Cardioprotection During Therapeutic Radiation Treatment

HomeCirculation: Heart FailureVol. 11, No. 8Cardioprotection During Therapeutic Radiation Treatment Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCardioprotection During Therapeutic Radiation TreatmentPeeling the Onion of Radiation Cardiotoxicity? Daniel J. Lenihan, MD and Phillip Cuculich, MD Daniel J. LenihanDaniel J. Lenihan Daniel J. Lenihan, MD, Cardiovascular Division, Washington University in St Louis, 660 S Euclid Ave, Campus Box 8086, St Louis, MO 63110. Email E-mail Address: [email protected] Department of Medicine, Division of Cardiology, Washington University in St Louis, MO. and Phillip CuculichPhillip Cuculich Department of Medicine, Division of Cardiology, Washington University in St Louis, MO. Originally published17 Aug 2018https://doi.org/10.1161/CIRCHEARTFAILURE.118.005294Circulation: Heart Failure. 2018;11:e005294This article is a commentary on the followingA Small Peptide Ac-SDKP Inhibits Radiation-Induced CardiomyopathySee Article by Sharma et alIn this issue of Circulation: Heart Failure, Sharma et al1 report on an innovative approach for cardioprotection in an animal model of radiation-induced cardiac injury. These investigators have demonstrated in an initial study that administration of a novel tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), seems to be cardioprotective principally by preventing the aggressive fibrotic response that is stimulated in cardiac tissue when exposed to radiation. Ideally, this finding could be important for patients who need radiation therapy for cancer or even localized cardiac radiation as part of experimental treatment for refractory ventricular arrhythmias. In general, this finding, if confirmed in a variety of subsequent studies in animals and then ultimately in humans, could have broad implications for enhanced cardiovascular safety during radiation therapy.Before we get too far ahead of ourselves hoping for a simple solution to a complex problem, perhaps we should consider the findings reported here in more detail and understand the exact implications. It is clear from the data presented that Ac-SDKP does, in fact, inhibit macrophage migration, profibrotic synthesis, and cardiomyocyte apoptosis in a rat model of cardiac injury analyzed 18 weeks from radiation exposure to the left hemithorax with a single fraction of 30 Gray. Interestingly, Mac-2 (Galectin-3) expression from macrophages is significantly reduced, and this may be the biological evidence that Ac-SDKP is exerting a positive effect for reducing fibrosis in this model. This is an attractive simple explanation for some aspects of radiation injury in humans.If we turn our attention to clinical medicine and therapeutic radiation in humans, the layers of complexity become obvious. It is established that fibrosis is a component of radiation-related cardiovascular injury, but this is not the only mechanism of damage.2 In general, cardiac myocytes should be resistant to the traditional radiation–related mechanism of inducing mitotic catastrophe via double-stranded DNA damage because cardiac myocytes largely reside in a post-mitotic state. Resident macrophages and endothelial cells are a more likely target for this mechanism of injury. By altering these cellular targets, cardiac radiation can result in increases in oxidative stress and activated proinflammatory pathways, such as adhesion molecules, matrix metalloproteinases, cytokines (IL-6 [interleukin-6] and TNF-α [tumor necrosis factor-α]), and nitric oxide. The specific impact of Ac-SDKP on these pathways of cardiac response to radiation remains to be investigated.There are many different tissue types in the heart, and these different tissues exposed to ionizing radiation may not be similarly affected. For example, Purkinje fibers may be susceptible while myocardial cells could be relatively resistant to damage. Movement of cardiac tissue during the cardiac cycle while undergoing radiation therapy can make all the difference between injury and no detectable injury. Other factors that are becoming increasingly important to minimizing potential damage include (1) maneuvers to displace the heart from the treatment field (breath-hold, prone positioning)3; (2) technological advances for highly conformal radiation treatment, such as stereotactic body radiation therapy4; (3) real-time tissue monitoring including image guidance, such as cone beam computed tomography or magnetic resonance imaging; (4) strategies to directly deliver the radiation source such as brachytherapy; and (5) alternative energy sources, such as proton or heavy particle therapy.Time from radiation exposure is a crucial determinant in the ability to detect the manifestations of cardiac damage. In the clinical world, most radiation damage is detected many years after exposure but can be detected early within just a few years and increases in frequency for at least 20 years after treatment.5 In the case of thoracic radiation for lung cancer, the preponderance of events occurs within the first 2 years, but long-term follow-up of this patient population is not as feasible as with other cancer populations with longer expected survival.6 In the report by Sharma et al,1 the