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Donor shortage in heart transplantation
Donor shortage in heart transplantation Is extension of donor age limits justified? Chronic shortage of donor organs for heart transplantation led us to extend donor age limits. To verify the effectiveness of such a policy we have compared the results of heart transplantation in 45 patients with donors more than 40 years of age (group 1) with those of 72 patients older than 50 years of age who had heart transplantation with younger donors (group 2) between November 1985 and December 1992. The two groups were comparable in terms of mean recipient age, recipient and donor sex, and indication for heart transplantation. Mean donor age was 46 ± 4 years (range 41 to 59 years) in group 1 and 23 ± 7 years (range 8 to 39 years) in group 2 (p < 0.001). In group 1 cerebrovascular accidents were more common as the cause of donor death (60 % versus 16%, p = 0.001), and no difference was found in ischemic time (144 ± 47 minutes versus 140 ± 48 minutes, p = not significant). There were 6 early «30 days) deaths in group 1 (13%) and 10 in group 2 (14%; p = not significant). Fatal acute graft failure was more prevalent, but not significantly so, in group 1 (10% versus 5.5%, p = not significant). Mean foUow-up was 29 ± 20 months (range 3 to 78 months) in group 1 and 30 ± 20 months (range 3 to 80 months) in group 2 (p = not significant). At 5 years actuarial survival was 80% ± 6% in both groups with comparable graft performance at echocardiographic and hemodynamic control studies. A significant difference was found in freedom from any type of coronary artery abnormality between group 1 (49 % ± 13 %) and group 2 (77 % ± 8 %) at 5 years (p < 0.05); however, freedom from coronary stenotic lesions only was similar. Major conduction disturbances have occurred more frequently in patients of group 1 (37 % versus 12%; p = 0.003) without any difference in the need for permanent pacing. Donors older than 40 years of age can be accepted for heart transplantation with early and long-term results comparable with those obtained with younger donors. The impact of a higher incidence of coronary abnormalities on late performance of older grafts must be assessed at longer follow-up. Our results indicate that, because of the current organ shortage, extension of donor age limits is justified, even up to the sixth decade of life in selected cases. (J THORAC CARDIOVASC SURG 1994;107:1346-55)
Ugolino Livi, MD (by invitation), Uberto Bortolotti, MD (by invitation), Giovanni B. Luciani, MD (by invitation), Giovanni M. Boffa, MD (by invitation)," Aldo Milano, MD (by invitation), Gaetano Thiene, MD (by invitation)," and Dino Casarotto, MD (by invitation), Padova, Italy Sponsored by Norman E. Shumway, MD, Stanford. Calif.
From the Department of Cardiovascular Surgery, Cardiology," and Pathology," University of Padova Medical School, Padova, Italy. Supported by the National Council for Research, Target Project "BTBS," Milan, and "FAT.MA," Rome, Italy. Read at the Seventy-third Annual Meeting of The American Association for Thoracic Surgery, Chicago, Ill., April 25-28, 1993. Address for reprints: U. Livi, MD, Istituto di Chirurgia Cardiovascolare, Centro di Cardiochirurgia V. Gallucci, Universita di Padova, Via Giustiniani, 2, 35128 Padova, Italy. Copyright
1994 by Mosby-Year Book, Inc.
0022-5223/94 $3.00
1346
+0
12/6/53998
h e steady increase of potential heart transplant recipients, because of the improved clinical results after transplantation, has made donor availability the true limiting factor to this procedure. 1 Data from the North Italy Transplant Program registry have demonstrated that organ availability satisfies less than 50% of requirement and that more than 25% of patients currently die before heart transplantation.i In an attempt to meet a continuously increasing demand for organs, in recent years several institutions worldwide have extended the standard criteria for donor graft acceptability.v 4 Indeed, the pre-
The Journal of Thoracic and Cardiovascular Surgery Volume 107, Number 5
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Table I. Characteristics of recipients Group 1 In = 45)
Age (yr) Mean Range Sex Male Female Diagnosis DeM IHD Other Transpulmonary gradient >15mmHg PVR (Wood units/rn-) >6 Reoperation Inotropic drugs/IABP Diabetes Peripheral vasculopathy Procedure Orthotopic HTx Heterotopic HTx
134 7
Table II. Characteristics of donors
Group 2 In = 72)
p Value
54 ± 6 38-63
55 ± 3 50-68
NS
37 (82*) 8 (18)
63 (87*) 9 (13)
NS
17 (38) 22 (49) 6 (13) 5 (11)
32 (44) 33 (46) 7 (10) 7 (10)
NS
NS
8 (18)
12 (17)
NS
10 (22) 4 (9) 5 (I I) 3 (6)
14 (20) II (15) 10 (14) 5 (7)
NS NS NS NS
43 (96) 2 (4)
68 (95) 4(5)
NS
NS, Not significant; DeM, dilatedcardiomyopathy; I HD, ischemic heart disease;
PVR, pulmonaryvascularresistance; IABP, intraaorticballoon pump;HTx, heart transplantation. 'Numbers in parentheses are percent of patients.
liminary results of heart transplantation with older donors have been so far encouraging.v 6 However, some concern still remains regarding the impact of an alleged higher incidence of acute graft failure and coronary artery disease (CAD) on survival and functional outcome in this patient population." Although multicenter studies have demonstrated the adverse effect of older donor age on survivaf and late graft function," reports from single institutions have often contradicted these findingsP- 10, 11 To assess whether an extension of donor age limits may still be justified, we compared the results of heart transplantation with donors more than 40 years of age with those obtained with younger donors. In the present study the effect of an older cardiac allograft was analyzed with respect to short- and long-term survival, hemodynamic performance, and prevalence and clinical relevance of posttransplantation CAD.
Patients and methods Recipient data. To verify the effect of older donor age on early and late outcome after heart transplantation, wecompared two groups of consecutivepatients from our entire series of 227 patients who had heart transplantation at our institution between November 1985 and December 1992. These two groups had similar characteristics as shown in Table I; particularly, they were comparable in terms of mean age and gender, indication for transplantation, and preoperative status, includ-
Age (yr) Mean Range Sex Male Female Cause of death Vascular Traumatic Other Mean duration of ventilation (days) Mean dopamine dose (ltg/kg/min) 2D-TE abnormalities Coronary angiography
Group 1
Group 2
In = 45)
In = 72)
p Value
46 ± 4 41-59
23 ± 7 8-39
<0.001
26 (58*) 19 (42)
53 (74*) 19 (26)
NS
27 (60)
12 (16) 58 (80) 3 (4) 2.8 ± 2.0
0.001
16 (36) 2 (4) 2.6 ± 1.8 4.7 ± 2.6
5.0 ± 4.0
NS
8 (17) 7 (15)
8 (11) 6 (8)
NS NS
NS
NS, Not significant.
'Numbers in parenthesesare percent of patients.
ing pulmonary vascular resistances and transpulmonary gradient. Group I included 45 patients (19% of entire series), 37 men and 8 women, with a mean age of 54 ± 6 years (range 38 to 63 years) who received hearts from donors older than 40 years of age, which is suggested by the American Heart Association as the limit for cardiac donationl-; orthotopic heart transplantation was done in 43 (96%) patients and 2 (4%) had heterotopic transplantation. Group 2 included 72 patients (32% of entire series), 63 men and 9 women, older than 50 years of age (mean age 55 ± 3, range 50 to 68 years), who received hearts from donors younger than 40 years of age and who were consecutively operated on for heart transplantation during the same period as group I patients; 68 (95%) had orthotopic and 4 (5%) heterotopic heart transplantation. Considering that in our program grafts from older donors have been preferentially assigned to older recipients (80% of group I patients being more than 50 years of age), in group 2 only recipients more than 50 years old were included to neutralize the potential adverse effect of advanced age on survival and to have two groups of patients matched for age and age-related clinical characteristics. Donor selection and characteristics. All donors were matched for ABO blood compatibility, and a maximum weight mismatch of 400/0 was accepted in recipients with normal pulmonary vascular resistance. Donor assessment was based on a complete clinical and laboratory evaluation, including twodimensional transthoracic echocardiography (2D-TE). Coronary angiography was not routinely done except in cases of clinicallysuspected CAD or, wheneveravailable, in the presence of clear risk factors for CAD, regardless of donor age. Extreme importance has been attributed to direct visualization of the heart and to coronary artery palpation; when this maneuver revealed gross coronary artery calcification the graft was considered unsuitable as occurred in about 20% of older potential donors evaluated by us. The main donor characteristics for both groups are summarized in Table II. Group I donors had a mean age of 46 ± 4 years (range 41 to 59 years), 58% being male, whereas group 2
I 348
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Fig. 1. Actuarial survival curve of patients who received hearts from donors older than 40 years of age (filled circles) plotted against survival curve of patients who received hearts from donors younger than 40 years of age (open circles). Numbers on x axis indicate patients at risk. donors were younger (mean age 23 ± 7 years, range 8 to 39 years) and predominantly male (74%). Besides age, donors of the two groups differed in the cause of death, with cerebrovascular accidents and head trauma being the most common causes in groups I and 2, respectively (p = 0.001). Abnormal2D-TE findings, represented by marked left ventricular (LV) hypertrophy and localized wall motion abnormalities, were detected in eight donors (17%) of group I and in eight (II %) of group 2 (p = NS*). Coronary angiography was done in seven donors (15%) of group I and in six (8%) of group 2 and showed normal results in all. Graft preservation was obtained by administration of a single dose of cold crystalloid cardioplegic solution (St. Thomas' Hospital No.2) during harvesting and by storage in cold saline until the time of implantation. The mean ischemic time was 144 ± 47 minutes (range 53 to 255 minutes) in group I and 140 ± 48 minutes (range 47 to 245) in group 2 (p = NS). Posttransplantation management. Immunosuppression consisted of cyclosporine and azathioprine with no routine administration of oral steroids. Cyclosporine dose was adjusted to maintain a whole trough blood level of 150 to 300 ng/rnl assessed by radioimmunoassay and based on the patient's renal function. Azathioprine dose was adjusted to maintain a total white blood cell count of at least 4000 cells/mm'. Most patients received anti thymocyte globulins for 3 to 5 days as early prophylaxis of rejection. Acute graft rejection, diagnosed by endomyocardial biopsy, was treated with pulse doses of methylprednisolone, and low-dose prednisone (5 to 10 mg/day) was added in cases of persistent or recurrent rejection. Infectious episodes were defined as clinically apparent infections that necessitated in-hospital treatment and were documented by cultures or serologic tests. In patients without symptoms, cytomegalovirus infection was considered in the presence of a fourfold increase in the immunoglobulin G titer or whenever cytomegalovirus was cultured from blood, urine, or sputum. Graft function and patient follow-up. Early posttransplan*NS
= Not significant.
