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Heart and heart-liver transplantation in patients with hemochromatosis
IJCA-25167; No of Pages 3 International Journal of Cardiology xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Short communication
Heart and heart-liver transplantation in patients with hemochromatosis Monique R. Robinson ⁎,1, Sadeer G. Al-Kindi 1, Guilherme H. Oliveira Advanced Heart Failure and Transplantation Center, Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.
a r t i c l e
i n f o
Article history: Received 3 March 2017 Received in revised form 26 May 2017 Accepted 20 June 2017 Available online xxxx
a b s t r a c t Background: Hemochromatosis predisposes to dilated or restrictive cardiomyopathy which can progress to endstage heart failure, requiring the use of advanced heart therapies including heart (HT) and heart liver (HLT) transplantation. Little is known about the characteristics and outcomes of these patients. Methods and results: We queried the United Network for Organ Sharing (UNOS) registry for all patients listed for HT or HLT for a diagnosis of ‘hemochromatosis’ between 1987 and 2014. Waitlist and post-transplantation outcomes were compared between patients with hemochromatosis (HT vs HLT) and other etiologies. Of the 81,356 adults listed for heart transplantation, 23 patients with hemochromatosis were identified (16 listed for HLT; and 7 listed for HT). Compared with other etiologies, HC patients were younger (39 vs 51 years, p b 0.0001), and more likely to need inotropes (56.5% vs 25.6%, p = 0.003) and mechanical ventilation (13% vs 3.4%, p = 0.041). Cumulative hazards of waitlist mortality or delisting were higher in hemochromatosis patients than for other etiologies of heart failure (p b 0.001). There were 4 HT and 4 HLT during the study period. Posttransplantation, patients with HC had a 1- and 2-year cumulative survival of 88% and 75%, respectively. Conclusions: Both HT and HLT are viable options for patients with hemochromatosis. Patients with hemochromatosis are younger with increased wait-list mortality compared with other etiologies. © 2017 Published by Elsevier Ireland Ltd.
1. Introduction
2. Methods 2.1. Dataset
Hemochromatosis, whether primary or secondary, predisposes to cardiomyopathy due to myocardial iron deposition. Phenotypically, this can manifest as a dilated or restrictive cardiomyopathy [1]. Over time, these patients can progress to end-stage heart failure, necessitating the use of advanced therapies. Heart transplantation (HT) alone and heart-liver transplantation (HLT) have been used to treat hemochromatosis patients with end-stage heart failure. The coexistence of hepatic disease with advanced heart failure of any etiology portends worse prognosis, even in ambulatory patients [2]. Little is known about the wait-list characteristics and prognosis of hemochromatosis awaiting HT or HLT. In this study, we interrogate a group of advanced heart failure patients with hemochromatosis listed for single (HT) and dual organ (HLT) transplantation and further compare them to patients listed for HT for non-hemochromatosis heart failure.
Abbreviations: HT, Heart transplantation; HLT, Heart and liver transplantation; LT, Liver transplantation; UNOS, United Network for Organ Sharing. ⁎ Corresponding author at: Section of Advanced Heart Failure and Transplantation, Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Mailstop Lakeside 5038, Cleveland, OH 44106, United States. E-mail address: [email protected] (M.R. Robinson). 1 MRR and SGA are co-first authors.
For this study, we used the United Network for Organ Sharing (UNOS) thoracic transplantation files. UNOS records and reports all solid organ listings in the United States through a mandatory program. Patient demographics and clinical characteristics are collected at listing, at transplantation, and at regular follow-ups. Data are entered through an electronic collection system by the transplantation centers and are reported by UNOS. 2.2. Cohort selection We included all adult patients listed for heart transplantation (1987–2014) with a diagnosis of “hemochromatosis” in the free text field. These were compared with adults with heart failure of other etiologies during the same period. 2.3. Statistical analysis Categorical variables are presented as numbers and percentages and compared with χ2 test. Continuous variables are presented as means and standard deviations, and compared with t-test. All tests are two sided. Time-dependent variables (death and delisting) were analyzed with the Kaplan-Meier method and compared among groups using the logrank test and Cox proportional hazard models, censoring for other outcomes.
3. Results Of the 81,356 adults listed for heart transplantation, 23 patients with hemochromatosis were identified. 16 of these patients were listed for HLT (Table 1).
http://dx.doi.org/10.1016/j.ijcard.2017.06.075 0167-5273/© 2017 Published by Elsevier Ireland Ltd.
