END STAGE CARDIAC AMYLOIDOSIS: PREDICTORS OF SURVIVAL TO CARDIAC TRANSPLANTATION AND LONG TERM OUTCOMES

Abstract

Background

Orthotopic heart transplant (OHT) followed by myeloablative chemotherapy and autologous stem cell transplant (ASCT) has been successful in the treatment of light chain (AL) cardiac amyloidosis. The purpose of this study is to identify predictors of survival to OHT in patients with end stage heart failure due to AL amyloidosis, and compare post-OHT survival of cardiac amyloid patients to that of other cardiomyopathy patients undergoing OHT.

Methods

From January 2000 to June 2011, 31 patients with end stage heart failure secondary to AL amyloidosis were listed for OHT at Massachusetts General Hospital (MGH). Univariate and multivariate regression analyses identified predictors of survival to OHT. Kaplan-Meier analysis compared survival between MGH amyloidosis patients and the Scientific Registry of Transplant Recipients (SRTR) non-amyloid cardiomyopathy patients.

Results

Low body mass index (BMI) was the only predictor of survival to OHT in patients with end stage heart failure due to cardiac amyloidosis. Survival of cardiac amyloid patients who died prior to receiving a donor heart was only 63 ± 45 days after listing. Patients who survived to OHT received a donor organ at 53 ± 48 days after listing. Survival of AL amyloidosis patients on the waitlist was less than patients waitlisted for all other non-amyloid diagnoses. The long-term survival of transplanted amyloid patients was no different than the survival of non-amyloid, restrictive (p=0.34), non-amyloid dilated (p=0.34) or all non-amyloid cardiomyopathy patients (p=0.22) in the SRTR database.

Conclusions

Those that survive to OHT followed by ASCT have a survival rate similar to other cardiomyopathy patients undergoing OHT. However, more than one third of the patients died awaiting OHT. The only predictor of survival to OHT in AL amyloidosis patients was low BMI, which correlated with shorter waitlist time. To optimize the survival of these patients, access to donor organs must be improved.

In light chain (AL) amyloidosis, amyloid fibrils derived from clonal lambda or kappa immunoglobulin light chains deposit abnormally in organs. Cardiac involvement is apparent echocardiographically in 60% of AL amyloidosis patients at the time of diagnosis, with clinical evidence of heart failure in 69% of patients.¹ The median survival of AL amyloidosis patients presenting with any heart failure symptom is 8.5 months² and even less for end-stage heart failure pateints.

Medical therapy for cardiac AL amyloidosis is directed at treating the underlying plasma cell dyscrasia and includes melphalan, proteasome inhibitors such as bortezomib and immunomodulators such as lenalidomide.^{3, 4} In select patients, high dose melphalan chemotherapy, supported by ASCT, is first-line therapy.⁵ However, patients with cardiac involvement are at an increased risk of treatment-related mortality.⁶ When both NT-proBNP and troponin I are elevated, patients have poorer outcomes and a median survival of only 7 months without chemotherapy and/or ASCT.⁷ These patients often require OHT for end stage heart failure symptoms prior to beginning medical therapy. Notably, OHT without treatment of the underlying plasma cell dyscrasia results in suboptimal results as well. Without subsequent medical therapy, patents’ post- transplant survival is only 39% at 48 months.^{8, 9} Furthermore, in patients who require cardiac transplant prior to initiation of medical therapy, without subsequent ASCT, amyloid recurres in cardiac allografts after a median of 11 months.⁹

Recently a number of centers have reported success treating patient with end stage heart failure due to cardiac amyloid with OHT followed by myeloablative chemotherapy and ASCT.^10–13 However, the limited availability of donor hearts results in significant waiting periods, during which light chain deposition continues, with consequent progression of organ dysfunction. The purpose of this study is to identify predictors of survival to OHT in patients with end stage cardiac amyloidosis, and compare the survival of transplanted, amyloid cardiomyopathy patients to transplanted, non-amyloid cardiomyopathy patients.

Methods

Patient Selection

The study population consisted of 31 patients with end stage cardiac amyloidosis presenting to the Massachusetts General Hospital Heart Failure Center or the Boston University School of Medicine/Boston Medical Center Amyloidosis Center with New York Heart Association (NYHA) Class III or IV heart failure despite optimal medical therapy. Institutional Review Board approval was obtained to analyze the outcomes of these patients. The diagnosis of AL amyloidosis was made using serum and urine electrophoresis with immunofixation studies, measurement of serum-free light-chain concentrations, and bone marrow biopsies. Cardiac amyloidosis was confirmed by endomyocardial biopsy with Congo red staining in all patients. All patients underwent both echocardiography and coronary angiography. The diagnosis of heart failure was confirmed by increased ventricular filling pressures, depressed cardiac index, or both.

