Results With Expanded Donor Acceptance Criteria in Heart Transplantation

Results With Expanded Donor Acceptance Criteria in Heart Transplantation A. Forni, G.B. Luciani, B. Chiominto, M. Pizzuti, A. Mazzucco, and G. Faggian ABSTRACT Objective. Over the past years both donor and recipient profiles have changed in heart transplantation. Satisfactory clinical outcomes of marginal donors in candidates ⬎60 years of age have led us to allocate suboptimal donors to younger recipients as well. Therefore, we retrospectively reviewed our experience. Methods. Among 199 patients undergoing heart transplantation from January 2000 to February 2010, there were 83 (41%) aged 61–72 years. The other 116 (59%) ranged in age between 18 and 60 years. According to their clinical conditions as heart transplantation candidates, They were classified into 4 groups: younger recipients (n ⫽ 116) of either optimal donors (n ⫽ 72; group 1 [G1]) or marginal donors (n ⫽ 44; group 2 [G2]) and older recipients (n ⫽ 83) of either marginal grafts (n ⫽ 70, group 3 [G3]) or optimal grafts (n ⫽ 13; group 4 [G4]). The gender distribution, cause of end-stage heart failure, preoperative pulmonary hypertension incidence, pretransplantation clinical status, and mean follow-up were not significantly different among the 4 groups. Results. Overall 30-day survival was 90 ⫾ 1% and 10-year rate was 78 ⫾ 9%. Among the groups, 30-day and 10-year actuarial survival rates were, respectively: 94 ⫾ 4% and 87 ⫾ 1% for G1; 86 ⫾ 5% and 84 ⫾ 7% for G2; 88 ⫾ 4% and 71 ⫾ 7% for G3 and were 100% and 82 ⫾ 7% for G4 (P ⫽ .7). In comparison among the 4 groups, there was no significant difference regarding freedom from graft failure (P ⫽ .3), right ventricular failure (P ⫽ .3), acute rejection episodes (P ⫽ .2), chronic rejection (P ⫽ .2), neoplasia (P ⫽ .5), or chronic renal failure (P ⫽ .1). Older recipients of marginal donors [G3] had a 4% (n ⫽ 3) prevalence of permanent pacemaker implant, versus G2: 3% (n ⫽ 2) among (P ⫽ .1). Conclusion. Our results suggest that extended donor and recipient criteria do not compromise clinical outcomes after transplantation. he Discrepancy between a rising number of heart transplantation candidates and a restricted donor pool has led to a reevaluation of organs that were previously not allocated for various reasons. In particular, advanced donor age, segmental anomalies and/or of mild left ventricular hypertrophy findings at the echocardiogram, angiographic occurrence of significant coronary artery lesion, and diagnoses of systemic diseases are now widely accepted. Gupta et al observed that candidates receiving hearts from donors ⱖ50 years old showed reduced survival rates. However, the reduced life expectancy was linked not only to donor age, but also to several other factors. They suggested that 40 years of age should be the cutoff.1 Marelli et al reported an initial experience using donor hearts affected by coronary artery disease. They concluded that donor hearts with

T

© 2011 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 43, 953–959 (2011)

coronary artery disease but a preserved ejection fraction at echocardiogram may be used, although they may require concomitant revascularization.2 Mild to moderate left ventricular hypertrophy may also not be considered to be an exclusion criterion any more. Because short- and long-term postoperative evaluations showed similar outcomes in 2 recipient groups engrafted with organs from elderly donors, Goland et al indicated that mild to moderate left ventricular hypertrophy could be tolerated.3 From the Division of Cardiovascular Surgery, University of Verona, Verona, Italy. Address reprint requests to Alberto Forni, Division of Cardiovascular Surgery, University of Verona, Piazzale Stefani, 1 37121 Verona, Italy. E-mail: [email protected] 0041-1345/–see front matter doi:10.1016/j.transproceed.2011.01.117 953

