insufficient data on whether this simple and inexpensive clinical tool can replace measurement of VO2max in the selection of heart transplantation candidates who have more severe heart failure. In summary, functional capacity, whether estimated by NYHA class or exercise testing, is an important determinant of mortality in heart failure patients.
Neurohumoral Factors
Reduction in ventricular
performance results
in complex activation of neurohumoral systems, the most important of
which are the renin-angiotensin and the sympathetic
nervous systems.40 41 Elevation in plasma
norepinephrine, renin, aldosterone, arginine
vasopressin, atrial natriuretic peptide, and
prostaglandins has been observed in patients with clinical
congestive heart failure.34 The net results of
compensatory neurohumoral activation are peripheral
vasoconstriction and sodium retention, both key elements in the
pathophysiology of heart failure. There is now considerable evidence
that neurohumoral activation contributes to progression of left
ventricular dysfunction, and the adverse effects of
neurohumoral activation on survival in patients with heart failure are
no longer disputed.21 40 In one study, 2-year
mortality
was 80% in heart failure patients with norepinephrine
levels of 1200 pg/mL compared with 50% in patients with a level of 200
pg/mL.40 The correlation between
norepinephrine levels and mortality in heart failure
patients initially reported by Cohn and colleagues has been
confirmed.21 However, the use of
norepinephrine levels to predict the outcome of patients
with heart failure and to aid in selection of candidates for heart
transplantation is limited by a wide variability of plasma
norepinephrine levels that may be related to patient
activity or anxiety levels and/or drug therapy. Requirements for the
test to be useful include (1) withdrawal of vasodilators at least 48
hours before the study; (2) withdrawal of digoxin and diuretics
on the day of the study; and (3) rest in the supine position for at
least 15 minutes. Because of these limitations, this variable is
seldom used to predict prognosis of persons with heart failure. Serial
norepinephrine levels may have greater prognostic value, as
patients with stable levels over time have a far better outcome than
those demonstrating progressive elevation.41
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Coronary Artery Disease and Left Ventricular Dysfunction: Revascularization or Heart Transplantation |
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TopAbstractIntroductionPrognostic Factors in Patients...Coronary Artery Disease and...Recommendations for Evaluation...Conclusion References |
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Patients with advanced left ventricular dysfunction due to CAD have a high mortality when treated medically, with a reported 2-year survival rate of only 31%.42 Severe left ventricular dysfunction in these patients is an indication for heart transplantation and accounts for 40% to 50% of heart transplants performed.43 However, as many as 20% to 30% of these patients will die while awaiting transplantation.44 Thus, it is crucial to identify those patients with severe left ventricular dysfunction due to CAD who may benefit from coronary revascularization despite eligibility for heart transplantation.45 A randomized, prospective trial comparing the outcome of coronary revascularization versus heart transplantation in patients with severe left ventricular dysfunction due to CAD has not been done. Therefore, the decision to recommend one surgical procedure over the other must be based on the findings of previous studies, most retrospective and uncontrolled, which have evaluated the preoperative profile and postoperative outcome of patients with CAD and left ventricular dysfunction. These studies have identified several factors that may affect postoperative outcome in patients with left ventricular dysfunction due to CAD. These include predominance of angina versus heart failure symptoms, severity of hemodynamic compromise, presence and extent of jeopardized but still viable myocardium, adequacy of vascular targets, need for concomitant surgical procedures, and the urgent versus elective indication for surgery.
The Coronary Artery Surgery Study (CASS) identified 420 medically and 231 surgically treated CAD patients with LVEF less than 40%.46 Compared with medically treated patients, those undergoing surgical revascularization had more angina, CAD, estimated extent of jeopardized myocardium, and heart failure. Even after adjusting for these differences, surgery independently prolonged survival. As a prognostic indicator, surgical revascularization ranked below severity of heart failure symptoms, age, LVEF, and presence of left main coronary artery stenosis greater than 70%. The benefit of surgical revascularization was greatest in patients in whom angina was the predominant symptom preoperatively and in patients with the lowest LVEF (less than 26%), in whom the 5-year survival rate was 63% with surgery and 43% with medical therapy. Surgery significantly relieved preoperative angina but not heart failure symptoms.46 Other studies have confirmed that when angina is the predominant preoperative symptom, the patients deriving the largest absolute benefit from coronary surgical revascularization are those with the strongest predictors of a poor medical outcome (lowest LVEF), despite an increased surgical risk.47 This apparent paradox raises the question of whether there is an LVEF value below which surgical revascularization is associated with unacceptable perioperative and postoperative mortality and for which heart transplantation should be recommended. Among 466 patients with LVEF less than 40% and angina, 36% of whom had clinical heart failure, survival with surgical revascularization was significantly greater (P=.001) in patients with LVEF greater than 20% than in those with LVEF less than 20%, both in hospital (89% versus 63%, respectively) and 3 years postoperatively (60% versus 15%, respectively).48 A larger study, however, has challenged the value of LVEF as a predictor of outcome after surgical revascularization. In a study of 25 000 patients undergoing isolated surgical revascularization at the Cleveland Clinic between 1970 and 1982, the association between left ventricular dysfunction and perioperative mortality identified in patients who underwent surgery in the 1970s was no longer present in the 1980s. In contrast, patients going to surgery without prior compensation of heart failure consistently had an increased perioperative mortality throughout the 12-year study period. Perioperative mortality decreased from 14% at study initiation to 7% at study end in patients with preoperative heart failure but remained 10 times higher than in patients without heart failure.49
A close correlation between decompensated preoperative heart failure and surgical mortality has been identified in other studies. It can be concluded from the results of these studies that it is imperative to optimize heart failure therapy before undertaking coronary revascularization, because improved surgical techniques, myocardial preservation, and postoperative intensive care have minimized the negative impact of a low LVEF but not that of decompensated heart failure on outcome of coronary revascularization.
