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Radiotherapy-induced Tako-tsubo Cardiomyopathy
Clinical Oncology (2009) 21: 361e364
Letters doi:10.1016/j.clon.2009.01.005
Radiotherapy-induced Tako-tsubo Cardiomyopathy Sir d A 66-year-old woman presented to our unit with cardiac-sounding chest pain. Three months previously she had had a total right mastectomy for carcinoma of the breast (T3G2N1) and during the last 12 days had undergone radiotherapy, receiving a cumulative dose of 21.36 Gy from medial, lateral and supraclavicular fields. Her only other past history was of treated hypertension. She was a nonsmoker with a low-risk lipid profile and no family history of ischaemic heart disease. Chest pain settled with standard measures, but serial electrocardiography revealed marked anterolateral T wave inversion (Fig. 1). Serial creatinine kinase and troponin I estimations were normal. Cardiac catheterisation revealed left ventricular apical ballooning in the presence of normal coronary arteries (Fig. 2). Recovery was complete and uneventful. We believe the diagnosis is one of Tako-tsubo cardiomyopathy caused by the physical and emotional stress of radiotherapy. Tako-tsubo cardiomyopathy is also known as transient left apical ballooning syndrome, ampulla cardiomyopathy, stress-induced cardiomyopathy and broken heart syndrome and has been reported extensively in recent years. It classically occurs in middle-aged women after emotional or
physical stress. Electrocardiography changes consistent with anterolateral myocardial infarction with normal coronary arteries and minimal myocardial enzyme release are the hallmarks of the syndrome, with left ventricular imaging showing apical ballooning resembling a Japanese octopus pot. Most cases are transient with complete functional recovery, but extreme cases can display severe mitral valvular dysfunction, left ventricular outflow obstruction or cardiogenic shock. The cause of the condition remains uncertain [1]. The increased incidence of premature cardiovascular disease in patients having undergone radiotherapy is also well established [2]. Radiation doses of less than 30 Gy, together with modern-day, multiple-portal, cardiacshielded radiotherapy are believed to reduce the overall risks [3]. The exact process by which disease is induced remains uncertain, but a number of pathologies are suggested. Among the more common theories are:
early acute pancarditic inflammation; latent diffuse myocardial fibrosis; capillary endothelial cell damage; reduced capillary regeneration; irradiated vessel rupture; classical premature atherosclerotic change.
Fig. 1 e Electrocardiogram showing marked T wave inversion in leads V2eV6. 0936-6555/09/210361þ04 $36.00/0
ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
362
CLINICAL ONCOLOGY
To our knowledge this is the first published report of radiation-induced Tako-tsubo cardiomyopathy in the world. Patients receiving mediastinal or thoracic radiotherapy, particularly those post-mastectomy, often experience nonspecific chest pain, which may otherwise be disregarded. In light of this we urge continued vigilance, not only for Takotsubo cardiomyopathy, but for other radiation-induced cardiovascular complications. S. MODI W. BAIG
The Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool L14 3PE, UK
References
Fig. 2 e Left ventriculography during systole (and diastole e insert) showing well-contracting mid-ventricular segments and classical apical ballooning (arrows).
Pericardial, valvular and conduction system inflammation, fibrosis and dysfunction have also been reported [4,5].
doi:10.1016/j.clon.2009.01.002
Neurotrophic Receptor, Tropomyosin-related Kinase B, as a Chemoresistant Marker in Oesophageal Cancer Sir d Brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor, tropomyosin-related kinase B (TrkB), are correlated with clinical outcome and chemotherapy resistance in neuroblastoma [1,2]. The BDNF/TrkB pathway has also been shown to play an important role in a number of human malignancies. Recently, TrkB has been reported as one of the potential genes related to anoikis (detachmentinduced apoptosis) resistance, which indicates increased metastatic activity [3e5]. There is no report regarding the biological role of TrkB in oesophageal cancer. In this study, we investigated the association between TrkB expression level and chemo/radiotherapy resistance in oesophageal squamous cell carcinoma (ESCC) tissue and cell lines. First, we determined the TrkB protein level in four human ESCC cell lines (TE2, TE3, KYSE30 and KYSE70) by Western blot analysis and then compared responses to 5-fluorouracil (5-FU), cisplatin (CDDP) and radiation in cell lines with different TrkB expression using WST-8 colorimetric assay. TE2 and TE3, with higher TrkB expression, showed greater resistance to 5-FU and CDDP at clinically relevant concentrations, as compared with KYSE30 and KYSE70 with lower TrkB expression. No significant association between TrkB expression and radiation resistance was observed.
