Cardiogenic Shock 14 Years Post Anthracyclines
Received Date: Nov 11, 2017 / Accepted Date: Feb 02, 2018 / Published Date: Feb 06, 2018
Significant advances in cancer treatment markedly improved survival rates of children diagnosed with cancer. However, chemotherapeutic or radiologic treatments might result in health consequences. For example, anthracycline agents were one of the most widely used chemotherapeutic drugs and known to cause cardiotoxicity.
We report on a 20-year old man with sudden onset of multi-organ-failure caused by a severe cardiogenic shock and the urgent need for implantation of a continuous-flow left ventricular assist device. Fourteen years before, he was diagnosed with childhood T-lymphocyte acute lymphoblastic leukaemia implying the application of the ALL-BFM-2000- protocol with a cumulative dose of 240 mg/m2 of anthracycline (120 mg/m2 daunorubicin + 120 mg/m2 doxorubicin). Postchemotherapeutic clinical monitoring lasted for two years till complete remission of leukaemia was diagnosed. Histology of intraoperatively taken endomyocardial biopsies showed an extensive fibrosis and vacuolated cardiomyocytes compatible with late-onset of anthracycline-induced cardiomyopathy. The patient recovered quickly and was discharged to rehabilitation 20 days after continuous-flow left ventricular assist device implant. Our case emphasized the need for consistent and detailed follow-ups to assess the global risk of premature cardiovascular disease prior to the development of congestive heart failure in cancer survivors of the childhood.
Keywords: Anthracycline; T-Lymphocyte Acute Lymphoblastic Leukaemia (T-ALL); Cardiomyopathy; Cardiogenic shock; Left ventricular assist device
cfLVAD: Continuous-Flow Left Ventricular Assist Device; cTnT: Cardiac Troponin T; EBV: Epstein-Barr Virus; INTERMACS: Interagency Registry For Mechanically Assisted Circulatory Support; LVSF: Left Ventricular Shortening Fraction; NTproBNP: N-Terminal Pro-Brain Natriuretic Peptide; PCR: Polymerase Chain Reaction; T-ALL: T-Lymphocyte Acute Lymphoblastic Leukaemia
Anthracyclines were commonly used in the anti-neoplastic treatment for childhood cancers [1,2]. Almost all children with common cancers and acute leukaemia (up to 94% ) were treated with anthracyclines. But there was no convincing evidence for a significant higher survival taking anthracyclines  compared to other chemotherapeutic drugs.
Among all chemotherapeutic drugs anthracyclines were probably the well-known initiator of cardiotoxicity with an incidence between 3% and 18% . This was mainly caused by disrupting the DNAstructure leading to the cessation of cell function . That could induce morphological changes in the cells such as cytoplasmic vacuolization [7,8] as well as a loss of myofilaments in cardiomyocytes  and an increase in the number of apoptotic cells . These changes were associated with dramatically reduced levels of various proteins including the transcription factor GATA4 and myosin heavy chain  and it also caused accumulation of autophagic vacuoles .
In September 2014, a 20-year old man was transferred to our hospital for rescue-therapy in a cardiogenic shock. In his past medical history, he suffered from a T-Lymphocyte Acute Lymphoblastic Leukaemia (T-ALL) in the year 2000. Hereupon, an anthracyclinebased therapy with curative intent was administered, according to the ALL-BFM-2000-study , combined with a cranial radiation (cumulative-dose: 12Gy). A pre-existing cardiac illness was not known, and his familial history for heart disease was negative, too. On the last time visit of a cardiologist, nine years before cardiogenic shock in July 2005, echocardiography and electrocardiogram were normal. The time until this emergency he was in healthy condition without any cardiac symptoms.