Careful scrutiny of surgical results in patients with CAD and left ventricular dysfunction reveals that while preoperative angina predicts a good surgical outcome because it connotes viable myocardium, its absence is not uniformly associated with a poor surgical result.50 51 An 83% 3-year survival rate and symptomatic improvement after surgical revascularization have been reported in 39 patients with CAD and LVEF less than 20% who predominantly had heart failure, not angina, as the presenting symptom.50 The challenge, then, is to identify patients with symptoms attributable mainly to heart failure who, despite the absence of angina, may benefit from surgical revascularization, because hibernating or ischemic myocardium may worsen left ventricular dysfunction caused by previous myocardial injury. Augmentation of coronary blood flow by revascularization to viable but ischemic or underperfused myocardium would be expected to improve left ventricular function.
Planar rest and redistribution thallium 201 imaging is useful in assessing myocardial viability in patients with CAD and a low LVEF. This imaging technique, performed in 21 patients with a mean LVEF of 27% before and 8 weeks after surgical coronary revascularization, revealed improved function in 62% of asynergic but viable segments but only in 23% of nonviable segments.52 Even fixed defects in myocardial thallium uptake may represent hibernating rather than irreversibly damaged myocardium. Reinjecting the isotope and delaying myocardial reperfusion imaging 24 hours may uncover still viable areas that on routine thallium 201 rest-redistribution imaging appear irreversibly damaged.52
Even when modified thallium imaging techniques are used, not all irreversible thallium defects represent irreparably damaged myocardium. Bonow and coworkers53 demonstrated that 38% to 47% of myocardial regions with irreversible perfusion defects at thallium scintigraphy are metabolically active and hence viable by positron emission tomography (PET). Revascularization was successful in 16 of 22 patients (73%) with severe left ventricular dysfunction and a low angina score. In another study, PET was performed in 12 patients who had irreversible ischemia by planar rest and redistribution thallium-201 imaging. Ischemic but viable myocardium was identified by PET in 10 patients, all of whom had successful revascularization as seen by an improvement in LVEF from 26±9% to 36±9% (P<.05) and in NYHA functional class from 3.9±0.4 to 1.2±0.4 (P<.05).45 In contrast, both patients with negative PET scans died postoperatively. These results suggest that PET can identify patients with CAD, severe left ventricular dysfunction, and little angina who will benefit from surgical revascularization even when myocardial perfusion defects are irreversible by thallium perfusion imaging. Coronary revascularization was performed instead of heart transplantation in 46 of 50 patients in whom the presence of viable myocardium was demonstrated by either thallium scintigraphy or, when this was negative, by PET scanning. Survival rates of 89.1% at 1 month and 86.95% at 1 and 2 years compare favorably with those achieved with heart transplantation. NYHA functional class and LVEF improved significantly after surgery in the 40 long-term survivors.54 The results of this study support the recommendation that surgical coronary revascularization should be undertaken instead of heart transplantation whenever myocardial viability is detected by thallium scintigraphy or PET. This approach may decrease the number of patients with CAD and left ventricular dysfunction who need heart transplants and ameliorate the critical shortage of donor hearts.
Valvular Heart Disease
Consideration of heart transplantation
in patients with severe
valvular heart disease requires that the outcome of valve
replacement surgery be weighed against that of heart transplantation.
Patients with mitral valve stenosis should very seldom be
considered for heart transplantation, because even patients with severe
pulmonary hypertension and NYHA functional Class IV symptoms
have excellent surgical outcome with mitral valve
replacement.55 56 Most patients with aortic
stenosis, depressed ventricular
performance, and severe congestive heart failure will benefit
from aortic valve replacement.56 57 In approximately
85%
of these patients, left ventricular dysfunction results
from both decreased contractility and afterload
mismatch. Surgical relief of the outflow obstruction decreases the
pressure gradient between the left ventricle and the aorta, thereby
reducing the afterload mismatch and acutely improving left
ventricular performance and cardiac
output.56 Patients with a mean transvalvular
gradient greater than 50 mm Hg and severely reduced LVEF may tolerate
surgery that produces rapid hemodynamic and functional
improvement. However, there is a small group of patients with severe
left ventricular dysfunction,
intraventricular pressure less than 140 mm Hg, and
transvalvular gradient less than 30 mm Hg, in whom cardiac
performance is not significantly improved by surgery. It is
likely that these patients have mild to moderate aortic
stenosis and a coincident cardiomyopathy.
If patients are unresponsive to optimal vasodilator therapy, it may be
necessary to consider heart transplantation.56
Valvular surgery relieves symptoms, increases long-term survival, and prevents irreversible left ventricular dysfunction in 70% to 80% of patients with chronic aortic and mitral valve regurgitation.58 Aortic valve replacement is recommended for patients with chronic aortic regurgitation when the symptoms of heart failure have progressed to NYHA Class III or IV or when signs of systolic left ventricular dysfunction have developed, even when only NYHA Class I or II symptoms are present.