954

FORNI, LUCIANI, CHIOMINTO ET AL

From May 1994 to December 1999 we allocated marginal donor hearts to marginal candidates.4,5 The satisfactory clinical outcomes among this population led us to reconsider our donor-recipient matching protocol. All donors were then considered to be suitable for every potential candidate. To verify the effect of this novel approach, we respectively reviewed our experience. MATERIALS AND METHODS Recipients (Table 1) Between January 2000 and March 2010, we performed heart transplantation on 199 subjects at our institution. There were 159 men (80%) and 40 women. The age range was 18 –70 years (mean, 45 ⫾ 12 years). Refractory heart failure was caused by dilated cardiomyopathy (n ⫽ 83; 42%), ischemic heart disease (n ⫽ 104; 53%), heart valve disease (n ⫽ 5; 2%), restrictive cardiomyopathy (n ⫽ 2; 1%), retransplantation (n ⫽ 2; 1%), or congenital heart disease (n ⫽ 3; 1%). Preoperative clinical conditions indicated that 113 patients (57%) were New York Heart Association (NYHA) functional class IV on inotropic drug support. An intra-aortic balloon pump was required in 33 patients (16%). Mechanical assist devices as bridge to transplant were used in 24 candidates (12%), namely, extracorporeal membrane oxygenators, 5 LVAD WorldHeart’s Novacor left ventricular assist system, 2 Thoratec Heart Mate II left ventricular assist devices, and 3 Medos Medizintechnik paracorporeal pumps. The reasons for mechanical assist devices were postcardiotomy syndrome (n ⫽ 13), refractory heart failure (n ⫽ 7), and cardiogenic shock after acute myocardial infarction (n ⫽ 4). Mean left ventricular ejection fraction was 18 ⫾ 2%, (range, 14%–23%). Transpulmonary gradient exceeded 6 mm Hg in 112 patients (56%). Serum creatinine level was ⬎200 mg/dL in 59 candidates (30%), and the total bilirubin was ⬎5 mg/dL in 41 candidates (20%). To evaluate the clinical impact of suboptimal donors, we divided the recipient population into 4 subgroups. The 116 younger recipients (18 – 60 years) were divided between G1 (optimal donors– optimal recipients) and G2 (marginal donors– optimal recipients). The remaining 83 candidates, who were ⱖ61 years were included as either G3 (older recipients–marginal donors) or G4 (older recipients–

optimal donors). Comparisons among the 4 group did not show significant difference for demographics as summarized in Table 1.

Donors (Table 2) Donor acceptance has rapidly evolved over the past decade. According to Laks et al,6 donors are regarded to be “marginal” when ⬎45 years old without coronary angiography, requiring high-dose inotropic support defined as the administration of ⱖ2 agents or of epinephrine, affected by left ventricular hypertrophy, or displaying hepatitis C virus (HCV) infection. Other inclusion criteria were coronary artery disease either isolated or in combination with left ventricular hypertrophy or HCV positivity; HCV positivity in HCV-negative recipients; chest trauma; smaller donor without another matching possibility; extensive drug abuse; prolonged cold ischemia time; hepatitis B or anti– hepatitis B core antigen positive; or a nonmetastatic tumor. Informed consent was always obtained from the recipient. Donor-recipient matching criteria were based on blood group compatibility, anthropometric dimensions, NYHA functional class, and clinical conditions. In particular, the diagnosis of a left anterior descending artery constriction ⬎90% lead us to perform a PTCA before thoracic and abdominal organ retrieval; all procedures were uneventful.

Surgical Harvest Technique After a median sternotomy and T-shaped pericardiectomy, the superior vena cava was isolated to its confluence in the innominate vein and separated from the right pulmonary artery. The inferior vena cava was freed at the level of its pericardial reflection. The great arteries were isolated at the origin of the innominate artery and of the pulmonary artery bifurcation. The aorta was then cross-clamped and cold cardioplegia solution infused into the aortic root. Ice slush was poured into the pericardial cavity. Heart venting was achieved by transection of both the inferior vena cava and the right superior pulmonary vein. The pulmonary artery was then sectioned at its bifurcation. The aorta were divided at the origin of the brachiocephalic trunk. After removal of the crossclamp, the superior vena cava was trimmed at the origin of the azygos vein. The procedure was then completed by dissecting the left pulmonary veins and the posterior pericardial reflections. Eventually, an incision was made in the left atrial wall to obtain a single cuff containing the ostia of all 4 pulmonary veins.

