Background
Anthracyclines and chest irradiation are known to cause cardiomyopathy and progressive heart failure (HF), requiring advanced therapies. Left ventricular assist devices (LVADs) and heart transplantation have traditionally been underused in cancer survivors owing to concerns regarding cancer-related life expectancy, cancer recurrence, bleeding complications, and lack of evidence of benefit and safety in this population.¹ Emerging new data from large HF registries have shed new light on the outcomes of cancer survivors undergoing LVAD and heart transplantation. In particular, the International Society for Heart & Lung Transplantation International Registry for Heart and Lung Transplantation (an international registry of thoracic transplantation performed since 1982), the United Network for Organ Sharing (UNOS) registry (a U.S. registry for solid organ transplantation performed since 1987), and the INTERagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) (a U.S. registry of durable ventricular assist devices implanted since 2006) provide unique aspects of advanced therapies in this population that require careful consideration.

Epidemiology
Although the exact number of patients with advanced HF as a result of cancer therapies is unknown, registry data suggest that chemotherapy-induced cardiomyopathy (CCMP) accounts for 1-2% of patients with advanced HF, and radiation-induced cardiomyopathy accounts for even less.^2-4 These percentages, however, most likely underestimate the true prevalence of advanced HF in cancer survivors because many are either ineligible or lack access. Nevertheless, the majority of these patients are younger female survivors of breast cancer and hematologic malignancies who have absent history of obesity, smoking, diabetes, and hypertension.

Biventricular Involvement in CCMP
Right ventricular failure is almost twice as common in CCMP as it is in other cardiomyopathies.² This is clinically important when considering these patients for LVAD. In fact, among patients who underwent LVAD implantation, 19% required right ventricular assist support concomitantly or post-operatively (compared with 11% in dilated cardiomyopathy and 9% in ischemic cardiomyopathy).² Not surprisingly, those who required biventricular support were at significantly higher risk of death. Thus, it is essential to meticulously assess right ventricle function before LVAD implantation in patients with CCMP.

Outcomes of LVAD and Heart Transplantation in CCMP
A review of the INTERMACS registry showed that the survival of patients with CCMP treated with LVADs is comparable to that of ischemic and dilated cardiomyopathies, despite different baseline characteristics between groups.^1-3 Patients with CCMP had higher risk of long-term bleeding but similar rates of infections, neurological events, or device malfunction. In a review of the International Society for Heart & Lung Transplantation International Registry for Heart and Lung Transplantation, patients with CCMP submitted to heart transplantation were more likely to develop post-transplant infection and malignancy but had comparable long-term survival and lower rejection rates compared with non-ischemic cardiomyopathies.³ Contrary to general belief, the higher rates of post-transplantation malignancies were from de-novo and not recurrent malignancies.

Heart Transplant in Radiation-Induced Cardiomyopathy
Chest irradiation is known to cause coronary artery disease, valvular heart disease, pericardial disease, and restrictive cardiomyopathy leading to HF.⁵ However, advanced HF therapies are limited in patients with radiation-induced cardiomyopathy because their restrictive physiology and small ventricles make LVADs unsuitable. Heart transplantation, however, has been performed in a small number of patients. In a series of all 75 patients in the UNOS registry transplanted for radiation-induced cardiomyopathy, early mortality was significantly higher than other restrictive and dilated cardiomyopathies (6-month mortality was 21% for radiation-induced restrictive cardiomyopathy, 8% for other restrictive cardiomyopathies, and 9% for other cardiomyopathies).⁴ This likely reflects complicated re-do sternotomies, with longer post-operative length of stay and high incidence of dialysis initiation. The outcomes of LVAD therapy in this cohort remain largely unknown.

Conclusions
Registry data suggest that LVAD and heart transplantation are safe and effective in carefully selected patients with CCMP. Biventricular failure, bleeding, and infections are more prevalent in patients with CCMP and require cautious evaluation prior to consideration of LVAD and heart transplantation. Patients with radiation-induced CCMP, however, have high early post-transplant mortality and worse outcomes.

Table 1: Characteristics of Chemotherapy and Radiation-Induced Cardiomyopathy in Advanced HF Registries

	Orthotopic Heart Transplantation for CCMP (UNOS)6	Mechanical Circulatory Support for CCMP (INTERMACS)2	Orthotopic Heart Transplantation for Restrictive Cardiomyopathies (UNOS)4
Number of patients	453	75	87
Percentage of overall population	0.8%	2%	0.2%
Age	44	53	49
Female	66%	72%	62%
White/Caucasian	74%	64%	85%
Body mass index	—	26	26
Diabetes mellitus	8%	25%	—
Inotropes	48%	89%	24%
Intra-aortic balloon pump	—	32%	2.3%
Implantable cardioverter defibrillator	—	66%	40%
Cardiac index	—	2.0	—
Ventilator	—	9%	2%
Creatinine	—	1.4	1.2
Mean pulmonary artery pressure	30.6	—	30.7
Previous malignancy
Breast	24%	52%	—
Hematologic	17%	33%	—
Other/Unknown	58.6%	15%	—

References

1. Oliveira GH, Qattan MY, Al-Kindi S, Park SJ. Advanced heart failure therapies for patients with chemotherapy-induced cardiomyopathy. Circ Heart Fail 2014;7:1050-8.
2. Oliveira GH, Dupont M, Naftel D, et al. Increased need for right ventricular support in patients with chemotherapy-induced cardiomyopathy undergoing mechanical circulatory support: outcomes from the INTERMACS Registry (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol 2014;63:240-8.
3. Oliveira GH, Hardaway BW, Kucheryavaya AY, Stehlik J, Edwards LB, Taylor DO. Characteristics and survival of patients with chemotherapy-induced cardiomyopathy undergoing heart transplantation. J Heart Lung Transplant 2012;31:805-10.
4. Al-Kindi SG, Oliveira GH. Heart Transplantation Outcomes in Radiation-Induced Restrictive Cardiomyopathy. J Card Fail 2016;22:475-8.
5. Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 2009;339:b4606.
6. Lenneman AJ, Wang L, Wigger M, et al. Heart transplant survival outcomes for adriamycin-dilated cardiomyopathy. Am J Cardiol 2013;111:609-12.

Keywords: Anthracyclines, Body Mass Index, Breast, Breast Neoplasms, Cardiomyopathy, Dilated, Cardiomyopathy, Restrictive, Coronary Artery Disease, Creatinine, Defibrillators, Implantable, Diabetes Mellitus, Heart Failure, Heart Transplantation, Heart, Heart Valve Diseases, Heart Ventricles, Heart-Assist Devices, Heart-Lung Transplantation, Hematologic Neoplasms, Hypertension, Obesity, Prevalence, Pulmonary Artery, Renal Dialysis, Smoking, Sternotomy, Cardiotoxicity, Cardiotoxins

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