Please cite this article as: M.R. Robinson, et al., Heart and heart-liver transplantation in patients with hemochromatosis, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.075
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M.R. Robinson et al. / International Journal of Cardiology xxx (2017) xxx–xxx
Table 1 Characteristics of patients by etiology of heart failure and organ involved. Heart-liver
Number of patients Age at listing (years) Male gender White Initial status 1A 1B Old 1 2 7 Systolic PAP (mm Hg) Diastolic PAP (mm Hg) Mean PAP (mm Hg) PCWP (mm Hg) CO (L/min) Serum albumin (mg/dL) Serum creatinine (mg/dL) IABP use Inotrope use Ventilator use Time on the waitlist (months)
Heart only
All
HC
Other
P
HC
Other
P
HC
Other
16 43 ± 10 14 (88%) 0
351 47 ± 13 262 (75%) 34 (10%)
– 0.247 0.376 0.380 0.022
7 30 ± 14 4 (57%) 7 (100%)
80,982 51 ± 12 62,731 (78%) 76,307 (94%)
– b0.001 0.194 1.00 0.004
23 39 ± 12 18 (78.3%) 20 (87.0%)
81,333 51 ± 12 62,993 (77.5%) 61,866 (76.1%)
6 (38%) 4 (25%) 0 6 (38%) 0 35 ± 11 19 ± 7 26 ± 8 18 ± 6 18.1 ± 6.2 3.1 ± 0.6 1.7 ± 1.0 2 (13%) 7 (44%) 1 (6%) 12 ± 25
38 (11%) 76 (22%) 14 (4%) 220 (63%) 2 (1%) 40 ± 15 20 ± 8 28 ± 10 20 ± 8 4.7 ± 1.7 3.6 ± 0.8 1.4 ± 1.0 8 (2%) 104 (30%) 7 (2%) 10 ± 14
0 1 (14%) 4 (57%) 1 (14%) 1 (14%) 44 ± 14 27 ± 5 30 ± 6 26 ± 6 3.7 ± 1.0 – – 1 (14%) 6 (86%) 2 (29%) 4±7
9119 (12%) 14,605 (19%) 10,108 (13%) 40,959 (53%) 3223 (4%) 45 ± 15 22 ± 9 31 ± 11 21 ± 9 4.3 ± 1.4 – – 3371 (4%) 20,749 (26%) 2737 (3%) 11 ± 20
6 (26.1%) 5 (21.7%) 4 (17.4%) 7 (30.4%) 1 (4.3%) 38 ± 12 21 ± 7 27 ± 8 20 ± 7 4.4 ± 1.2 3.2 ± 0.6 1.6 ± 1.0 3 (13%) 13 (56.5%) 3 (13%) 10 ± 21
9157 (11.7%) 14,681 (18.7%) 41,179 (52.5%) 10,122 (12.9%) 3225 (4.1%) 45 ± 15 22 ± 9 31 ± 11 21 ± 9 4.3 ± 1.4 3.7 ± 0.7 1.4 ± 1.0 3379 (4.2%) 20,853 (25.6%) 2744 (3.4%) 11 ± 20
0.254 0.776 0.629 0.488 0.874 0.07 0.479 0.065 0.267 0.302 0.698
0.917 0.256 0.837 0.190 0.364 – – 0.26 0.002 0.02 0.368
P b0.001 1.0 0.005 0.153
0.03 0.649 0.149 0.775 0.857 0.061 0.424 0.068 0.003 0.041 0.682
Abbreviations: HC = hemochromatosis; HF = heart failure; PAP = pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; CO = cardiac output; IABP = intra-aortic balloon pump.
Compared with other etiologies, patients with hemochromatosis were younger (39 vs. 51 years, p b 0.0001), and more likely to be of white ethnicity (87 vs. 76%, p = 0.005). Hemochromatosis patients had lower systolic pulmonary artery pressures (37.5 vs. 44.9 mm Hg, p = 0.03), were more likely to receive inotropes (56.5% vs. 25.6%, p = 0.003) and more often needed mechanical ventilation (13% vs. 3.4%, p = 0.041) pre-transplantation. Time on the waitlist for transplantation was similar between hemochromatosis and non-hemochromatosis heart failure patients. Table 1 shows the characteristics of patients by etiology and organ. Compared with patients listed for HT alone, HLT listed patients were older (42.8 vs. 30.3 years, p = 0.022), and more likely to be listed as status 1A (37.5 vs. 0%, p = 0.004). Hemodynamically, patients listed for HLT, had lower diastolic pulmonary artery pressure (19.4 vs. 26.8 mm Hg, p = 0.048) and lower pulmonary capillary wedge pressure (18 vs. 26 mm Hg, p = 0.026). There was also a trend towards lower use of inotrope use in the HLT group compared to the HT group (43.8% vs. 85.7%, p = 0.089).
