Abstract
Background
Doxorubicin is a cornerstone in lymphoma treatment, but is limited by dose-dependent cardiotoxicity. Rubidium-82 positron emission tomography (82Rb PET) assesses coronary microvascular function through absolute quantification of myocardial perfusion and myocardial perfusion reserve (MPR). Doxorubicin-induced microvascular injury represents a potential early marker of cardiotoxicity.
Methods and results
We included 70 lymphoma patients scheduled for doxorubicin-based treatment. Cardiotoxicity was evaluated with 82Rb PET myocardial perfusion imaging during rest and adenosine stress before chemotherapy and shortly after the first doxorubicin exposure. Patients with a MPR decline > 20% were defined as having a low threshold for cardiotoxicity. In the 54 patients with complete data sets, MPR was significantly lower after the initial doxorubicin exposure (2.69 vs 2.51, P = .03). We registered a non-significant decline in stress perfusion (3.18 vs 3.02 ml/g/min, P = .08), but no change in resting myocardial perfusion. There were 13 patients with a low cardiotoxic threshold. These patients had a significantly higher age, but were otherwise similar to the remaining part of the study population.
Conclusion
Decreases in MPR after initial doxorubicin exposure in lymphoma patients may represent an early marker of doxorubicin-induced cardiotoxicity. The prognostic value of acute doxorubicin-induced changes in MPR remains to be investigated.
Similar content being viewed by others
Abbreviations
- HF:
-
Heart failure
- LVEF:
-
Left ventricular ejection fraction
- MPR:
-
Myocardial perfusion reserve
- PET:
-
Positron emission tomography
- Rb:
-
Rubidium
- SRS:
-
Summed rest score
- SSS:
-
Summed stress score
- SDS:
-
Summed difference score
References
Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 European Society of Cardiology position paper on cancer treatments and cardiovascular toxicity. Eur Heart J 2016;37:2768-801.
Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: A report from the American society of echocardiography and the European association of cardiovascular imaging. J Am Soc Echocardiogr 2014;27:911-39.
Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015;131:1981-8.
Lefrak E, Pitha J, Rosenheim S, Gottlieb J. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 1973;32:302-14.
Von Hoff DD, Layard MW, Basa P, Davis HLJ, Von Hoff AL, Rozencweig M, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med US 1979;91:710-7.
Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin a retrospective analysis of three trials. Cancer 2003;97:2869-79.
Armenian SH, Sun C, Shannon T, Mills G, Francisco L, Venkataraman K, et al. Incidence and predictors of congestive heart failure after autologous hematopoietic cell transplantation. Blood 2011;118:6023-9.
Oliveira GH, Al-Kindi SG, Caimi PF, Lazarus HM. Maximizing anthracycline tolerability in hematologic malignancies: Treat to each heart’s content. Blood Rev 2016;30:169-78.
Wu S, Ko Y, Teng M, Ko Y, Hsu L, Hsueh C, et al. Adriamycin-induced cardiomyocyte and endothelial cell apoptosis: In vitro and in vivo studies. J Mol Cell Cardiol 2002;34:1595-607.
Murata T, Yamawaki H, Yoshimoto R, Hori M. Chronic effect of doxorubicin on vascular endothelium assessed by organ culture study. Life Sci 2001;69:2685-95.
Kalivendi SV, Kotamraju S, Zhao H, Joseph J, Kalyanaraman B. Doxorubicin-induced apoptosis is associated with increased transcription of endothelial nitric-oxide synthase: Effect of antiapoptotic antioxidants and calcium. J Biol Chem 2001;276:47266-76.
Duquaine D, Hirsch GA, Chakrabarti A, Han Z, Kehrer C, Brook R, et al. Rapid-onset endothelial dysfunction with adriamycin : evidence for a dysfunctional nitric oxide synthase. Vasc Med 2003;8:101-7.
Kotamraju S, Konorev EA, Joseph J, Kalyanaraman B. Doxorubicin-induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen. Role of reactive oxygen and nitrogen species. J Biol Chem 2000;275:33585-92.
Hagemann CE, Ghotbi AA, Kjær A, Hasbak P. Quantitative myocardial blood flow with Rubidium-82 PET: A clinical perspective. Am J Nucl Mol Imaging 2015;5:457-68.
Henzlova MJ, Duvall WL, Einstein AJ, Travin MI, Verberne HJ. ASNC imaging guidelines imaging guidelines for SPECT nuclear cardiology procedures: Stress, protocols, and tracers. J Nucl Cardiol 2016;23:606-39.
Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: Evolving concepts and practical applications. Blood 2014;117:5019-32.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375-90.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and Non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol 2018;32:3059-68.
Kitkungvan D, Johnson NP, Roby AE, Patel MB, Kirkeeide R, Gould KL. Routine clinical quantitative rest stress myocardial perfusion for managing coronary artery disease. JACC Cardiovasc Imaging 2017;10:565-77.
Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. Circulation 2002;105:539-42.
Lortie M, Beanlands RSB, Yoshinaga K, Klein R, Dasilva JN, DeKemp RA. Quantification of myocardial blood flow with dynamic PET imaging. Eur J Nucl Med Mol Imaging 2007;34:1765-74.