In addition to the routine cardiac transplant evaluation, patients underwent testing to assess the extent and functional impact of their extracardiac amyloid involvement (Table 1). Glomerular filtration rate was calculated using the MDRD equation.¹⁴ Patients with a serum creatinine greater than 2.0 mg/dl and/or greater than 1g/day proteinuria underwent renal biopsy. Gastric, duodenal and/or colonic biopsies were obtained at both random sites and areas suspicious for amyloid infiltration. The presence of autonomic dysfunction was determined by presence of orthostatic hypotension, defined as ≥20 mmHg fall in systolic blood pressure within 2–5minutes of standing.

Table 1.

Functional and anatomic assessment of amyloid organ involvement

Cardiac	Pulmonary	Renal	Gastrointestinal	Neurological
Right Heart Catheterization	Chest Radiograph	Estimated Glomerular Filtration Rate	AST, ALT, Alkaline Phosphatase, Total Bilirubin, Direct Bilirubin	Orthostatic Vital Signs
Endomyocardial Biopsy	Chest CT	24 Hour Urine Protein Excretion	Right Upper Quadrant Ultrasound
Echocardiography	Pulmonary Function Tests with Diffusion Capacity	Renal Biopsy (if indicated)*	Upper and Lower Endoscopy with Biopsy

AST, aspartate aminotransferase; ALT, alanine aminotransferase; CT, computed tomography

^*Indications include: serum creatinine greater than 2.0 mg/dl or greater than 1 g/day proteinuria

Cardiac Transplantation

The 31 patients were listed with the Organ Procurement and Transplantation Network (OPTN). Inotropic or mechanical support was used to optimize patients for transplant, and waiting list status was determined without consideration of the underlying diagnosis. OHT was performed using the bicaval anastomatic technique. Immunosuppression was administered according to the standard institutional protocol. All patients discharged from the hospital received a calcineurin inhibitor (cyclosporine 4–8 mg/kg/d with a target trough level of 200–300 ng/mL or tacrolimus 0.15– 0.30 mg/kg/d with a target trough level of 5–15 ng/mL), mycophenolate mofetil (1.0 –2.0 g/day), and prednisone (0.4–0.5 mg/kg/day).

Autologous Stem-Cell Transplantation (ASCT)

The protocol for ASCT has been described previously.¹³ After OHT, when prednisone was decreased to ≤10 mg/day and mycophenolate therapy could be tapered off, granulocyte colony stimulating factor (G-CSF, 5mg/kg) was administered for 3 days and apheresis was performed on the fourth day. High dose melphalan was then administered (140– 200 mg/m² over 2 days). Stem cell infusions (day 0) were performed 48 hours after the second dose of melphalan. The intended total target cell dose was ≥2×10⁶ CD34 cells/kg.

Follow-Up of Recipients of Cardiac and Stem-Cell Transplants

Patients were followed with serial endomyocardial biopsies, stained with hematoxylin-eosin to assess for cardiac rejection and with Congo red to assess for amyloid recurrance. Specimens with positive Congo red staining underwent indirect immunofluorescence staining for light chain proteins. Patients underwent echocardiography, right and left heart catheterization with endomyocardial biopsy, and coronary angiography annually. Serum protein electrophoresis and urine protein electrophoresis with immunofixation and serum free light chains were obtained at 3, 6, 9, and 12 months after ASCT, then annually. Bone marrow biopsy was performed between 3 and 12 months after ASCT, then annually.

Data Collection

From January 2000 to June 2011, 31 patients with end stage heart failure from AL cardiac amyloid infiltration were listed for cardiac transplantation at Massachusetts General Hospital. Baseline weight for calculation of BMI was obtained at patients’ evaluation for cardiac transplant listing after cardiac filling pressures were medically optimized based on data obtained at right heart catheterization. Cardiac data was obtained by physical exam, laboratory testing, right heart catheterization and echocardiography. Bone marrow dyscrasia characteristics and the ratio of kappa and lambda light chain concentrations were recorded. The extent of extracardiac amyloid involvement in the lungs, kidneys, gastrointestinal tract and neurological system was also assessed as outlined in Table 1. The time from diagnosis, evaluation initiation and listing to OHT or death, was recorded. The characteristics of those that survived to OHT were compared with those that died before OHT in order to identify predictors to survival.