Of the 23 patients with hemochromatosis listed for transplantation, 9 (39%) died on the wait list, 2 (8.7%) became too sick and were delisted, 2 (9%) recovered and were assessed as not requiring transplantation, and 8 (35%) underwent transplantation (4 HT and 4 HLT). 1 patient remains on the waiting list for HLT and the fate of 1 patient is unknown. Cumulative hazards of waitlist mortality or delisting were higher in hemochromatosis patients than for other etiologies of heart failure (6-month rate of 51% vs 15%, p b 0.001) (Fig. 1). When stratified by organ, there was no statistically-significant difference in wait-list mortality/delisting between hemochromatosis and other etiologies when listed for dual heart-liver transplantation (p = 0.113); however, hemochromatosis patients listed for heart transplantation had significantly higher wait-list mortality/delisting than other etiologies listed for heart transplantation (p = 0.006) (Fig. 1). In patients with HC, univariable predictors of wait-list mortality/ delisting include serum creatinine (HR 3.74 per 1 mg/dL increment, p = 0.012), mechanical ventilation (HR 32.6, p = 0.003) and a trend
Fig. 1. Wait-list and post-transplantation outcomes of transplantation: (A) wait-list outcomes by etiology, (B) wait-list outcomes by etiology and organ, and (C) post transplantation outcomes.
Please cite this article as: M.R. Robinson, et al., Heart and heart-liver transplantation in patients with hemochromatosis, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.075
M.R. Robinson et al. / International Journal of Cardiology xxx (2017) xxx–xxx
for inotrope use (HR 3.39, p = 0.078). There was no association between wait-list mortality/delisting and age (p = 0.81), sex (p = 0.38), co-listing for liver transplantation (p = 0.99), systolic PAP (p = 0.80), diastolic PAP (p = 0.83), PCWP (p = 0.83), cardiac output (p = 0.75), list year (p = 0.91), serum albumin (p = 0.78), UNOS status 2 vs 1A (p = 0.30), or status 1B vs 1A (p = 0.15), or BMI (p = 0.86). Following transplantation, 4 hemochromatosis patients had died (3 following HT and 1 following HLT) after a median follow-up of 7.9 years. This represented a 1-, and 2-year cumulative survival of 88% and 75%, respectively compared with 86% and 82% for other etiologies (p = 0.573 for hemochromatosis vs. non-hemochromatosis).
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In conclusion, hemochromatosis patients with end stage cardiomyopathy are younger, sicker and have increased wait-list mortality/ delisting. Earlier listing for transplantation might reduce waitlist mortality and morbidity. While HT and HLT seem to be viable options for treatment, future research should explore the role for durable mechanical support in these patients. Disclosures The authors declare no conflicts of interest. No funding was received for this study.
4. Discussion Funding Cardiomyopathy is a major risk factor for death in patients with hemochromatosis [1,3,4]. There is a small case series of patients with iron-overload cardiomyopathy who underwent heart transplantation with good outcomes [5]. Heart [6] and heart-liver transplantation [7] have been used as treatment modalities in hemochromatosis patients with end-stage cardiomyopathy [6]. Earlier work had suggested that patients with hereditary hemochromatosis had worse outcomes following liver transplantation (LT) compared to those who underwent LT for other causes of liver failure [8,9]. One of the postulated reasons for this disparity was coexisting cardiac pathology, including cardiomyopathy [10]. More recent retrospective analyses [11] have demonstrated better LT outcomes for patients with hemochromatosis but do not directly address the potential role of cardiomyopathy or dual organ transplantation in improved survival. Our analysis highlights the increased morbidity of patients with hemochromatosis awaiting transplantation who are more likely to die or become too ill for transplantation. Patients with hemochromatosis represent a younger, sicker population more commonly requiring hemodynamic and ventilatory support. A more aggressive approach to the hemochromatosis patient with hepatopathy and cardiomyopathy, with earlier listing for transplantation might be one way to mitigate their waitlist morbidity. There was a trend for hemochromatosis patients to have increased use of intra-aortic balloon pumps and less use of ventricular assist devices, than patients without hemochromatosis. This raises the question as to whether durable mechanical support might be useful as a bridge to transplantation or as destination therapy in patients with hemochromatosis [12]. This is an interesting area of clinical research as these may be viable treatment options for patients ineligible or waiting for transplantation. Although patients with hemochromatosis require more support as they wait for transplantation, once transplanted they have mortality outcomes comparable to those transplanted for other heart failure causes. However, this finding should be interpreted with caution given the small sample size. Prior case reports were unable to opine on the advisability for HLT due to the short period of follow up that had elapsed before their publication. In our observation with a longer follow up (~ 8 years), there was no clear increase in mortality among patients with hemochromatosis who underwent HLT. This is consistent with previous studies that showed satisfactory outcomes with HLT [13], probably similar to those for HT or LT alone [14,15]. Treatment strategies for patients with HC and cardiomyopathy require further investigation. Prior reports of iron-depletion therapies have shown promising results in reversing iron-overload cardiomyopathy in selected patients [12,16,17]. It is also unclear if those patients benefit from mechanical circulatory support as a bridge to transplantation, recovery, or as destination therapy [12]. This study is limited by the retrospective design and the small sample size, which is reflective of the rarity of the disease. We lack data on the etiology of hemochromatosis (i.e. primary vs secondary), the duration of the disease, and the management of hemochromatosis prior to transplantation (e.g. venipuncture and erythrocytaphersis).
