Cardiac transplantation for amyloid heart disease: The United Kingdom experience

CLINICAL HEART TRANSPLANTATION

Cardiac Transplantation for Amyloid Heart Disease: The United Kingdom Experience Simon W. Dubrey, FRCP,a Margaret M. Burke, FRCPath,b Philip N. Hawkins, FRCP,c and Nicholas R. Banner, FRCPa,b Background: Heart transplantation (TX) for cardiac amyloidosis is uncommon because of concern about progression of amyloid in other organs and the possibility of amyloid deposition in the donor heart. Methods: Records of all 24 patients with amyloid heart disease who have undergone TX in the United Kingdom were examined. Seventeen patients had AL amyloidosis (AL) and 7 had non-AL forms of amyloidosis (non-AL). Results: Survival of the 10 patients with AL who underwent TX but had no additional chemotherapy was 50%, 50%, and 20% at 1, 2, and 5 years, respectively; amyloid recurred in the grafts of these patients after a median of 11 months, and extra-cardiac amyloid deposition contributed to mortality in 70% of these patients. Survival of 7 patients with AL who also had chemotherapy was 71%, 71%, and 36% respectively and 2 patients remain alive. Survival of the 7 patients with non-AL was 86%, 86%, and 64% at 1, 2, and 5 years, respectively; 5 patients remain alive. One patient from this group had recurrence of amyloid in the graft at 60 months. Five-year survival for all 24 amyloid patients was 38%, compared to patients undergoing TX in the UK for other indications (n ⫽ 4,058) for whom it was 67% (p ⫽ 0.013). Conclusion: Regardless of the use of adjunctive chemotherapy, the 5-year survival after TX for cardiac AL amyloidosis was less than that after TX for other indications, and progression of the systemic disease contributed substantially to the increased mortality. In contrast, the 5-year survival after TX for non-AL amyloid, combined as necessary with liver or kidney TX, was similar to that after TX in general. J Heart Lung Transplant 2004;23:1142-53.

Amyloidosis is the generic term for a group of disorders characterized by extracellular deposition of protein in a characteristic fibrilar form. In systemic AL amyloidosis, where most cases are associated with a plasma cell dyscrasia,1,2 some patients benefit from chemotherapy directed towards the underlying monoclonal gammopathy. This approach is rarely effective in patients with severe cardiac involvement whose median survival is about 6 months.3,4 Hereditary systemic amyloidosis is caused by deposition of amyloid fibrils derived from a range of genetically variant proteins.5,6 The first report of successful heart transplantation for cardiac amyloidosis appeared in 1988.7 Later publica-

From the aThe Imperial College School of Medicine, National Heart and Lung Institute, London, the bTransplant Unit and Department of Pathology, Royal Brompton and Harefield Hospitals NHS Trust, Middlesex, and cDepartment of Medicine, The National Amyloidosis Centre, The Royal Free Hospital, London, United Kingdom. Submitted June 5, 2003; accepted August 22, 2003. Reprint requests: NR Banner, FRCP, Harefield Hospital, Royal Brompton and Harefield NHS Trust, Harefield, Middlesex UB9 6JH, United Kingdom. E-mail: [email protected] Copyright © 2004 by the International Society for Heart and Lung Transplantation. 1053-2498/04/$–see front matter. doi:10.1016/ j.healun.2003.08.027

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tions revealed that patients had received heart transplants for end-stage cardiac amyloid as early as 1984.8 Aside from individual case reports, only two series have described the experience at individual transplant centers.9,10 More than 10 years have elapsed since the only multi-center survey reported the longer term outcome following heart transplantation.11 Among centers performing heart transplantation, its application in AL amyloidosis remains contentious.12 We report here the complete United Kingdom (UK) experience of heart transplantation for amyloid heart disease from its inception in 1984. PATIENTS AND METHODS All patients undergoing heart transplantation for amyloidosis in the UK between 1982 and 2002 were identified from their explant pathology report by interrogating the pathology databases of all UK transplant centers. Their clinical and pathology records were reviewed with the agreement of the participating pathologists and clinicians. Documentation was cross checked with the National Transplant Database (UK Transplant) and with information held at the National Amyloidosis Center. Patients with AL amyloid were considered separately from those with non-AL types.

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Table 1. Demographic Data on Patients with AL Amyloidosis, Organ Involvement on Preoperative SAP Scan, NYHA Class of Heart Failure, and Additional Therapies Prescribed to Treat the Systemic Amyloid Disease Process

Patient number 1 2 3 4 5* 6 7 8 9 10 11 12 13 14 15 16 17

Age (years) Sex 56 M 59 M 57 F 50 F 55 F 52 F 61 64 46 59 52 49 43 56 39 48 59

M M M M M M M F M F M

Extracardiac organs involved on preoperative SAP scintigraphy Not performed Not performed Not performed Not performed Liver, kidney, spleen Spleen, liver, kidneys, bone marrow No visceral involvement Kidneys Spleen Kidneys, spleen Liver, kidneys, spleen No visceral involvement No visceral involvement Not performed Spleen Spleen Liver, kidneys, spleen

Heart failure (NYHA I–IV) III IV IV IV ⫹ IABP III IV

Adjunctive therapies given to treat amyloidosis None None None None 6 cycles of VAD for multiple myeloma Prior short course of cyclophosphamide

IV IV IV ⫹ IABP IV IV IV III III/IV IV IV III/IV

None None None None 8 cycles of Epid/Carm/cyclophosphamide 6 cycles of oral melphalan PBSCT 1 course of oral melphalan PBSCT followed by cyclophosphamide 3 courses of VAD PBSCT

*Patient (#5) had underlying multiple myeloma that had responded to VAD chemotherapy prior to heart transplantation and did not relapse afterwards. AL, AL amyloidosis; Carm, carmustine; Epid, epidoxorubicin; F, female; IABP, intra-aortic balloon pump; M, male; MM, multiple myeloma; NYHA ⫽ New York Heart Association functional class; PBSCT, peripheral blood stem cell transplant; SAP, serum amyloid P component; VAD, vincristine, adriamycin, and dexamethasone.

