Can peripartum cardiomyopathy be caused by chemotherapy and radiation of breast cancer?

Introduction

Peripartum cardiomyopathy (PPCM) is a serious form of dilated cardiomyopathy that is defined as left ventricular systolic dysfunction associated with the development of heart failure in the last month of pregnancy or within 5 months of delivery. According to the existing literature most patients with PPCM develop histologic signs of myocarditis; however, the cause of this inflammatory reaction remains obscure [2, 13, 16].

Case presentation

A 35-year old primigravida was transferred to our department at 35+5 weeks with a diagnosis of HELLP syndrome.

Seven years previously, the patient was diagnosed with invasive multifocal cancer of the left breast (mcT2, cN0, cM0). After six cycles of neoadjuvant chemotherapy with docetaxel 75 g/m², doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m² (TAC, study protocol GeparTrio) [9], she had a left total mastectomy with latissimus dorsi flap primary reconstruction and lymphadenectomy (ympT1c, ypN0, cM0, Grading 2, steroid hormonereceptor positive, HER2 overexpression negative) with subsequent radiation therapy of 66.4 Gy in our hospital, followed by anti-hormone therapy with GnRH and Tamoxifen for 5 years. Due to the infertility of her husband, in vitro fertilization combined with intacytoplasmatic sperm injection (IVF/ICSI) with a single embryo transfer was performed at our center.

After admission, the patient had values of creatine 1.48 mg/dL, a platelet count of 85.000/mm³, liver function tests were all elevated: GOT/GPT of 328 U/L and 122 U/L, respectively, and an LDH of 740 I/L, which led to the diagnosis of HELLP syndrome and the indication of a cesarean delivery. The height of the patient was 169 cm and the weight was 90 kg. The weight gain during the pregnancy was 14 kg. The blood pressure at admission was 140/90 mm Hg. A healthy female infant with a birth weight of 2160 g (<10 percentile) was born. The APGAR score was 6/8/9 and the pH in the umbilical artery was 7,36. The newborn was transferred to our neonatal unit and was discharged with the mother on day 11.

Postnatally, 7 h after the cesarean, the patient was transferred to the intensive care unit due to symptoms of cardiopulmonary decompensation, such as dyspnea and paleness. On examination, the patient was oriented to person and date. The temperature was normal, the blood pressure was 145/90 mm Hg, the pulse 120 beats per minute and regular, the respiratory rate 18 breaths per minute and the oxygen saturation 85%, while she was breathing ambient air. The heart sounds were rapid and irregular, without murmurs and there were signs of bilateral edema of the lungs, computer tomography excluded pulmonary embolism but detected cardiomegaly and lung edema (Figure 1). The laboratory findings showed a troponine I increase up to 4.7 µg/L and subsequent maternal echocardiography revealed a borderline dilatation of the left chamber with an impaired left ventricular systolic function (EDV of 77 mL/m² and ESV of 46 mL/m²) and a left ventricular ejection fraction (LVEF) of 40%. No pericardial effusion was seen. Thus, the diagnosis of peripartum cardiomyopathy was established. Left ventricle arterial catheterization excluded coronary artery disease, additional left ventricular biopsy was refused by the patient. The patient was treated at the cardiac intensive care unit with oxygen, diuretics and ACE inhibitors. A secondary weaning by bromocriptine, furosemide, metoprolol (beta blocking agent), ramipril (ACE-inhibitor) and thrombosis prophylaxis with a LMWH (Clexane 40 mg sc) took place. ACE-inhibitors are excreted in the breast milk, thus breastfeeding should be discontinued in patients requiring this medication. A secondary weaning by bromocriptine, a prolactine suppressant, inhibits lactation after the first milk secretion. Cardiac magnetic resonance imaging (cMRI) was performed 5 days after the start of therapy and showed an impaired systolic function (LVEF 40%) but no signs of myocarditis (Figure 2). Five days after the start of therapy and 11 days after cesarean delivery, mother and child were discharged when her EF was 55% and was able to ambulate without clinical limitation. The medication with ACE inhibitors was continued up to 6 months post-partum, when a follow-up echocardiography was conducted and revealed no chamber dilatation and an ejection fraction >55%.