Table 1. Recipients

Age range, y Female Male Indication DCMP Other TPG ⬎6 mm Hg NYHA IV MCS: IABP ECMO MEDOS NOVACOR HM II

OR/OD (n ⫽ 72)

OR/MD (n ⫽ 44)

MR/MD (n ⫽ 70)

MR/OD (n ⫽ 13)

Overall (n ⫽ 199)

P Value

18–58 12 (16%) 60 (84%)

21–60 12 (28%) 32 (72%)

61–70 11 (16%) 59 (84%)

61–70 3 (23%) 10 (77%)

18–70 38 (19%) 16 (81%)

ns ns ns

38 (52%) 48% 37 (51%) 30 (42%)

21 (48%) 52% 24 (55%) 27 (61%)

21 (30%) 70% 41 (59%) 48 (69%)

3 (23%) 77% 10 (76%) 8 (62%)

83 (42%) 68% 112 (56%) 113 (57%)

ns ns ns ns

11 (15%) 4 (5%) 0 1 (1%) 1 (1%)

6 (14%) 4 (9%) 1 (2%) 3 (8%) 1 (2%)

12 (17%) 4 (6%) 1 (1%) 1 (1%) 0

4 (30%) 2 (15%) 1 (8%) 0 0

33 (16%) 14 (7%) 3 (2%) 5 (3%) 2 (1%)

ns ns ns ns ns

Abbreviations: OR, optimal recipient; OD, optimal donor; MR, marginal recipient; MD, marginal donor; NYHA, New York Heart Association functional class; MCS, mechanical circulatory support.

OUTCOMES FROM MARGINAL HEART DONORS

955 Table 2. Donors

Age range, y Female Male Cause of death RTA CH other Inotropes (high dosage) Echocardiographic anomalies CGF Infections: Pos. Blood cult. HCV (REC: HCV ⫺) Ag Au pos. Pneumoc. (mening.)

OR/OD (n ⫽ 72)

OR/MD (n ⫽ 44)

MR/MD (n ⫽ 70)

MR/OD (n ⫽ 13)

Overall (n ⫽ 199)

P Value

14–41 19 (26%) 74%

39–64 16 (36%) 64%

10–69 14 (20%) 80%

16–39 6 (46%) 54%

10–68 55 (28%) 144 (72%)

ns ns ns

38 (53%) 24 (33%) 10 (14%) 18 (25%) 0 0

11 (25%) 32 (73%) 1 (2%) 27 (61%) 53% 12/25 (25 CGF)*

22 (31%) 36 (51%) 12 (18%) 41 (58%) 22% 18/38 (38 CGF)*

8 (62%) 5 (38%) 0 5 (38%) 0 0

79 (40%) 97 (49%) 23 (11%) 91 (46%) 18% 30/63

ns ns ns ns ns

0 0 0 0

9 (20%) 4 (9%) 3 (7%) 0

6 (9%) 8 (11%) 4 (5%) 6 (9%)

0 0 0 0

15 (8%) 12 (6%) 7 (4%) 6 (3%)

ns ns ns ns

Other abbreviations as in Table 1. *1 case of LAD lesion ⬎ 90%: PTCA on LAD before heart retrieval.

Surgical Implantation Technique Through a midline sternotomy and a T-shaped pericardiectomy, we commenced cardiopulmonary bypass after insertion of a cannula into the ascending aorta and 2 separate right-angled cannulas in the inferior and superior vena caval. Caval snares were used as well. Moderate hypothermia (30°C) was maintained throughout the operation. The aorta was then cross-clamped. The cardiectomy was performed by a complete section of the aorta at the level of the innominate artery origin followed by complete transection of the pulmonary artery at its bifurcation. We preserved a 3– 4-cm margin around the inferior vena cava orifice. The superior vena cava was maintained as long as possible. The left atrial excision was carried beyond the groove at the base of the left atrium. We preserved a 2-cm margin of the cuff around the ostia of the pulmonary veins. The donor left atrium was sutured to the recipient left atrial stump. The inferior vena cava was terminoterminally sutured to the donor inferior vena cava. Both pulmonary artery and aorta were terminoterminally anastomosed. Before release of the cross-clamp, 1 liter of warm blood cardioplegia solution was administered. Air was removed from the cardiac chambers though the double-outlet cannula used for anterograde cardioplegia delivery. With a beating heart, we directly sutured the superior vena cava to the recipient superior vena cava.