The latter group comprised patients with hereditary systemic amyloidosis associated with mutations in genes for transthyretin (3 patients)13 and apolipoprotein AI (ApoAI; 2 patients),14 and 2 patients with “senile” (wild type transthyretin [TTR]) amyloidosis.15 Cardiac dysfunction is rare in AA (secondary) amyloidosis,16 and no patients with this type have been transplanted in the UK. In the AL group, 17 patients (11 male, 6 female) underwent heart transplantation for end-stage cardiac amyloidosis. Twelve of these were in New York Heart Association (NYHA) class IV heart failure, 2 patients were severe enough to require intra-aortic balloon counterpulsation, and another 2 patient required inotropic support to provide an adequate hemodynamic status (Table 1). Three patients in the AL group had required insertion of a permanent pacemaker before transplantation for symptoms related to varying degrees of atrioventricular block. Among the 7 patients (6 male, 1 female) in the non-AL amyloid group, 2 patients were in NYHA class IV heart failure and the remaining 5 in class III. None of the non-AL patient group required inotropic support in the pretransplant period. One non-AL amyloid patient had a permanent pacemaker inserted before transplantation. All 5 patients with familial forms of non-AL amyloidosis underwent either simultaneous liver (3 patients with variant TTR type) or kidney (2 patients with variant ApoAI type) transplantation, to correct the inherited amyloido-

genic disorder,17 or because of concomitant amyloidrelated renal failure respectively. Diagnosis and Evaluation of Amyloidosis Where possible the diagnosis of amyloidosis was made histologically before transplantation and confirmed on examination of the explanted heart. The fibril type was determined by immunohistochemical analysis supported by the demonstration of either a clonal plasma cell dyscrasia or by the results of DNA studies. Where available, preoperative whole body 123I-serum amyloid P-component (SAP) scintigraphy18,19 was done to determine the extent of extra-cardiac amyloid deposition. The results of all histologic investigations, including endomyocardial biopsies, surgical specimens and post mortem material were recorded. Pre-Transplant Clinical Evaluation Assessment included electrocardiographic and echocardiographic studies, right- and left-sided cardiac catheterization, measurements of hepatic and renal function (including creatinine clearance), and 24-hour urinary protein excretion. Post-Transplant Clinical Evaluation Evaluation was by clinical assessment, biochemical evaluation of hepatic and renal function, electrocardiography, echocardiography, and endomyocardial biopsy

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(EMB), according to the follow-up protocol of each transplant center. The perioperative period was defined as 1 month following the date of heart transplantation. Severity of heart failure was classified using the NYHA criteria.20 Echocardiographic features common to AL4,21 and familial22 cardiac amyloidosis were recorded. A low voltage electrocardiogram was defined as a tracing with a mean QRS voltage amplitude in the limb leads of ⬍0.5 mV. Cardiac biopsies were routinely performed to detect acute rejection during the first year after surgery. Rejection changes were classified according to the International Society of Heart and Lung Transplantation (ISHLT) grading system.23 All patients surviving after 1 year underwent evaluations every 6 months as described above, but biopsies were only performed when clinically indicated. Right heart catheterization, coronary angiography, and left ventriculography were performed at 12 months following transplantation and then as clinically indicated. Pathology The explanted hearts were fixed in 10% formalin and sections of routinely processed paraffin blocks were stained with hematoxylin-eosin for cell morphology and elastic Van Gierson for connective tissue. Biopsies were positive for amyloid when they contained amorphous extracellular material that stained with Congo red and produced green birefringence when viewed under cross-polarized light. Where feasible, routine post-transplant EMBs taken to monitor acute allograft rejection were also stained with Congo red for amyloid. Cause of death was ascertained from autopsy findings or from death certificates when the latter had not been performed. Histologic material obtained at autopsy was reviewed. Statistical Methods Survival data were summarized using Kaplan-Meier survival curves. The log rank test was used to determine differences between groups, where a p value of ⱕ 0.05 was considered statistically significant. Demographic patient data are shown as mean ⫾ standard deviation (SD). Survival data are reported as median values and range. RESULTS Between November 1984 and April 2002 a total of 24 patients underwent heart transplantation in six of the seven UK heart transplant centers for end-stage amyloid heart disease. The diagnosis was confirmed before transplantation in 23 patients, and was an unexpected diagnosis on the explanted heart in 1 patient. The extent of amyloid deposition was evaluated pre-operatively by SAP scintigraphy in 17 patients. The median survival for the patients overall was 29 months, with a

The Journal of Heart and Lung Transplantation October 2004

range from 1 day to 127 months. Among the 17 patients with AL amyloidosis, 15 patients (88%) survived 1 month, and 10 of 17 (59%) were alive at 1 year post-transplantation. Six of 7 non-AL patients (86%) survived 1 month and 5 patients have survived more than 1 year post-transplantation. Actuarial survival at 1, 2, and 5 years was 50%, 50%, and 20% among AL patients who did not receive chemotherapy; 71%, 71%, and 36% in the AL patients who did have chemotherapy; and 86%, 86%, and 64% for the non-AL patients, respectively. The overall 5-year post-transplantation survival among the amyloid patients was 38% compared to 67% of patients undergoing heart transplant for other causes (n ⫽ 4,058) in the United Kingdom (p ⫽ 0.013). AL Amyloid Patients Receiving no Additional PostTransplant Chemotherapy Ten patients did not undergo post-transplant chemotherapy in an attempt to modify the course of their underlying amyloid disease, although 2 of these patients had received some form of chemotherapy beforehand. Six patients were males and four were females, and their mean age (SD) was 56 ⫾ 5 years. Demographic data are shown in Table 1; 9 patients were caucasian and 1 black. Donor age (SD) for these 10 patients was 45 ⫾ 8 years. Preoperatively, all patients in this group had low voltage electrocardiograms (⬍0.5 mV) and 7 of 8 documented patients had marked thickening (⬎1.4 cm) of the left ventricular wall. Table 2 illustrates the clinical features of organ function and hemodynamic variables at the pre-transplant assessment. Six patients underwent 123I-labeled serum amyloid P component (SAP) scintigraphy before transplantation, demonstrating extra-cardiac involvement by amyloid in 5 patients (83%; Table 1). Two patients died in the immediate perioperative period; one was a 46-year-old man (Patient 9) who died intraoperatively due to right ventricular failure and previously unidentified pulmonary vascular amyloid, and the other was a 59-year-old man (Patient 10) who died 4 days after transplantation due to multiple organ failure. Amyloid Recurrence in the Graft. Routine EMBs in 4 of 6 patients who survived for more than 3 months after transplantation were reviewed for recurrence of graft amyloid. Microscopic amyloid deposits were identified in each patient, first noted 5, 10.5, 11.5, and 29.5 months, respectively (median 11 months), following transplantation. Post-Transplant Progress, Duration of Survival, and Cause of Death. The median survival for this group was 29 months (range 1 day to 97 months). All 10 patients have now died. The year of transplant and the