tation graft performance was indirectly evaluated by comparing the mean duration of assisted ventilation, length of intensivecare unit and hospital stay, and amount and duration of inotropic support and directly by comparing the LV ejection fraction (EF) by 2D-TE at I and 4 weeks after heart transplantation. After discharge from the hospital all patients returned to our department for periodic follow-up visits. To evaluate the impact of donor age on prevalence of CAD in the recipient, we collected data on major risk factors for CAD,13 such as hypertension, diabetes, dyslipidemia, number of rejection and infection episodes, and need for steroid immunosuppression, on a yearly basis and compared them between the two groups. Late graft performance was assessed by means of 2D-TE approximately every 3 months unless otherwise required and by complete hemodynamic studies at yearly intervals. Graft CAD was diagnosed, in the presence of any focal or diffuse coronary stenosis of any degree or any vessel dilatation, by careful review of multiple angiograms by two independent observers. Presence of major conduction disturbances, defined as bifascicular (right bundle branch block with abnormal left axis deviation) or complete atrioventricular block, was ascertained by means of daily standard resting electrocardiograms and after discharge at each follow-up visit; diagnosis was confirmed in selected patients by 24-hour electrocardiographic recording and invasive electrophysiologic studies, and permanent pacemaker implantation was done when indicated. Statistical analysis. The SAS program (Statistical Analysis System, SAS Institute Inc., Cary, N .Ci) was used for statistical analysis. The influence on early deaths caused by graft failure or all causes was investigated by means of univariate analysis of the following variables: age, sex, cause of death, and inotropic support for the donor; age, sex, indication for heart transplantation, previous cardiac operation, pretransplantation status, diabetes, pulmonary vascular resistance, and transpulmonary pressure gradient for the recipient; and, additionally, ischemic time. Continuous data are expressed as the mean plus or minus standard deviation of the mean and evaluated for differences between groups with a two-tailed t test or analysis of
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Table III. Early graft f unction Group I Hours supported by ventilator Mean 32 ± 24 Range 8- 120 le u stay (day s) Mean 8 ± 4 Range 2-2 1 Hospital stay (days) Mean 29 ± 11 Range 2-60 Catech olamin es Mean No. used 2.5 ± 0.5 Days (mean) 4.9 ± 2.5 Days (range) 1-13 Dopamine (rug /kg) Mean dose 26 ± 12 Epinephrine (mgjkg) Mean dose 0.2 ± 0.1
Group 2
p Value
25 ± 32 6-236
NS
7 ± 3 2·2 1
NS
27 ± 10 4-63
NS
2.2 ± 0.5 4.8 ± 2.8 1-21
NS NS
27 ± 16
NS
0.2 ± 0.2
NS
NS. Not significant; l CU, intensive care unit.
variance. Discrete data were anal yzed for differences between groups with the x 2 test and two-tailed Fisher's exact test when appropriate. Life-table actuarial curves for survival and freedom from CAD were constructed and differences between groups assessed with the generalized Wilcoxon test. Significance was assumed when the p value was less than 0.05.
Results Ea rly and late survival. Overall actu arial survival was 83% ± 6% versus 82% ± 5% at I year and 80% ± 6% versus 80% ± 6% at 5 years in group I and group 2, respectively (p = NS; Fig. I), with a comparable mean follow-up (29 ± 20 months versus 30 ± 20 months, p = NS) and a maximum follow-up of 78 months in group I and 80 months in group 2. There were six (13%) early «30 days) deaths in group I; four patients died of acute graft failure, one of undiagnosed preoperative aortic dissection, and one of acute encephalitis. There were 10 (14%) early deaths in group 2 as a result of acute graft failure in four, poor recipient condition in three, and acute pancreatitis, intraoperative hemorrhage, and infection in one each. In all cases graft failure became evident during the first posttransplantation hours and was unresponsive to any pharmacologic and mechanical support and led to death after a mean interval of 9 ± 5 days. Necropsy showedabsence of acute rejection in all eight patients who died of acute graft failure and relevant gross pathologic findingsonly in two of group I patients , which consisted of right ventricular wall lipomatosis in one and severe CAD in another and signs of subendocardial necrosis at histologic study in three . Fatal acute graft failure was more common in group I than in group 2 (9% versus 5.5%), although the difference was not statistically significant
Fig. 2. Chronic rejection with obstructive CAD. Intimal proliferation superimposed on atherosclerotic plaque , most probably present in donor heart at time of transplantation . (WeigertVan Gieson stain, original magnification X 18.)
(p = NS). Univariate analysis of preoperative variables, particularly donor age, failed to show any significant incremental risk factor for early death as a result of graft failure or any other cause. The prevalence of late deaths was also comparable in the two groups, being 5% (two patients) in group I and 6% (4 patients) in group 2 (p = NS). In group I, one patient died of traumatic rupture of the spleen 2 months after heart transplantation and one with insulin-dependent diabetes died of CAD after 15 month s (Fig . 2). In group 2 acute rejection was responsible for three late deaths at 2, 24, and 66 months after transplantation, and one patient died of pulmonary infection 2 months after emergency heart transplantation. Specific donor variables, such as age «49 or > 49 years), sex, dopamine dose «5 or > 5 JLg/kg per minute), and total ischemic time (< 180 or> 180 minutes) , did not influence 5-year survival in group 1 patients. Early graft function. Comparison of duration of mechanical ventilation, length of intensive care unit and hospital sta y, duration and type of inotropic support, and number and total dose of catecholamines required showed no statistical difference between the two groups, as shown in Table III. In group I mean LVEF by 2D-TE was 64% ± 7% (range 50% to 74%) and 66% ± 5% (range 53% to 76%) at I and 4 weeks, respectively, not significantly different from that observed in group 2 at the same intervals (65% ± 6%; range 51% to 79%, and 67% ± 6%; range 54% to 79%; p = NS). Posttransplantation complications. The incidence of acute rejection and infection was comparable in the two
I 350
The Journal of Thoracic and Cardiovascular Surgery May 1994
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groups, being 1.6 episodes per patient and 0.4 episodes per patient in group I and 1.8 episodes per patient and 0.3 episodes per patient in group 2, respectively (p = NS). The percentages of patients who had asymptomatic and symptomatic cytomegalovirus infections were also similar: 69% and 22% in group 1 and 77% and 14% in group 2 (p = NS). No difference was also noted in the prevalence ofhypertension (45% in group 1versus 47% in group 2), of diabetes necessitating oral hypoglycemic drugs or insulin (10% versus 11%), or of hyperlipidemia necessitating treatment (23% versus 24%; p = NS). Major conduction disturbances, diagnosed in 14 patients (37%) of group 1 and in 8 (12%) of group 2 (p < 0.05), consisted of bifascicular block in 16 (10 in group I and 6 in group 2) and complete atrioventricular block in 6 (4 in group 1 and 2 in group 2). Permanent pacemaker implantation was necessary in four patients of group 1 (10%), because of early complete atrioventricular block in three and late (after 7 months) paroxysmal complete atrioventricular block in one, and in four (6%) of group 2 (p = NS), because of early complete atrioventricular block in two and bifascicular block with infraHisian block in two (Fig. 3). Late follow-up and graft function. Assessment of clinical status at follow-up showed that 92% of group 1 and 93% of group 2 patients were in New York Heart Association class 1. Most recent 2D-TE examination showed a comparable LVEF in the two groups (63% ± 8% versus 66% ± 7%,p = NS), whereas group I patients had a higher LV mass/Lv end-diastolic volume ratio (1.2 ± 0.3 versus 1.1 ± 0.4) and LV mass (74 ± 14 gm/rrr' versus 64 ± 15 gm/rn-), although the
difference was not statistically significant (p = NS). In 18% of group 1 patients and in none of group 2, 2D-TE showed evidence of fibrotic thickening of the aortic valve cusps, with small nodular calcification in the oldest (59 years) donor accepted, causing trivial to mild aortic regurgitation in 70% of cases; these changes, already noted at the first posttransplantation 2D-TE, did not show any progression at subsequent follow-up investigations. Complete hemodynamic studies were done in 29 patients of group 1 and 47 of group 2 at 1 year, in 21 and 33 at 2 years, in 17 and 24 at 3 years, in 10 and 16 at 4 years, and in 6 and 10 at 5 years, respectively. Thus a total of 83 and 130 coronary angiographic studies were available in groups 1 and 2, respectively. Comparison of hemodynamic data in the two groups in the posttransplantation period is shown in Table IV. The only significant difference was found in a higher LV end-diastolic pressure and a higher LV mass at the first year after heart transplantation in group 1 with comparable values of mean arterial aortic pressure. Review of coronary angiograms showed that coronary abnormalities of any type were present in 10 patients of group 1 and in 7 of group 2. In particular, coronary artery dilatation was found only in group 1patients (5 cases) and was already present at the first angiographic follow-up examination and was not associated with obstructing lesions in three patients. Actuarial freedom from all types of coronary abnormalities was 49% ± 13% in group I and 77% ± 8% in group 2 (p < 0.05; Fig. 4). However, when only coronary stenoses of any degree were considered the difference was not significant (60% ± 14% in group 1 and 77% ± 8% in group 2; Fig. 5) . No difference
The Journal of Thoracic and Cardiovascular Surgery Volume 107, Number 5
Livi et al.