Despite compromised preoperative left ventricular function (left ventricular end systolic volume greater than 60 mL/m2 and LVEF less than 45%), aortic valve replacement is not precluded and should not be postponed in symptomatic patients.59 60 Most patients improve symptomatically even without marked postoperative changes in left ventricular mass or volume or improvement in left ventricular systolic function. Reversibility of left ventricular dysfunction depends greatly on its duration. If aortic valve replacement is performed more than 18 months after development of left ventricular dysfunction, myocardial damage is irreversible.59 60 While a delay in performing aortic valve replacement lessens the chance for recovery and allows further deterioration of left ventricular function, aortic valve replacement can and should be performed as long as LVEF exceeds 20% to 30%.59 60
When surgery is contemplated for patients with chronic mitral valve regurgitation, the often slowly progressive nature of mitral regurgitation must be weighed against the immediate risks and long-term uncertainties of surgery. Surgical mortality depends on the patient's left ventricular function and the presence of comorbid conditions, as well as on the skill and experience of the surgical team. The decision to replace or reconstruct the valve is critically important, because surgical mortality associated with mitral valve reconstruction appears to be lower than that associated with replacement, although patients selected for the two procedures differ.61 Reconstructive procedures have been useful in patients who have severe, noncalcific mitral regurgitation with pliable valves, a dilated mitral annulus, mitral regurgitation secondary to ruptured chordae to the posterior leaflet, or perforation of a mitral leaflet due to infective endocarditis in the absence of severe subvalvular chordal thickening and major loss of leaflet substance.
Long-term survival in patients with predominant mitral regurgitation who undergo mitral valve replacement is poorer than in those with mixed stenotic and regurgitant lesions, because left ventricular dysfunction may be more advanced and largely irreversible when patients with pure mitral regurgitation become symptomatic. However, surgery is still indicated in the majority of patients with mitral regurgitation and severe left ventricular failure, because conservative therapy has little to offer. Although the 5-year survival rate is approximately 30% in patients with mitral regurgitation secondary to CAD, some postoperative improvement can be expected even in patients with heart failure refractory to medical therapy, as long as the cardiac index is greater than 1.5 L/min/m2 and LVEF is greater than 35%. When left ventricular dysfunction is more severe, the risk of death after mitral valve surgery becomes prohibitive, and heart transplantation should be considered instead.58 Patients with aortic or mitral valve disease and CAD pose a special therapeutic challenge.61 The results of several studies indicate that mortality is greater in patients requiring both aortic valve replacement and coronary revascularization than in those undergoing aortic valve replacement alone. However, ignoring coexisting CAD at the time of aortic valve replacement increases perioperative risk and late mortality. Poor prognostic indexes in patients undergoing combined procedures include older age, cardiothoracic ratio greater than 50%, preoperative NYHA Class III or IV, and use of a mechanical prosthesis without adequate anticoagulation.61 These characteristics identify patients whose condition may deteriorate enough postoperatively to require consideration for heart transplantation. If CAD is present, aortic valve replacement is performed for severe aortic insufficiency. When left ventricular function is normal and aortic insufficiency is mild to moderate, a valve-conserving procedure rather than aortic valve replacement is preferred.62
The best approach to patients with mild to moderate aortic insufficiency and abnormal left ventricular function remains controversial. Early and late mortality are greater when coronary revascularization is combined with mitral valve replacement than with aortic valve replacement.61 Indexes of poor prognosis in patients undergoing combined mitral valve and coronary revascularization surgery include ischemic etiology of mitral valve dysfunction, age greater than 60 years, preoperative NYHA Class IV, decreased LVEF, and concomitant ventricular arrhythmias.61 Since the most common late complication is congestive heart failure, heart transplantation may become a therapeutic consideration for these patients. In one study, 77 of 278 subjects had late heart failure, and 55 of 77 died. The high heart failure and death rates suggest that mitral valve disease continues to have a negative impact on survival even with improved surgical techniques (mitral valve repair) and perioperative critical care.61
Arrhythmias
How arrhythmias should influence the decision
about
and timing of listing heart failure patients for heart transplantation
is an important question. While most studies have identified a relation
between asymptomatic ventricular
arrhythmias and total mortality, only a few have shown a
correlation with sudden death, which may be the mode of death in 22%
to 86% of patients with heart failure.63 In the
digoxin/captopril study, only nonsustained ventricular
tachycardia (NSVT) frequency (more than 2.1 episodes per 24
hours), but not the mere presence of NSVT, was an independent predictor
of mortality and the strongest predictor of sudden
death.10 Electrophysiological
testing has not significantly improved the ability to identify heart
failure patients at high risk for sudden death. Except in patients with
ischemic cardiomyopathy, in whom lack of
inducible ventricular tachycardia predicts a
low risk of arrhythmic death,
electrophysiological testing is not useful
in risk stratification of heart failure patients with
NSVT.64 In comparison with patients with a normal LVEF, a
larger number of patients with LVEF less than 50% have inducible
ventricular tachycardia, which is not
necessarily a specific predictor of the subsequent risk of
arrhythmogenic death.65 The prognostic value of
noninvasive markers obtained with signal-averaged
electrocardiography remains uncertain. The
specificity and predictive value of late potentials in forecasting an
increased risk of life-threatening ventricular
arrhythmias is greater in post–myocardial infarction than
in nonischemic heart failure patients (60% versus 45% and
60% versus 52%, respectively).65 66
Two other important issues must be considered when determining candidacy for heart transplantation in patients with heart failure complicated by ventricular arrhythmias. Therapeutic agents shown to reduce mortality of patients with heart failure, such as ACE inhibitors and ß-receptor blocking agents, have not decreased the incidence of sudden death.21 Due to altered pharmacodynamics and pharmacokinetics, the potential of drugs used to suppress ventricular arrhythmias to worsen heart failure and arrhythmias increases as LVEF decreases.68 69 In one study the risk of proarrhythmic events was 0.8% in patients with LVEF greater than 30% and increased sixfold in patients with LVEF less than 30%.69 No data support the notion that suppressing arrhythmias will prevent sudden death. Rather, the Cardiac Arrhythmias Suppression Trial (CAST) found an increased mortality in post–myocardial infarction patients treated with encainide and flecainide.69 The addition of low-dose amiodarone (300 mg/d) to digoxin, diuretics, and vasodilators reduced mortality by 28% and hospitalizations by 31% in patients with severe heart failure independent of the presence of ventricular arrhythmias.70
In summary, the impact of arrhythmias on survival in heart failure patients must be carefully considered when evaluating candidacy for heart transplantation. Sudden death due to tachyarrhythmias or bradyarrhythmias accounts for a large number of deaths in heart failure patients. The prognostic value of both invasive and noninvasive arrhythmia markers is greater for ischemic than nonischemic heart failure patients. The proarrhythmic effects of drugs used to suppress arrhythmias increase as left ventricular dysfunction worsens. To date, only low-dose amiodarone has been shown to decrease both sudden and progressive heart failure death rates in patients with severe left ventricular dysfunction. The implantable cardioverter defibrillator is often the best option for patients with severe left ventricular dysfunction who are at high risk of dying suddenly and in whom antiarrhythmic agents are ineffective or poorly tolerated.