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Table 2. Clinical Features of Organ Function and Hemodynamic Variables at Pre-Transplant Assessment AL patients Organ Kidney

Liver

Heart

Not receiving chemotherapy 9 ⫾ 3 (6–14)

Receiving chemotherapy 7 ⫾ 2 (5–10)

Serum creatinine (␮mol/L)

122 ⫾ 23 (88–159)

98 ⫾ 10 (30–117)

Creatinine clearance (ml/min) Bilirubin (␮mol/L) Aspartate transaminase (IU/L) Alkaline phosphatase (IU/L) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Right atrial pressure (mm Hg) Pulmonary artery pressure (mm Hg) PCW pressure (mm Hg) ECG limb lead voltage (mV) Left ventricular wall thickness* (cm)

43 ⫾ 24 (13–86) 23 ⫾ 11 (7–40) 52 ⫾ 64 (19–209) 180 ⫾ 75 (80–328) 103 ⫾ 25 (70–150) 65 ⫾ 13 (50–90) 11 ⫾ 2 (9–15) 32 ⫾ 5 (25–38) 22 ⫾ 3 (19–28) 0.3 ⫾ 0.1 (0.3–0.4) 1.9 ⫾ 0.4 (1.2–2.3)

64 ⫾ 21 (33–87) 24 ⫾ 14 (12–50) 37 ⫾ 19 (25–70) 150 ⫾ 88 (65–285) 105 ⫾ 14 (90–130) 72 ⫾ 12 (55–85) 13 ⫾ 7 (2–20) 28 ⫾ 9 (12–36) 22 ⫾ 8 (7–30) 0.3 ⫾ 0.1 (0.2–0.5) 1.8 ⫾ 0.5 (1.4–2.8)

Variable Blood urea (mmol/L)

Non-AL patients 8 ⫾ 4 (4–14) 28 (25–30) 101 ⫾ 38 (67–165) 433 (406–460) 73 ⫾ 18 (45–93) 20 ⫾ 8 (14–37) 27 ⫾ 9 (18–46) 285 ⫾ 195 (70–595) 112 ⫾ 16 (85–130) 75 ⫾ 10 (60–90) 12 ⫾ 5 (5–20) 28 ⫾ 6 (21–36) 21 ⫾ 4 (17–28) 0.4 ⫾ 0.1 (0.3–0.5) 1.8 ⫾ 0.3 (1.5–2.2)

Values are expressed as mean ⫾ SD (range). Data for renal performance is shown separately for non-AL patients without renal involvement (TTR mutations and wild type); and below this in italics for the ApoAI mutation non-AL patients with renal failure prior to transplantation. *Left ventricular wall thickness was derived from the mean of the sum of interventricular septal and left ventricular posterior wall thickness. AL, AL amyloidosis; ApoAI, apolipoprotein AI; ECG, electrocardiogram; PCW, pulmonary capillary wedge; TTR, transthyretin.

duration of each individual patients survival is depicted in the upper portion of Figure 1. Survival is illustrated in Figure 2. In this group, actuarial survival at both 1 and 2 years was 50%, and at 5 years was 20%. Individual data for duration of post-transplant survival, cause of death, and significant postmortem examination findings are presented in Table 3. Systemic amyloid disease contributed significantly to the deaths of 7 out of these 10 patients, including 2 within the peri-operative period (Patients 9 and 10). Two of the remaining 3 patients died of overwhelming infection, and the third of metastatic carcinoma. AL Amyloid Patients Who Received Post-Transplant Chemotherapy Seven patients with AL amyloid who underwent heart transplantation received additional chemotherapy. Five patients were males and 2 were females, and 6 patients were caucasian and 1 black. Demographic data are listed in the lower part of Table 1. Patients in this group were slightly younger than the AL patients who did not receive chemotherapy following transplantation (mean [SD] 56 ⫾ 5 years vs 49 ⫾ 7 years, p ⫽ 0.047). In addition, the donor age was on average 10 years younger in this group than in those not receiving chemotherapy (mean [SD] 45 ⫾ 8 years vs 32 ⫾ 15 years, p ⫽ 0.041). Several different regimens of chemotherapy were administered in the post-transplant phase in an attempt to suppress the amyloidogenic process. Two patients received oral courses of melphalan, 3

patients had high-dose melphalan (140 to 200 mg/m2) with autologous stem cell rescue, and the remaining 2 patients were treated with cyclical multi-agent myeloma regimens vincristine, adriamycin and dexamethasone (VAD), and epidoxorubicin, carmustine and cyclophosphamide, respectively, as shown in Table 1. Preoperatively, 5 patients (83%) in this group had low voltage electrocardiograms (⬍0.5 mV) and all 7 patients had marked thickening (⬎1.4 cm) of the left ventricular wall. Table 2 illustrates clinical and hemodynamic data collected at the pre-transplant assessment. Six patients underwent pre-operative SAP scintigraphy, with 4 demonstrating extra-cardiac amyloid deposition (Table 1). Amyloid Recurrence in the Graft. Routine EMBs in 4 of 7 patients were reviewed to look for recurrence of amyloid in their graft. Deposits became evident 28 months after transplantation in 1 patient, and in a second patient echocardiographic features of amyloid developed in the donor heart at 22 months. No cardiac biopsy or subsequent autopsy was performed in this latter patient. Post-Transplant Progress, Duration of Survival, and Cause of Death. All 7 patients in this group survived the peri-operative period. Median follow up in these patients was 33 months (range 4 to 116). Two patients are currently alive and both have received high-dose intravenous melphalan with autologous stem cell rescue. The year of transplant and the duration of each individual patients survival is shown in the middle

