Familial Dilated Cardiomyopathy: Another Risk Factor for Anthracycline-Induced Cardiotoxicity?

Since their introduction in the late 1960s, anthracyclines such as daunorubicin and doxorubicin have been successfully used in the treatment of a wide variety of tumours. However, their use is limited by the occurrence of cardiotoxicity, which may result in left ventricular (LV) dysfunction/dilated cardiomyopathy (DCM) and eventually heart failure.1,2 Several risk factors have been identified for anthracycline-induced cardiotoxicity: the most important one is the total cumulative dose of anthracycline given, with a cumulative dose of daunorubicin and doxorubicin up to 450 mg/m2 being considered relatively safe.1,2 However, in some patients, LV dysfunction/DCM develops after anthracycline treatment which is not fully explicable in terms of the established risk factors, suggesting that other factors, probably including genetic ones, play a role. Here, we report two patients who were treated for cancer and who later developed DCM; a genetic predisposition for DCM is believed to have played a role. Among other patients with possible hereditary cardiac disorders, we see at the cardiogenetics outpatient clinic of the University Medical Centre Groningen patients with idiopathic DCM. As part of routine procedures, the patients’ clinical characteristics are collected, pedigrees are constructed, full family histories are obtained, and family members at risk are invited for pre-symptomatic (‘cascade’) screening using family letters.3,4 Dilated cardiomyopathy is diagnosed if there is both a reduced systolic function (ejection fraction 117% of the predicted value corrected for body surface area and age). If only one of these criteria is fulfilled, the case is labelled mild DCM. In addition, identifiable causes like severe hypertension, coronary artery disease, and systemic diseases should have been excluded.5,6 Familial DCM (fDCM) is diagnosed if two or more affected individuals are present in a family or if the patient with DCM has a first-degree relative who died suddenly before the age of 35 years.6 All patients are asked to give permission for their clinical data to be used for scientific research. Genomic DNA is isolated from blood samples obtained from the index patients, using DNA samples from 300 ethnically matched control alleles. As part of our routine clinical care, DNA analysis is performed for the following major DCM-related genes: lamin A/C (LMNA), cardiac troponin T (TNNT2), and β-myosin heavy chain (MYH7), using established techniques.7 Patient A had had acute lymphoid leukaemia at the age of 9 years for which he received several non-cardiotoxic agents. At the age of 12 years, he had a relapse which was treated with daunorubicin (cumulative dose 175 mg/m2) and allogenic stem cell transplantation (including total body radiation (12 Gy)). At the age of 17 years, he presented with reduced exercise tolerance and LV dysfunction, which at that time was attributed to the earlier anti-cancer treatment. He is now 30 years old and he is in New York Heart Association functional class II. Left ventricular ejection fraction and LV end-diastolic dimension are at present 0.40 and 28 mm/m2, respectively. As part of a research project on the late effects of childhood cancer treatment, his 24-year-old brother recently participated as a ‘healthy’ sibling control and was found to have an LV ejection fraction of 0.42 and an LV end-diastolic dimension of 27 mm/m2. After this unexpected finding, the attending oncologist considered the possibility of fDCM and referred the two brothers to our cardiogenetics outpatient clinic for further analysis. The family history revealed that their father had been diagnosed with heart failure due to idiopathic DCM in a regional hospital 3 years earlier at the age of 56 years. Since both Patient A's brother and father were affected with idiopathic (mild) DCM, fDCM was considered in this family (Figure 1, left panel). However, DNA analysis of LMNA, MYH7, and TNNT2 did not reveal an underlying mutation in this family. Patient B had had a neuroblastoma at the age of 2 years for which he had been treated with cyclophosphamide and doxorubicin (cumulative dose 420 mg/m2). At the age of 16 years, he presented with heart failure due to severe LV dysfunction, which at that time was attributed to the chemotherapy. He is now 29 years old and although he has relatively mild symptoms, the LV function is severely depressed (ejection fraction 0.25) and the LV is dilated (LV end-diastolic dimension 31 mm/m2). At a recent routine follow-up, the patient told the attending oncologist that his father had just been diagnosed with ‘heart failure’ in a regional hospital. The possibility of fDCM was considered and the patient was referred to our cardiogenetics outpatient clinic for further analysis. The review of the available cardiac data from Patient B's father indicated that he had been diagnosed with heart failure due to idiopathic DCM at the age of 57 years. Two family members, Patient B's brother and a paternal uncle, responded to the family letters and were investigated. The uncle was 66 years old and asymptomatic but echocardiography revealed mild DCM. The brother was 24 years old, asymptomatic but echocardiography also revealed mild DCM. Since Patient B's father, uncle, and brother were affected with (mild) idiopathic DCM, fDCM was also considered likely in Family B (Figure 1, right panel). Two mutations in MYH7 were identified in Patient B and his affected family members: c.1633G > A (p.Asp545Asn) in exon 16 and c.2863G > A (p.Asp955Asn) in exon 23. Both mutations have been published previously8 and segregation analysis demonstrated that these two MYH7 mutations were on the same allele (in cis) that also segregated with the disease in this family. Our two cases suggest the presence of a previously unrecognized risk factor for the development of anthracycline-induced cardiotoxicity, namely a genetic/familial predisposition for DCM. Patient A developed DCM at a young age, despite having received only a low dose of daunorubicin.1,2,9 Even though other factors may have contributed to the anthracycline cardiotoxicity, in particular radiation therapy and young age, it remains difficult to accept that the anti-cancer treatment was solely responsible. Rather, it is conceivable that Patient A is a carrier of a yet unidentified mutation causing DCM in his family and that this contributed to the development of his DCM. In the case of Patient B, a proven carrier of DCM-causing mutations, it is also likely that his genetic predisposition for DCM contributed to its actual development. Our study not only provides new insight for the oncologist but also for the cardiogeneticist dealing with DCM patients and their families. fDCM is characterized by variable penetrance,10 implying that even within a single family, proven disease-causing mutation carriers may live into senescence without showing any clinical signs of DCM, whereas other mutation carriers may experience the early onset of disease and progression to heart failure. Variable penetrance was also evident in our two families, the two fathers presenting with DCM at a later age than their sons. The phenomenon of variable penetrance suggests that in addition to the specific genetic predisposition, other factors, including environmental ones, must also play a role in the pathogenesis of fDCM. Our two cases represent probable examples of an environmental factor, namely anti-cancer treatment with known cardiotoxic agents. Our study thus provides evidence for a ‘gene–environment interaction’ with regard to the development of DCM after anti-cancer treatment, with an environmental factor (cardiotoxic treatment) eliciting early-onset and/or severe DCM in the setting of a genetic predisposition for DCM. In terms of practicality, we recommend careful evaluation of the family history for fDCM before treating a cancer patient with cardiotoxic agents. And conversely, clinicians should be aware of the possibility that disproportionate LV dilatation and systolic dysfunction after chemotherapy may be a manifestation of fDCM. In conclusion, our study suggests that a family history of DCM is another risk factor for the development of anthracycline-induced cardiotoxicity. A way to further explore this concept would be to perform genetic research (investigation of family members and DNA analysis) in patients with disproportionate LV dilatation and systolic dysfunction after chemotherapy. We thank Dr Jan Jongbloed for performing the DNA analyses and Jackie Senior for editing this paper. Conflict of interest: none declared.