Selection of Pediatric Patients for Heart
Transplantation
Unfortunately, similar objective prognostic indexes
have not been
identified for infants and children with complex forms of congenital
heart disease and dilated cardiomyopathy who are
potential heart transplant recipients.
Heart transplantation may provide a survival benefit for patients with hypoplastic left heart syndrome who rarely live beyond a month without surgical treatment.5 It is unknown at this time whether heart transplantation is superior or inferior to the long-term results of the Norwood procedure, which consists of creating a communication between the right ventricle and the aorta and enlargement of the ascending aorta. However, therapeutic strategies sequentially incorporating both these options, depending on the anatomic details of the defect and availability of donor organs, seem reasonable. In addition, continued efforts to identify the determinants of good long-term survival after heart transplantation for infants with hypoplastic left heart syndrome are critical to allow appropriate selection of patients for heart transplantation, efficient use of donor organs, and use of other treatments for patients unlikely to benefit from a heart transplant. Clinical experience suggests that in patients with hypoplastic left heart syndrome, prognosis after heart transplantation worsens as preoperative waiting times lengthen, and thus infants should have priority.
Patients with congenital heart defects other than hypoplastic left heart syndrome may also be candidates for heart transplantation. In general, heart transplantation is considered when these patients develop myocardial failure in addition to the underlying congenital cardiac defect.5 Superficially, it would seem reasonable to select these patients for heart transplantation using guidelines similar to those used for patients with dilated cardiomyopathy. However, as detailed below, guidelines for heart transplantation for children with dilated cardiomyopathy and no congenital heart disease are unclear. Also, the outcome of patients with congenital heart disease and myocardial dysfunction may be different than that of patients with dilated cardiomyopathy without congenital heart disease. Finally, measurement of ventricular function in a patient with congenital heart disease and myocardial dysfunction with unusually shaped ventricles is much more difficult than in a patient with an anatomically normal heart.
The natural history of dilated
cardiomyopathy in
children is unclear.71 As illustrated in Fig 1,
5-year survival can range from less than 40% to 80%. Undoubtedly this
variability is due to the source of patients in individual studies. For
example, Taliercio et al72 studied patients evaluated in a
major tertiary referral practice. The 5-year survival rate was low.
Wiles et al,73 however, reported a population-based
study; the 5-year survival rate was approximately 80%. Predictors of
survival and death are not consistent among the
studies.73 74 75 76 Thus, at
present there appears to be no
reliable way to determine the likelihood of death for an individual
patient subsequent to cardiac evaluation. In view of these unknowns,
the following guidelines may be helpful in identifying the child or
adolescent with end-stage cardiac disease who may benefit from a
heart transplant:
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1. Progressive deterioration of ventricular function or functional status despite optimal medical therapy, including use of digitalis, diuretics, and ACE inhibitors
2. Growth failure secondary to severe congestive heart failure unresponsive to conventional medical treatment
3. Malignant arrhythmias or survival of cardiac arrest, unresponsive to conventional medical treatment and not likely to be successfully treated with an implantable cardioverter defibrillator
4. Need for ongoing intravenous inotropic support
5. Unacceptably poor quality of life
6. Progressive pulmonary hypertension that would predictably preclude heart transplantation at a later date.77
Evaluation of Comorbid Conditions
Evaluation of potential
heart transplant recipients
should include a careful analysis of comorbid conditions that
may negatively affect outcome after transplantation (Table
2).5 6 Any coexistent systemic
illness that limits survival independent of heart disease should be
considered a possible contraindication to heart
transplantation.5 6
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Age
Traditionally, age 55 has been considered the acceptable upper age
limit beyond which heart transplantation should not be considered.