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was also found either in freedom from significant (>70% obstruction) coronary lesions (Fig. 6) or in morphologic features (focal versus diffuse) and distribution of CAD or progression of CAD at subsequent follow-up studies in the two groups. Moreover, comparison of the hemodynamic data of patients of group I in whom CAD developed and of those who did not have CAD at 4 years showed comparable results: mean LVEF of 67% ± II % versus 68% ± 12%,meancardiacindexof3.2 ± 0.7 Ljminjm 2 versus 3.4 ± 0.7 Ljminjm 2, and mean LV end-diastolic pressure of 14 ± 5 mm Hg versus 13 ± 2 mm Hg (p = NS).
Discussion Strict recipient and donor selection criteria have been followed to minimize mortality and morbidity after heart transplantation. 14 The significant improvement in survival and the decrease in the prevalence of major complications with the use of cyclosporine'" has allowed extension of heart transplantation to patients who do not fit the original selection criteria. To face a continuous need for heart transplantation, acceptance of donors who do not fit the original selection criteria, particularly in terms of age, has increased worldwide with encouraging results. 3, 4-6, 10, II Nevertheless, great concern has remained with regard to the long-term function of older cardiac allografts. Several reports have suggested that these organs might be more susceptible to posttransplantation CAD, partly because of a higher risk of donortransmitted coronary arteriopathy.l'' The present study reviews our clinical experience with older cardiac donors (>40 years) and analyzes short- and long-term patient survival, hemodynamic graft perfor-
Table IV. Summary of hemodynamic data Group 1 LVEF (%) 1 year 64 ± 3 years 68 ± 5 years 69 ± CI (Ljminjm 2) 3.5 ± I year 3 years 3.6 ± 5 years 3.2 ± LVEDP (mm Hg) I year II ± 3 years II ± 5 years 13 ± LV mass (gm/m/) I year 98 ± 95 ± 3 years 5 years 102 ± MjV ratio I year l.l ± 3 years 1.2 ± 5 years 1.3 ± Mean AoP I year 101 ± 101 ± 3 years 5 years 96 ±
Group 2
p Value
13 7 6
66 ± 9 66 ± 12 65 ± II
NS NS NS
0.6 0.6 0.3
3.6 ± 0.9 3.5 ± 0.7 3.5 ± 0.9
NS NS NS
5 3 7
9± 3 10 ± 4 10 ± I
<0.05
26 21 20
84 ± 14 84 ± 15 80 ± 20
<0.05
0.4 0.3 0.5
1.2 ± 0.2 l.l ± 0.2 1.2 ± 0.2
NS NS NS
13 10 13
101 ± 16 97 ± 15 96 ± 9
NS NS NS
NS NS NS NS
NS, Not significant; CI, cardiac index; LVEDP, LV end-diastolic pressure; M/V, LV mass/Lv end-diastolic volume; AoP, aortic pressure.
mance, and prevalence and clinical relevance of posttransplantation CAD, to verify whether extension of donor age limits is justified. Our results demonstrate that short- and long-term survival in this patient population are comparable with those of patients who received transplantation with younger donors. Furthermore, specific variables such as
1352
The Journal of Thoracic and Cardiovascular Surgery May 1994
Livi et al.
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Fig. 6. Actuarial freedom from significant coronary lesions (>70%). donor age, gender, dopamine support, and ischemic time had no influence on survival in group 1 patients. Thus our data differ from those of a previous multiinstitutional study that identified donor age as a risk factor for death, when this was analyzed as a continuous variable.!? most likely because of the small size of our series. On the contrary our results seem to support the results by others that have failed to recognize any influence of older donor age on survival when evaluated as either a continuous or a discrete variable.P: 18 The early mortality rates of 13%and 14% in groups 1 and 2, respectively, are higher than that reported by the International Registry for Heart and Lung Transplantation. 19 This may be partly the result of the learning curve in donor and recipient selection and of
the acceptance of some marginal donors in the face of the donor shortage. We have observed a slightly higher prevalence of fatal acute graft failure in recipients of older grafts. None of these deaths was due to acute rejection; rather, they were most likely related to poor donor condition and possible inadequate graft preservation. As previously observed by others, II early graft function assessed by means of 2D-TE was comparable with that observed in recipients of younger hearts. Interestingly enough, no differences in the postoperative course, as evaluated by the length of intensive care unit and hospital stay and of inotropic support required, were observed in the two groups. Recipients of older grafts have shown
The Journal of Thoracic' and Cardiovascular Surgery Volume 107, Number 5
a higher likelihood of major conduction disturbances without, however, an increased need for permanent pacing. Because most of these anomalies were detected in the early postoperative period they may be related to an increased susceptibility to ischemia of the conduction tissue of older hearts as already shown for the sinus node.i" Late occurrence of complete atrioventricular block in a patient of group I could either be the result of cyclosporine-induced myocardial fibrosis or be the first sign of chronic rejection, not yet detectable by coronary angiography. Long-term follow-up has shown a complete recovery in almost all patients, the vast majority being in functional class I. Evaluation of graft performance with 2D-TE showed comparable results in the two groups with a similar LVEF and a slightly increased LV mass and LV mass/Lv end-diastolic volume ratio in group I patients; such values, already found at the first posttransplantation 2D-TE, did not show any trend to progression with further follow-up, as also observed by Tischler and associates." These findings, which support the belief of a donor-transmitted cardiac morphologic condition, are in agreement with previous reports that show that LV mass increases with age 22 and are most likely of negligible clinical significance. At first 2D-TE follow-up examination, aortic cusp thickening was noted in 18% of group I patients, although it was clinically insignificant. Whether progression of valve degeneration, a normal aging process in older hearts, will be influenced by chronic immunosuppression is still unknown. Hemodynamic studies showed no significant differences between the two groups, apart from a higher LV mass, LV mass/Lv end-diastolic volume ratio, and LV end-diastolic pressure, at the first-year follow-up study; all parameters evaluated remained unchanged up to 5 years, as also previously noted.P A higher incidence of CAD after heart transplantation has been reported in older grafts," mainly consisting of focal and proximal coronary artery stenoses.i" It has been suggested that the presence of single or multiple coronary dilatations at angiography without any coronary stenosis should be regarded as a form of posttransplantation graft CAD.25 The patients we compared had a similar incidence of risk factors for CAD, onset of CAD being therefore influenced mainly by donor age. Posttransplantation CAD proved to be more prevalent in older donors only when all types of coronary lesions, both stenotic and dilated, were included. However, when only stenoses were considered, regardless of their degree or morphology, the difference between the two groups lost its significance. Furthermore, at variance with previous reports.i" no specific morphologic characteristics of CAD were found in
Livi et al.