At first, the patient complained about two weeks history of intermittent vomiting and increasing abdominal pain, which was stronger in standing position. Oral proton-pump inhibitors prescribed by the general practitioner did not affect the symptoms. Reaching the emergency ward he suddenly became dizzy with low blood pressure and tachycardia. Fast abdominal sonography ruled out any abdominal focus of his symptoms or abnormality but showed incidentally a highly reduced cardiac function. Echocardiography confirmed the diagnosis of heart failure by showing an enlarged left and right ventricle with a calculated left ventricular ejection fraction of 20%. Despite a moderately mitral regurgitation, no valvular dysfunction was detected. This result combined with a cardiogenic shock and nearly normal inflammatory parameters (CRP 10 mg/l and leucocytes 11.900/ml) made a gastrointestinal viral infection implausible. There was no anamnestic consumption of alcohol or drugs and moreover, acute infections or common cold in the recent past were not recognized by the patient. In consideration of his pre-existing diseases an anthracycline-induced cardiomyopathy seems most supposable.
Clinical examination (~100/min and ~85/45 mmHg) and laboratory diagnostics acknowledged the diagnosis of acute cardiogenic shock (NT-proBNP 14283 ng/l and cTnT 20 pg/ml, cvSO2 60%) with acute renal failure (creatinine 1.83 mg/dl) and congested liver (AST 68U/l, ALT 116U/l and GGT 78U/l). Therefore, rigorous treatment including catecholamines was immediately started. However, in spite of intensive medical treatment the multi-organ-failure was not possible to be stabilized. Consequently, the decision was made to implant a continuous-flow left ventricular assist device (cfLVAD, HVAD® from HeartWare) as a last resource. This was performed in a minimalinvasive surgery technique with two small mini-thoracotomies and partial sternotomy.
Intraoperative the macroscopically picture appeared as a dilated cardiomyopathy. Samples of the pericardium liquid did not prove any evidence of viral infection (PCR negative for adenovirus, influenza, mycoplasma pneumoniae, chlamydia trachomatis, EBV, enterovirus, mumps-virus and parvovirus) or bacterial infection (microscopic no bacteria after 48 hours). The myocardium biopsies did not show acute myocardial inflammation or necrosis on histology and immunohistochemistry. In contrast, an extensive fibrosis and vacuolated cardiomyocytes compatibly with a former damage were diagnosed – correlating with a late-onset of anthracycline-induced cardiomyopathy (Figures 1A-1H).
Figure 1: Hematoxilin and eosin stain (A and zoomed-in B) showed multiple vacuoles without stainable content in myocytes (arrows) which varied in diameter, density and shape of their nuclei. The interstitial space displayed a low rate of fibres and in some areas (not depicted here) fibrosis around vessels and small scars. Immunohistological stains CD3 (C), CD11a (D), CD11b (E), CD54 (F), HLA1 (G) and Perforin (H) demonstrated a small number of inflammatory cells, that indicated small level of a chronic cellular reaction and a small increase of fibrous tissue. Positively stained cells displayed a brownish reaction product of the antibodies.
After successful surgical implant of the cfLVAD and a primarily prophylactic intracutaneous defibrillator to prevent ventricular arrhythmia, organ functions improved and the general state of health ameliorated appreciably. The right ventricular function represented itself as satisfactory. Twenty days after cfLVAD implantation the patient was discharged to a rehabilitation clinic.
We Our case emphasized the need for a consistent and detailed follow-up to assess the global risk of premature cardiovascular disease prior to prevent irreversible cardiac dysfunction , as it might arise in more than one third of these patients .
However, late-onset cardiomyopathy after more than one year was a rare complication 1.6% to 5%  but was regularly irreversible and in this context usually fatal . Both the early- and the lateonset chronic progressive cardiotoxicity characteristically presented as dilated cardiomyopathy in adults . The reason and the mechanism for a delayed onset as well as the molecular basis of memory of the applied dose were not known .