None. Authorship Monique R. Robinson designed the study, analyzed the data and wrote the manuscript. Sadeer G Al-Kindi designed the study, obtained data, performed the statistical analyses, analyzed the data, and wrote the first draft. Guilherme H Oliveira designed the study, analyzed the data, and revised the manuscript. All authors approved the final manuscript. References [1] D.T. Kremastinos, D. Farmakis, Iron overload cardiomyopathy in clinical practice, Circulation 124 (2011) 2253–2263. [2] T.S. Kato, G.R. Stevens, J. Jiang, P.C. Schulze, N. Gukasyan, M. Lippel, et al., Risk stratification of ambulatory patients with advanced heart failure undergoing evaluation for heart transplantation, J Heart Lung Transplant 32 (2013) 333–340. [3] C. Niederau, R. Fischer, A. Purschel, W. Stremmel, D. Haussinger, G. Strohmeyer, Long-term survival in patients with hereditary hemochromatosis, Gastroenterology 110 (1996) 1107–1119. [4] A. Pietrangelo, Hereditary hemochromatosis—a new look at an old disease, N. Engl. J. Med. 350 (2004) 2383–2397. [5] A.E. Caines, J. Kpodonu, M.G. Massad, R. Chaer, A. Evans, J.C. Lee, et al., Cardiac transplantation in patients with iron overload cardiomyopathy, J Heart Lung Transplant 24 (2005) 486–488. [6] M.M. Koerner, G. Tenderich, K. Minami, E. zu Knyphausen, H. Mannebach, K. Kleesiek, et al., Heart transplantation for end-stage heart failure caused by iron overload, Br. J. Haematol. 97 (1997) 293–296. [7] N.F. Olivieri, P.P. Liu, G.D. Sher, P.A. Daly, P.D. Greig, P.J. McCusker, et al., Brief report: combined liver and heart transplantation for end-stage iron-induced organ failure in an adult with homozygous beta-thalassemia, N. Engl. J. Med. 330 (1994) 1125–1127. [8] V.E. Kilpe, H. Krakauer, R.E. Wren, An analysis of liver transplant experience from 37 transplant centers as reported to Medicare, Transplantation 56 (1993) 554–561. [9] K.V. Kowdley, T. Hassanein, S. Kaur, F.J. Farrell, D.H. Van Thiel, E.B. Keeffe, et al., Primary liver cancer and survival in patients undergoing liver transplantation for hemochromatosis, Liver Transpl. Surg. 1 (1995) 237–241. [10] N.D. Grace, Liver transplantation for hemochromatosis: an ironic dilemma, Liver Transpl. Surg. 1 (1995) 234–236. [11] L. Yu, G.N. Ioannou, Survival of liver transplant recipients with hemochromatosis in the United States, Gastroenterology 133 (2007) 489–495. [12] E. Rombout-Sestrienkova, N. De Jonge, K. Martinakova, C. Klopping, K.P. van Galen, A. Vink, et al., End-stage cardiomyopathy because of hereditary hemochromatosis successfully treated with erythrocytapheresis in combination with left ventricular assist device support, Circ. Heart Fail. 7 (2014) 541–543. [13] H.J. Reich, M. Awad, A. Ruzza, M.A. De Robertis, D. Ramzy, N. Nissen, et al., Combined heart and liver transplantation: the Cedars-Sinai experience, Transplant. Proc. 47 (2015) 2722–2726. [14] E.C.N.A. DePasquale, M. Gayheart, L. Reardon, M. Deng, A. Ardehali, Outcomes of heart vs. heart liver transplantation: UNOS registry analysis, J. Heart Lung Transplant. 33 (2014) S158-S. [15] R.M. Cannon, M.G. Hughes, C.M. Jones, M. Eng, M.R. Marvin, A review of the United States experience with combined heart-liver transplantation, Transpl. Int. 25 (2012) 1223–1228. [16] L. Tauchenová, B. Křížová, M. Kubánek, S. Fraňková, V. Melenovský, J. Tintěra, et al., Successful treatment of iron-overload cardiomyopathy in hereditary hemochromatosis with deferoxamine and deferiprone, Can. J. Cardiol. 32 (2016) (1574. e1-. e3). [17] R. Huijskes, K. Hoogenberg, A. Wiesfeld, M. Pijl, I. van Gelder, Phlebotomies as a treatment of serious heart failure due to haemochromatosis: a case report, Neth. Heart J. 17 (2009) 438–441.