I 353
older grafts, thus rendering questionable the real existence of two distinct CAD processes, one being typical of older donor hearts. Unlike stenotic lesions, coronary artery dilatations were usually already detected by firstyear angiography and were often isolated, suggesting that this pathologic condition is most likely transmitted to the recipient with the graft itself. However, the importance of dilated coronary artery lesions in late graft function is at present still unclear. Development of CAD has apparently not influenced graft performance up to 5 years; although group I patients with CAD and those free from this complication showed similar hemodynamic parameters at 4 years, a longer follow-up is required to assess the evolution of the disease and its potential effects on longterm graft function. In contrast to the reports of others, 19,26 CAD has been an infrequent cause of late death in both groups of our series. In fact, only one obese, insulin-dependent patient with diabetes, who received the heart of a 42-year-old donor, died of CAD IS months after heart transplantation. Postmortem histologic study revealed diffuse intimal coronary hyperplasia superimposed on preexisting atheromatous plaques. It should be emphasized that acute rejection was responsible for late death in three cases of group 2 and particularly in two patients with diabetes who arbitrarily suspended the use of oral steroids in the attempt to better control glucose metabolism. In conclusion, the present study shows that early and long-term results of heart transplantation with donors older than 40 years of age are comparable with those obtained in patients who received hearts from younger donors, with satisfactory clinical status and graft function up to 5 years after transplantation. However, in older donors a higher incidence of age-related pathologic conditions can be expected that may adversely affect surgical outcome. Therefore we currently accept donors older than 40 of age after a thorough evaluation of patient history and careful noninvasive assessment of graft function and morphologic condition: coronary angiography is considered mandatory whenever major risk factors for CAD are present and CAD is clinically suspected. Extension of age limits for cardiac donation seems justified in selected cases. In this way hearts from donors even up to 60 years of age, usually reserved for the oldest recipients, may be used, thus partially overcoming the chronic donor shortage. We wish to thank Giuseppe Fasoli, MD, and Gianfranco Buja, MD, Department of Cardiology, University of Padova Medical School, for performing the echocardiographic and electrophysiologic studiesand allowing us to use such information, and Agostino Leorin for his skilled technical assistance. This paper is dedicated to the memory of Professor Vincenzo
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Gallucci, former member of The American Association for Thoracic Surgery, unforgettable pioneer of heart transplantation in our country. REFERENCES I. Evans RW, Manninen DL, Garrison LP, Maier AM. Donor availability as the primary determinant of the future of heart transplantation. JAMA 1986;255:1892-8. 2. Mascaretti L, Pappalettera M, Pizzi C, Bossi G, Scalamogna M, Sirchia G. Four years of heart transplantation in the North Italy Transplant program (NITp). Transplant Proc 1991;23:1186-8. 3. Schueler S, Parnt H, Warnecke H, Matheis G, Hetzer R. Extended donor criteria for heart transplantation. J Heart Transplant 1988;7:326-30. 4. Menkis A, Novick RJ, Kostuk WJ, et al. Successful use of the "unacceptable" heart donor. J Heart Lung Transplant 1991;10:28-32. 5. Luciani GB, Livi U, Faggian G, Chiominto B, Bortolotti U, Mazzucco A. Heart transplantation with donors over 40. years of age. Transplant Proc 1991;23:2596-7. 6. Schueler S, Warnecke H, Loebe M, Fleck E, Hetzer R. Extended donor age in cardiac transplantation. Circulation 1989;80(Suppl):III 133-9. 7. Billingham ME. Cardiac transplant atherosclerosis. Transplant Proc 1987;19;19-25. 8. Alexander JW, Vaughn WK, Carey MA. The use of marginal donors for organ transplantation: the older and younger donors. Transplant Proc 1991;23:905-9. 9. Zerbe TR, Kormos RL, Uretsky B, Griffith BP, Hardesty RL, Duquesnoy RJ. Cardiac obliterative arteriopathy: impact of cellular rejection and donor factors [Abstract]. J Heart Lung Transplant 1992;11:193. 10. Luciani GB, Livi U, Faggian G, Mazzucco A. Clinical results of heart transplantation in recipients over 55 years of age with donors over 40 years of age. J Heart Lung Transplant 1992;11:1177-87. II. Mulvagh SL, Thornton B, Frazier OH, et al. The older cardiac transplant donor: relation to graft function and recipient survival longer than 6 years. Circulation 1989; 80(Suppl):IIII26-32. 12. O'Connell JB, Bourge RC, Costanzo-Nordin MR, et al. Cardiac transplantation: recipient selection, donor procurement, and medical follow-up-s-a statement for health professionals from the Committee on Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation 1992;86:1061-79. 13. Gao SZ, Schroeder JS, Aldermann EL, et al. Clinical and laboratory correlates of accelerated coronary artery disease in the cardiac transplant patient. Circulation I987;76(Suppl):V56-61. 14. Griepp RB, Stinson EB, Clark DA, Dong E, Shumway NE. The cardiac donor. Surg Gynecol Obstet 1971;133:792-8. 15. Bolman RM, Elick B, Olivari MT, Ring WS, Arentzen CEo Improved immunosuppression for heart transplantation. J Heart Transplant 1985;4:315-8. 16. DeBakey ME, Dietrich EB, Glick G, et al. Human cardiac
transplantation: clinical experience. J THORAC CARDIOVASC SURG 1969;58:303-9. 17. Bourge RC, Naftel DC, Costanzo-Nordin MR, Kirklin JW, Young JB, and the Transplant Cardiologists Research Database Group. Risk factors for death after cardiac transplantation: a multi-institutional study [Abstract]. J Heart Lung Transplant 1992;11:191. 18. Forester A, Abdelnoor M, Geiran D, et al. Risk factors for total and cause-specific mortality in human heart transplantation. Eur J Cardiothorac Surg 1991;5:641-7. 19. Kriett JM, Kaye MP. The registry of the International Society for Heart Transplantation: the seventh official report-1990. J Heart Transplant 1990;9:323-30. 20. Heinz G, Ohner T, Laufer G, Gossinger H, Gasic S, Laczkovics A. Demographic and perioperative factors associated with initial and prolonged sinus node dysfunction after orthotopic heart transplantation: the impact of ischemic time. Transplantation 1991;51:1217-32. 21. Tischler MD, Lee RT, Plappert T, Mudge GH, St. John Sutton M, Parker JD. Serial assessment of left ventricular function and mass after orthotopic heart transplantation: a 4-year longitudinal study. J Am Coil Cardiol 1992;19: 60-6. 22. Dannenberg AL, Levy D, Garrison RJ. Impact of age on echocardiographic left ventricular mass in healthy population (the Framingham study). Am J Cardiol 1989;64: 1066-8. 23. Frist WM, Stinson EB, Oyer PE, Baldwin JC, Shumway NE. Long-term hemodynamic results after cardiac transplantation. J THORAC CARDIOVASC SURG 1987;94:68593. 24. Schueler S, Matschke K, Loebe M, Hummel M, Fleck E, Hetzer R. Coronary artery disease in patients with hearts from older donors: morphologic features and therapeutic implications. J Heart Lung Transplant 1993;12:100-9. 25. Von Scheidt W, Erdmann E. Dilated angiopathy: a specific subtype of allograft coronary artery disease. J Heart Lung Transplant 1991;10:698-703. 26. Bieber CP, Hunt SA, Schwinn DA, et al. Complications in long-term survivors of cardiac transplantation. Transplant Proc 1981;13:207-1 I.
Discussion Dr. Christian Cabral (Paris, France). Heart transplantation was started in Europe 25 years ago on April 27, 1968, when we performed in La Pitie the first heart transplant in Europe and the seventh in the world. Since that time our group has performed a little more than 1000 heart transplantations. Our first recipient was 66 years old; now we have recipients up to 70 years old in some cases, so we are accepting donors up to 55 or even 60 years old. And we have the same results as with younger donors if we select very carefully those old donor hearts, especially with hemodynamic and echocardiographic studies. My question is this: in view of the higher rate of coronary artery disease you reported in such patients, do you perform coronary arteriography on the donor heart to be sure that the donor heart has no coronary lesions before transplantation?
The Journal of Thoracic and Cardiovascular Surgery Volume 107, Number 5
Dr. Henry J. Sullivan (Maywood, Ill.;. I have three short questions. First, I noted in both group I and group 2 that about eight or nine donors in each group had an abnormal result on echocardiogram. In these donors did you proceed to a cardiac catheterization? Second, do you routinely do cardiac catheterization in your patients before they are discharged from the hospital and at l-year intervals? Third, in this group of patients with abnormal coronary arteriograrns are you seeing discrete arterial sclerosis or allograft arteriopathy? Dr.Livi. Our current policy concerning patient selection is to reserve older donors for older recipients or for urgent and emergency situations. Of course, if the longer follow-up will demonstrate that grafts from older donors have comparable function at late follow-up, we can change this policy. In Italy we have a big problem with donor shortage. Therefore we try to reserve the scarce donors for first transplantation and not for retransplantation; thus retransplantation in our series is quite unusual.