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Figure 1. Bar chart illustrating survival over time following the date of each individual patient’s heart transplant. Patients numbered 1 to 10 received a heart transplant (H) but underwent no chemotherapy to modify the course of the underlying plasma cell dyscrasia. Patients numbered 11 to 17 received a heart transplant and chemotherapy (H⫹C) to modify the course of the underlying plasma cell dyscrasia. Vertical cross hatching indicates the 3 patients (Patients 13, 15, and 17) that received intravenous melphalan chemotherapy with peripheral stem-cell transplantation. Patients 18 to 24 had non-AL amyloid heart disease. Patients 19, 21, and 23 underwent combined heart and liver transplantation (H⫹L). Patients 20 and 22 underwent combined heart and kidney transplantation (H⫹K). Patients 18 and 24 with “wild” transthyretin type cardiac amyloid underwent cardiac transplantation alone (H).

section of Figure 1. The patients (Patients 13, 15, and 17) who underwent high-dose melphalan and peripheral stem cell rescue are illustrated with vertical crosshatched bars. Survival is illustrated in Figure 2, the actuarial survival at both 1 and 2 years was 71%, and at 5 years was 36%. This was not significantly different to that of AL patients who did not receive chemotherapy (p ⫽ 0.14). Individual data for duration of post-transplant survival, cause of death, and significant autopsy findings are listed in Table 3.

Non-AL Amyloid Patients Six of the patients with non-AL amyloidosis were male and 1 was female. Their mean age (SD) at transplantation, 54 years old (⫾ 9 years), was similar to that for the total AL amyloid patient group of 53 years old (⫾ 7 years). Demographic data are illustrated in Table 4; all 7 patients were caucasian. Donor age for the non-AL amyloid group was 41 years old (⫾ 13 years). Preoperatively, all 4 patients who were not paced had low voltage electrocardiograms (⬍0.5 mV). All 7

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Figure 2. Kaplan-Meier survival curves for patients who have undergone heart transplantation with AL amyloid disease, both without chemotherapy (— ● — ● —) and with chemotherapy (– – –) and in patients with non-AL amyloid disease (——). There is a trend in favor of the non-AL amyloid group, in whom 5 of 7 patients remain alive.

patients had marked thickening (⬎1.4 cm) of the left ventricular wall. Six patients underwent pre-operative 123 I-labeled serum amyloid P component (SAP) scintigraphy, with 2 patients (40%) exhibiting amyloid deposits in extra-cardiac viscera (Table 4). Patients 19, 21, and 23 in Figure 1, who had transthyretin mutations, underwent combined heart and liver transplantation, with the objective of replacing failing cardiac function and removing the hepatic source of their variant amyloidogenic protein.17 Patients 20 and 22 in (Figure 1, lower portion), with ApoAI mutations underwent combined heart and kidney transplantation for end-stage failure of both these organs, and the remaining 2 patients who had wild type (senile) transthyretin cardiac amyloidosis underwent heart transplantation alone. Amyloid Recurrence in the Graft. Routine EMBs in 6 patients, who survived more than 3 months after transplantation, were reviewed for recurrence and have manifested amyloid deposits in only 1 patient. This woman with hereditary ApoAI Arg 60 amyloidosis was 35 years old at the time of surgery, and despite developing histologic evidence of amyloid on cardiac biopsy 60 months after transplantation, she continues to have normal cardiac function on echocardiography at 45 years of age. Post-Transplantation Progress, Duration of Survival, and Cause of Death. Two deaths have occurred in this group. A 62-year-old male with variant TTR amyloid (Patient 23) died 6 days after combined heart

and liver transplant due to heart failure, which was classified as peri-operative mortality. Another 62-yearold male with variant TTR amyloid (Patient 19) died 32 months after heart and liver transplantation due to renal failure associated with carcinoma of the prostate. The median follow-up for the 6 patients who survived the perioperative period is 31 months (range 3 to 127 months), and 5 of these patients remain alive. Table 5 summarizes the survival and autopsy data of the non-AL patient group. The transplant date and the duration of each individual patients survival is shown in the lower section of Figure 1. Survival is shown in Figure 2. For the non-AL group, actuarial survival at both 1 and 2 years was 86% and at 5 years was 64%. There was no significant difference in the survival of the AL and non-AL patients (p ⫽ 0.353). DISCUSSION This study provides the most comprehensive review of outcome of heart transplantation for amyloid heart disease within the United Kingdom. It is the largest series of patients reported so far and provides the longest clinical follow-up data. Mc Gregor et al9 reported the Mayo Clinic experience of 8 patients undergoing heart transplantation for AL amyloid heart disease in 1998. Six patients were alive when reported with a mean survival of 34 months, and the longest survival in this series was 65 months. Two patients had died, one at 16 months and another at 31 months, of gastrointestinal (GI) tract amyloid and lymphoma respectively.