Please cite this article as: M.R. Robinson, et al., Heart and heart-liver transplantation in patients with hemochromatosis, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.075
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Short communication
Heart and heart-liver transplantation in patients with hemochromatosis Monique R. Robinson ⁎,1, Sadeer G. Al-Kindi 1, Guilherme H. Oliveira Advanced Heart Failure and Transplantation Center, Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, United States.
a r t i c l e
i n f o
Article history: Received 3 March 2017 Received in revised form 26 May 2017 Accepted 20 June 2017 Available online xxxx
a b s t r a c t Background: Hemochromatosis predisposes to dilated or restrictive cardiomyopathy which can progress to endstage heart failure, requiring the use of advanced heart therapies including heart (HT) and heart liver (HLT) transplantation. Little is known about the characteristics and outcomes of these patients. Methods and results: We queried the United Network for Organ Sharing (UNOS) registry for all patients listed for HT or HLT for a diagnosis of ‘hemochromatosis’ between 1987 and 2014. Waitlist and post-transplantation outcomes were compared between patients with hemochromatosis (HT vs HLT) and other etiologies. Of the 81,356 adults listed for heart transplantation, 23 patients with hemochromatosis were identified (16 listed for HLT; and 7 listed for HT). Compared with other etiologies, HC patients were younger (39 vs 51 years, p b 0.0001), and more likely to need inotropes (56.5% vs 25.6%, p = 0.003) and mechanical ventilation (13% vs 3.4%, p = 0.041). Cumulative hazards of waitlist mortality or delisting were higher in hemochromatosis patients than for other etiologies of heart failure (p b 0.001). There were 4 HT and 4 HLT during the study period. Posttransplantation, patients with HC had a 1- and 2-year cumulative survival of 88% and 75%, respectively. Conclusions: Both HT and HLT are viable options for patients with hemochromatosis. Patients with hemochromatosis are younger with increased wait-list mortality compared with other etiologies. © 2017 Published by Elsevier Ireland Ltd.
1. Introduction
2. Methods 2.1. Dataset
Hemochromatosis, whether primary or secondary, predisposes to cardiomyopathy due to myocardial iron deposition. Phenotypically, this can manifest as a dilated or restrictive cardiomyopathy [1]. Over time, these patients can progress to end-stage heart failure, necessitating the use of advanced therapies. Heart transplantation (HT) alone and heart-liver transplantation (HLT) have been used to treat hemochromatosis patients with end-stage heart failure. The coexistence of hepatic disease with advanced heart failure of any etiology portends worse prognosis, even in ambulatory patients [2]. Little is known about the wait-list characteristics and prognosis of hemochromatosis awaiting HT or HLT. In this study, we interrogate a group of advanced heart failure patients with hemochromatosis listed for single (HT) and dual organ (HLT) transplantation and further compare them to patients listed for HT for non-hemochromatosis heart failure.
Abbreviations: HT, Heart transplantation; HLT, Heart and liver transplantation; LT, Liver transplantation; UNOS, United Network for Organ Sharing. ⁎ Corresponding author at: Section of Advanced Heart Failure and Transplantation, Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Mailstop Lakeside 5038, Cleveland, OH 44106, United States. E-mail address: [email protected] (M.R. Robinson). 1 MRR and SGA are co-first authors.
For this study, we used the United Network for Organ Sharing (UNOS) thoracic transplantation files. UNOS records and reports all solid organ listings in the United States through a mandatory program. Patient demographics and clinical characteristics are collected at listing, at transplantation, and at regular follow-ups. Data are entered through an electronic collection system by the transplantation centers and are reported by UNOS. 2.2. Cohort selection We included all adult patients listed for heart transplantation (1987–2014) with a diagnosis of “hemochromatosis” in the free text field. These were compared with adults with heart failure of other etiologies during the same period. 2.3. Statistical analysis Categorical variables are presented as numbers and percentages and compared with χ2 test. Continuous variables are presented as means and standard deviations, and compared with t-test. All tests are two sided. Time-dependent variables (death and delisting) were analyzed with the Kaplan-Meier method and compared among groups using the logrank test and Cox proportional hazard models, censoring for other outcomes.
3. Results Of the 81,356 adults listed for heart transplantation, 23 patients with hemochromatosis were identified. 16 of these patients were listed for HLT (Table 1).
http://dx.doi.org/10.1016/j.ijcard.2017.06.075 0167-5273/© 2017 Published by Elsevier Ireland Ltd.
