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Journal of the American College of Cardiology Ó 2014 by the American College of Cardiology Foundation Published by Elsevier Inc. EDITORIAL COMMENT Cardiac Biomarkers, Cardiotoxicity, and Active Collaboration Is This the Final Frontier or the Wave We Should Catch?* Daniel J. Lenihan, MD Nashville, Tennessee The development of new “targeted” cancer therapy or investigation of new strategies for delivering previously established treatments for specific cancers is a major concern in oncology. It is clear that minimizing the potential for cardiac-related toxicity during cancer therapy is of significant interest, and establishing cardiac safety during chemotherapy is critical for the development of new therapeutics. In addition, the concept of cardiac disease exacerbated by or resulting from cancer therapy in survivors of cancer is a major issue faced by patients and providers alike (1). Cardiac See page 809 toxicity occurs more frequently than anticipated, largely because of the success of cancer therapy, which allows patients to live much longer; subsequently, this treatment can result in chronic cardiac conditions (2,3). It is notable that cardiotoxicity and cardiac disease in patients with cancer are not exactly the same, so an improved understanding of the semantics of this area of cardiology is necessary to provide optimal patient care and ensure cardiac safety in the most productive manner (4). In this issue of the Journal, Ky et al. (5) present a careful analysis of a host of plasma biomarkers obtained in a serial fashion in patients who were undergoing chemotherapy for breast cancer with several chemotherapeutics. Overall, cardiotoxicity (specifically new-onset left ventricular dysfunction) was predicted by a significant rise in high-sensitivity troponin I (TnI) and myeloperoxidase (MPO) values compared with baseline. Each marker was modestly predictive by itself, but the combination allowed for a more confident association with subsequent left ventricular *Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Division of Cardiovascular Medicine, Vanderbilt University, Nashville, Tennessee. Dr. Lenihan has served as a consultant for Roche, Onyx, and AstraZeneca; and has received research support from Acorda Therapeutics. Vol. 63, No. 8, 2014 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.10.060 dysfunction. Five other biomarkers were similarly measured, including N-terminal pro–B-type natriuretic peptide, and there were not clear patterns associated with the detection of left ventricular dysfunction. These data are quite important in the respect that a plasma biomarker can provide early insight into those at risk for cardiac dysfunction and could help define a more aggressive strategy for cardioprotection while a patient undergoes life-saving chemotherapy. There are also important limitations of this report, many of which are acknowledged by the authors in their discussion. Obviously, a larger patient population would be helpful and provide potentially stronger associations with biomarker elevations and subsequent left ventricular dysfunction, but a careful initial analysis has to be performed to commit to future studies. There have been some initial data on highsensitivity TnI as a marker of cardiotoxicity, with a threshold that is clinically measurable (6), but the timing of the biomarker measurement and the absolute threshold for abnormality are not established and have not been studied well enough to make a strong recommendation for the detection of cardiotoxicity at this time. The data presented in this report do not inform a practicing cardiologist or oncologist when or how to measure TnI or MPO in a clinical manner or what to do with a result that is considered abnormal. In terms of biomarkers, this is absolutely a charge that the cardiology world should strive to meet, because there is a tsunami of biomarker studies to consider (7). Possibly the most important concept that these data suggest is that a highly sophisticated cardiology-based evaluation during chemotherapy can be critical to the early detection and ultimately the prevention of heart failure in a patient population at high risk for the development of heart failure. Cardiology needs to be involved in these patients with cancer to interpret subtle imaging findings but also to help place the biomarker measurements in a proper clinical context, help educate about cardiac risk factors, and optimally modify those risk factors when appropriate. Only then will we actually be able to truly prevent heart failure in a manner that was recently shown in a multicenter trial using biomarkers as a guide (8,9). There is some evidence that use of cardioprotective therapy (carvedilol or enalapril) in patients at very high risk is beneficial (10); however, it would seem that using biomarker elevations to indicate those at highest risk for cardiotoxicity and guide therapy based on those values is the most useful, cost-effective, and sophisticated approach. The use of highly sophisticated and expensive imaging that is subject to local availability and expertise is not a widely applicable strategy to detect cardiotoxicity in the broadest clinical manner. It is quite apparent that the participation of cardiology in the care of patients with cancer is absolutely needed (11) and is certainly consistent with having the patient as the focal point of the team provider approach that is believed to be the future of medicine. The impact of cardiac disease on patients with cancer is profound and could be mitigated or prevented with careful cardiology input. Furthermore, 818 JACC Vol. 63, No. 8, 2014 March 4, 2014:817–8 Lenihan Biomarkers, Cardiotoxicity, and Collaboration confirming cardiac safety during drug development, especially with the investigation of more potent and ubiquitous molecular targets in anticancer therapy, by using cardiacrelated biomarkers in an understandable and reliable manner would be a major advance in the field. Additionally, the opportunity for cardiologists to work closely with our oncology colleagues in a collegial manner (12) allows us to learn from and teach each other for the betterment of our patients. It is this wave of collaboration that we should all experience and from which we should benefit. Reprint requests and correspondence: Dr. Daniel J. Lenihan, Division of Cardiovascular Medicine, Vanderbilt University, 1215 21st Avenue South, Suite 5209, Nashville, Tennessee 37232. E-mail: [email protected]. REFERENCES 1. Lenihan DJ, Cardinale DM. Late cardiac effects of cancer treatment. J Clin Oncol 2012;30:3657–64. 2. Chen J, Long JB, Hurria A, Owusu C, Steingart RM, Gross CP. Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Coll Cardiol 2012;60:2504–12. 3. Bowles EJ, Wellman R, Feigelson HS, et al. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst 2012;104: 1293–305. 4. Hossain A, Chen A, Ivy P, et al. The importance of clinical grading of heart failure and other cardiac toxicities during chemotherapy: updating the common terminology criteria for clinical trial reporting. Heart Fail Clin 2011;7:373–84. 5. Ky B, Putt M, Sawaya H, et al. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol 2014; 63:809–16. 6. Cardinale D, Colombo A, Torrisi R, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol 2010;28:3910–6. 7. Januzzi J, Felker GM. Surfing the biomarker tsunami at JACC: Heart Failure. J Am Coll Cardiol HF 2013;1:213–5. 8. Ledwidge M, Gallagher J, Conlon C, et al. Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial. JAMA 2013;310:66–74. 9. Hernandez AF. Preventing heart failure. JAMA 2013;310:44–5. 10. Bosch X, Rovira M, Sitges M, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol 2013;61: 2355–62. 11. Lenihan DJ, Cardinale D, Cipolla CM. The compelling need for a cardiology and oncology partnership and the birth of the International CardiOncology Society. Prog Cardiovasc Dis 2010;53:88–93. 12. van Heeckeren WJ, Bhakta S, Ortiz J, et al. Promise of new vasculardisrupting agents balanced with cardiac toxicity: is it time for oncologists to get to know their cardiologists? J Clin Oncol 2006;24:1485–8. Key Words: cardio-oncology trastuzumab cardiotoxicity. - chemotherapy cardiotoxicity -