Immunosuppression A conventional 3-drug regimen was administered to the entire population. Methylprednisolone (1 g) was given intraoperatively before removal of the aortic cross-clamp, followed by 3 125-mg pulses on the first postoperative day. For induction immunotherapy course, antithymocyte globulin (3 mg/kg) was given during the 1st week. Cyclosporine (CsA) was begun on the 2nd day, initially at 7 mg/kg/d tapered to 4 mg/kg/d by the sixth 6th month. Oral daily doses were adjusted to achieve a cyclosporine trough level of 350 ng/dL at the 1 postoperative month. From 1994 to 1997, we started azathioprine (Imuran, Wellcome) orally at a daily dosage of 2 mg/kg/d progressively reduced to 1 mg/kg/d by the 6th postoperative month. Beginning in 1997, we administered mycophenolate mofetil at a uniform dosage of 2 g/d. However, we adjusted daily dosage according to a white blood cell count between 4,000 and

6,000 cells/mL. The oral initial prednisone (Deltacortene, Lepetit) dosage of 1 mg/kg/d was rapidly tapered to 0.1 mg/kg/d by the 6th postoperative month.

Endomyocardial Biopsy Rejection surveillance was accomplished by endomyocardial biopsies, which were performed weekly in the 1 month, biweekly until the 3rd month, and then monthly from the 4th to 9th month. A diagnosis of cardiac acute rejection was established according to the revised International Society for Heart and Lung Transplantation (ISHLT) criteria. Treatment of acute cellular rejection episodes exceeding grade 2 R included methylprednisolone (1 g) for 3 days.7

Follow-Up The entire population underwent the same postoperative evaluations. An epicardial 2D echocardiogram was performed in the operating room. The graft’s performance was determined by physical examination, 12-lead electrocardiogram followed by voltage summation, and by chest X-ray on a daily basis. Routine echocardiography was performed every other day. The ejection fraction was calculated according to the Teichholz formula.8 Left ventricular mass (in g) was determined from the m-mode measurements of left ventricular end-diastolic diameter, interventricular septum thickness, and left ventricular posterior wall thickness, according to the Deveroux and Reichek formula.9 The assessment of TVI was semiquantitative with severity determined by color flow mapping of the ratio between the regurgitant area and the atrial area as mild (⬍10% grade 1), moderate (25%–50%) (grade 2), or severe (⬎50%, grade 3). In grade 1 the regurgitant jet reached the right atrial long axis; in grade 2, it went beyond the halfway point of the right atrial point; and in grade 3, there was a major regurgitation into the hepatic veins. Measurement of pulmonary artery pressure was performed by echocardiography ECHO as well. Right heart catheterization via a Swan-Ganz catheter was used for the first 96 hours. The right ventricular flow-directed pulmonary artery catheter was advanced into the pulmonary artery to determine the wedge pressure. We recorded pulmonary artery wedge and central venous pressures, cardiac index, and cardiac output.