1 Pilgrim TM, Wyss TR. Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: a systematic review. Int J Cardiol 2008;124:283e292. 2 Basavaraju SR, Easterly CE. Pathophysiological effects of radiation on atherosclerosis development and progression, and the incidence of cardiovascular complications. Med Phys 2002;29: 2391e2403. 3 Corn BW, Trock BJ, Goodman RL. Irradiation-related ischemic heart disease. J Clin Oncol 1990;8:741e750. 4 Stewart JR. Normal tissue tolerance to irradiation of the cardiovascular system. Front Radiat Ther Oncol 1989;23: 302e309. 5 Virmani R, Farb A, Carter AJ, Jones RM. Pathology of radiationinduced coronary artery disease in human and pig. Cardiovasc Radiat Med 1999;1:98e101.
Second, we analysed TrkB mRNA levels in 19 ESCC patients by real-time reverse-transcriptase polymerase chain reaction. There were 16 male and three female patients, with a mean age of 63 years (range 53e91). Pre-treatment TrkB levels from endoscopic tumour biopsies were 32.10 (inter-quartile range, 6.0e194.0), whereas in adjacent normal biopsies it was 7.30 (interquartile range, 1.9e21.8). No significant association between clinicopathological characteristics and TrkB expression was observed. However, ESCC tissues had significantly higher TrkB levels than normal tissues (P ¼ 0.02). TrkB levels were significantly higher in primary tumours with invasiveness to adjacent structures (T4) than in those invading up to the adventitia (T1e3) (P ¼ 0.03). When the ratio of TrkB mRNA in cancer tissue (C) to that in normal tissue (N) was defined as the C/N ratio, a trend towards a worse clinical response to chemoradiotherapy was found in patients with a higher TrkB C/N ratio (P ¼ 0.07). In summary, TrkB was associated with resistance to 5-FU and CDDP in vitro, and also in a highly invasive phenotype in ESCC patients. We also observed a trend towards higher TrkB in ESCC patients with extensive lymphatic invasion (P ¼ 0.07) and vascular invasion (P ¼ 0.06), respectively (data not shown). These results suggest that TrkB expressing oesophageal cancer may have a more metastatic phenotype (anoikis-resistant phenotype).
Letters doi:10.1016/j.clon.2009.01.005
Radiotherapy-induced Tako-tsubo Cardiomyopathy Sir d A 66-year-old woman presented to our unit with cardiac-sounding chest pain. Three months previously she had had a total right mastectomy for carcinoma of the breast (T3G2N1) and during the last 12 days had undergone radiotherapy, receiving a cumulative dose of 21.36 Gy from medial, lateral and supraclavicular fields. Her only other past history was of treated hypertension. She was a nonsmoker with a low-risk lipid profile and no family history of ischaemic heart disease. Chest pain settled with standard measures, but serial electrocardiography revealed marked anterolateral T wave inversion (Fig. 1). Serial creatinine kinase and troponin I estimations were normal. Cardiac catheterisation revealed left ventricular apical ballooning in the presence of normal coronary arteries (Fig. 2). Recovery was complete and uneventful. We believe the diagnosis is one of Tako-tsubo cardiomyopathy caused by the physical and emotional stress of radiotherapy. Tako-tsubo cardiomyopathy is also known as transient left apical ballooning syndrome, ampulla cardiomyopathy, stress-induced cardiomyopathy and broken heart syndrome and has been reported extensively in recent years. It classically occurs in middle-aged women after emotional or
physical stress. Electrocardiography changes consistent with anterolateral myocardial infarction with normal coronary arteries and minimal myocardial enzyme release are the hallmarks of the syndrome, with left ventricular imaging showing apical ballooning resembling a Japanese octopus pot. Most cases are transient with complete functional recovery, but extreme cases can display severe mitral valvular dysfunction, left ventricular outflow obstruction or cardiogenic shock. The cause of the condition remains uncertain [1]. The increased incidence of premature cardiovascular disease in patients having undergone radiotherapy is also well established [2]. Radiation doses of less than 30 Gy, together with modern-day, multiple-portal, cardiacshielded radiotherapy are believed to reduce the overall risks [3]. The exact process by which disease is induced remains uncertain, but a number of pathologies are suggested. Among the more common theories are:
early acute pancarditic inflammation; latent diffuse myocardial fibrosis; capillary endothelial cell damage; reduced capillary regeneration; irradiated vessel rupture; classical premature atherosclerotic change.