Statistical Analysis

Statistical analyses were performed using Stata 8.0 (StataCorp, TX). All data is presented as mean ± standard deviation or standard error. The Shapiro-Wilk test was used to test for normality of variables obtained from baseline demographic, hemodynamic and organ involvement data. The Student’s t-test or Mann-Whitney test, depending on the underlying normality of the variable, was used to assess for differences in continuous variables between the two groups. Univariate and multivariate Cox regression analyses were performed to identify predictors of survival to OHT.

To assess for post-transplant survival differences, the Scientific Registry of Transplant Recipients (SRTR) was queried for patients between January 2000 and June 2011. The survival of SRTR patients was compared to the survival of the amyloid patients who underwent transplantation using Kaplan-Meier analysis. All amyloid cardiomyopathy patients were excluded from the SRTR database for comparison. Remaining SRTR patients were divided into 3 subgroups: non-amyloid restrictive cardiomyopathy, dilated cardiomyopathy and all (non-amyloid) cardiomyopathy patients.

Results

The 31 listed patients were evaluated for cardiac transplantation using standard UNOS criteria (Figure 1). Of those listed, 18 (58.1%) survived to OHT while 11 (35.4%) did not. Two remained on the cardiac waiting list at the end of this study. After OHT, 4 patients died. One patient died after OHT but before ASCT of gastrointestinal hemorrhage and sepsis. The other 3 patients died after ASCT, 2 of recurrent amyloid and 1 of sepsis (Figure 1). The average time from OHT to ASCT was 157 ± 28d in those without recurrence (n=10) and the average time from OHT to ASCT in those with recurrence was 202± 61d (n= 4; p=0.72).

Figure 1.

Flow chart of all AL amyloidosis patients listed for OHT at Massachusetts General Hospital between 2000 and 2011. Eighteen of the thirty-one listed underwent transplant. Of those 18, 14 went on to ASCT, 1 died prior to ASCT and 3 were awaiting ASCT at the end of the study. Of the 14 that underwent both heart and stem cell transplant, 11 were alive at follow-up and 3 died after both procedures. Eleven patients listed for heart transplant did not survive to transplant. Two patients remain listed for transplant at the time of this analysis.

There was no difference in age, gender, race or NYHA class at the time of transplant evaluation between those patients who survived to OHT compared to those that did not (Table 2). For those ultimately receiving OHT, the average time from listing to transplant was 53 ± 48 days and for those who died prior to OHT, the average waitlist time was 63 ± 45 days (p=0.58). The hazard rate for mortality while awaiting cardiac transplant was 0.24/month.

Table 2.

Characteristics of patients listed as candidates for orthotopic heart transplantation (OHT) who either underwent OHT or died prior to receiving a donor organ

	OHT	Died before OHT	p-value
N	18	11
Age (years)	56 ± 7	54 ± 9	0.53
Gender (# male, %)	13 (72%)	7 (64%)	0.69
Race (# white, %)	16 (89%)	9 (82%)	0.62
NYHA Class (3,4)	14, 4	9, 2	1.00
Weight (kg)	73 ± 9	84 ± 22	0.08
BMI (kg/m2)	25 ± 3	26 ± 4	0.24
Troponin-T (ng/mL)	0.23 ± 0.44 (n=10)	0.17 ± 0.13 (n=7)	0.48
NT-proBNP (pg/mL)	8815 ± 6417 (n=10)	4702 ± 4242 (n=4)	0.24
PT-INR	1.3 ± 0.3	1.3 ± 0.2	0.75
Time from Diagnosis to OHT or to death (days)	205 ± 94	309 ± 300	0.18
Time from Evaluation to OHT or to death (days)	77 ± 51	85 ± 64	0.73
Time from Listing to OHT or to death (days)	53 ± 48	63 ± 45	0.58

NYHA, New York Heart Association; BMI, body mass index. Reported as mean ± standard deviation.

There were no differences in hemodynamic or echocardiographic characteristics between those patients that survived to OHT and those that did not (Table 3). Patients who died before OHT more frequently required intra-aortic balloon pump placement (IABP; p=0.05). Patients who survived to OHT had a higher rate of milrinone use (p=0.05) or multiple inotrope therapy (p=0.01).

Table 3.