Livi et al.
13 5 5
Dr. Hetzer described an experience with focal or diffuse coronary atherosclerosis that is quite different from ours. This kind of discrepancy may be because his group of patients included more donors older than 50 years of age, and I think in his recipients you have more focal stenoses and other kinds of coronary lesions that may be donor transmitted. Professor Cabrol, all of us are indebted to you for your contributions to cardiac transplantation in the past 25 years. In reply to your question, we do not routinely do coronary angiography in older donors unless there are clear signs of coronary atherosclerosis or in the presence of risk factors for coronary atherosclerosis. Regarding the questions from Dr. Sullivan, we always require an echocardiographic study of the donor heart with a careful assessment of LV function. The presence of hypertrophy and of areas oflocalized hypokinesis is evaluated on an individual basis. We do not usually perform any coronary angiography before discharging the patients from the hospital, but we are planning to do it in the future. We are currently starting a new protocol that includes routine angiography before discharge.
Ugolino Livi, MD (by invitation), Uberto Bortolotti, MD (by invitation), Giovanni B. Luciani, MD (by invitation), Giovanni M. Boffa, MD (by invitation)," Aldo Milano, MD (by invitation), Gaetano Thiene, MD (by invitation)," and Dino Casarotto, MD (by invitation), Padova, Italy Sponsored by Norman E. Shumway, MD, Stanford. Calif.
From the Department of Cardiovascular Surgery, Cardiology," and Pathology," University of Padova Medical School, Padova, Italy. Supported by the National Council for Research, Target Project "BTBS," Milan, and "FAT.MA," Rome, Italy. Read at the Seventy-third Annual Meeting of The American Association for Thoracic Surgery, Chicago, Ill., April 25-28, 1993. Address for reprints: U. Livi, MD, Istituto di Chirurgia Cardiovascolare, Centro di Cardiochirurgia V. Gallucci, Universita di Padova, Via Giustiniani, 2, 35128 Padova, Italy. Copyright
1994 by Mosby-Year Book, Inc.
0022-5223/94 $3.00
1346
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h e steady increase of potential heart transplant recipients, because of the improved clinical results after transplantation, has made donor availability the true limiting factor to this procedure. 1 Data from the North Italy Transplant Program registry have demonstrated that organ availability satisfies less than 50% of requirement and that more than 25% of patients currently die before heart transplantation.i In an attempt to meet a continuously increasing demand for organs, in recent years several institutions worldwide have extended the standard criteria for donor graft acceptability.v 4 Indeed, the pre-
The Journal of Thoracic and Cardiovascular Surgery Volume 107, Number 5
Livi et al.
Table I. Characteristics of recipients Group 1 In = 45)
Age (yr) Mean Range Sex Male Female Diagnosis DeM IHD Other Transpulmonary gradient >15mmHg PVR (Wood units/rn-) >6 Reoperation Inotropic drugs/IABP Diabetes Peripheral vasculopathy Procedure Orthotopic HTx Heterotopic HTx
134 7
Table II. Characteristics of donors
Group 2 In = 72)
p Value
54 ± 6 38-63
55 ± 3 50-68
NS
37 (82*) 8 (18)
63 (87*) 9 (13)
NS
17 (38) 22 (49) 6 (13) 5 (11)
32 (44) 33 (46) 7 (10) 7 (10)
NS
NS
8 (18)
12 (17)
NS
10 (22) 4 (9) 5 (I I) 3 (6)
14 (20) II (15) 10 (14) 5 (7)
NS NS NS NS
43 (96) 2 (4)
68 (95) 4(5)
NS
NS, Not significant; DeM, dilatedcardiomyopathy; I HD, ischemic heart disease;
PVR, pulmonaryvascularresistance; IABP, intraaorticballoon pump;HTx, heart transplantation. 'Numbers in parentheses are percent of patients.
liminary results of heart transplantation with older donors have been so far encouraging.v 6 However, some concern still remains regarding the impact of an alleged higher incidence of acute graft failure and coronary artery disease (CAD) on survival and functional outcome in this patient population." Although multicenter studies have demonstrated the adverse effect of older donor age on survivaf and late graft function," reports from single institutions have often contradicted these findingsP- 10, 11 To assess whether an extension of donor age limits may still be justified, we compared the results of heart transplantation with donors more than 40 years of age with those obtained with younger donors. In the present study the effect of an older cardiac allograft was analyzed with respect to short- and long-term survival, hemodynamic performance, and prevalence and clinical relevance of posttransplantation CAD.
Patients and methods Recipient data. To verify the effect of older donor age on early and late outcome after heart transplantation, wecompared two groups of consecutivepatients from our entire series of 227 patients who had heart transplantation at our institution between November 1985 and December 1992. These two groups had similar characteristics as shown in Table I; particularly, they were comparable in terms of mean age and gender, indication for transplantation, and preoperative status, includ-
Age (yr) Mean Range Sex Male Female Cause of death Vascular Traumatic Other Mean duration of ventilation (days) Mean dopamine dose (ltg/kg/min) 2D-TE abnormalities Coronary angiography
Group 1
Group 2
In = 45)
In = 72)
p Value
46 ± 4 41-59
23 ± 7 8-39
<0.001
26 (58*) 19 (42)
53 (74*) 19 (26)
NS
27 (60)
12 (16) 58 (80) 3 (4) 2.8 ± 2.0
0.001
16 (36) 2 (4) 2.6 ± 1.8 4.7 ± 2.6
5.0 ± 4.0
NS
8 (17) 7 (15)
8 (11) 6 (8)
NS NS
NS
NS, Not significant.
'Numbers in parenthesesare percent of patients.
ing pulmonary vascular resistances and transpulmonary gradient. Group I included 45 patients (19% of entire series), 37 men and 8 women, with a mean age of 54 ± 6 years (range 38 to 63 years) who received hearts from donors older than 40 years of age, which is suggested by the American Heart Association as the limit for cardiac donationl-; orthotopic heart transplantation was done in 43 (96%) patients and 2 (4%) had heterotopic transplantation. Group 2 included 72 patients (32% of entire series), 63 men and 9 women, older than 50 years of age (mean age 55 ± 3, range 50 to 68 years), who received hearts from donors younger than 40 years of age and who were consecutively operated on for heart transplantation during the same period as group I patients; 68 (95%) had orthotopic and 4 (5%) heterotopic heart transplantation. Considering that in our program grafts from older donors have been preferentially assigned to older recipients (80% of group I patients being more than 50 years of age), in group 2 only recipients more than 50 years old were included to neutralize the potential adverse effect of advanced age on survival and to have two groups of patients matched for age and age-related clinical characteristics. Donor selection and characteristics. All donors were matched for ABO blood compatibility, and a maximum weight mismatch of 400/0 was accepted in recipients with normal pulmonary vascular resistance. Donor assessment was based on a complete clinical and laboratory evaluation, including twodimensional transthoracic echocardiography (2D-TE). Coronary angiography was not routinely done except in cases of clinicallysuspected CAD or, wheneveravailable, in the presence of clear risk factors for CAD, regardless of donor age. Extreme importance has been attributed to direct visualization of the heart and to coronary artery palpation; when this maneuver revealed gross coronary artery calcification the graft was considered unsuitable as occurred in about 20% of older potential donors evaluated by us. The main donor characteristics for both groups are summarized in Table II. Group I donors had a mean age of 46 ± 4 years (range 41 to 59 years), 58% being male, whereas group 2
I 348
The Journal of Thoracic and Cardiovascular Surgery May 1994
Livi et al.