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Table 3. Duration of Survival, Cause of Death, Pathologic Features of Note, and Latest SAP Scan (at Months Post-Transplantation) Findings in the Patients with AL Amyloidosis Patient Age Survival number sex (months) Mode of death 1 56 M 85.4 Sudden death 2

59 M

3.0

3 4

57 F 50 F

82.5 11.4

5

55 F

49

6

52 F

32

7

61 M

26.2

8

64 M

1.3

9

46 M

0

10

59 M

0

11

52 M

116.3

12

49 M

54.5

13

43 M

57 A

14

56 F

10.7

15

39 M

33

16

48 F

4

17

59 M

16 A

Amyloid distribution at Procedure postmortem examination/on biopsy Autopsy Vascular and interstitial in heart; vessels in kidney Multiorgan failure; Colectomy Vascular and interstitial amyloid in membranous colitis submucosa and mesentery Pneumonia Autopsy Herpes pneumonia and — encephalomyelitis Heart and renal failure Autopsy Vessels in heart, lungs, liver, spleen, colon, thyroid, pancreas and adrenals — Cachexia due to GI tract amyloid (gut and liver) and renal failure Metastatic colonic ad- Colectomy Vessels and mesentery of colon enocarcinoma Multiorgan failure Autopsy Lungs, heart and GI tract

Right heart failure sec- Autopsy ondary to pulmonary hypertension Kidney and heart fail- Autopsy ure Septicemia; ischemic colitis

Autopsy

Heart failure

Autopsy —

Fecal peritonitis due to Autopsy ruptured diverticulum Progressive cardiac, — pulmonary, liver and GI tract amyloid Bronchopneumonia Autopsy and extensive systemic amyloid —

SAP scans and other features Mild acute rejection

Graft vascular disease

Graft vascular disease

SAP scan (28), extensive and widespread amyloid

ISHLT grade 3A rejection Extensive amyloid on lung biopsy

Lungs (perivascular ⫹⫹), vessels in tongue, liver, lymph nodes, adrenals, testes, prostate, spleen Kidneys, vessels in liver, spleen, lymph Subendocardial infarction; connodes, pancreas, sem vesicles, traction band necrosis prostate, thyroid, lungs Vessels in colon, stomach, lung, adre- Graft vascular disease nals, liver, spleen, skin, testes, bladder, ureter, pancreas, bone marrow, aorta, interstium of heart Extensive pulmonary amyloid with biSAP scan (41), amyloid in kidneys lateral pulmonary emboli and spleen SAP scan (57), equivocal renal amyloid Kidneys, vessels of liver, spleen, intes- No amyloid in heart at autopsy tine, and adrenal gland SAP scan (29), amyloid in liver and spleen; Echo (23) suggested amyloid Stomach, duodenal, small bowel, liver, pancreas, kidneys, bladder, ovaries, thyroid, and abdominal wall

Numbers in brackets ( ) following SAP and Echo refer to the time in months post-heart transplantation. A, patient currently alive; AL, AL amyloidosis; Echo, echocardiogram; F, female; GI, gastrointestinal; ISHLT, International Society of Heart Lung Tranplantation; M, male; SAP, 123I serum amyloid P component.

Survival at 1 and 2 years post-transplant were 100% and 83%, respectively. In another single UK center report of 10 patients receiving heart transplants, survival at both 1 and 2 years was 60%, and at 5 years was 30%.10 A previous multi-center study that has examined the outcome for heart transplantation in patients with AL amyloid was published in 1991.11 This survey involved centers in the United States, Canada, and Europe but

included only 10 patients. Recurrence in the allograft was found in 4 of 9 patients who survived the perioperative period, and survival at 4 years was reported as 39%. In common with our results, late survival in this multi-center study was poorer than for patients undergoing heart transplantation generally. Five-year survival following heart transplantation in the United Kingdom for amyloidosis (n ⫽ 24) was 38% (confidence interval

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Table 4. Demographic Data of the Patients with Non-AL Amyloidosis, Organ Involvement on Preoperative SAP Scan, Class of Heart Failure, Amyloid Variants, and Organs Transplanted Patient number 18 19 20 21 22 23 24

Age (years) sex 59 M 62 M 35 F 51 M 54 M 62 M 57 M

Organs involved on preoperative SAP scan — No visceral involvement Heart, liver, kidneys, spleen No visceral involvement No visceral involvement Kidneys No visceral involvement

Heart failure NYHA (I–IV) III III IV III IV III III

Amyloid type (variant) TTR (Wild type) TTR (Tyr 77) ApoAI (Arg 60) TTR (Glu 89) ApoAI (Pro 173) TTR (Leu 33) TTR (Wild type)

Organs transplanted Heart Heart and Liver Heart and Kidney Heart and Liver Heart and Kidney Heart and Liver Heart

ApoA1, apoprotein A1 mutation; Arg, arginine; F, female; Glu, glutamate; Leu, leucine; M, male; NYHA, New York Heart Association; Pro, proline; SAP, serum amyloid P component scintigraphy; TTR, transthyretin; Tyr, tyrosine; —, not performed.

[CI] ⫽ 16 –59) compared with 67% (CI 66 – 69) for all other conditions (n ⫽ 4,058; Figure 3) (Data from National Transplant Statistics supplied by UK Transplant). Diagnosis of Amyloidosis In this series, 2 patients (Patients 13 and 14) with AL amyloid heart disease were initially thought to have hypertrophic cardiomyopathy; in one of these (Patient 14), the diagnosis of amyloidosis was only made after transplantation on histology of the explanted heart. A third patient (Patient 6) underwent a pericardectomy for constrictive pericardial disease causing heart failure. Histology revealed amyloid deposition in and around the small blood vessels, including veins on the pericardial surface. This patient underwent heart transplantation for cardiac amyloidosis 3 months after pericardectomy. A fourth patient (Patient 18), initially thought to have AL amyloidosis, was subsequently characterized to have wild-type (senile) transthyretin amyloid. This discovery was made 61 months after the patient had received his transplant in 1991 and reflects progress in the methods available for typing amyloid deposits. Difficulty in the diagnosis of amyloidosis is a well recognized problem.24 The UK National Amyloid Center recently demonstrated that 34 out of 350 (10%)

patients with apparent sporadic AL amyloidosis do in fact have hereditary forms of the disease despite their lack of family history.25 All patients who are diagnosed to have amyloidosis should undergo immunohistochemical analysis of amyloid fibril type coupled with investigation of associated underlying disorders including DNA analysis when, as is often the case, definitive confirmation of AL type cannot be obtained.25–27 Precise characterization of hereditary amyloidosis is essential to enable consideration of curative liver transplantation in patients with variant TTR type, and to facilitate appropriate genetic counseling. Eligibility and Pre-Transplant Assessment Comprehensive assessment of patients with amyloid heart disease is required. Cardiac amyloidosis is always part of a systemic disease process, although the spectrum and likelihood of clinically significant extra-cardiac involvement varies substantially among the different fibril types. Clinically isolated cardiac involvement in AL amyloid, the commonest form, is rare and occurs in only about 4% of cases.4 In contrast, wild-type TTR (senile) amyloid virtually never causes dysfunction of other organs but is exceptionally rare in patients who are young enough to be considered for transplantation. SAP scintigraphy, although useful in determining the