Please cite this article as: M.R. Robinson, et al., Heart and heart-liver transplantation in patients with hemochromatosis, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.075
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M.R. Robinson et al. / International Journal of Cardiology xxx (2017) xxx–xxx
Table 1 Characteristics of patients by etiology of heart failure and organ involved. Heart-liver
Number of patients Age at listing (years) Male gender White Initial status 1A 1B Old 1 2 7 Systolic PAP (mm Hg) Diastolic PAP (mm Hg) Mean PAP (mm Hg) PCWP (mm Hg) CO (L/min) Serum albumin (mg/dL) Serum creatinine (mg/dL) IABP use Inotrope use Ventilator use Time on the waitlist (months)
Heart only
All
HC
Other
P
HC
Other
P
HC
Other
16 43 ± 10 14 (88%) 0
351 47 ± 13 262 (75%) 34 (10%)
– 0.247 0.376 0.380 0.022
7 30 ± 14 4 (57%) 7 (100%)
80,982 51 ± 12 62,731 (78%) 76,307 (94%)
– b0.001 0.194 1.00 0.004
23 39 ± 12 18 (78.3%) 20 (87.0%)
81,333 51 ± 12 62,993 (77.5%) 61,866 (76.1%)
6 (38%) 4 (25%) 0 6 (38%) 0 35 ± 11 19 ± 7 26 ± 8 18 ± 6 18.1 ± 6.2 3.1 ± 0.6 1.7 ± 1.0 2 (13%) 7 (44%) 1 (6%) 12 ± 25
38 (11%) 76 (22%) 14 (4%) 220 (63%) 2 (1%) 40 ± 15 20 ± 8 28 ± 10 20 ± 8 4.7 ± 1.7 3.6 ± 0.8 1.4 ± 1.0 8 (2%) 104 (30%) 7 (2%) 10 ± 14
0 1 (14%) 4 (57%) 1 (14%) 1 (14%) 44 ± 14 27 ± 5 30 ± 6 26 ± 6 3.7 ± 1.0 – – 1 (14%) 6 (86%) 2 (29%) 4±7
9119 (12%) 14,605 (19%) 10,108 (13%) 40,959 (53%) 3223 (4%) 45 ± 15 22 ± 9 31 ± 11 21 ± 9 4.3 ± 1.4 – – 3371 (4%) 20,749 (26%) 2737 (3%) 11 ± 20
6 (26.1%) 5 (21.7%) 4 (17.4%) 7 (30.4%) 1 (4.3%) 38 ± 12 21 ± 7 27 ± 8 20 ± 7 4.4 ± 1.2 3.2 ± 0.6 1.6 ± 1.0 3 (13%) 13 (56.5%) 3 (13%) 10 ± 21
9157 (11.7%) 14,681 (18.7%) 41,179 (52.5%) 10,122 (12.9%) 3225 (4.1%) 45 ± 15 22 ± 9 31 ± 11 21 ± 9 4.3 ± 1.4 3.7 ± 0.7 1.4 ± 1.0 3379 (4.2%) 20,853 (25.6%) 2744 (3.4%) 11 ± 20
0.254 0.776 0.629 0.488 0.874 0.07 0.479 0.065 0.267 0.302 0.698
0.917 0.256 0.837 0.190 0.364 – – 0.26 0.002 0.02 0.368
P b0.001 1.0 0.005 0.153
0.03 0.649 0.149 0.775 0.857 0.061 0.424 0.068 0.003 0.041 0.682
Abbreviations: HC = hemochromatosis; HF = heart failure; PAP = pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; CO = cardiac output; IABP = intra-aortic balloon pump.
Compared with other etiologies, patients with hemochromatosis were younger (39 vs. 51 years, p b 0.0001), and more likely to be of white ethnicity (87 vs. 76%, p = 0.005). Hemochromatosis patients had lower systolic pulmonary artery pressures (37.5 vs. 44.9 mm Hg, p = 0.03), were more likely to receive inotropes (56.5% vs. 25.6%, p = 0.003) and more often needed mechanical ventilation (13% vs. 3.4%, p = 0.041) pre-transplantation. Time on the waitlist for transplantation was similar between hemochromatosis and non-hemochromatosis heart failure patients. Table 1 shows the characteristics of patients by etiology and organ. Compared with patients listed for HT alone, HLT listed patients were older (42.8 vs. 30.3 years, p = 0.022), and more likely to be listed as status 1A (37.5 vs. 0%, p = 0.004). Hemodynamically, patients listed for HLT, had lower diastolic pulmonary artery pressure (19.4 vs. 26.8 mm Hg, p = 0.048) and lower pulmonary capillary wedge pressure (18 vs. 26 mm Hg, p = 0.026). There was also a trend towards lower use of inotrope use in the HLT group compared to the HT group (43.8% vs. 85.7%, p = 0.089).