Fig. 1 e Electrocardiogram showing marked T wave inversion in leads V2eV6. 0936-6555/09/210361þ04 $36.00/0
ª 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
362
CLINICAL ONCOLOGY
To our knowledge this is the first published report of radiation-induced Tako-tsubo cardiomyopathy in the world. Patients receiving mediastinal or thoracic radiotherapy, particularly those post-mastectomy, often experience nonspecific chest pain, which may otherwise be disregarded. In light of this we urge continued vigilance, not only for Takotsubo cardiomyopathy, but for other radiation-induced cardiovascular complications. S. MODI W. BAIG
The Liverpool Heart and Chest Hospital, Thomas Drive, Liverpool L14 3PE, UK
References
Fig. 2 e Left ventriculography during systole (and diastole e insert) showing well-contracting mid-ventricular segments and classical apical ballooning (arrows).
Pericardial, valvular and conduction system inflammation, fibrosis and dysfunction have also been reported [4,5].
doi:10.1016/j.clon.2009.01.002
Neurotrophic Receptor, Tropomyosin-related Kinase B, as a Chemoresistant Marker in Oesophageal Cancer Sir d Brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor, tropomyosin-related kinase B (TrkB), are correlated with clinical outcome and chemotherapy resistance in neuroblastoma [1,2]. The BDNF/TrkB pathway has also been shown to play an important role in a number of human malignancies. Recently, TrkB has been reported as one of the potential genes related to anoikis (detachmentinduced apoptosis) resistance, which indicates increased metastatic activity [3e5]. There is no report regarding the biological role of TrkB in oesophageal cancer. In this study, we investigated the association between TrkB expression level and chemo/radiotherapy resistance in oesophageal squamous cell carcinoma (ESCC) tissue and cell lines. First, we determined the TrkB protein level in four human ESCC cell lines (TE2, TE3, KYSE30 and KYSE70) by Western blot analysis and then compared responses to 5-fluorouracil (5-FU), cisplatin (CDDP) and radiation in cell lines with different TrkB expression using WST-8 colorimetric assay. TE2 and TE3, with higher TrkB expression, showed greater resistance to 5-FU and CDDP at clinically relevant concentrations, as compared with KYSE30 and KYSE70 with lower TrkB expression. No significant association between TrkB expression and radiation resistance was observed.
1 Pilgrim TM, Wyss TR. Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: a systematic review. Int J Cardiol 2008;124:283e292. 2 Basavaraju SR, Easterly CE. Pathophysiological effects of radiation on atherosclerosis development and progression, and the incidence of cardiovascular complications. Med Phys 2002;29: 2391e2403. 3 Corn BW, Trock BJ, Goodman RL. Irradiation-related ischemic heart disease. J Clin Oncol 1990;8:741e750. 4 Stewart JR. Normal tissue tolerance to irradiation of the cardiovascular system. Front Radiat Ther Oncol 1989;23: 302e309. 5 Virmani R, Farb A, Carter AJ, Jones RM. Pathology of radiationinduced coronary artery disease in human and pig. Cardiovasc Radiat Med 1999;1:98e101.
Second, we analysed TrkB mRNA levels in 19 ESCC patients by real-time reverse-transcriptase polymerase chain reaction. There were 16 male and three female patients, with a mean age of 63 years (range 53e91). Pre-treatment TrkB levels from endoscopic tumour biopsies were 32.10 (inter-quartile range, 6.0e194.0), whereas in adjacent normal biopsies it was 7.30 (interquartile range, 1.9e21.8). No significant association between clinicopathological characteristics and TrkB expression was observed. However, ESCC tissues had significantly higher TrkB levels than normal tissues (P ¼ 0.02). TrkB levels were significantly higher in primary tumours with invasiveness to adjacent structures (T4) than in those invading up to the adventitia (T1e3) (P ¼ 0.03). When the ratio of TrkB mRNA in cancer tissue (C) to that in normal tissue (N) was defined as the C/N ratio, a trend towards a worse clinical response to chemoradiotherapy was found in patients with a higher TrkB C/N ratio (P ¼ 0.07). In summary, TrkB was associated with resistance to 5-FU and CDDP in vitro, and also in a highly invasive phenotype in ESCC patients. We also observed a trend towards higher TrkB in ESCC patients with extensive lymphatic invasion (P ¼ 0.07) and vascular invasion (P ¼ 0.06), respectively (data not shown). These results suggest that TrkB expressing oesophageal cancer may have a more metastatic phenotype (anoikis-resistant phenotype).