Hemodynamic characteristic at evaluation for orthotopic heart transplant

	OHT (n=18)	Died before OHT (n=11)	p-value
Heart Rate (bpm)	86 ± 9	81 ± 15	0.26
Mean Arterial Pressure (mmHg)	72.1 ± 2	71.6 ± 2	0.61
Pulse Pressure (mmHg)	36 ± 12	32 ± 9	0.38
Stroke Volume Index (mL/m2)	25 ± 6	24 ± 9	0.76
Right Atrial Pressure (mmHg)	13 ± 6	14 ±4	0.65
Pulmonary Capillary Wedge Pressure (mmHg)	21 ± 6	21 ± 5	0.95
Cardiac Index (L/min/m2)	2.1 ± 0.5	1.9 ± 0.7	0.23
Pulmonary Vascular Resistance (dyne-sec/cm5)	179 ± 73	171 ± 158	0.85
Left Ventricular Ejection Fraction (%)	39 ± 11	46 ± 8	0.08
Left Ventricular Mass Index (g/m2)	308 ± 92	258 ± 64	0.09
Mechanical Support (# patients, %)
LVAD	1 (6%)	1 (9%)	1.00
IABP	3 (17%)	6 (55%)	0.05
Inotropic Support (# patients, %)
Levophed	0	1 (9%)	0.33
Dopamine	4 (22%)	1 (9%)	0.62
Dobutamine	12 (67%)	6 (55%)	0.70
Milrinone	11 (61%)	2 (18%)	0.05
Multiple Inotropes	12 (67%)	1 (9%)	0.01
Electrophysiologic Devices (# patients, %)
PPM	1 (6%)	2 (18%)	0.54
AICD	3 (17%)	2 (18%)	1.00

LVAD, left ventricular assist device; IABP, intra-aortic balloon pump; PPM, permanent pacemaker; AICD, automatic implantable cardioverter defibrillator. Reported as mean ± standard deviation.

Pulmonary, renal, gastrointestinal and neurologic function was assessed in all patients undergoing evaluation, and biopsy was performed, if necessary, to assess for amyloid deposition (Table 4). Patients who survived to OHT had a lower free light chain difference than those who did not survive to OHT (p=0.05). There was also a trend toward a higher light chain ratio in those survived to OHT (p=0.06). There were no significant differences in pulmonary or renal involvement. There was no difference in the localization of amyloid deposition in the gastrointestinal biopsies between those that survived to OHT and those that did not (Table 4).

Table 4.

Hematologic characteristics and extracardiac organ involvement of patients listed for OHT

	OHT (n=18)	Died before OHT (n=11)	p-value
% Plasma cells in bone marrow	10 ± 5	13 ± 4	0.17
Light Chain Type (lambda, kappa)	14,4	10, 1	0.62
Light Chain Ratio (lower/higher)	0.08 ± 0.06 (n=13)	0.03 ± 0.03 (n=9)	0.06
Free Light Chain Difference (higher-lower, mg/L)	242 ± 214 (n=13)	680 ± 657 (n=9)	0.04
Pleural Effusions (# patients, %)	7 (39%)	6 (55%)	0.47
FEV1 (% predicted)	72 ± 14	80 ± 14	0.22
FVC (% predicted)	75 ± 14	78 ± 16	0.66
FEV1/FVC (% predicted)	97 ± 8	103 ± 6	0.06
DLCO/VA (% predicted)	68 ± 20	85 ± 18	0.06
eGFR(mL/mm/1.73m2)	59 ± 14	60 ± 19	0.88
24h Urinary Protein Excretion (mg)	959 ± 1710	539 ± 480	0.72
Total Bilirubin (mg/dL)	1.2± 1.7	0.9 ± 0.6	0.84
Alkaline Phosphatase (U/L)	102 ± 63	97 ± 42	0.80
Amyloid Involvement by GI Biopsy (# patients, %)
Mucosal	8 (44%)	5 (45%)	0.14
Submucosal	5 (28%)	2 (18%)	0.21
Perivascular	6 (33%)	2 (18%)	0.21
Autonomic Dysfunction (# patients, %)	3 (17%)	1 (9%)	1.00

FEV1, forced expiratory volume in one second; FVC, forced vital capacity; DLCO/VA, diffusing capacity corrected for alveolar ventilation; eGFR, estimated glomerular filtration rate.¹⁴ Reported as mean ± standard deviation.