956 Graft failure was defined as a clinical scenario characterized by a consistent elevation of left atrial pressure, low mean arterial pressure, persistent low output state, and perioperative echocardiographic imaging of complete left ventricular akinesia. A diagnosis of severe right ventricular failure was established by the presence of right atrial pressure ⬎10 mm Hg, low arterial blood pressure, and perioperative echocardiographic imaging of severe right ventricular akinesia eventually leading to multiple organ failure. Oligoanuria was always observed. Immediate postoperative prophylaxis of infection was achieved by short-term antibiotic therapy with ceftazidime, piperacillin, and oral nystatin. In cases of donors positive and recipient negative for cytomegalovirus (CMV) infection, we prescribed acyclovir (5 mg/ kg/d) for 15 days. Postoperatively we monitored CMV through routine of PP65 evaluation by enzyme-linked immunosorbent assay. Levels ⬎100 cells led to administration of acyclovir (5 mg/kg twice a day). Patients were followed from 6 to 98 months (mean, 54 ⫾ 8 months). All subjects were admitted weekly during the 1st month, biweekly until the 3 month, and then monthly from the 4th to 12th month. The diagnosis of cardiac acute rejection was established according to the ISHLT criteria.7 Patients showing grade 2R (III A equivalent) or greater acute rejection were given 1 g of methylprednisolone for 3 days.7 An ongoing acute rejection was treated by switching from CsA to oral tacrolimus, mycophenolate mofetil, and prednisone. Chronic allograft vasculopathy recognized by an angiographic study was confirmed by intravascular ultrasound. Lesions were categorized according to Gao et al.9,10 Costanzo et al.11 Beginning in 2010, all coronary artery lesions were classified according to Mehra et al.23 Heart rate was monitored by routine 12-lead electrocardiography and an annual 24-hour Holter examination. Possible neoplasia was evaluated by an annual computerized tomographic scan. We frequently monitored renal and hepatic function and performed an annual abdominal ECHO. Chronic renal failure was defined as a serum creatinine level ⬎200 mg/dL, and liver failure as a total bilirubin ⬎5 mg/dL.

Statistical Analysis The endpoints were actuarial survival and freedom from acute or chronic rejection, neoplasia, renal failure, or infection among a nonrandomized population. The statistical Package for Social Science for Windows was the method of choice. Data were considered as mean ⫾ SD. Categoric variables were analyzed by ␹2 test. Comparison of values among subjects was performed by Student t test for independent samples. Values within the groups were compared by t tests. Differences were considered to be significant when the P value was ⬍.05%. Kaplan Meier Curved were Compared using the log-rank test.

RESULTS Mortality

Overall 30-day survival was 90 ⫾ 1%; 10 year survival, 78 ⫾ 9%. Among the groups, the 30-day and 10-year actuarial survival rates were, respectively: G1 94 ⫾ 4% and 87 ⫾ 1%; G2 86 ⫾ 5% and 84 ⫾ 7%; G3 88 ⫾ 4% and 71 ⫾ 7%; and G4 100% and 82 ⫾ 7% (P ⫽ .7; Fig 1). The causes of death are summarized in Table 3 for perioperative and in Table 4 for long-term events.

FORNI, LUCIANI, CHIOMINTO ET AL

Fig 1.

120-month actuarial survival (P ⫽ .702).

Morbidity

Graft failure was observed in 5 G1 (7%) and 2 G3 (6%) subjects. Comparisons among the various groups were not significant (P ⫽ .4). Causes of graft failure were prolonged cold ischemia time due to a long-range retrieval in 4 G1 subjects (mean ⫽ 230 ⫾ 22 min.) and cardiac arrest episodes (n ⫽ 3; 2 G3 and 1 G1). Severe right ventricular failure was observed in 7 G1 (10%), 8 G2 (19%), and 7 G3 (10%) recipients. (P ⫽ .3). The main reasons were donor-recipient anthropometric mismatch, (n ⫽ 15; 68%) and preoperative TPG ⬎ 5 WU (n ⫽ 18; 81%; Table 5). Long-Term Complications (Table 6)

Overall, 10-year freedom from an acute rejection episode was observed among 52 ⫾ 5% of the subjects: namely, 57 ⫾ 5% in G1, 67 ⫾ 8% in G2, 47 ⫾ 2% in G3, and 27 ⫾ 2% in G4 (P ⫽ .1). Acute rejection episodes exceeding grade 2R were observed among 36 G1 (50%), 15 G2 (34%), 34 G3 (49%), and 2 G4 (15%) patients. All acute rejection episodes were successfully treated with 1 g/d boluses of methylprednisolone intravenously over 3 days. Three subjects (3 G3, 1 G2) died after an acute rejection episode. Ten-year overall chronic rejection incidence was 84 ⫾ 2% including 88 ⫾ 4% in G1, 83 ⫾ 7% in G2, 79 ⫾ 4% in G3, and and 83 ⫾ 8% in G4 (P ⫽ .2). After a mean follow-up of 35 months (range 15– 65 mo), chronic rejection was identified in 11 G1 (15%), 8 G2 (18%), 16 G3 (22%), and 2 G4 (18%) patients. Overall freedom from infections at 10-year follow-up was 66 ⫾ 9%, and 72 ⫾ 5% in G1, 67 ⫾ 3% in G2, 56 ⫾ 2% in G3, and 65 ⫾ 2% in G4 (P ⫽ ns). The most frequently diagnosed infections were due to (n ⫽ 32) CMV. The other infections were due to herpes zoster virus (n ⫽ 13), papova virus (n ⫽ 9), Candida albicans (n ⫽ 15), and Legionella pneumoniae (n ⫽ 1). 10-year overall freedom from neoplasia was 85 ⫾ 1%, including 96 ⫾ 6% in G1, 88 ⫾ 4% in G2; 95 ⫾ 6% in G3, and 74 ⫾ 6% in G4, (P ⫽ .5). Malignancies were diagnosed in 8 G1 patients (11%), 4 G2 (11%), 8 G3 (11%), and 2 G4 (11%). Basal cell skin lesions were the most frequent type.