Table 5. Duration of survival, cause of death, and pathologic features of note in the patients with non-AL amyloidosis Patient number 18 19

Age (years) sex 59 M 62 M

Survival (months) 124 ⫹ alive 31.7

20 21 22 23

35 51 54 62

F M M M

113⫹ alive 28⫹ alive 12⫹ alive 0.02

24

57 M

0.2⫹ alive

Mode of death Renal failure

Procedure — Autopsy

Amyloid distribution at postmortem examination/on biopsy

Other pathologic findings and features of note

Vessels of lung, spleen, bowel, prostate, adrenals, and nerves

Prostate carcinoma

— — — Heart failure

RVAD inserted Day 4 post-transplant for RV failure —

F, female; M, male; RV, right ventricle; RVAD, right ventricular assist device.

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graft amyloid was the norm.11,28,29 The inherent nature of certain amyloidogenic light chains regarding their propensity to cause cardiac disease has been elegantly demonstrated by infusing light chains from patients with cardiac AL amyloidosis into mice, which subsequently developed diastolic impairment.30 It is therefore imperative to suppress the supply of monoclonal light chains.

Figure 3. Five-year transplant survival plot following heart transplantation for patients with amyloid heart disease (solid line, n ⫽ 24) against patients transplanted for other causes (dotted line, n ⫽ 4,058) in the United Kingdom since 1980.

distribution and extent of amyloid in solid viscera, can fail to detect disease in some important sites. This occurred in one of our patients (Patient 9) who died in the peri-operative period due to extensive and undetected pulmonary involvement by AL amyloid. Although cardiac transplantation is feasible in amyloid, most patients with amyloidosis do not meet conventional criteria for eligibility. This is reflected by the fact that the 24 patients presented in this analysis represent less than 2% of patients with amyloidosis who have been referred to the UK National Amyloid Center. Survival in the AL Amyloid Patients Within the peri-operative period, mortality in the AL patient group was related to undetected extra-cardiac amyloid disease in 2 patients and to donor organ (heart) failure in the remaining patient. Among patients with AL amyloid who did not receive chemotherapy, amyloid deposition occurred in the graft in every case in which it was sought histologically, and progressive systemic amyloidosis contributed to mortality in 70% of patients. The United Kingdom experience with AL amyloid had gained initial optimism from what can now be appreciated to have been the extraordinarily successful outcome of the first patient to be transplanted.8 This patient developed graft amyloid involvement and underwent a multiple agent chemotherapy regimen 3 years after his transplant. The need for adjunctive chemotherapy generally became obvious from the findings of several series that confirmed that relatively rapid development of

Adjunctive Chemotherapy for AL Patients All forms of chemotherapy are unusually toxic in this group of patients due to impairment of vital organ function, and clinical improvement in successful cases is typically very delayed. Few, if any, therapies have been reported to be effective in treating diastolic heart failure, and low intensity oral chemotherapy usually acts too slowly to benefit patients with severe cardiac amyloid. Important developments in the management of AL amyloidosis include the introduction of doseintensive intravenous melphalan with peripheral blood stem cell rescue (autologous stem-cell transplantation),31,32 but this carries a procedural mortality of about 30% in patients with significant cardiac amyloid. We and others33,34 have confirmed that autologous stem-cell transplantation is feasible after heart transplantation, but even this complex tandem therapeutic protocol does not guarantee successful outcome since about 33% of plasma cell dyscrasias are refractory to high-dose chemotherapy. Recurrence of Amyloid in the Graft and Progression of Extra-Cardiac Amyloid By 1996, the United Network of Organ Sharing estimated that only 44 of 36,000 heart transplants performed in North America had been performed for cardiac amyloid.35 We have found that recurrence of amyloid in the donor heart occurred at an early stage in patients who did not receive chemotherapy (median period 11 months, range 5–30 months), but was confirmed histologically in the cardiac graft in only one of the AL patients who underwent post-transplant chemotherapy, 28 months after cardiac transplantation. Non-AL Amyloid Patients The non-AL patients are a heterogeneous group comprising individuals with amyloidosis of “wild type” TTR, variant TTR, and variant ApoAI types. The distinctions in fibril type are important in terms of the distribution and extent of systemic amyloid deposition, the natural history and extra-cardiac prognosis, and the potential for adjunctive treatments to suppress the supply of the respective amyloid fibril precursor proteins. The outcome in this group was influenced by the fact that 5 of 7 patients underwent multi-organ transplantation, comprising either combined heart and kidney or heart and

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liver. Our 12 and 24 month survival probabilities of 86% compare favorably with those reported from the International Society of Heart and Lung Transplantation study of multi-organ (heart and kidney) outcome of 76% and 67%, respectively.36 Although wild type TTR amyloid is a systemic process, clinically significant deposits are confined to the heart. It is usually a disease of the elderly, and both our patients were very unusual in presenting before 60 years of age.37 It is not known why wild-type transthyretin amyloidosis only occurs in the elderly, and whether recurrence of amyloid may eventually occur in cardiac grafts, but long-term recurrence-free survival demonstrated in our study supports the approach. About a dozen ApoAI variants cause hereditary amyloidosis, some of which are associated with predominant amyloid cardiomyopathy. Hereditary ApoAI amyloid deposits are often very extensive, but progression of the disease is often remarkably slow. For example, liver function may remain preserved for decades after very sub-stantial hepatic amyloid has been deposited. Although liver transplantation may ameliorate the course of the disease by reducing production of variant ApoAI, limited experience in renal transplantation in this particular form of hereditary amyloidosis suggests that clinically significant graft involvement tends to occur remarkably slowly. Indeed, renal grafts have continued to function well for over 20 years in 2 other patients under our care.38 In our patient with ApoAI Arg60, although histologic recurrence of ApoAI amyloid occurred in the donor heart 5 years after transplantation, both her cardiac and renal grafts continue to function normally after 10 years. The most recent SAP scan at 8 years post-transplant shows no measurable progression of her amyloid since her surgery. Current echocardiography in this patient shows normal left ventricular wall thickness (1.2 cm) and an ejection fraction of 77%. In variant transthyretin amyloidosis, virtually all of the genetically abnormal amyloidogenic protein is made in the liver, and liver transplantation has proved very effective in halting the progress of the associated amyloid neuropathy.17 However, severe cardiac involvement is frequent among patients with hereditary transthyretin amyloidosis, and it has become apparent that wild-type transthyretin is often laid down very rapidly on pre-existing amyloid deposits in the heart, but not in most other sites, following liver transplantation.39 – 42 The specificity of this phenomenon probably reflects the inherent propensity for wild-type TTR to be processed into amyloid fibrils in the heart. In our series here, 3 patients with hereditary transthyretin amyloidosis underwent heart and liver transplantation, 2 of whom survived the perioperative period. There has