Univariate analysis of all demographic, hemodynamic and organ-involvement characteristics identified lower body weight (p=0.04) and body mass indices (BMI; p=0.05) as predictors of survival to OHT from the time waitlisted (Table 5A). Multivariate analysis yielded BMI as the only significant predictor of survival to OHT (p=0.012, Table 5B). The relative risk of survival to OHT for patients with BMI above the median was 0.8163 (95% CI = 0.6891–0.9670). Correlation analysis demonstrated that both increased weight (p=0.027) and increased BMI (p=0.004) positively correlated with increased waitlist time (Table 5C).

Table 5.

Predictors of survival to orthotopic heart transplant

A. Univariate analysis, using Cox regression
Covariate	Relative risk of survival to OHT	95% CI	p-value
Weight (per lb)	0.9834	0.9677 to 0.9993	0.04
BMI (per kg/m2)	0.8679	0.7520 to 1.0017	0.05

B. Multivariate analysis, using Cox regression
Covariate	Relative risk of survival to OHT	95% CI	p-value
BMI (per kg/m2)	0.8163	0.6891 to 0.9670	0.02

C. Correlation analysis to time on the wait list
Covariate	Correlation coefficient	95% CI	p-value
Weight (per lb)	0.4112	0.0526 to 0.6758	0.03
BMI (per kg/m2)	0.5225	0.1929 to 0.7461	0.01

OHT, orthotopic heart transplant; BMI, body mass index, CI, confidence interval

Patients with AL amyloidosis had a lower cumulative probability of survival on the transplant waitlist when compared to patients with non-amyloid indications listed for transplantation at Massachusetts General Hospital during the same time period (Figure 2, p<0.001). To compare the waitlist survival of patients with AL amyloidosis and end stage heart failure to non-amyloid patients, Cox regression analysis adjusting for age and BMI was performed. Amyloidosis patients had a mortality hazard ratio of 4.7 (95% CI 2.8–11.8, p<0.001) while waitlisted relative to non-amyloid patients.

Figure 2.

Kaplan-Meier survival curves for AL amyloidosis patients and non-amyloid patients waitlisted for heart transplantation at Massachusetts General Hospital from 2000–2011. The cumulative probability of survival on the transplant waitlist was lower for patients with AL amyloidosis than for patients with other diagnoses listed for transplant during the same time period (p<0.001).

There was no difference in the long term survival of cardiac amyloid patients who underwent OHT and age and gender-matched non-amyloid, restrictive (p=0.34) or dilated cardiomypathy (p=0.34) patients who underwent OHT during the same period of time from the SRTR database. Furthermore, the survival of transplanted cardiac amyloid patients compared to all (non-amyloid) SRTR patients who underwent OHT was not significantly different (p=0.22; Figure 3).

Figure 3.

Kaplan-Meier survival curves for amyloidosis patients who underwent heart transplant and a contemporaneous age-matched control group of patients from the Scientific Registry of Transplant Recipients (SRTR) database. There was no difference in survival between amyloidosis patients and non-amyloid restrictive cardiomyopathy patients (p=0.34), dilated cardiomyopathy patients (p=0.34), or all non-amyloid patients who underwent heart transplant (p=0.22).

Discussion

In this study, the only predictor of survival to OHT among patients with end stage heart failure secondary to cardiac amyloidosis was a low BMI, which correlated with a shorter wait list time. In addition, we observed that survival after OHT was similar to the survival of restrictive, dilated and all non-amyloid SRTR cardiomyopathy patients.

Survival after OHT/ASCT was primarily determined by the successful treatment of the underlying plasma cell dyscrasia and its systemic complications, as two of the three patients that died had a recurrence of their underlying light chain disease. This was evidenced by re-elevation of light chain amyloid levels and the reappearance of amyloid deposition in the transplanted heart. One patient who underwent OHT but was unable to undergo ASCT died because of amyloid involvement of the duodenum and jejunum leading to uncontrollable gastrointestinal hemorrhage and sepsis. Three patients whose amyloid recurred after high dose melphalan/ASCT received newer disease modifying therapies such as lenalidomide^15–17 and bortezomib.^18–21 These therapies decrease light chain production^21–23 and may prevent the progression of amyloidosis in patients with continued or recurrent light chain production after undergoing OHT/ASCT. We postulate that survival after OHT for patients with end stage cardiomyopathy secondary to cardiac amyloidosis will improve even further as these therapies become more widely used.