timing of the experimental design included an in-depth analysis within 18 weeks of radiation treatment which may be appropriate for an early or acute injury but would not address longer term toxicity that may take years to develop, including a fibrotic response in cardiomyocytes.7Considering the full implications of this report, it is certainly encouraging and exciting that a therapy may be directly cardioprotective for cardiomyocytes in a rat model of radiation injury. However, radiation injury in a human has many complex subtleties, including the specific mechanism of cellular change, exact tissue targeted, the intrinsic susceptibility, movement with respiration or the cardiac cycle, time from exposure, existing cardiovascular disease, concomitant cardiovascular-based therapy, technique utilized in different medical eras, and the sensitivity of detection of injury; the layers of the onion of radiation cardiotoxicity can go on and on (Table). We would emphasize that efforts like those reported here are critically important and have improved clinical practice over the years as we collectively enhance our radiation treatment protocols to be safer and more effective. If Ac-SDKP can, in fact, be developed as a cardioprotectant for radiation treatment, then we are truly getting to the heart of the matter.Table. Important Layers of the Onion of Radiation CardiotoxicityTissue susceptibilityHost tissue response to injuryMovement during respiration or the cardiac cycleTime from exposureCoexistent cardiovascular risk factorsConcomitant cardiovascular medicationRadiation techniqueSensitivity for the detection of injuryDisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circheartfailureDaniel J. Lenihan, MD, Cardiovascular Division, Washington University in St Louis, 660 S Euclid Ave, Campus Box 8086, St Louis, MO 63110. Email [email protected]eduReferences1. Sharma UC, Sonkawade SD, Spernyak JA, Sexton S, Nguyen J, Dahal S, Attwood KM, Singh AK, van Berlo JH, Pokharel S. Small peptide N-acetyl-Ser-Asp-Lys-Pro inhibits radiation-induced cardiomyopathy.Circ Heart Fail. 2018; 11:e004867. doi: 10.1161/CIRCHEARTFAILURE.117.004867LinkGoogle Scholar2. Groarke JD, Nguyen PL, Nohria A, Ferrari R, Cheng S,, Moslehi J. Cardiovascular complications of radiation therapy for thoracic malignancies: the role for non-invasive imaging for detection of cardiovascular disease.Eur Heart J. 2014; 25:612–623. doi: 10.1093/eurheartj/eht114CrossrefGoogle Scholar3. Shah C, Badiyan S, Berry S, Khan AJ, Goyal S, Schulte K, Nanavati A, Lynch M, Vicini FA. Cardiac dose sparing and avoidance techniques in breast cancer radiotherapy.Radiother Oncol. 2014; 112:9–16. doi: 10.1016/j.radonc.2014.04.009CrossrefMedlineGoogle Scholar4. Cuculich PS, Schill MR, Kashani R, Mutic S, Lang A, Cooper D, Faddis M, Gleva M, Noheria A, Smith TW, Hallahan D, Rudy Y, Robinson CG. Noninvasive cardiac radiation for ablation of ventricular tachycardia.N Engl J Med. 2017; 377:2325–2336. doi: 10.1056/NEJMoa1613773CrossrefMedlineGoogle Scholar5. Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Brønnum D, Correa C, Cutter D, Gagliardi G, Gigante B, Jensen MB, Nisbet A, Peto R, Rahimi K, Taylor C, Hall P. Risk of ischemic heart disease in women after radiotherapy for breast cancer.N Engl J Med. 2013; 368:987–998. doi: 10.1056/NEJMoa1209825CrossrefMedlineGoogle Scholar6. Dess RT, Sun Y, Matuszak MM, Sun G, Soni PD, Bazzi L, Murthy VL, Hearn JWD, Kong FM, Kalemkerian GP, Hayman JA, Ten Haken RK, Lawrence TS, Schipper MJ, Jolly S. Cardiac events after radiation therapy: combined analysis of prospective multicenter trials for locally advanced non-small-cell lung cancer.J Clin Oncol. 2017; 35:1395–1402. doi: 10.1200/JCO.2016.71.6142CrossrefMedlineGoogle Scholar7. González A, Schelbert EB, Díez J, Butler J. Myocardial interstitial fibrosis in heart failure: biological and translational perspectives.J Am Coll Cardiol. 2018; 71:1696–1706. doi: 10.1016/j.jacc.2018.02.021CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Vo J, Ramin C, Barac A, Berrington de Gonzalez A and Veiga L (2022) Trends in heart disease mortality among breast cancer survivors in the US, 1975–2017, Breast Cancer Research and Treatment, 10.1007/s10549-022-06515-5, 192:3, (611-622), Online publication date: 1-Apr-2022. Andres M, Pan J and Lyon A (2021) What Does a Cardio-oncology Service Offer to the Oncologist and the Haematologist?, Clinical Oncology, 10.1016/j.clon.2021.03.012, 33:8, (483-493), Online publication date: 1-Aug-2021. Pushparaji B, Marmagkiolis K, Miller C, Aziz M, Balanescu D, Donisan T, Palaskas N, Kim P, Lopez-Mattei J, Cilingiroglu M, Hassan S and Iliescu C (2020) State-of-the-art Review: Interventional Onco-Cardiology, Current Treatment Options in Cardiovascular Medicine, 10.1007/s11936-020-00809-x, 22:5, Online publication date: 1-May-2020. Related articlesA Small Peptide Ac-SDKP Inhibits Radiation-Induced CardiomyopathyUmesh C. Sharma, et al. Circulation: Heart Failure. 2018;11 August 2018Vol 11, Issue 8 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.118.005294PMID: 30354569 Originally publishedAugust 17, 2018 KeywordsEditorialscardiotoxicityGalectin-3apoptosisheart failuremacrophagesPDF download Advertisement SubjectsCardio-Oncology