OUTCOMES FROM MARGINAL HEART DONORS

957

Table 3. Perioperative Mortality

Perioperative mortality 30-d survival Cause of death GF-MOF RVF-MOF Abd. Infarct. Acute Rejection Sepsis

OR/OD (n ⫽ 72)

OR/MD (n ⫽ 44)

MR/MD (n ⫽ 70)

MR/OD (n ⫽ 13)

Overall (n ⫽ 199)

P Value

5 (7%) 94 ⫾ 4%

6 (16%) 86 ⫾ 5%

7 (10%) 88 ⫾ 4%

0 100%

18 (9.%) 90 ⫾ 1%

ns .7

0 4 (5%) 0 0 0

4 (8%) 4 (9%) 0 0 0

3 (3%) 5 (7%) 1 (1%) 0 0

0 0 0 0 0

7 (3%) 13 (7%) 1 (0.5%) 0 0

ns ns ns

Other abbreviations as in Table 1.

Type B lymphoma was diagnosed in 7 patients. Prostate cancer was was diagnosed in 8 patients, Other neoplastic diseases were renal carcinoma (n ⫽ 3), lung adenocarcinoma (n ⫽ 2), and colorectal carcinoma (n ⫽ 2). The causes of death were B-Cell lymphoma (n ⫽ 2), prostate adenocarcinoma (n ⫽ 3), lung adenocarcinoma (n ⫽ 1), and colorectal carcinoma (n ⫽ 1). The 10-year freedom from renal failure was 85 ⫾ 3% in G1, 78 ⫾ 5% in G2, 84 ⫾ 4% in G3, and 64 ⫾ 5% in G4 (P ⫽ 0.1). Overall freedom from chronic renal failure was 82 ⫾ 8%. Permanent pacemaker implantation was necessary in 2 G2 (4%) and 3 G3 patients (4%) (Table 6). DISCUSSION

Heart transplantation represents the treatment of choice for patients with refractory heart failure. However, the reduced donor pool and increased number of potential candidates has forced many centers to revise donor and recipient criteria.12,13 At the beginning of present decade, Blanche et al compared the clinical outcome of heart transplantation among 15 subjects ⬎70 years old with 98 younger patients. Although the first group showed a greater numbers of female donors and prolonged ischemia time, there was no difference in actuarial survivals at 1 and 4 years (93% vs 88%). Length of hospital stay and occurrence of CMV infection were similar. They concluded that heart transplantation could be performed in patients ⬎70 years old as successfully as in younger patients.14 Evaluating the experience at Stanford University of 81 heart transplantations in recipients between 1986 and 2001, 60 –70 years old and 403 younger recipients. Demers et al