Figure 1

Computed tomography angiography 4 h post-partum. No central or peripheral pulmonary embolism. Bilateral alveolar and interstitial pulmonary edema and left ventricular decompensation.

Figure 2

Magnetic Resonance tomography without contrast medium 5 days post-partum. Borderline enlarged left ventricle with impaired systolic function without pericardial effusion but no late enhancement (valve insufficiency).

Discussion

This case report might suggest a relationship between peripartum cardiomyopathy and the earlier treatment with combination chemotherapy with antracycline and radiation of the left side of the chest.

Anthracyclines are agents with well-known cardiotoxicity [17]. Furthermore, peripartum heart failure may develop several years or even decades after doxorubicin treatment due to breast cancer [4, 10]. As such, late-onset cardiac toxicity combined with pregnancy is considered in the present case. The efficacy of anthracyclines in treating cancer is limited by a cumulative dose-dependent cardiotoxicity, which typically occurs at an average total dose of 500 mg/m², however it has been reported by cumulative dose as low as 300 mg/m² [15, 18]. Our patient received a cumulative dose of 300 mg/m²(total dose of 495 mg). No symptoms during or just after her chemotherapy were recorded.

Local radiation is known to affect the myocardium, pericardium and coronary vasculature through tissue degeneration and small vessel damage. These changes may lead to both systolic and diastolic dysfunction [7] and thus to dilated cardiomyopathy. Left-sided breast irradiation has been associated with increased risk of cardiac morbidity and mortality [11]. A synergistic effect of the combination chemotherapy and the radiation of the left chest wall with 66.4 Gy, dominated by the long-term effects of doxorubicine could have possibly contributed as a risk factor for developing peripartum cardiomyopathy. Their independent role in the development of our patient’s cardiomyopathy is uncertain.

Peripartum cardiomyopathy is characterized by the rapid onset of heart failure during the last weeks of pregnancy and up to 6 months post-partum. The clinical picture of PPCM has the appearance of a dilated cardiomyopathy (DCM), but differs from other forms of DCM in its rapid progression. The leading symptoms of PPCM are a new onset of systolic dysfunction characterized by left ventricular EF <45% and left ventricular dilation. Prompt treatment is needed in order to avoid potentially life-threatening consequences [1, 3]. How far the combination with HELLP syndrome and combined endothelial leakage predisposing lung edema had as an additional impact on the onset of PPCM remains unknown. Most recently, it has been shown in an article published in Nature that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia [12].

The first step of management of PPCM consists of pharmacological and non-pharmacological therapy, similar to that of other types of heart failure [3]. The patient’s heart function successfully recovered under this therapy to an EF >55%. Only in very severe cases when pharmacological treatment is not sufficient have patients been treated with a heart transplant [14]. Felker etal. [6] examined the association between the specific cause of cardiomyopathy and long-term survival and stated that patients with peripartum cardiomyopathy had a substantially better prognosis (94% survival rate) than those with other causes of heart failure. Before discharge the patient was advised about the high risks in case of any further pregnancy.

Recently, insights into the pathogenetic mechanisms of PPCM indicate that prolactin inhibition supports recovery from heart failure. Administration of the prolactin-inhibitor bromocriptine has been suggested as a specific therapy. As such, findings showed that a derivate of the postpartum upregulated hormone prolactin mediates PPCM by initiating cell apoptosis and disruption of capillaries, thereby inducing heart failure and myocardial damage [5, 8].

In conclusion, the history of chemotherapy with anthracyclines, radiation to the left chest wall and a pregnancy complicated by pre-eclampsia and HELLP syndrome could have reinforced the symptoms of PPCM. As breast cancer survivors increasingly become pregnant at a higher age, they should be informed about early symptoms of cardiac decompensation when pregnant, and when they present with claims, prompt diagnosis and therapy should be initiated. Regular cardiac monitoring during pregnancy and within 6 months of delivery should be considered in these patients.