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Fig. 1. Actuarial survival curve of patients who received hearts from donors older than 40 years of age (filled circles) plotted against survival curve of patients who received hearts from donors younger than 40 years of age (open circles). Numbers on x axis indicate patients at risk. donors were younger (mean age 23 ± 7 years, range 8 to 39 years) and predominantly male (74%). Besides age, donors of the two groups differed in the cause of death, with cerebrovascular accidents and head trauma being the most common causes in groups I and 2, respectively (p = 0.001). Abnormal2D-TE findings, represented by marked left ventricular (LV) hypertrophy and localized wall motion abnormalities, were detected in eight donors (17%) of group I and in eight (II %) of group 2 (p = NS*). Coronary angiography was done in seven donors (15%) of group I and in six (8%) of group 2 and showed normal results in all. Graft preservation was obtained by administration of a single dose of cold crystalloid cardioplegic solution (St. Thomas' Hospital No.2) during harvesting and by storage in cold saline until the time of implantation. The mean ischemic time was 144 ± 47 minutes (range 53 to 255 minutes) in group I and 140 ± 48 minutes (range 47 to 245) in group 2 (p = NS). Posttransplantation management. Immunosuppression consisted of cyclosporine and azathioprine with no routine administration of oral steroids. Cyclosporine dose was adjusted to maintain a whole trough blood level of 150 to 300 ng/rnl assessed by radioimmunoassay and based on the patient's renal function. Azathioprine dose was adjusted to maintain a total white blood cell count of at least 4000 cells/mm'. Most patients received anti thymocyte globulins for 3 to 5 days as early prophylaxis of rejection. Acute graft rejection, diagnosed by endomyocardial biopsy, was treated with pulse doses of methylprednisolone, and low-dose prednisone (5 to 10 mg/day) was added in cases of persistent or recurrent rejection. Infectious episodes were defined as clinically apparent infections that necessitated in-hospital treatment and were documented by cultures or serologic tests. In patients without symptoms, cytomegalovirus infection was considered in the presence of a fourfold increase in the immunoglobulin G titer or whenever cytomegalovirus was cultured from blood, urine, or sputum. Graft function and patient follow-up. Early posttransplan*NS
= Not significant.
tation graft performance was indirectly evaluated by comparing the mean duration of assisted ventilation, length of intensivecare unit and hospital stay, and amount and duration of inotropic support and directly by comparing the LV ejection fraction (EF) by 2D-TE at I and 4 weeks after heart transplantation. After discharge from the hospital all patients returned to our department for periodic follow-up visits. To evaluate the impact of donor age on prevalence of CAD in the recipient, we collected data on major risk factors for CAD,13 such as hypertension, diabetes, dyslipidemia, number of rejection and infection episodes, and need for steroid immunosuppression, on a yearly basis and compared them between the two groups. Late graft performance was assessed by means of 2D-TE approximately every 3 months unless otherwise required and by complete hemodynamic studies at yearly intervals. Graft CAD was diagnosed, in the presence of any focal or diffuse coronary stenosis of any degree or any vessel dilatation, by careful review of multiple angiograms by two independent observers. Presence of major conduction disturbances, defined as bifascicular (right bundle branch block with abnormal left axis deviation) or complete atrioventricular block, was ascertained by means of daily standard resting electrocardiograms and after discharge at each follow-up visit; diagnosis was confirmed in selected patients by 24-hour electrocardiographic recording and invasive electrophysiologic studies, and permanent pacemaker implantation was done when indicated. Statistical analysis. The SAS program (Statistical Analysis System, SAS Institute Inc., Cary, N .Ci) was used for statistical analysis. The influence on early deaths caused by graft failure or all causes was investigated by means of univariate analysis of the following variables: age, sex, cause of death, and inotropic support for the donor; age, sex, indication for heart transplantation, previous cardiac operation, pretransplantation status, diabetes, pulmonary vascular resistance, and transpulmonary pressure gradient for the recipient; and, additionally, ischemic time. Continuous data are expressed as the mean plus or minus standard deviation of the mean and evaluated for differences between groups with a two-tailed t test or analysis of
The Journal of Thoracic and Cardiovascular Surgery Volume 107, Number 5
Livi et al.
I 34 9
Table III. Early graft f unction Group I Hours supported by ventilator Mean 32 ± 24 Range 8- 120 le u stay (day s) Mean 8 ± 4 Range 2-2 1 Hospital stay (days) Mean 29 ± 11 Range 2-60 Catech olamin es Mean No. used 2.5 ± 0.5 Days (mean) 4.9 ± 2.5 Days (range) 1-13 Dopamine (rug /kg) Mean dose 26 ± 12 Epinephrine (mgjkg) Mean dose 0.2 ± 0.1
Group 2
p Value
25 ± 32 6-236
NS
7 ± 3 2·2 1
NS
27 ± 10 4-63
NS
2.2 ± 0.5 4.8 ± 2.8 1-21
NS NS
27 ± 16
NS
0.2 ± 0.2
NS
NS. Not significant; l CU, intensive care unit.
variance. Discrete data were anal yzed for differences between groups with the x 2 test and two-tailed Fisher's exact test when appropriate. Life-table actuarial curves for survival and freedom from CAD were constructed and differences between groups assessed with the generalized Wilcoxon test. Significance was assumed when the p value was less than 0.05.
Results Ea rly and late survival. Overall actu arial survival was 83% ± 6% versus 82% ± 5% at I year and 80% ± 6% versus 80% ± 6% at 5 years in group I and group 2, respectively (p = NS; Fig. I), with a comparable mean follow-up (29 ± 20 months versus 30 ± 20 months, p = NS) and a maximum follow-up of 78 months in group I and 80 months in group 2. There were six (13%) early «30 days) deaths in group I; four patients died of acute graft failure, one of undiagnosed preoperative aortic dissection, and one of acute encephalitis. There were 10 (14%) early deaths in group 2 as a result of acute graft failure in four, poor recipient condition in three, and acute pancreatitis, intraoperative hemorrhage, and infection in one each. In all cases graft failure became evident during the first posttransplantation hours and was unresponsive to any pharmacologic and mechanical support and led to death after a mean interval of 9 ± 5 days. Necropsy showedabsence of acute rejection in all eight patients who died of acute graft failure and relevant gross pathologic findingsonly in two of group I patients , which consisted of right ventricular wall lipomatosis in one and severe CAD in another and signs of subendocardial necrosis at histologic study in three . Fatal acute graft failure was more common in group I than in group 2 (9% versus 5.5%), although the difference was not statistically significant
Fig. 2. Chronic rejection with obstructive CAD. Intimal proliferation superimposed on atherosclerotic plaque , most probably present in donor heart at time of transplantation . (WeigertVan Gieson stain, original magnification X 18.)
(p = NS). Univariate analysis of preoperative variables, particularly donor age, failed to show any significant incremental risk factor for early death as a result of graft failure or any other cause. The prevalence of late deaths was also comparable in the two groups, being 5% (two patients) in group I and 6% (4 patients) in group 2 (p = NS). In group I, one patient died of traumatic rupture of the spleen 2 months after heart transplantation and one with insulin-dependent diabetes died of CAD after 15 month s (Fig . 2). In group 2 acute rejection was responsible for three late deaths at 2, 24, and 66 months after transplantation, and one patient died of pulmonary infection 2 months after emergency heart transplantation. Specific donor variables, such as age «49 or > 49 years), sex, dopamine dose «5 or > 5 JLg/kg per minute), and total ischemic time (< 180 or> 180 minutes) , did not influence 5-year survival in group 1 patients. Early graft function. Comparison of duration of mechanical ventilation, length of intensive care unit and hospital sta y, duration and type of inotropic support, and number and total dose of catecholamines required showed no statistical difference between the two groups, as shown in Table III. In group I mean LVEF by 2D-TE was 64% ± 7% (range 50% to 74%) and 66% ± 5% (range 53% to 76%) at I and 4 weeks, respectively, not significantly different from that observed in group 2 at the same intervals (65% ± 6%; range 51% to 79%, and 67% ± 6%; range 54% to 79%; p = NS). Posttransplantation complications. The incidence of acute rejection and infection was comparable in the two
I 350
The Journal of Thoracic and Cardiovascular Surgery May 1994
Livi et al.
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groups, being 1.6 episodes per patient and 0.4 episodes per patient in group I and 1.8 episodes per patient and 0.3 episodes per patient in group 2, respectively (p = NS). The percentages of patients who had asymptomatic and symptomatic cytomegalovirus infections were also similar: 69% and 22% in group 1 and 77% and 14% in group 2 (p = NS). No difference was also noted in the prevalence ofhypertension (45% in group 1versus 47% in group 2), of diabetes necessitating oral hypoglycemic drugs or insulin (10% versus 11%), or of hyperlipidemia necessitating treatment (23% versus 24%; p = NS). Major conduction disturbances, diagnosed in 14 patients (37%) of group 1 and in 8 (12%) of group 2 (p < 0.05), consisted of bifascicular block in 16 (10 in group I and 6 in group 2) and complete atrioventricular block in 6 (4 in group 1 and 2 in group 2). Permanent pacemaker implantation was necessary in four patients of group 1 (10%), because of early complete atrioventricular block in three and late (after 7 months) paroxysmal complete atrioventricular block in one, and in four (6%) of group 2 (p = NS), because of early complete atrioventricular block in two and bifascicular block with infraHisian block in two (Fig. 3). Late follow-up and graft function. Assessment of clinical status at follow-up showed that 92% of group 1 and 93% of group 2 patients were in New York Heart Association class 1. Most recent 2D-TE examination showed a comparable LVEF in the two groups (63% ± 8% versus 66% ± 7%,p = NS), whereas group I patients had a higher LV mass/Lv end-diastolic volume ratio (1.2 ± 0.3 versus 1.1 ± 0.4) and LV mass (74 ± 14 gm/rrr' versus 64 ± 15 gm/rn-), although the
difference was not statistically significant (p = NS). In 18% of group 1 patients and in none of group 2, 2D-TE showed evidence of fibrotic thickening of the aortic valve cusps, with small nodular calcification in the oldest (59 years) donor accepted, causing trivial to mild aortic regurgitation in 70% of cases; these changes, already noted at the first posttransplantation 2D-TE, did not show any progression at subsequent follow-up investigations. Complete hemodynamic studies were done in 29 patients of group 1 and 47 of group 2 at 1 year, in 21 and 33 at 2 years, in 17 and 24 at 3 years, in 10 and 16 at 4 years, and in 6 and 10 at 5 years, respectively. Thus a total of 83 and 130 coronary angiographic studies were available in groups 1 and 2, respectively. Comparison of hemodynamic data in the two groups in the posttransplantation period is shown in Table IV. The only significant difference was found in a higher LV end-diastolic pressure and a higher LV mass at the first year after heart transplantation in group 1 with comparable values of mean arterial aortic pressure. Review of coronary angiograms showed that coronary abnormalities of any type were present in 10 patients of group 1 and in 7 of group 2. In particular, coronary artery dilatation was found only in group 1patients (5 cases) and was already present at the first angiographic follow-up examination and was not associated with obstructing lesions in three patients. Actuarial freedom from all types of coronary abnormalities was 49% ± 13% in group I and 77% ± 8% in group 2 (p < 0.05; Fig. 4). However, when only coronary stenoses of any degree were considered the difference was not significant (60% ± 14% in group 1 and 77% ± 8% in group 2; Fig. 5) . No difference
The Journal of Thoracic and Cardiovascular Surgery Volume 107, Number 5
Livi et al.