In general, cardiotoxicity was a dose-dependent consequence of chemotherapy. For anthracyclines cumulative doses of less than 240 mg/m2 did not have direct toxic effects but might lead to subclinical cardiac alterations (reduced left ventricular shortening fraction), which were found in 30% of the patients . Instead, cumulative doses of anthracyclines under 100 mg/m2 were not known to be associated with late cardiac damage . Therefore, we would recommend using lower doses in future cases, if there is any possibility.
Operative rescue-therapy with a cfLVAD was a rather new idea to deal with cases in which maximum medical treatment was not sufficient. Since low INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support)-levels 1+2 were attended by worst outcome , a primary implantation of a cfLVAD seemed justified in these cases of acute onset of heart failure in patients without a history of comorbidities. Similar cases had already been described in toxic cardiac shock cases [17,23,24]. Compared to these cases with an onset of five month to ten years, this patient had a very late onset of fourteen years until he had a cardiogenic shock.
Both researchers and clinicians agreed in a need of established guidelines to monitor cardiac function in children after cardiotoxic chemotherapy, but the most effective mode or frequence of monitoring were still not determined . A good predictor for left ventricular decline was the left ventricular shortening fraction (LVSF). More than 50% of the patients showed a LVSF-decline of -8.4 ± 2.8% from baseline to the post-treatment echocardiography . An early decline directly after the end of anthracycline-treatment was associated with late-onset LVSF decrease after more than 12 years . Promising biomarkers in children for monitoring cardiac function after treatment with cardiotoxic chemotherapy were N-terminal pro-brain natriuretic peptide (NT-proBNP)  as well as cardiac troponin T (cTnT) , which were similarly used in regular heart failure clinics for progresscontrol.
A regular echocardiographic monitoring, as also advised by other cooperative groups , with measuring the LVSF should be established in all patients for at least 20 years after the last anthracycline therapy. Additionally, in children with anthracycline therapy a co-medication with cardioprotectors like dexrazoxane or carvedilol should be considered. Dexrazoxane acted by binding free iron or removing iron from anthracycline–iron complexes , without compromising the oncological efficacy, in particular in survivors of high-risk ALL . Carvedilol offered cardiac protection by inhibiting reactive oxygen species [33,34]. The body configuration also seemed to influence the cardiotoxicity , as a high BMI (body fat >30%) was associated with a lower doxorubicinol, which was expected to contribute cardiotoxicity .
Moreover, in young patients with cardiogenic shock without comorbidities a primary mechanical circulatory support with a cfLVAD seemed justified regardless of the INTERMACS level.
• St. S., N.H.T., M.R. and U.M.G. as well as S.B. have no competing interests.
• F.M.W. and M.J.B. received honoraria from HeartWare, Inc.
• T.D. received travel funds from HeartWare, Inc.
• H.R. has a consulting agreement with HeartWare Inc.
• St. S wrote the manuscript and participated in the postoperative hospital care.
• N.H.T. is an oncologist and was responsible for the oncology care and prognosis statements.
• M.R. participated in the preoperative medical hospital care.
• F.M.W. was the surgeon, who implanted the LVAD.
• U.M.G. is the pathologist, who did the histological analysis (Figure 1).
• T.D. is also a surgeon implanting LVAD.
• S.B. has, as the chief cardiologist, a big expertise in heart failure-treatment and was revising the script critically for important intellectual content.
• H.R. has, as the chief physician, a great expertise in LVAD care and has revising the script critically for important intellectual content.
• M.J.B. helped writing the script and has given final approval of the version to be published.
• All authors read and approved the manuscript.
• All authors meet to the ICMJE-Guidelines.
We thank Dirk Labner from IKDT, who managed the correspondence between our group and Ulrich M. Gross.
- Long ZJ, Hu Y, Li XD, He Y, Xiao RZ, et al. (2014) ATO/ATRA/anthracycline-chemotherapy sequential consolidation achieves long-term efficacy in primary acute promyelocytic leukemia. PLoS One 9: 2014.