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been no evidence of amyloid deposition in the transplanted hearts in these 2 latter patients, who had variant transthyretin Tyr77 and Glu89, respectively, supporting the hypothesis that myocardial deposition of wild-type transthyretin amyloid following liver transplantation requires there to be a pre-existing template of variant transthyretin amyloid. Limitations This study documents all patients within the UK who have undergone heart transplantation for amyloid heart disease, and although patient numbers are small, the study nevertheless represents the largest series to date. Analysis of survival and other measures of outcome are hampered by the heterogeneous nature of the acquired and hereditary amyloid types. Although differences in survival between the AL and non-AL groups were not significant, there was a trend in favor of the latter. Data from 10 of 24 patients included in this national review have previously been reported.8,10 This study is retrospective in nature and covers a period of 18 years, during which there have been substantial advances in both diagnostic techniques and therapies to treat the amyloidoses, as well as in the management of heart transplantation in general. Treatments were not allocated randomly and chemotherapy regimens for AL amyloid were not standardized. A treatment bias is unintentionally introduced by the retrospective selection of patients who have received post transplant chemotherapy, which cannot include those who did not survive the peri-operative period. CONCLUSIONS Overall, the survival of patients in the UK who have had cardiac transplants for amyloid heart disease has been poorer than those who have undergone heart transplantation generally, regardless of the type of amyloidosis, use of adjunctive chemotherapy or simultaneous transplantation of other organs. Recurrence of amyloid in the transplanted heart is common in AL patients, but this did not affect graft function or contribute to the mortality in the majority of cases. Recent improvements in the rationale and management of chemotherapy in AL amyloidosis, particularly the use of high-dose melphalan with stem cell rescue as a single procedure following cardiac transplantation, holds promise. Combined heart and liver or heart and kidney transplantation are feasible in patients with hereditary transthyretin and ApoAI amyloidosis respectively, and the results of heart transplantation are generally more favorable in patients with cardiac amyloid of non-AL type. This reflects the essentially isolated late onset nature of cardiac involvement in wild-type transthyretin amyloidosis, the very slow deposition of hereditary ApoAI amyloid, and correction of the inher-

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ited metabolic defect by simultaneous liver transplantation in variant transthyretin amyloidosis. The less favorable results of heart transplantation for amyloidosis than in general, and the frequent need for either adjuvant chemotherapy or combined organ transplantation indicate that stringent selection criteria and specialist therapeutic approaches need to be applied to this group of patients when considering heart transplantation. We wish to acknowledge the surgeons, physicians, and pathologists who gave permission and help in the collection of this data and the cooperation of the respective UK Transplant Units involved in this review: Dr Susan Stewart, Consultant Histopathologist, and Dr Jayan Parameshwar, Consultant Cardiologist, Papworth Hospital NHS Trust, Cambridge; Dr Cathy Corbishley, Consultant Histopathologist, St Georges Hospital, London; Dr Nicholas Brooks, Consultant Cardiologist, and Dr Paul Bishop, Consultant Histopathologist, South Manchester Hospitals NHS Trust, Manchester; Dr Allan McPhaden, Consultant Histopathologist, Glasgow Royal Infirmary, Glasgow; and Mr Peter Braidley, Consultant Cardiac Surgeon, and Dr Kim Suvarna, Consultant Histopathologist, Northern General Hospital; Sheffield. We also acknowledge the help of Pam Baldock and Aine Mooney, Transplant Coordinators at Royal Brompton and Harefield NHS Trust and of Phil Pocock, Senior Biostatistician, UK Transplant, Bristol. National transplant statistics were prepared by UK Transplant from the National Transplant Database maintained on behalf of transplant services in the UK and Republic of Ireland. REFERENCES 1. Glenner GG, Terry W, Harada M, Isersky C, Page D. Amyloid fibril proteins: proof of homology with immunoglobulin light chains by sequence analyses. Science 1971; 172:1150 –1. 2. Falk RH, Commenzo RL, Skinner M. The systemic amyloidosis. New Engl J Med 1997;337:898 –909. 3. Gertz MA, Kyle RA, Greipp PR. Response rates and survival in primary systemic amyloidosis. Blood 1991;77: 257–62. 4. Dubrey S, Cha K, Chamarsee B, Anderson J, Skinner M, Falk RH. Primary (AL) cardiac amyloidosis: symptoms, signs and non-invasive investigations in 232 patients. Q J Med 1998;91:141–57. 5. Benson MD. Inherited amyloidosis. J Med Genet 1991;28: 73–8. 6. Connors LH, Richardson AM, Theberge R, Costello CE. Tabulation of transthyretin (TTR) variants as of 1/1/2000. Amyloid 2000;7:54 –69. 7. Conner R, Hosenpud JD, Norman DJ, Pantely GA, Cobanoglu A, Starr A. Heart transplantation for cardiac amyloidosis: successful one year outcome despite recurrence of the disease. J Heart Transplantation 1988;7: 165–7.