However, many single center studies have shown that, in the absence of
comorbid conditions, carefully selected persons older than 55 years may
successfully undergo heart transplantation.78 The
definition of an upper age limit becomes more of an ethical than a
medical issue, because expansion of the upper age limit beyond 55
dramatically increases the already alarming discrepancy between
patients who need heart transplantation and those fortunate enough to
receive a donor heart.1 5
Pulmonary Vascular Hypertension
Significant
pulmonary vascular hypertension is a common
complication of severe long-standing heart failure due to elevated
left ventricular filling pressures from impaired left
ventricular systolic function, increased
circulating levels of catecholamines from neurohormonal
activation, and pulmonary vasoconstriction resulting from
chronic hypoxia. These
pathophysiological events cause an increase in
resistance by the pulmonary vasculature to blood flow.
Depending on the severity and duration of heart failure, the abnormal
increase of pulmonary vascular resistance may be predominantly
reversible or irreversible. After heart transplantation, the inability
of the relatively thin walled, "normal" donor right ventricle to
function adequately in the face of abnormally elevated
pulmonary vascular resistance may result in right
ventricular failure and death.79 80 Many
studies have shown that pulmonary hypertension and increased
pulmonary vascular resistance correlate with increased
morbidity and mortality both early and as late as 1 year after heart
transplantation.81 Thus, a critical component of the
evaluation of potential heart transplantation candidates is to
determine whether pulmonary vascular resistance is elevated
and, if so, whether it can be lowered by therapeutic maneuvers that
improve left ventricular function and decrease preload and
afterload. Pulmonary vascular resistance is calculated by
dividing the difference between mean pulmonary
arterial pressure and pulmonary artery wedge
pressure by cardiac output. The pulmonary vascular resistance
index is obtained by multiplying the absolute pulmonary
vascular resistance by body surface area.82 Use of the
transpulmonary gradient, which represents the
pressure gradient across the pulmonary vascular bed (mean
pulmonary arterial pressure-pulmonary
artery wedge pressure) independent of blood flow, may avoid erroneous
estimations of pulmonary vascular resistance as may occur in
patients with low cardiac output. The level of pulmonary
vascular resistance above which postoperative morbidity and mortality
increase varies between studies. It is generally agreed, however, that
pulmonary vascular resistance greater than 6 Wood units
unresponsive to the vasodilators and inotropic agents used to
"test" reversibility of pulmonary vascular hypertension
is a serious contraindication to orthotopic heart
transplantation.5 6 The hemodynamic
response of pulmonary pressures to vasodilators may have a
greater prognostic value than baseline pulmonary
hemodynamic values. The hemodynamic
response of 301 patients undergoing heart transplantation to sodium
nitroprusside challenge was a stronger predictor of right
ventricular failure and death after heart transplantation
than baseline pulmonary
hemodynamics.83 In some patients baseline
pulmonary vascular resistance was reduced to less than 2.5 Wood
units with sodium nitroprusside while systolic
arterial blood pressure was maintained at or greater than
85 mm Hg. These patients had a 3-month mortality of 3.8%, similar to
that of patients with a baseline pulmonary vascular resistance
less than 2.5 Wood units. In contrast, patients with a
pulmonary vascular resistance that could not be lowered below
2.5 Wood units with sodium nitroprusside, as well as patients in whom
this hemodynamic goal could be achieved only at the
expense of systemic hypotension, had a significantly higher mortality
than the low risk groups (40.6% and 27.5%,
respectively).83 The immediate response in the
catheterization laboratory does not always predict the
effect on pulmonary vascular resistance of a longer term
reduction in left atrial pressure.5 6 In addition,
multivariable analysis of data from the Cardiac
Transplant Research Database confirmed that preoperative
pulmonary vascular resistance is an independent risk factor for
death early after heart transplantation but failed to identify a
specific level of resistance above which the risk of death after heart
transplantation is unacceptable. Instead, the continuous positive
relation between pulmonary vascular resistance and death after
heart transplantation supports the notion that pulmonary
vascular resistance should be considered a relative rather than an
absolute contraindication to heart transplantation, because the risk of
death rises with increasing pulmonary vascular
resistance.84 Guidelines for evaluation and treatment of
pulmonary vascular hypertension are provided below. It should
be stressed that adequate assessment of pulmonary vascular
hypertension requires referral to a center with experience in treatment
of heart failure and performance of heart transplantation.
Lung Disease
Severe chronic bronchitis or
obstructive pulmonary disease
may predispose patients to pulmonary infections after heart
transplantation and may also make removal of ventilatory support after
heart transplantation difficult, especially if diaphragmatic paralysis
results from intraoperative damage to the phrenic nerve. The
contribution of primary pulmonary disease to dyspnea and
functional impairment in patients with heart failure is difficult to
evaluate because severe heart failure itself compromises
pulmonary function. Thus, it is very important to assess
pulmonary function only after optimal medical therapy for heart
failure. In general, patients who have a ratio of forced expiratory
volume in 1 second to forced vital capacity
(FEV1/FVC) of less than 40% to 50% of predicted or
severe obstructive disease (FEV1 less than 50% of that
predicted) despite optimal medical therapy are poor candidates for
heart transplantation.85
Pulmonary infarction, a not infrequent complication of end-stage heart failure, has been considered a contraindication to heart transplantation because of the risk of recurrent emboli and abscess formation in the area of pulmonary infarction after institution of immunosuppression.86 However, patients with pulmonary infarction or even endocarditis have undergone successful transplantation when the affected pulmonary lobe or organ is removed at the time of transplantation.87 88
Renal Dysfunction
Because many patients with
advanced heart failure have mild to
moderate abnormalities in serum urea nitrogen and
creatinine levels, a dilemma often emerges in evaluation of
heart transplantation candidates. Is progressive renal dysfunction due
to underlying intrinsic renal disease, which is a relative
contraindication to heart transplantation? There are data that suggest
that an abnormal renal function before surgery (serum
creatinine greater than 2 mg/dL, creatinine
clearance less than 50 mL/min) portends a worse prognosis in adult
recipients after heart transplantation. However, when serum
creatinine was evaluated as a continuous variable, no
specific level was identified beyond which the risk of heart
transplantation was unacceptable.84 To avoid
cyclosporine nephrotoxicity, pre–heart transplantation
renal function can be used to determine cyclosporine dosage
in the perioperative period.89 If primary
renal disease is suspected, renal ultrasound is helpful. The presence
of normal-size kidneys and improvement of renal function after a
short-term trial of inotropic therapy favors the possibility that
renal dysfunction is due to heart failure.