showed a higher incidence of acute rejection episodes among the younger population, whereas neoplasia occurred more frequently in older patients. Otherwise, short- and long-term mortality and incidences of chronic rejection and infective diseases did not differ. They concluded that older age should not be considered to be an independent risk factor.15 Using the United Network for Organ Sharing database of 14,401 subjects who underwent heart transplantation between 1999 and 2006, Weiss et al subdivided them with a cutoff age of 60 years. The primary endpoint was mortality for any causes. Patients ⬎60 years old exhibited a higher mortality, with a 5-year survival rate close to 70%. The authors concluded that heart transplantation should not be restricted on the basis of recipient age.16 A less enthusiastic report was presented by Tjang et al among 540 heart transplant recipients ⬍55 years old and 722 ⬎55 years old grafted between March 1989 and December 2004. They observed less favorable outcomes among older than younger recipients.17 Donor evaluation criteria have rapidly evolved. In 2004, Gupta et al1 reported their experience regarding the use of heart donors ⬎50 years old between 1990 and 2002. The 611 younger recipients (mean age, 53 years) received organs from donors ⬍50 years old, and 56 patients had organs from donors ⬎50 years old who had died due to a cerebrovascular accident and were mainly women. A markedly by reduced 1- (65.7% vs 81.7%; P ⬍ .005) and 5-year (48.3% vs 68.4%; P ⬍ .005) survivals. Their conclusion was that donor age should be restricted at 40 years. Left ventricular hypertrophy has always been regarded to be a consistent risk factor among heart donors, owing to its impact on

Table 4. Long-Term Mortality

Late death 10-y actuarial survival Cause of death Acute rejection Sepsis Chronic rejection Neoplasia Abbreviations as in Table 1. *1 suicide?

OR/OD (n ⫽ 72)

OR/MD (n ⫽ 44)

MR/MD (n ⫽ 70)

MR/OD (n ⫽ 13)

Overall (n ⫽ 199)

P Value

4 (5%) 87 ⫾ 1%

5 (11%) 84 ⫾ 7%

13 (18%) 71 ⫾ 8%

2 (15%) 82 ⫾ 7%

24 (12%) 78 ⫾ 9%

ns .7

0 2 (3%) 1 (1%) 2 (3%)

1 (2%) 1 (2%) 1 (2%) 2 (4%)

3 (4%)* 3 (4%) 5 (7%) 2 (3%)

0 1 (8%) 0 1 (8%)

4 (2%) 7 (3%) 7 (3%) 7 (3%)

ns ns ns ns

958

FORNI, LUCIANI, CHIOMINTO ET AL Table 5. Perioperative Morbidity OR/OD (n ⫽ 72)

GF No. of patients ECMO treatment RVF No. of patients treatment: ECMO centr pumps MEDOS Levitronix (rvad)

OR/MD (n ⫽ 44)

MR/MD (n ⫽ 70)

MR/OD (n ⫽ 13)

Overall (n ⫽ 199)

P Value

5 (7%) 5

0

4 (6%) 2

0 0

9 (4%)

.3

7 (10%) 2 2 1 2

8 (19%) 1 2 1 2

7 (10%) 1 2 1 3

0 0 0 0 0

23 (11%) 0 0 0 0

.3

Abbreviations as in Tables 1 and 3.

mortality rate.18 However, Goland et al investigated the clinical courses of 427 graft recipients among whom 62 had an intraventricular sertum thickness ⬎12 mm. Left ventricular wall thickness occurred in both intraventricular sertum and PW. Survival rates were similar regardless of left ventricular hypertrophy.3 The presence coronary artery lesions in a donor has been considered to be an exclusion criteria. Marelli et al reviewed the clinical outcomes of 22 recipients whose grafts were affected by mild to moderate coronary artey disease but showed normal echocardiographic left ventricular function. Recipients were subdivided into 2 groups: those facing imminent death (n ⫽ 4) and those who would not have otherwise been transplanted (n ⫽ 18). Owing to significant coronary lesions, 3/4 grafts implanted in group 1 underwent revascularization with either a saphenous vein graft or a donor left internal mammary artery. Endpoints were survival and freedom from chronic rejection. The results revealed early death to be related to both the recipient’s and the donors’ conditions. Therefore, they recommended that coronary artery plaques should not preclude organ donation, but the organs should be limited to risk-matched subjects.19 The impact of donor coronary artery atherosclerosis was analyzed by Grauhan et al seeking to determine the acceptable extent of disease. They concluded that donor screening without coronary artery arterography overlooked lesions in 7% of cases. Donors with single vessel disease were marginal donors suitable for concomitant revascularization. Double- or triple-vessel disease produced a consis-