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8. Hall R, Hawkins PN. Cardiac transplantation for AL amyloidosis; good quality of life is possible for several years. Br Med J 1994;309:1135–7. 9. Mc Gregor CGA, Rodeheffer RJ, Daly RC, et al. Heart transplantation in primary systemic amyloidosis. J Heart Lung Tranplant 1998;17:51 [Abstract]. 10. Dubrey SW, Burke M, Khaghani A, Hawkins P, Yacoub M, Banner N. Long term results of heart transplantation in patients with amyloid heart disease. Heart 2001;85: 202–7. 11. Hosenpud JD, DeMarco T, Frazier H, et al. Progression of systemic disease and reduced long term survival in patients with cardiac amyloidosis undergoing heart transplantation. Circulation 1991;84:338 –43. 12. McCarthy RE, Kasper EK. A review of the amyloidoses that infiltrate the heart. Clin Cardiol 1998;21:547–52. 13. Benson MD, Uemichi T. Transthyretin amyloidosis. Amyloid 1996;3:45–56. 14. Nichols WC, Dwulet FE, Liepnieks J, Benson MD. Variant apolipoprotein AI as a major constituent of a human hereditary amyloid. Biochem Biophys Res Commun 1988; 156:762–8. 15. Olsen LJ, Gertz MA, Edwards WD, et al. Senile cardiac amyloidosis with myocardial dysfunction: diagnosis by endomyocardial biopsy and immunohistochemistry. N Eng J Med 1987;317:738 –42. 16. Dubrey SW, Cha K, Simms RW, Skinner M, Falk RH. Electrocardiography, and Doppler echocardiography in secondary (AA) amyloidosis. Am J Cardiol 1996;77:313–5. 17. Holmgren G, Ericzon BG, Groth CG, et al. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 1993; 341:1113–6. 18. Hawkins PN, Lavender JP, Pepys MB. Evaluation of systemic amyloidosis by scintigraphy with labelled 123Ilabelled serum amyloid P component. N Engl J Med 1990;323:508 –13. 19. Hawkins PN, Pepys MB. Imaging amyloidosis with radiolabelled SAP. Eur J Nucl Med 1995;22:595–9. 20. Criteria Committee of the New York Heart Association. Diseases of the heart and blood vessels. Nomenclature and criteria for diagnosis Sixth edition 1964. Boston: Little, Brown and Co.. 21. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 1995;32:45–59. 22. Hongo M, Ikeda S. Echocardiographic assessment of the evolution of amyloid heart disease: a study with familial amyloid polyneuropathy. Circulation 1986;73:249 –56. 23. Billingham ME, Cary NRB, Hammond EM, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: heart rejection study group. J Heart Transplant 1990;9:587–93. 24. Conraads VM, Colpaert CG, Van Hoof V, Suhr OB, Vrints CJ. Systemic amyloidosis: diagnosis before treatment. J Heart Lung Transplant 2002;21:932–4. 25. Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. New Eng J Med 2002;346:1786 –91.

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26. Tan SY, Pepys MB. Amyloidosis. Histopathology 1994;25: 403–14. 27. Tennent GA. Isolation and characterization of amyloid fibrils from tissue. In Wetzel R, ed. Methods in enzymology. Amyloid, prions and other protein aggregates. Volume 309. San Diego: Academic Press, 1999, p.26 –47. 28. Valantine HA, Billingham ME. Recurrence of amyloid in a cardiac allograft four months after transplantation. J Heart Transplantation 1989;8:337–41. 29. Dubrey S, Simms RW, Skinner M, Falk R. Recurrence of primary (AL) amyloidosis in a transplanted heart with four-year survival. Am J Cardiol 1995;76:739 –41. 30. Liao R, Jain M, Teller P, Connors LH, et al. Infusions of light chains from patients with cardiac amyloidosis causes diastolic dysfunction in mouse hearts. Ciculation 2001; 104:1594 –7. 31. Comenzo RL, Vosburgh E, Falk RH, et al. Dose-intensive melphalan with blood stem-cell support for the treatment of AL amyloidosis: survival and responses in 25 patients. Blood 1998;91:3662–70. 32. Gertz MA, Lacy MQ, Dispenzieri A. Myeloablative chemotherapy with stem cell rescue for the treatment of primary systemic amyloidosis: a status report. Bone Marrow Transplant 2000;25:465–70. 33. Mohty M, Albat B, Fegeux N, Rossi JF. Autologous peripheral blood stem transplantation following heart transplantation for primary systemic amyloidosis. Leukemia Lymphoma 2001;41:221–3. 34. Comenzo RL. Primary systemic amyloidosis. Curr Treatment Options Oncol 2000;1:83–9. 35. Pelosi F, Jr, Capehart J, Roberts WC. Effectiveness of

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36.

37.

38.

39.

40.

41.

42.

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cardiac transplantation for primary (AL) cardiac amyloidosis. Am J Cardiol 1997;79:532–5. Narula J, Bennett LE, DiSalvo T, Hosenpud JD, Semigran MJ, Dec GW. Outcomes in recipients of combined heart-kidney transplantation: multiorgan, same-donor transplant study of the International Society of Heart and Lung Transplantation/United Network for Organ Sharing Scientific Registry. Transplantation 1997;63: 861–7. Westermark P, Sletten K, Johansson B, Cornwell GG, III. Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci USA 1990;87:2843–5. Persey MR, Booth DR, Booth SE, et al. Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I. Kidney Int 1998;53:276 –81. Dubrey SW, Davidoff R, Skinner M, Bergethon P, Lewis D, Falk R. Progression of ventricular wall thickening after liver transplantation for familial amyloidosis. Transplant 1997;64:74 –80. Pomfret EA, Lewis WD, Jenkins RL, et al. Effect of orthotopic liver transplantation on the progression of familial amyloidotic polyneuropathy. Transplantation 1998;65:918 –25. Stangou AJ, Hawkins PN, Heaton ND, et al. Progressive cardiac amyloidosis following liver transplantation for familial amyloid polyneuropathy. Transplantation 1998;66:229 – 33. Yazaki M, Tokuda T, Nakamura A, et al. Cardiac amyloid in patients with familial amyloid polyneuropathy consists of abundant wild-type transthyretin. Biochem Biophys Res Commun 2000;274:702–6.