Knudsen A, Christensen TE, Ghotbi AA, Hasbak P, Lebech A, Kjær A, et al. Normal myocardial flow reserve in HIV-infected patients on stable antiretroviral therapy—A cross-sectional study using Rubidium-82 PET/CT. Medicine (Baltimore) 2015;94:e1886.
R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/. 2015.
Volkova M, Russell R. Anthracycline cardiotoxicity: Prevalence, pathogenesis and treatment. Curr Cardiol Rev 2011;7:214-20.
Bugger H, Guzman C, Zechner C, Palmeri M, Russell KS, Russell RR. Uncoupling protein downregulation in doxorubicin-induced heart failure improves mitochondrial coupling but increases reactive oxygen species generation. Cancer Chemother Pharmacol 2011;67:1381-8.
Zhang S, Liu X, Bawa-Khalfe T, Lu L-S, Lyu YL, Liu LF, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012;18:1639-45.
Khiati S, Rosa ID, Sourbier C, Ma X, Rao VA, Neckers LM. Mitochondrial topoisomerase I (Top1mt) is a novel limiting factor of doxorubicin cardiotoxicity. Clin Cancer Res 2014;20:4873-82.
Davidson SM, Duchen MR. Endothelial mitochondria: Contributing to vascular function and disease. Circ Res 2007;100:1128-41.
Davidson SM. Endothelial mitochondria and heart disease. Cardiovasc Res 2010;88:58-66.
Dengel DR, Ness KK, Glasser SP, Williamson EB, Baker KS, Gurney JG. Endothelial function in young adult survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2008;30:20-5.
Glass CK, Mitchell RN. Winning the battle, but losing the war: Mechanisms and morphology of cancer-therapy-associated cardiovascular toxicity. Cardiovasc Pathol 2017;30:55-63.
Chatterjee K, Zhang J, Honbo N, Karliner JS. Doxorubicin cardiomyopathy. Cardiology 2010;115:155-62.
Farhad H, Dunet V, Bachelard K, Allenbach G, Kaufmann PA, Prior JO. Added prognostic value of myocardial blood flow quantitation in rubidium-82 positron emission tomography imaging. Eur Heart J Cardiovasc Imaging 2013;14:1203-10.
Fukushima K, Javadi MS, Higuchi T, Lautam R, Merrill J, Nekolla SG, et al. Prediction of short-term cardiovascular events using quantification of global myocardial flow reserve in patients referred for clinical 82 Rb PET perfusion imaging. J Nucl Med 2011;52:726-32.
Taqueti VR, Everett BM, Murthy VL, Gaber M, Foster CR, Hainer J, et al. Coronary heart disease interaction of impaired coronary flow reserve and cardiomyocyte injury on adverse cardiovascular outcomes in patients without overt coronary artery disease. Circulation 2015;131:528-35.
Ziadi MC, Robert A, Williams KA, Guo A, Ng ME, Chow BJW, et al. Impaired myocardial flow reserve on Rubidium-82 positron emission tomography imaging predicts adverse outcomes in patients assessed for myocardial ischemia. J Am Coll Cardiol 2011;58:740-8.
Wang X, Sun CL, Quiñones-Lombraña A, Singh P, Landier W, Hageman L, et al. CELF4 variant and anthracycline-related cardiomyopathy: A children’s oncology group genome-wide association study. J Clin Oncol 2016;34:863-70.
Olivotto I, Cecchi F, Gistri R, Lorenzoni R, Chiriatti G, Girolami F, et al. Relevance of coronary microvascular flow impairment to long-term remodeling and systolic dysfunction in hypertrophic cardiomyopathy. J Am Coll Cardiol 2006;47:1043.
Van Tosh A, Votaw JR, Cooke CD, Cao JJ, Palestro CJ, Nichols KJ. Relationship of 82 Rb PET territorial myocardial asynchrony to arterial stenosis. J Nucl Cardiol 2018;24:34.
Acknowledgements
The authors would like to gratefully acknowledge the following research funds for their financial support: The Danish Cancer Society; Rigshospitalet Research Fund; Brødrene Hartmanns Fond; Eva og Henry Frænkels Mindefond; Dagmar Marshalls Fond; KV Fonden; Fabrikant Einar Willumsens Mindelegat; LM Byg; and lastly the research funds of the Department of Cardiology and the Department of Haematology, Rigshospitalet. Furthermore, we sincerely thank all the patients who agreed to participate in our study.
Disclosure
None.
Author information
Authors and Affiliations
Corresponding author
Additional information
The authors of this article have provided a PowerPoint file, available for download at SpringerLink, which summarizes the contents of the paper and is free for re-use at meetings and presentations. Search for the article DOI on SpringerLink.com.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Laursen, A.H., Elming, M.B., Ripa, R.S. et al. Rubidium-82 positron emission tomography for detection of acute doxorubicin-induced cardiac effects in lymphoma patients. J. Nucl. Cardiol. 27, 1698–1707 (2020). https://doi.org/10.1007/s12350-018-1458-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12350-018-1458-6