tent risk of early graft failure. However, after the 1 year, the angiographic outcome was similar in all cases.20 The use of organs from donors who were deceased due to sepsis has always been considered to be a high risk for potential infection transmission. Kubak et al reviewed the medical records of 9 donors who were deceased between 1999 and 2007 due to infection. No evidence of donortransmitted infection was found.21 A possible solution to the current organ scarcity may be alternative waiting lists. Laks et al observed that nonstandard recipients on an alternative waiting list should receive marginal organs. They concluded that use of 2 candidate lists facilitated allocation of unused donor organs. Furthermore, they observed that recipient predictors of early mortality were previous cardiac surgery and renal dysfunction.6 Russo et al analyzed the clinical outcomes of 13,024 heart transplantations performed between 1999 and 2005, concluding that an alternative list was associated with a greater mortality rate and resource use, although the strategy allowed a median survival of 5.2 years in subjects who otherwise were expected to live ⬍1 years.22 Given the above considerations, we have experienced a stimulus to extend donor and recipient criteria and optimize matching during the past decade.4,5 Therefore, the endpoint of the present retrospective nonrandomized trial was to demonstrate a reduction in the increasing discrepancy between the number of potential heart transplantation candidates and the effective donor pool. Our results indicated that better outcomes can be achieved by using

Table 6. Long-Term Complications (120 Months)

10-y freedom from 10-y freedom from 10-y freedom from 10-y freedom from 10-y freedom from 10-y freedom from PPM implanted

acute rejection chronic rejection infection neoplasia chronic renal failure chronic renal failure

OR/OD (n ⫽ 72)

OR/MD (n ⫽ 44)

MR/MD (n ⫽ 70)

MR/OD (n ⫽ 13)

Overall (n ⫽ 199)

P Value

57 ⫾ 5% 86 ⫾ 2% 73 ⫾ 5% 96 ⫾ 6% 85 ⫾ 3% 85 ⫾ 3% 0

67 ⫾ 6% 83 ⫾ 7.2% 69 ⫾ 3% 88 ⫾ 4% 78 ⫾ 5% 78 ⫾ 5% 2 (4%)

47 ⫾ 4% 78 ⫾ 4% 55 ⫾ 2% 95 ⫾ 6% 85 ⫾ 4% 84 ⫾ 4% 3 (4%)

27 ⫾ 2.7% 81 ⫾ 12% 65 ⫾ 2% 76 ⫾ 6% 64 ⫾ 5% 64 ⫾ 5% 0

51 ⫾ 5 84 ⫾ 2% 66 ⫾ 11% 85 ⫾ 1.8% 82 ⫾ 8% 82 ⫾ 8% 5 (2%)

.1 .2 .3 .5 .1 .1 .1

Abbreviations: PPM, permanent pacemaker; other abbreviations as in Table 1.

OUTCOMES FROM MARGINAL HEART DONORS

optimal donors regardless of the recipient’s age. In the immediate postoperative period, mortality, graft failure, and right ventricular failure showed the same incidence among the 4 groups, even though the majority of candidates were on intravenous inotropic drug infusions, were mainly NYHA functional class IV, and were frequently supported by mechanical circulatory support devices. The use of marginal donors has always been harmful regarding the presence of 2 aged-dependent risk factors: right ventricular performance after heart transplantation and left ventricular hypertrophy. Therefore, the contemporaneous presence of both acute (harvesting-related) and chronic coronary artery–related ischemia may lead to posttransplantation graft failure. However, in our experience the impact of this complication seems to be limited. Not surprisingly, graft failure was much more frequent among NYHA functional class IV and or candidates having mechanical circulatory support devices. Although our data need to be further expanded, graft failure occurrence seemed to be related to the recipient’s condition rather than to the donor profile. Furthermore, analysis of intermediate-term follow-up revealed that freedom from an acute rejection episode was reduced in older recipients. Senescence of the immune system may explain this finding. Otherwise freedom from infection and from chronic rejection were greater among younger patients. None of the candidates receiving organs from infected donors developed sepsis. The occurrence of neoplasia was not different among the groups. Neoplastic lesions were in the majority of cases were age related. Owing to the administration of immunosuppressive agents, the most aggressive neoplastic lesions were observed among older recipients. In conclusion, the use of marginal donors was associated with satisfactory outcomes after heart transplantation.

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