- Lipshultz SE, Sambatakos P, Maguire M, Karnik R, Ross SW, et al. (2014) Cardiotoxicity and cardioprotection in childhood cancer. Acta Haematol 132: 391-399.
- Suzumiya J, Ohshima K, Tamura K, Karube K, Uike N, et al. (2009) The International Prognostic Index predicts outcome in aggressive adult T-cell leukemia/lymphoma: Analysis of 126 patients from the International Peripheral T-Cell Lymphoma Project. Ann Oncol 20: 715-721.
- Dalen VEC, Raphael MF, Caron HN, Kremer LC (2009) Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer. Cochrane Database Syst Rev 21.
- Swain SM, Whaley FS, Ewer MS (2003) Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97: 2869-2879.
- Broder H, Gottlieb RA, Lepor NE (2008) Chemotherapy and cardiotoxicity. Rev Cardiovasc Med 9: 75-83.
- Vleet VJF, Ferrans VJ, Weirich WE (1980) Cardiac disease induced by chronic adriamycin administration in dogs and an evaluation of vitamin E and selenium as cardioprotectants. Am J Pathol 99: 13-42.
- Kobayashi S, Volden P, Timm D, Mao K, Xu X, et al. (2010) Transcription factor GATA4 inhibits doxorubicin-induced autophagy and cardiomyocyte death. J Biol Chem 285: 793-804.
- Toko H, Oka T, Zou Y, Sakamoto M, Mizukami M, et al. (2002) Angiotensin II type 1a receptor mediates doxorubicin-induced cardiomyopathy. Hypertens Res 25: 597-603.
- Kucharska W, Negrusz-Kawecka M, Gromkowska M (2012) Cardiotoxicity of oncological treatment in children. Adv. Clin Exp Med 21: 281-288.
- Krischer JP, Epstein S, Cuthbertson DD, Goorin AM, Epstein ML, et al. (1997) Clinical cardiotoxicity following anthracycline treatment for childhood cancer: The Pediatric Oncology Group experience. J Clin Oncol 15: 1544-1552.
- Lipshultz SE, Lipsitz SR, Mone SM, Goorin AM, Sallan SE, et al. (1995) Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 332: 1738-1743.
- Cario G, Rhein P, Mitlohner R, Zimmermann M, Bandapalli OR, et al. (2014) High CD45 surface expression determines relapse risk in children with precursor B-cell and T-cell acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol. Haematologica 99: 103-110.
- Kumar S, Marfatia R, Tannenbaum S, Yang C, Avelar E (2012) Doxorubicin-induced cardiomyopathy 17 years after chemotherapy. Tex Heart Inst J 39: 424-427.
- Aiken MJ, Suhag V, Garcia CA, Acio E, Moreau S, et al. (2009) Doxorubicin-induced cardiac toxicity and cardiac rest gated blood pool imaging. Clin Nucl Med 34: 762-767.
- Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE (2005) Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol 131: 561-578.
- Khan N, Husain SA, Husain SI, Khalaf N, George J, et al. (2012) Remission of chronic anthracycline-induced heart failure with support from a continuous-flow left ventricular assist device. Tex Heart Inst J 39: 554-556.
- Yeh ET, Bickford CL (2009) Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 53: 2231-2247.
- Lebrecht D, Setzer B, Ketelsen UP, Haberstroh J, Walker UA (2003) Time-dependent and tissue-specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy. Circulation 108: 2423-2429.
- Vandecruys E, Mondelaers V, De Wolf D, Benoit Y, Suys B (2012) Late cardiotoxicity after low dose of anthracycline therapy for acute lymphoblastic leukemia in childhood. J Cancer Surviv 6: 95-101.
- Rammeloo LA, Postma A, Sobotka-Plojhar MA, Bink-Boelkens MT, Berg A, et al. (2000) Low-dose daunorubicin in induction treatment of childhood acute lymphoblastic leukemia: no long-term cardiac damage in a randomized study of the Dutch Childhood Leukemia Study Group. Med Pediatr Oncol 35: 13-19.