Hepatic
Dysfunction
Irreversible hepatic dysfunction has implications similar
to renal
dysfunction.90 If transaminase levels are more than twice
their normal value and associated with coagulation abnormalities, the
patient should not be listed for heart transplantation until primary
liver disease has been excluded. The absence of hepatic cirrhosis and
other progressive hepatic diseases must be proven with
percutaneous liver biopsy because these conditions can
cause rapid death in heart transplant recipients due to hepatic
failure.
The wide spectrum of peripheral and cerebrovascular disease makes it difficult to establish specific exclusion criteria for heart transplantation in patients with these conditions. In such patients, the physician must consider (1) the possibility that stress and hemodynamic changes associated with heart transplantation may precipitate an acute thrombotic or embolic event; (2) the potential need for postoperative intra-aortic balloon support if graft function is poor in the immediate postoperative period; (3) the effect of corticosteroids on progression of the atherosclerotic vascular disease; (4) the effects of previous cerebrovascular events on ability to follow the medical regimen, rehabilitation, and mortality after heart transplantation; and (5) feasibility of surgical revascularization if symptoms due to peripheral or cerebrovascular disease worsen after transplantation. In some instances carotid endarterectomy has been performed before heart transplantation to minimize the risk of postoperative cerebrovascular events.
Active peptic ulcer disease may lead to gastrointestinal hemorrhage during cardiopulmonary bypass or in the postoperative period. Therefore, medical therapy should be instituted early after diagnosis in a recipient awaiting transplantation. Many programs use prophylactic H2 blockade or other measures in very ill patients awaiting heart transplantation. These programs insist on endoscopic confirmation of healing of diagnosed gastritis or peptic ulcer disease before transplantation.91
Diabetes was considered a contraindication to heart transplantation at many centers in the past. However, recent experience supports the intermediate-term safety of heart transplantation in selected patients with diabetes who are without end-organ damage such as nephropathy, neuropathy, or retinopathy.92 93 However, it is important to be aware of the patient's diabetes status because corticosteroid therapy may worsen glucose intolerance or induce diabetes mellitus. In insulin-dependent persons with diabetes, higher doses of insulin may be needed. Persons with diabetes who are treated with oral agents may require insulin after heart transplantation.
Obesity before heart transplantation makes it difficult to identify an appropriately sized donor heart. In addition, long-term morbidity associated with obesity is accentuated by the effects of long-term corticosteroid therapy.5 A strict weight loss program may improve heart failure and reduce postoperative risk in obese patients with heart failure.5
Severe osteoporosis may not increase mortality after heart transplantation, but its long-term morbidity is accentuated by the effects of long-term corticosteroid therapy.5
The presence of an active infection is usually a temporary contraindication to heart transplantation until it is adequately treated, because of the negative effects of the institution of global immunosuppression on the predicted course of an infectious disease.5
Screening for malignancy in the potential heart transplant recipient should include a rectal examination and stool occult blood examination, a pelvic examination, pap smear and mammography for women, and prostate specific antigen determination for men. Heart transplantation has been successfully performed in patients with a remote history of malignancy considered "cured"; recent or active malignancy is a contraindication to heart transplantation.94 Transplantation in patients with tumors localized to the heart has also been reported.95
Although spontaneous improvement may occur, patients with active lymphocytic myocarditis may be considered for heart transplantation. There are no data establishing the exact amount of time beyond which spontaneous improvement is improbable.14
Patients with myocarditis established by biopsy have greater early morbidity due to higher rejection rates than patients undergoing heart transplantation for other indications.96 Thus, confirmation of the presence of myocarditis by endomyocardial biopsy may be helpful in planning the postoperative immunosuppressive regimen to minimize rejection in this high-risk group.
The wisdom of performing heart transplantation in patients with systemic diseases associated with myocardial infiltration has been questioned.97 Patients in whom sarcoid granulomas are detected only in the heart may undergo successful transplantation, although recurrent sarcoid in the heart allograft has been reported.98 The extent of extracardiac sarcoidosis should be determined before heart transplantation to assess the potential for postoperative morbidity associated with this disease. Patients with cardiac amyloid may only receive short-term benefit from heart transplantation, because this disease often recurs in the transplanted heart and progresses to the other organs after transplantation.97
Social and psychological factors should be carefully evaluated when heart transplantation is considered.99 100 101 102 103 104 105 Underlying mental illness or personality disorders may render a patient unwilling or unable to comply with the rigors of medical follow-up. The medical and financial stresses as well as the uncertainties of life after heart transplantation may accentuate or precipitate underlying emotional problems and worsen fragile family relationships. Evidence of preoperative noncompliance, especially if recurrent, may predict poor compliance after heart transplantation.100 101 Tobacco abuse before heart transplantation will likely continue after heart transplantation and increase morbidity and mortality. A history of alcohol and drug abuse should be carefully evaluated; recidivism after heart transplantation may be fatal. The financial hardship of transplantation can be extremely stressful, and mechanisms to ensure that patients will continue to receive adequate postoperative care and medications must be in place before heart transplantation.