Of the 23 patients with hemochromatosis listed for transplantation, 9 (39%) died on the wait list, 2 (8.7%) became too sick and were delisted, 2 (9%) recovered and were assessed as not requiring transplantation, and 8 (35%) underwent transplantation (4 HT and 4 HLT). 1 patient remains on the waiting list for HLT and the fate of 1 patient is unknown. Cumulative hazards of waitlist mortality or delisting were higher in hemochromatosis patients than for other etiologies of heart failure (6-month rate of 51% vs 15%, p b 0.001) (Fig. 1). When stratified by organ, there was no statistically-significant difference in wait-list mortality/delisting between hemochromatosis and other etiologies when listed for dual heart-liver transplantation (p = 0.113); however, hemochromatosis patients listed for heart transplantation had significantly higher wait-list mortality/delisting than other etiologies listed for heart transplantation (p = 0.006) (Fig. 1). In patients with HC, univariable predictors of wait-list mortality/ delisting include serum creatinine (HR 3.74 per 1 mg/dL increment, p = 0.012), mechanical ventilation (HR 32.6, p = 0.003) and a trend
Fig. 1. Wait-list and post-transplantation outcomes of transplantation: (A) wait-list outcomes by etiology, (B) wait-list outcomes by etiology and organ, and (C) post transplantation outcomes.
Please cite this article as: M.R. Robinson, et al., Heart and heart-liver transplantation in patients with hemochromatosis, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.075
M.R. Robinson et al. / International Journal of Cardiology xxx (2017) xxx–xxx
for inotrope use (HR 3.39, p = 0.078). There was no association between wait-list mortality/delisting and age (p = 0.81), sex (p = 0.38), co-listing for liver transplantation (p = 0.99), systolic PAP (p = 0.80), diastolic PAP (p = 0.83), PCWP (p = 0.83), cardiac output (p = 0.75), list year (p = 0.91), serum albumin (p = 0.78), UNOS status 2 vs 1A (p = 0.30), or status 1B vs 1A (p = 0.15), or BMI (p = 0.86). Following transplantation, 4 hemochromatosis patients had died (3 following HT and 1 following HLT) after a median follow-up of 7.9 years. This represented a 1-, and 2-year cumulative survival of 88% and 75%, respectively compared with 86% and 82% for other etiologies (p = 0.573 for hemochromatosis vs. non-hemochromatosis).
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In conclusion, hemochromatosis patients with end stage cardiomyopathy are younger, sicker and have increased wait-list mortality/ delisting. Earlier listing for transplantation might reduce waitlist mortality and morbidity. While HT and HLT seem to be viable options for treatment, future research should explore the role for durable mechanical support in these patients. Disclosures The authors declare no conflicts of interest. No funding was received for this study.
4. Discussion Funding Cardiomyopathy is a major risk factor for death in patients with hemochromatosis [1,3,4]. There is a small case series of patients with iron-overload cardiomyopathy who underwent heart transplantation with good outcomes [5]. Heart [6] and heart-liver transplantation [7] have been used as treatment modalities in hemochromatosis patients with end-stage cardiomyopathy [6]. Earlier work had suggested that patients with hereditary hemochromatosis had worse outcomes following liver transplantation (LT) compared to those who underwent LT for other causes of liver failure [8,9]. One of the postulated reasons for this disparity was coexisting cardiac pathology, including cardiomyopathy [10]. More recent retrospective analyses [11] have demonstrated better LT outcomes for patients with hemochromatosis but do not directly address the potential role of cardiomyopathy or dual organ transplantation in improved survival. Our analysis highlights the increased morbidity of patients with hemochromatosis awaiting transplantation who are more likely to die or become too ill for transplantation. Patients with hemochromatosis represent a younger, sicker population more commonly requiring hemodynamic and ventilatory support. A more aggressive approach to the hemochromatosis patient with hepatopathy and cardiomyopathy, with earlier listing for transplantation might be one way to mitigate their waitlist morbidity. There was a trend for hemochromatosis patients to have increased use of intra-aortic balloon pumps and less use of ventricular assist devices, than patients without hemochromatosis. This raises the question as to whether durable mechanical support might be useful as a bridge to transplantation or as destination therapy in patients with hemochromatosis [12]. This is an interesting area of clinical research as these may be viable treatment options for patients ineligible or waiting for transplantation. Although patients with hemochromatosis require more support as they wait for transplantation, once transplanted they have mortality outcomes comparable to those transplanted for other heart failure causes. However, this finding should be interpreted with caution given the small sample size. Prior case reports were unable to opine on the advisability for HLT due to the short period of follow up that had elapsed before their publication. In our observation with a longer follow up (~ 8 years), there was no clear increase in mortality among patients with hemochromatosis who underwent HLT. This is consistent with previous studies that showed satisfactory outcomes with HLT [13], probably similar to those for HT or LT alone [14,15]. Treatment strategies for patients with HC and cardiomyopathy require further investigation. Prior reports of iron-depletion therapies have shown promising results in reversing iron-overload cardiomyopathy in selected patients [12,16,17]. It is also unclear if those patients benefit from mechanical circulatory support as a bridge to transplantation, recovery, or as destination therapy [12]. This study is limited by the retrospective design and the small sample size, which is reflective of the rarity of the disease. We lack data on the etiology of hemochromatosis (i.e. primary vs secondary), the duration of the disease, and the management of hemochromatosis prior to transplantation (e.g. venipuncture and erythrocytaphersis).