- Barge-Caballero E, Segovia-Cubero J, Almenar-Bonet L, Gonzalez-Vilchez F, Villa-Arranz A, et al. (2013) Preoperative INTERMACS profiles determine postoperative outcomes in critically ill patients undergoing emergency heart transplantation: Analysis of the Spanish National Heart Transplant Registry. Circ Heart Fail 6: 763-772.
- Schweiger M, Dave H, Lemme F, Cavigelli-Brunner A, Romanchenko O, et al. (2013) Acute chemotherapy-induced cardiomyopathy treated with intracorporeal left ventricular assist device in an 8-year-old child. Asaio J 59: 520-522.
- Kurihara C, Nishimura T, Nawata K, Kinoshita O, Hisagi M, et al. (2011) Successful bridge to recovery with VAD implantation for anthracycline-induced cardiomyopathy. J Artif Organs 14: 249-252.
- Lipshultz SE, Franco VI, Cochran TR (2013) Cardiotoxicity in childhood cancer survivors: a problem with long-term consequences in need of early detection and prevention. Pediatr Blood Cancer 60: 1395-1396.
- Orgel E, Zung L, Ji L, Finklestein J, Feusner J, et al. (2013) Early cardiac outcomes following contemporary treatment for childhood acute myeloid leukemia: A North American perspective. Pediatr Blood Cancer 60: 1528-1533.
- Lipshultz SE, Lipsitz SR, Sallan SE, Dalton VM, Mone SM, et al. (2005) Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol 23: 2629-2636.
- Palazzuoli A, Gallotta M, Quatrini I, Nuti R (2010) Natriuretic peptides (BNP and NT-proBNP): measurement and relevance in heart failure. Vasc Health Risk Manag 6: 411-418.
- Lipshultz SE, Miller TL, Scully RE, Lipsitz SR, Rifai N, et al. (2012) Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: Associations with long-term echocardiographic outcomes. J Clin Oncol 30: 1042-1049.
- Armenian SH, Hudson MM, Mulder RL, Chen MH, Constine LS, et al. (2015) Recommendations for cardiomyopathy surveillance for survivors of childhood cancer: A report from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol 16: 123-136.
- Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE (2012) Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. Future Cardiol 8: 647-670.
- Lipshultz SE, Scully RE, Lipsitz SR, Sallan SE, Silverman LB, et al. (2010) Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: Long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 11: 950-961.
- Feuerstein GZ, Ruffolo RR (1995) Carvedilol, a novel multiple action antihypertensive agent with antioxidant activity and the potential for myocardial and vascular protection. Eur Heart J 16: 38-42.
- Arozal W, Sari FR, Watanabe K, Arumugam S, Veeraveedu PT, et al. (2011) Carvedilol-afforded protection against daunorubicin-induced cardiomyopathic rats in vivo: Effects on cardiac fibrosis and hypertrophy. ISRN Pharmacol 2011: 430549.
- Goldberg JM, Scully RE, Sallan SE, Lipshultz SE (2012) Cardiac failure 30 years after treatment containing anthracycline for childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 34: 395-397.
- Thompson PA, Rosner GL, Matthay KK, Moore TB, Bomgaars LR, et al. (2009) Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study. Cancer Chemother Pharmacol 64: 243-251.
Citation: Schmidt S, Blankenberg S, Rybczynski M, Thoennissen NH, Reichenspurner H, et al. (2018) A Rare Case Report in Maxillary Sinus with Weber-Ferguson Approach. Oncol Cancer Case Rep 4: 141. DOI: 10.4172/2471-8556.1000141
Copyright: © 2018 Schmidt S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Select your language of interest to view the total content in your interested language
Share This Article
- Total views: 1616
- [From(publication date): 0-2018 - Sep 16, 2019]
- Breakdown by view type
- HTML page views: 1563
- PDF downloads: 53