When determining the impact of individual comorbid conditions on a patient's candidacy for heart transplantation, the physician must consider the patient's risk of death without heart transplantation, along with the presence and severity of other potential contraindications to heart transplantation. The analysis of comorbid conditions as continuous variables underscores the difficulty in defining precise limits beyond which heart transplantation outcome is unacceptable. Each comorbid condition may be at least additive, requiring individual assessment of risk.
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Recommendations for Evaluation and Follow-up of Potential Candidates for Heart Transplantation |
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TopAbstractIntroductionPrognostic Factors in Patients...Coronary Artery Disease and...Recommendations for Evaluation...Conclusion References |
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Improved heart failure prognosis and the critical donor organ shortage make it imperative that potential heart transplant candidates be identified as those patients with the greatest need and who are likely to derive the maximum benefit from transplantation. While a thorough approach is key to achieving this goal, the cost-effectiveness of the evaluation process is a foremost concern in the current healthcare environment. Most patients with heart failure referred for consideration of heart transplantation initially present in the ambulatory care setting.
When a patient is first referred for consideration of a heart
transplant, it is appropriate to exclude comorbid noncardiac conditions
that may seriously compromise the outcome of transplantation or shorten
patient survival independent of heart disease (Table 2
). If
contraindications are absent, the logical next step in the evaluation
process should consist of history, physical examination, and
diagnostic tests tailored to uncover potentially reversible
causes of heart failure.
The most cost-effective and widely available tool to evaluate cardiac function is echocardiography with Doppler. This technology defines physiological and anatomic characteristics, including wall thickness, wall motion, systolic and diastolic function, valvular and congenital lesions, and left atrial size. Ventricular mural thrombi and pericardial effusions can also be detected by echocardiography.106 107 However, the echocardiogram may be technically inadequate in patients with pulmonary disease and in up to 18% of patients under optimal circumstances. Moreover, the echocardiogram provides only a semiquantitative estimate of LVEF. Radionuclide ventriculography should be performed when a more precise measurement of LVEF and a better assessment of right ventricular function is needed.107 The etiology and severity of heart disease should then be further defined with cardiac catheterization and coronary angiography.
If CAD is found, it should be determined whether the coronary arteries are adequate for revascularization. If suitable vessels are demonstrated, the presence and extent of reversible myocardial ischemia should be evaluated with the methods described above, including myocardial thallium rest-redistribution imaging and, if indicated and available, PET.52 53 When adequate vessels and viable myocardium are present, coronary surgical revascularization can be performed in patients with a low LVEF. If surgery does not produce significant symptomatic and functional improvement, further evaluation and optimization of medical therapy are warranted. When cardiac catheterization reveals correctable valvular disease, valve surgery can be performed. If surgery is unsuccessful or valvular abnormalities cannot be surgically corrected, further evaluation and medical treatment should be pursued. A similar approach can be followed when cardiac evaluation reveals the presence of congenital heart disease. If congenital heart disease is not amenable to surgical correction and is complicated by irreversible pulmonary hypertension, heart-lung transplantation should be considered.71
If evaluation yields the diagnosis of nonischemic dilated cardiomyopathy, duration of illness should be ascertained, because a short duration of heart failure symptoms appears to be associated with a greater likelihood of spontaneous improvement. The approach to nonischemic cardiomyopathy is also influenced by the etiology of cardiac dysfunction. Observation for 3 to 6 months after optimization of medical therapy is reasonable when cardiac dysfunction is due to excessive alcohol intake, which can improve with abstinence, or to peripartum cardiomyopathy, which improves spontaneously in 50% of cases. Another potentially reversible cause of nonischemic cardiomyopathy is active lymphocytic myocarditis.108 Endomyocardial biopsy to prove or exclude the presence of this condition is recommended when duration of cardiac dysfunction is less than 2 years. To date the role of immunosuppressive therapy in myocarditis confirmed by biopsy is unclear.109 Only one published study supports the use of corticosteroid therapy in patients with some evidence of myocardial inflammation.108 Even in this study, however, the improvement in cardiac function occurring during corticosteroid therapy was not sustained after discontinuation of immunosuppression. Despite these uncertainties, some experts still recommend initiating a short trial of immunosuppression in an effort to improve cardiac function of patients with myocarditis and thus eliminate or delay the need for heart transplantation. Regardless of therapeutic choices, it is important to know if patients being considered for heart transplantation have myocardial inflammation. These patients may require intensified immunosuppression after heart transplantation because they have been found to succumb to early rejection more often than age-matched patients undergoing heart transplantation for all other indications.96
In patients with nonischemic cardiomyopathy being considered for heart transplantation, endomyocardial biopsy is also indicated to confirm or exclude other potentially reversible causes of heart failure such as hemochromatosis or conditions that may preclude heart transplantation, such as amyloidosis. The latter has been shown to recur in the allograft and to run a rapidly fatal course.97
Other potentially reversible conditions should be carefully evaluated
and treated in patients referred for heart transplantation. If atrial
fibrillation is present, every attempt should be made to restore
sinus rhythm with pharmacological or electrical cardioversion. Often,
restoration of sinus rhythm produces enough symptomatic and
hemodynamic improvement that heart failure becomes
compensated and consideration of heart transplantation can be deferred.