The excellent survival after OHT/ASCT, similar to that observed at other centers^{8, 9, 11–13} and similar to other patients undergoing transplant for restrictive and dilated cardiomyopathies, suggests that OHT/ASCT is an appropriate therapy for selected AL amyloidosis patients with end stage heart failure. The major reason for death prior to OHT in patients awaiting a donor heart was refractory heart failure secondary to cardiac amyloidosis and the limited utility of traditional support modalities. Neurohormonal blockade with ACE inhibitors or beta blockers is poorly tolerated in cardiac amyloidosis patients due to adverse hemodynamic effects on patients with diastolic dysfunction. Autonomic dysfunction may also contribute to intolerance of these medications.²⁶ In addition, β-adrenergic antagonists can exacerbate cardiac conduction abnormalities in patients with cardiac amyloid infiltration.

Decompensated heart failure patients with cardiac amyloid are also difficult to support with both inotropic agents^27–32 and/or mechanical devices.³³ In this study, patients who survived to OHT had higher rates of milrinone and multiple-inotrope use than those that died before OHT. On the other hand, the vasodilatory side effects associated with milrinone limit its use in patients with end stage amyloid cardiomyopathy who often have vascular infiltration and preexisting autonomic dysfunction. Patients that died prior to OHT had a higher use of IABP’s - which likely reflects their poorer clinical status. Previous small case studies suggest that IABP’s may be effective at hemodynamic support for amyloid patients, but their utility in long term support is limited.^{34, 35} There was only one patient in each group that was supported with a left ventricular assist device (LVAD). This is likely due to the infiltrative nature of cardiac amyloid which makes the left ventricular (LV) cavity size small, rendering patients susceptible to inadequate filling and “suction events” with left ventricular assist devices.³³ We have observed that a small LV cavity size also limits the use of catheter-based cardiac assist devices (Impella) because of dislodgement and hemolysis. Of the six patients in this study who died of cardiac arrest or progressive heart failure while awaiting a donor organ, all were on inotropes and two had mechanical circulatory support devices.

The limited survival of patients once waitlisted for OHT, and the fact that the period of time on the waitlist was similar between those that those that died prior to OHT and those successfully transplanted, suggests that there is finite window of time for end stage cardiac amyloid patients to receive a donor heart. The cause of death in the majority of patients who died prior to OHT was either primary cardiac death or related to poor systemic organ perfusion. This observation reflects the limited means of providing sustained circulatory support for end stage cardiac amyloidosis patients, either pharmacologic or mechanical.³⁶ One of the important implications of our study is that patients with end stage cardiac amyloid must undergo expeditious evaluation of their eligibility for OHT. In addition, current criteria for level of support used to determine waitlist status appears to disadvantage cardiac amyloid patients because it does not adequately capture the deadly combination of a rapidly progressive disease and the ineffectiveness of ionotropic and mechanical support, compared to patients with other causes of advanced heart failure. Given this, earlier transplant referral of amyloid patients with cardiac involvement and an expedited transplant work up and listing may improve survival.

We also observed that the only predictor of survival of end stage cardiac amyloid patients to OHT was low BMI, a variable that correlated with a shorter waitlist time. It is important to note that these weights were obtained at the time of listing, when all patients were optimized on diuretic, inotropic and mechanical therapy. The favorable prognostic value of a lower weights and BMI likely reflects the eligibility of these patients for a greater number of donor organs, thereby improving their odds of receiving an organ. Neither the type of light chain amyloidosis nor the extent of systemic disease affected the likelihood of survival to transplant. This supports our contention that the first major barrier to the long term survival of patients with end stage cardiac amyloidosis is access to donor hearts.

There are several limitations to our retrospective cohort study. First, the sample size was small due to the rare incidence of AL cardiac amyloidosis. This may have limited our ability to detect other clinical variables that predict survival to transplant. Second, this was a retrospective, observational study which may have led to selection bias. Nonetheless, this cohort of end stage cardiac amyloidosis patients waitlisted for OHT is among the largest to date.

Further investigations are needed to determine additional characteristics that predict survival in cardiac amyloidosis patients. A multi-institutional effort is currently underway to identify these characteristics as well as the most effective treatments targeting light chain production as patients await a donor organ. Given the aggressive nature of cardiac AL amyloidosis, revision of the definition of transplant waitlist status should be considered, in order to give these patients priority based on their diagnosis. This can permit the allocation of donor organs to patients with a limited survival who do not benefit from standard approaches used for hemodynamic support, such as inotropes and mechanical circulatory support.