Background

Anthracyclines are chemotherapeutic agents widely used in the treatment of cancer such as sarcomas, breast cancer, and lymphomas. Their clinical effectiveness is contrasted with myocardial injury which is the main adverse effect of these drugs¹. Anthracycline-associated cardiomyopathy (ACM) can be presented as a very mild and asymptomatic form to advanced heart failure requiring heart transplantation as definitive therapy². Incidence of cardiotoxicity varies from 5 to 48% depending on the accumulated dose³.

In a large prospective study (incidence of cardiotoxicity 9%), it was observed that 98% of these patients did not present symptoms of heart failure in the 1^st year, highlighting the importance of close surveillance of the left ventricular ejection fraction (LVEF)⁴.

The correct selection of candidates for heart transplantation is a particular challenge in this population. An exhaustive pre-transplant evaluation is essential to ensure a low probability of neoplastic recurrence after starting immunosuppressive treatment.

Recently, Ramu et al. have published a study where they reported the clinical characteristics as well as clinical outcomes of patients undergoing heart transplantation for ACM in the United States, but we do not have data from our local media².

The objective of this study was to describe the clinical characteristics and outcomes of a series of patients with diagnosis of ACM undergoing heart transplantation in a high-complexity hospital in Argentina.

Methods

We designed a series of cases of consecutive patients who received a heart transplantation with a diagnosis of ACM in our hospital. The analysis included all patients with a diagnosis of ACM and development of heart failure requiring a heart transplantation in the period November 2009-April 2021. To arrive at the diagnosis of ACM, other causes of cardiomyopathy (such as ischemic, valvular disease, and myocarditis) were ruled out by the advanced heart failure team in the pre-transplant evaluation and all were confirmed in the pathology study of the explanted hearts (Fig. 1).

Figure 1 CMR and pathological study of the explanted heart of a patient with diagnosis of anthracycline associated cardiomyopathy. Steady state free precession (SSFP) sequences showed enlarged left and right ventricular volumes with severe biventricular dysfunction (A). Late gadolinium enhancement sequences of four chamber (B) and short axis (C) showed a non-specific pattern with septal midwall fibrosis. Longitudinal section showing mild-to-moderate interstitial fibrosis (Hematoxylin & Eosin, 100×, original magnification) (D). 

The clinical characteristics, pre-transplant studies, and clinical outcomes after heart transplantation were collected retrospectively from the electronic medical record. Categorical variables were described as percentages and absolute frequency. As it is a small sample, continuous values were described as median and interquartile ranges. For the analysis, software STATA-64-version 15 was used.

Results

In the period of November 2009-April 2021, a total of 292 heart transplants were performed in our institution. A total of 11 patients (3.7%) were due to ACM and were included in this series. Eight patients were females, and three were male. The median age at the time of cancer diagnosis and chemotherapy treatment was 15 years (IQR 10-37 years), while the median age at the time of receiving a heart transplant was 56 years (IQR 39-62 years). The median time between chemotherapy and heart transplantation was 30 years (IQR 21-37 years).

Regarding the clinical presentation, six patients presented with parameters of cardiogenic shock, requiring mechanical respiratory assistance, or left ventricular assist devices, so they were included on the emergency list for heart transplantation. Table 1 shows the characteristics of the patients.

The most frequent types of primary tumors were different types of sarcoma (45.5%), followed by breast cancer (27.3%) and non-Hodgkin's lymphoma (18.2%). None of the patients presented metastasis during their oncological history and all of them had complete remission before heart transplantation. The pre-transplant studies showed that a median of LVEF by transthoracic echocardiography was 25.6% (IQR 21-28.6%) and six patients also had a decrease in the right ventricle ejection fraction. Cardiovascular magnetic resonance was performed in five patients before heart transplant. The LVEF estimated by this method was similar to that measured by echocardiography. Figure 1 shows a typical pattern of ACM with a great left ventricle volume and minimal late gadolinium enhancement.

All patients underwent right catheterization in the pre-transplant evaluation. The median cardiac index was 1.9 ml/min/m² (IQR 1.7-2 ml/min/m²) and the median of pulmonary resistance was 3.6 wood units (IQR 2.5-4.8 wood units). Table 2 resumes the principal findings of pre-transplant studies.