None. Authorship Monique R. Robinson designed the study, analyzed the data and wrote the manuscript. Sadeer G Al-Kindi designed the study, obtained data, performed the statistical analyses, analyzed the data, and wrote the first draft. Guilherme H Oliveira designed the study, analyzed the data, and revised the manuscript. All authors approved the final manuscript. References [1] D.T. Kremastinos, D. Farmakis, Iron overload cardiomyopathy in clinical practice, Circulation 124 (2011) 2253–2263. [2] T.S. Kato, G.R. Stevens, J. Jiang, P.C. Schulze, N. Gukasyan, M. Lippel, et al., Risk stratification of ambulatory patients with advanced heart failure undergoing evaluation for heart transplantation, J Heart Lung Transplant 32 (2013) 333–340. [3] C. Niederau, R. Fischer, A. Purschel, W. Stremmel, D. Haussinger, G. Strohmeyer, Long-term survival in patients with hereditary hemochromatosis, Gastroenterology 110 (1996) 1107–1119. [4] A. Pietrangelo, Hereditary hemochromatosis—a new look at an old disease, N. Engl. J. Med. 350 (2004) 2383–2397. [5] A.E. Caines, J. Kpodonu, M.G. Massad, R. Chaer, A. Evans, J.C. Lee, et al., Cardiac transplantation in patients with iron overload cardiomyopathy, J Heart Lung Transplant 24 (2005) 486–488. [6] M.M. Koerner, G. Tenderich, K. Minami, E. zu Knyphausen, H. Mannebach, K. Kleesiek, et al., Heart transplantation for end-stage heart failure caused by iron overload, Br. J. Haematol. 97 (1997) 293–296. [7] N.F. Olivieri, P.P. Liu, G.D. Sher, P.A. Daly, P.D. Greig, P.J. McCusker, et al., Brief report: combined liver and heart transplantation for end-stage iron-induced organ failure in an adult with homozygous beta-thalassemia, N. Engl. J. Med. 330 (1994) 1125–1127. [8] V.E. Kilpe, H. Krakauer, R.E. Wren, An analysis of liver transplant experience from 37 transplant centers as reported to Medicare, Transplantation 56 (1993) 554–561. [9] K.V. Kowdley, T. Hassanein, S. Kaur, F.J. Farrell, D.H. Van Thiel, E.B. Keeffe, et al., Primary liver cancer and survival in patients undergoing liver transplantation for hemochromatosis, Liver Transpl. Surg. 1 (1995) 237–241. [10] N.D. Grace, Liver transplantation for hemochromatosis: an ironic dilemma, Liver Transpl. Surg. 1 (1995) 234–236. [11] L. Yu, G.N. Ioannou, Survival of liver transplant recipients with hemochromatosis in the United States, Gastroenterology 133 (2007) 489–495. [12] E. Rombout-Sestrienkova, N. De Jonge, K. Martinakova, C. Klopping, K.P. van Galen, A. Vink, et al., End-stage cardiomyopathy because of hereditary hemochromatosis successfully treated with erythrocytapheresis in combination with left ventricular assist device support, Circ. Heart Fail. 7 (2014) 541–543. [13] H.J. Reich, M. Awad, A. Ruzza, M.A. De Robertis, D. Ramzy, N. Nissen, et al., Combined heart and liver transplantation: the Cedars-Sinai experience, Transplant. Proc. 47 (2015) 2722–2726. [14] E.C.N.A. DePasquale, M. Gayheart, L. Reardon, M. Deng, A. Ardehali, Outcomes of heart vs. heart liver transplantation: UNOS registry analysis, J. Heart Lung Transplant. 33 (2014) S158-S. [15] R.M. Cannon, M.G. Hughes, C.M. Jones, M. Eng, M.R. Marvin, A review of the United States experience with combined heart-liver transplantation, Transpl. Int. 25 (2012) 1223–1228. [16] L. Tauchenová, B. Křížová, M. Kubánek, S. Fraňková, V. Melenovský, J. Tintěra, et al., Successful treatment of iron-overload cardiomyopathy in hereditary hemochromatosis with deferoxamine and deferiprone, Can. J. Cardiol. 32 (2016) (1574. e1-. e3). [17] R. Huijskes, K. Hoogenberg, A. Wiesfeld, M. Pijl, I. van Gelder, Phlebotomies as a treatment of serious heart failure due to haemochromatosis: a case report, Neth. Heart J. 17 (2009) 438–441.
Please cite this article as: M.R. Robinson, et al., Heart and heart-liver transplantation in patients with hemochromatosis, Int J Cardiol (2017), http://dx.doi.org/10.1016/j.ijcard.2017.06.075