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was also found either in freedom from significant (>70% obstruction) coronary lesions (Fig. 6) or in morphologic features (focal versus diffuse) and distribution of CAD or progression of CAD at subsequent follow-up studies in the two groups. Moreover, comparison of the hemodynamic data of patients of group I in whom CAD developed and of those who did not have CAD at 4 years showed comparable results: mean LVEF of 67% ± II % versus 68% ± 12%,meancardiacindexof3.2 ± 0.7 Ljminjm 2 versus 3.4 ± 0.7 Ljminjm 2, and mean LV end-diastolic pressure of 14 ± 5 mm Hg versus 13 ± 2 mm Hg (p = NS).
Discussion Strict recipient and donor selection criteria have been followed to minimize mortality and morbidity after heart transplantation. 14 The significant improvement in survival and the decrease in the prevalence of major complications with the use of cyclosporine'" has allowed extension of heart transplantation to patients who do not fit the original selection criteria. To face a continuous need for heart transplantation, acceptance of donors who do not fit the original selection criteria, particularly in terms of age, has increased worldwide with encouraging results. 3, 4-6, 10, II Nevertheless, great concern has remained with regard to the long-term function of older cardiac allografts. Several reports have suggested that these organs might be more susceptible to posttransplantation CAD, partly because of a higher risk of donortransmitted coronary arteriopathy.l'' The present study reviews our clinical experience with older cardiac donors (>40 years) and analyzes short- and long-term patient survival, hemodynamic graft perfor-
Table IV. Summary of hemodynamic data Group 1 LVEF (%) 1 year 64 ± 3 years 68 ± 5 years 69 ± CI (Ljminjm 2) 3.5 ± I year 3 years 3.6 ± 5 years 3.2 ± LVEDP (mm Hg) I year II ± 3 years II ± 5 years 13 ± LV mass (gm/m/) I year 98 ± 95 ± 3 years 5 years 102 ± MjV ratio I year l.l ± 3 years 1.2 ± 5 years 1.3 ± Mean AoP I year 101 ± 101 ± 3 years 5 years 96 ±
Group 2
p Value
13 7 6
66 ± 9 66 ± 12 65 ± II
NS NS NS
0.6 0.6 0.3
3.6 ± 0.9 3.5 ± 0.7 3.5 ± 0.9
NS NS NS
5 3 7
9± 3 10 ± 4 10 ± I
<0.05
26 21 20
84 ± 14 84 ± 15 80 ± 20
<0.05
0.4 0.3 0.5
1.2 ± 0.2 l.l ± 0.2 1.2 ± 0.2
NS NS NS
13 10 13
101 ± 16 97 ± 15 96 ± 9
NS NS NS
NS NS NS NS
NS, Not significant; CI, cardiac index; LVEDP, LV end-diastolic pressure; M/V, LV mass/Lv end-diastolic volume; AoP, aortic pressure.
mance, and prevalence and clinical relevance of posttransplantation CAD, to verify whether extension of donor age limits is justified. Our results demonstrate that short- and long-term survival in this patient population are comparable with those of patients who received transplantation with younger donors. Furthermore, specific variables such as
1352
The Journal of Thoracic and Cardiovascular Surgery May 1994
Livi et al.
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0
2
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Fig. 6. Actuarial freedom from significant coronary lesions (>70%). donor age, gender, dopamine support, and ischemic time had no influence on survival in group 1 patients. Thus our data differ from those of a previous multiinstitutional study that identified donor age as a risk factor for death, when this was analyzed as a continuous variable.!? most likely because of the small size of our series. On the contrary our results seem to support the results by others that have failed to recognize any influence of older donor age on survival when evaluated as either a continuous or a discrete variable.P: 18 The early mortality rates of 13%and 14% in groups 1 and 2, respectively, are higher than that reported by the International Registry for Heart and Lung Transplantation. 19 This may be partly the result of the learning curve in donor and recipient selection and of
the acceptance of some marginal donors in the face of the donor shortage. We have observed a slightly higher prevalence of fatal acute graft failure in recipients of older grafts. None of these deaths was due to acute rejection; rather, they were most likely related to poor donor condition and possible inadequate graft preservation. As previously observed by others, II early graft function assessed by means of 2D-TE was comparable with that observed in recipients of younger hearts. Interestingly enough, no differences in the postoperative course, as evaluated by the length of intensive care unit and hospital stay and of inotropic support required, were observed in the two groups. Recipients of older grafts have shown
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a higher likelihood of major conduction disturbances without, however, an increased need for permanent pacing. Because most of these anomalies were detected in the early postoperative period they may be related to an increased susceptibility to ischemia of the conduction tissue of older hearts as already shown for the sinus node.i" Late occurrence of complete atrioventricular block in a patient of group I could either be the result of cyclosporine-induced myocardial fibrosis or be the first sign of chronic rejection, not yet detectable by coronary angiography. Long-term follow-up has shown a complete recovery in almost all patients, the vast majority being in functional class I. Evaluation of graft performance with 2D-TE showed comparable results in the two groups with a similar LVEF and a slightly increased LV mass and LV mass/Lv end-diastolic volume ratio in group I patients; such values, already found at the first posttransplantation 2D-TE, did not show any trend to progression with further follow-up, as also observed by Tischler and associates." These findings, which support the belief of a donor-transmitted cardiac morphologic condition, are in agreement with previous reports that show that LV mass increases with age 22 and are most likely of negligible clinical significance. At first 2D-TE follow-up examination, aortic cusp thickening was noted in 18% of group I patients, although it was clinically insignificant. Whether progression of valve degeneration, a normal aging process in older hearts, will be influenced by chronic immunosuppression is still unknown. Hemodynamic studies showed no significant differences between the two groups, apart from a higher LV mass, LV mass/Lv end-diastolic volume ratio, and LV end-diastolic pressure, at the first-year follow-up study; all parameters evaluated remained unchanged up to 5 years, as also previously noted.P A higher incidence of CAD after heart transplantation has been reported in older grafts," mainly consisting of focal and proximal coronary artery stenoses.i" It has been suggested that the presence of single or multiple coronary dilatations at angiography without any coronary stenosis should be regarded as a form of posttransplantation graft CAD.25 The patients we compared had a similar incidence of risk factors for CAD, onset of CAD being therefore influenced mainly by donor age. Posttransplantation CAD proved to be more prevalent in older donors only when all types of coronary lesions, both stenotic and dilated, were included. However, when only stenoses were considered, regardless of their degree or morphology, the difference between the two groups lost its significance. Furthermore, at variance with previous reports.i" no specific morphologic characteristics of CAD were found in
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older grafts, thus rendering questionable the real existence of two distinct CAD processes, one being typical of older donor hearts. Unlike stenotic lesions, coronary artery dilatations were usually already detected by firstyear angiography and were often isolated, suggesting that this pathologic condition is most likely transmitted to the recipient with the graft itself. However, the importance of dilated coronary artery lesions in late graft function is at present still unclear. Development of CAD has apparently not influenced graft performance up to 5 years; although group I patients with CAD and those free from this complication showed similar hemodynamic parameters at 4 years, a longer follow-up is required to assess the evolution of the disease and its potential effects on longterm graft function. In contrast to the reports of others, 19,26 CAD has been an infrequent cause of late death in both groups of our series. In fact, only one obese, insulin-dependent patient with diabetes, who received the heart of a 42-year-old donor, died of CAD IS months after heart transplantation. Postmortem histologic study revealed diffuse intimal coronary hyperplasia superimposed on preexisting atheromatous plaques. It should be emphasized that acute rejection was responsible for late death in three cases of group 2 and particularly in two patients with diabetes who arbitrarily suspended the use of oral steroids in the attempt to better control glucose metabolism. In conclusion, the present study shows that early and long-term results of heart transplantation with donors older than 40 years of age are comparable with those obtained in patients who received hearts from younger donors, with satisfactory clinical status and graft function up to 5 years after transplantation. However, in older donors a higher incidence of age-related pathologic conditions can be expected that may adversely affect surgical outcome. Therefore we currently accept donors older than 40 of age after a thorough evaluation of patient history and careful noninvasive assessment of graft function and morphologic condition: coronary angiography is considered mandatory whenever major risk factors for CAD are present and CAD is clinically suspected. Extension of age limits for cardiac donation seems justified in selected cases. In this way hearts from donors even up to 60 years of age, usually reserved for the oldest recipients, may be used, thus partially overcoming the chronic donor shortage. We wish to thank Giuseppe Fasoli, MD, and Gianfranco Buja, MD, Department of Cardiology, University of Padova Medical School, for performing the echocardiographic and electrophysiologic studiesand allowing us to use such information, and Agostino Leorin for his skilled technical assistance. This paper is dedicated to the memory of Professor Vincenzo