Drugs with negative inotropic effects, such as antiarrhythmic agents,
calcium channel- and ß-receptor blocking drugs or medications
that worsen heart failure by decreasing renal blood flow, such as
nonsteroidal anti-inflammatory drugs, should be discontinued if
possible. Finally, noncardiac causes of heart failure, such as anemia,
infections, and endocrine disorders, should be identified and treated
before heart transplantation is considered (Table 3).
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After potentially reversible causes of heart failure have been adequately corrected and medical therapy optimized according to the guidelines below, further evaluation should focus on establishing the presence and reversibility of pulmonary vascular hypertension and timing for listing patients for heart transplantation.
Patients with persistent heart failure symptoms despite optimal medical therapy should uniformly undergo right heart catheterization and hemodynamic measurements to measure pulmonary arterial pressure, transpulmonary gradient, and pulmonary vascular resistance. If pulmonary hypertension is present (pulmonary vascular resistance is greater than 2.5 Wood units and transpulmonary gradient is greater than 12 mm Hg), incremental doses of sodium nitroprusside can be administered to assess its reversibility. Sodium nitroprusside is usually begun at doses of 0.5 µg/kg per minute and increased by 0.5 µg/kg per minute every 3 to 5 minutes until pulmonary vascular resistance drops to acceptable levels or systemic symptomatic hypotension occurs. If sodium nitroprusside lowers pulmonary vascular resistance sufficiently without causing systemic hypotension, oral vasodilators can be further increased and the patient can be listed for heart transplantation.5 If pulmonary vascular resistance is not sufficiently decreased by sodium nitroprusside and blood pressure remains greater than 90 mm Hg, other vasodilators such as prostaglandin E1 (PGE1), prostacyclin, adenosine, or inhaled nitric oxide can then be used.110 111 112 113 114 115 The use of PGE1 is limited by the occurrence of systemic symptoms, including nausea, flushing, and tremor. Prostacyclin is a potent vasodilator that is 85% to 90% cleared by a single pass through the lungs. This makes it useful as a relatively selective pulmonary vasodilator because its systemic effects are minimized by this first-pass effect. Effective pulmonary vasodilatation can usually be achieved with doses of 2 to 10 µg/kg per minute. In one study, prostacyclin was more effective in decreasing the pulmonary vascular resistance of 66 heart transplant candidates than nitroglycerin, sodium nitroprusside, dobutamine, and enoximone.112 Adenosine is another agent that produces selective pulmonary vasodilatation. At a dose of 100 µg/kg per minute, adenosine lowered the transpulmonary gradient more than sodium nitroprusside while increasing left atrial pressure. Because of its negative inotropic effect and high cost, adenosine is poorly suited for long-term reduction of pulmonary vascular resistance in patients with chronic heart failure.113 Similar observations have been made for nitric oxide.114 115
When nitroprusside infusion produces hypotension without lowering pulmonary vascular resistance to acceptable levels, or when infusion of other vasodilators is unsuccessful, inotropic vasodilator drugs, such as ß-adrenergic agonists (dobutamine) and/or phosphodiesterase inhibitors (milrinone), can be administered in the hospital. If the response is inadequate, long-term intermittent or continuous outpatient therapy with these drugs can be considered. In some patients pulmonary vascular resistance fails to decrease in response to a single short-term infusion of ß-adrenergic agonists and/or phosphodiesterase inhibitors but may gradually decline in response to long-term intermittent or continuous parenteral inotropic therapy.
Once reversibility of pulmonary hypertension has been conclusively demonstrated, VO2max should be measured. If VO2max is less than 14 mL/kg per minute, patients can be listed for heart transplantation. If the results of cardiac evaluation suggest that consideration of a heart transplant is premature, periodic reassessment (at least annually) is warranted.6 The frequency of reevaluation of cardiac function may be increased if the patient's clinical condition deteriorates.6 If the results of the initial evaluation suggest that the patient's condition warrants immediate placement on a waiting list for a heart transplant, serial right heart catheterizations should be performed. They should be biannual in the absence of severe pulmonary hypertension, or every 3 months if, at the previous cardiac catheterization, pulmonary arterial pressure and vascular resistance were sufficiently elevated that vasodilators were needed to assess reversibility of pulmonary vascular hypertension.6 Furthermore, hemodynamic measurements obtained at the time of right heart catheterization can be used to optimize heart failure therapy.13 Measurement of VO2max should be repeated if a significant symptomatic improvement occurs while the patient is awaiting heart transplantation.31
Deteriorating clinical circumstances may dictate readmission to the hospital and a change in priority status. A recent study found that each month 4.7% of patients listed for heart transplantation as Status II (not requiring pharmacological or mechanical support) deteriorate to the point of requiring an upgrade in their priority status, and two thirds of patients who were Status I (ICU bound, requiring pharmacological or mechanical support) at the time of heart transplantation were Status II at the time they were listed.116
For listed ambulatory patients, visits every 4 to 6 weeks are necessary to reassess prognosis, optimize therapy, and reevaluate the need for heart transplantation.
Effect of Medical Therapy on Prognosis of Advanced Heart
Failure
In the past decade certain types of medical therapy have been
shown to improve survival in subjects with heart failure. The first
trial to demonstrate a mortality redu