The immunosuppression regimen consisted on: 1 g of methylprednisolone plus 1200 mg of mycophenolate mofetil and 20 mg of basiliximab before unclamping followed by tacrolimus, mycophenolate mofetil, and prednisone as maintenance. There were no differences in the regimen used between the patients in the cohort or with other transplant recipients for different cardiomyopathies.

Regarding post-transplant outcomes, three patients died in the post-operative period, two of them due to cardiogenic shock secondary to acute graft rejection and the other patient due to subarachnoid hemorrhage in the context of prolonged requirements of extracorporeal membrane oxygenation. In the long follow-up, one patient died 4 years after the intervention due to chronic rejection, while the other seven patients had a favorable evolution without readmissions for heart failure. In these patients who survived the post-operative period, no oncological relapse was observed with a median follow-up of 2.5 years (IQR 1.86-3.85 years).

Discussion

In this case series, clinical characteristics and evolution of heart transplant patients due to ACM were presented.

The first interesting finding of this series is the early age of cancer diagnosis and chemotherapy treatment (15 years [IQR 10-37]), so at the time of cancer diagnosis, it is a predominantly pediatric population, which could explain why the most frequent tumors were sarcomas (45.5%, n = 5). It was also noted that the median time to require a heart transplant was 30 years (IQR 21-37). These data highlight the importance of the link between pediatric and adult cardiology to ensure the correct continuity of cardiovascular care of this population.

Another important issue is the importance of the early initiation of ventricular dysfunction treatment. In a prospective cohort by Cardinale et al., which included 2625 patients treated with anthracyclines (incidence of ACM: 9%), 98% of patients who developed toxicity did so within the 1^st year after completion of treatment. All of them received treatment for ventricular dysfunction and 82% showed total or partial recovery of the LVEF⁴. Previously, the same group had demonstrated the importance of the early initiation of the treatment for ACM in a 201 patients cohort. In this study, no improvement in LVEF was observed in those patients who began treatment for ventricular dysfunction 6 months after diagnosis⁵. For this reason, current clinical practice guidelines recommend exhaustive surveillance in the 1^st year of chemotherapy treatment and then annual follow-up³,⁶,⁷.

Heart transplantation in this population is a particular challenge due to the importance of the correct selection of candidates to minimize the risk of oncological relapse. The current recommendation for the inclusion of patients with a history of cancer on heart transplant list should consider a low probability of oncological recurrence. For this, joint work with oncology service is essential and it is determined by the tumor type, the therapeutic response, and the absence of metastasis, without taking into account arbitrary disease-free periods⁸. In this cohort, all patients underwent an exhaustive interdisciplinary evaluation before admission to the transplant list, with a median time free of oncological disease of 20 years [IQR 5-30]. None of the patients who survived the immediate post-operative period presented oncological relapse.

In a recently published study, Ramu et al. described the clinical course of patients undergoing heart transplantation due to ACM. This study included 18,270 patients undergoing heart transplantation. Three hundred and fifty-seven had a diagnosis of ACM, 10,662 of dilated cardiomyopathy, and 7651 of ischemic cardiomyopathy. Post-transplant mortality was similar in the three groups². In our series, immediate post-transplant mortality was 27 % (n = 3). This high mortality could be explained by the fact that more than half of the patients were transplanted at an advanced stage (INTERMACS 1). Therefore, we think that it is crucial to highlight the importance of properly selecting patients for heart transplantation. Of the eight patients who survived the acute post-transplant phase, only one patient died during the 3-year follow-up.

There are some limitations of our series. First, the low number of patients included in the study. Second, due to the long time elapsed since cancer treatment, we do not know the accumulated dose of anthracyclines received, which is crucial to estimate the potential cardiotoxic damage of these chemotherapy agents. Finally, it is noteworthy that we do not have a sufficient follow-up time to assess long-term outcomes.

Conclusion

The terminal phase of anthracycline-induced cardiomyopathy can occur many years after chemotherapy treatment, so close cardiovascular follow-up is extremely important. In those eligible cases, heart transplantation is a treatment option after an exhaustive multidisciplinary evaluation to minimize the risks of oncological relapse.