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Gallucci, former member of The American Association for Thoracic Surgery, unforgettable pioneer of heart transplantation in our country. REFERENCES I. Evans RW, Manninen DL, Garrison LP, Maier AM. Donor availability as the primary determinant of the future of heart transplantation. JAMA 1986;255:1892-8. 2. Mascaretti L, Pappalettera M, Pizzi C, Bossi G, Scalamogna M, Sirchia G. Four years of heart transplantation in the North Italy Transplant program (NITp). Transplant Proc 1991;23:1186-8. 3. Schueler S, Parnt H, Warnecke H, Matheis G, Hetzer R. Extended donor criteria for heart transplantation. J Heart Transplant 1988;7:326-30. 4. Menkis A, Novick RJ, Kostuk WJ, et al. Successful use of the "unacceptable" heart donor. J Heart Lung Transplant 1991;10:28-32. 5. Luciani GB, Livi U, Faggian G, Chiominto B, Bortolotti U, Mazzucco A. Heart transplantation with donors over 40. years of age. Transplant Proc 1991;23:2596-7. 6. Schueler S, Warnecke H, Loebe M, Fleck E, Hetzer R. Extended donor age in cardiac transplantation. Circulation 1989;80(Suppl):III 133-9. 7. Billingham ME. Cardiac transplant atherosclerosis. Transplant Proc 1987;19;19-25. 8. Alexander JW, Vaughn WK, Carey MA. The use of marginal donors for organ transplantation: the older and younger donors. Transplant Proc 1991;23:905-9. 9. Zerbe TR, Kormos RL, Uretsky B, Griffith BP, Hardesty RL, Duquesnoy RJ. Cardiac obliterative arteriopathy: impact of cellular rejection and donor factors [Abstract]. J Heart Lung Transplant 1992;11:193. 10. Luciani GB, Livi U, Faggian G, Mazzucco A. Clinical results of heart transplantation in recipients over 55 years of age with donors over 40 years of age. J Heart Lung Transplant 1992;11:1177-87. II. Mulvagh SL, Thornton B, Frazier OH, et al. The older cardiac transplant donor: relation to graft function and recipient survival longer than 6 years. Circulation 1989; 80(Suppl):IIII26-32. 12. O'Connell JB, Bourge RC, Costanzo-Nordin MR, et al. Cardiac transplantation: recipient selection, donor procurement, and medical follow-up-s-a statement for health professionals from the Committee on Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation 1992;86:1061-79. 13. Gao SZ, Schroeder JS, Aldermann EL, et al. Clinical and laboratory correlates of accelerated coronary artery disease in the cardiac transplant patient. Circulation I987;76(Suppl):V56-61. 14. Griepp RB, Stinson EB, Clark DA, Dong E, Shumway NE. The cardiac donor. Surg Gynecol Obstet 1971;133:792-8. 15. Bolman RM, Elick B, Olivari MT, Ring WS, Arentzen CEo Improved immunosuppression for heart transplantation. J Heart Transplant 1985;4:315-8. 16. DeBakey ME, Dietrich EB, Glick G, et al. Human cardiac
transplantation: clinical experience. J THORAC CARDIOVASC SURG 1969;58:303-9. 17. Bourge RC, Naftel DC, Costanzo-Nordin MR, Kirklin JW, Young JB, and the Transplant Cardiologists Research Database Group. Risk factors for death after cardiac transplantation: a multi-institutional study [Abstract]. J Heart Lung Transplant 1992;11:191. 18. Forester A, Abdelnoor M, Geiran D, et al. Risk factors for total and cause-specific mortality in human heart transplantation. Eur J Cardiothorac Surg 1991;5:641-7. 19. Kriett JM, Kaye MP. The registry of the International Society for Heart Transplantation: the seventh official report-1990. J Heart Transplant 1990;9:323-30. 20. Heinz G, Ohner T, Laufer G, Gossinger H, Gasic S, Laczkovics A. Demographic and perioperative factors associated with initial and prolonged sinus node dysfunction after orthotopic heart transplantation: the impact of ischemic time. Transplantation 1991;51:1217-32. 21. Tischler MD, Lee RT, Plappert T, Mudge GH, St. John Sutton M, Parker JD. Serial assessment of left ventricular function and mass after orthotopic heart transplantation: a 4-year longitudinal study. J Am Coil Cardiol 1992;19: 60-6. 22. Dannenberg AL, Levy D, Garrison RJ. Impact of age on echocardiographic left ventricular mass in healthy population (the Framingham study). Am J Cardiol 1989;64: 1066-8. 23. Frist WM, Stinson EB, Oyer PE, Baldwin JC, Shumway NE. Long-term hemodynamic results after cardiac transplantation. J THORAC CARDIOVASC SURG 1987;94:68593. 24. Schueler S, Matschke K, Loebe M, Hummel M, Fleck E, Hetzer R. Coronary artery disease in patients with hearts from older donors: morphologic features and therapeutic implications. J Heart Lung Transplant 1993;12:100-9. 25. Von Scheidt W, Erdmann E. Dilated angiopathy: a specific subtype of allograft coronary artery disease. J Heart Lung Transplant 1991;10:698-703. 26. Bieber CP, Hunt SA, Schwinn DA, et al. Complications in long-term survivors of cardiac transplantation. Transplant Proc 1981;13:207-1 I.
Discussion Dr. Christian Cabral (Paris, France). Heart transplantation was started in Europe 25 years ago on April 27, 1968, when we performed in La Pitie the first heart transplant in Europe and the seventh in the world. Since that time our group has performed a little more than 1000 heart transplantations. Our first recipient was 66 years old; now we have recipients up to 70 years old in some cases, so we are accepting donors up to 55 or even 60 years old. And we have the same results as with younger donors if we select very carefully those old donor hearts, especially with hemodynamic and echocardiographic studies. My question is this: in view of the higher rate of coronary artery disease you reported in such patients, do you perform coronary arteriography on the donor heart to be sure that the donor heart has no coronary lesions before transplantation?
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Dr. Henry J. Sullivan (Maywood, Ill.;. I have three short questions. First, I noted in both group I and group 2 that about eight or nine donors in each group had an abnormal result on echocardiogram. In these donors did you proceed to a cardiac catheterization? Second, do you routinely do cardiac catheterization in your patients before they are discharged from the hospital and at l-year intervals? Third, in this group of patients with abnormal coronary arteriograrns are you seeing discrete arterial sclerosis or allograft arteriopathy? Dr.Livi. Our current policy concerning patient selection is to reserve older donors for older recipients or for urgent and emergency situations. Of course, if the longer follow-up will demonstrate that grafts from older donors have comparable function at late follow-up, we can change this policy. In Italy we have a big problem with donor shortage. Therefore we try to reserve the scarce donors for first transplantation and not for retransplantation; thus retransplantation in our series is quite unusual.
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Dr. Hetzer described an experience with focal or diffuse coronary atherosclerosis that is quite different from ours. This kind of discrepancy may be because his group of patients included more donors older than 50 years of age, and I think in his recipients you have more focal stenoses and other kinds of coronary lesions that may be donor transmitted. Professor Cabrol, all of us are indebted to you for your contributions to cardiac transplantation in the past 25 years. In reply to your question, we do not routinely do coronary angiography in older donors unless there are clear signs of coronary atherosclerosis or in the presence of risk factors for coronary atherosclerosis. Regarding the questions from Dr. Sullivan, we always require an echocardiographic study of the donor heart with a careful assessment of LV function. The presence of hypertrophy and of areas oflocalized hypokinesis is evaluated on an individual basis. We do not usually perform any coronary angiography before discharging the patients from the hospital, but we are planning to do it in the future. We are currently starting a new protocol that includes routine angiography before discharge.