Chong, JH

Hausenloy, DJ

Ng, CT

English

UCL Discovery

J A C C : C A R D I O O N C O L O G Y V O L . 2 , N O . 1 , 2 0 2 0ª 2 0 2 0 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E A M E R I C A NC O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E RT H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .EDITORIAL COMMENTRepeated Remote Ischemic ConditioningProtects Against DoxorubicinCardiotoxicityNever Too Much of a Good Thing*Derek J. Hausenloy, MD, PHD,a,b,c,d,e,f Choon Ta Ng, MD,g Jun Hua Chong, MDb,gT he anthracycline chemotherapeutic, doxoru-bicin (DOX), is one of the most efficaciousanticancer agents for treating a number ofsolid and hematological malignancies, but its usehas been limited by its dose-dependent cardiotoxiceffects, which can increase the risk of developingISSN 2666-0873*Editorials published in JACC: CardioOncology reflect the views of theauthors and do not necessarily represent the views of JACC:CardioOncology or the American College of Cardiology.From the aNational Heart Research Institute Singapore, National HeartCentre Singapore, Singapore; bCardiovascular & Metabolic DisordersProgram, Duke-National University of Singapore Medical School,Singapore; cYong Loo Lin School of Medicine, National UniversitySingapore, Singapore; dThe Hatter Cardiovascular Institute, UniversityCollege London, London, United Kingdom; eCardiovascular ResearchCenter, College of Medical and Health Sciences, Asia University, TaichungCity, Taiwan; fTecnologico de Monterrey, Centro de Biotecnologia-FEMSA, Nuevo Leon, Mexico; and the gDepartment of Cardiology, Na-tional Heart Centre Singapore, Singapore. Dr. Hausenloy has been sup-ported by the British Heart Foundation (CS/14/3/31002), the NationalInstitute for Health Research University College London HospitalsBiomedical Research Centre, Duke-National University Singapore MedicalSchool, Singapore Ministry of Health’s National Medical Research Councilunder its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/0011/2017) and Collaborative Centre Grant scheme (NMRC/CGAug16C006), and the Singapore Ministry of Education AcademicResearch Fund Tier 2 (MOE2016-T2–2–021). This paper is based on workfrom COST Action EU-CARDIOPROTECTION CA16225 supported by COST(European Cooperation in Science and Technology). Dr. Chong has beensupported by the Singapore Ministry of Health’s National MedicalResearch Council Research Training Fellowship (FLWSHP19may-0013)and the National Medical Research Council Collaborative Centre GrantSeed Funding (NHCS-CCGSF/2019/002). All other authors have reportedthat they have no relationships relevant to the contents of this paper todisclose.The authors attest they are in compliance with human studies commit-tees and animal welfare regulations of the authors’ institutions and Foodand Drug Administration guidelines, including patient consent whereappropriate. For more information, visit the JACC: CardioOncology authorinstructions page.early or late-onset cardiomyopathy, and heart failurein cancer survivors. Postulated mechanisms underly-ing DOX cardiotoxicity include oxidative stress,iron overload, mitochondrial injury, topoisomeraseIIb inhibition, and DNA intercalation (1). Therapeuticinterventions to mitigate DOX cardiotoxicity, suchas limiting the cumulative dose of DOX, use ofliposomal DOX, dexrazoxane therapy, and cardiopro-tective therapies (such as beta-blockers and renin-angiotensin antagonists), have shown some benefit,but cardiovascular morbidity and mortality fromcardiotoxicity in cancer survivors is still significantdespite these measures (2). Therefore, new therapeu-tic strategies are needed to protect the myocardiumagainst DOX cardiotoxicity to improve cardiac out-comes in oncology patients undergoing anthracyclinechemotherapy. In this regard, the endogenous cardio-protective strategy, “remote ischemic conditioning”(RIC), has the therapeutic potential to protect themyocardium against DOX cardiotoxicity.RIC refers to the phenomenon in which briefnonlethal cycles of ischemia and reperfusion to anorgan or tissue remote from the heart confer car-dioprotection against an episode of lethal acutemyocardial ischemia/reperfusion injury (IRI) (3).Importantly, the RIC stimulus can be applied to thelimb by simply inflating and deflating a pneumaticcuff placed on the upper arm or thigh (termed limbRIC) (4), making it a low-cost and noninvasive car-dioprotective strategy that can be easily tested in theclinical setting. Although a single-limb RIC stimulushas been reported to reduce myocardial infarct size inpatients with acute myocardial infarction (AMI) (5), alarge multicenter study failed to demonstrate anybeneficial effects on clinical outcomes (6). Themechanisms underlying the cardioprotective effect ofhttps://doi.org/10.1016/j.jaccao.2020.02.001SEE PAGE 41Hausenloy et al. J A C C : C A R D I O O N C O L O G Y , V O L . 2 , N O . 1 , 2 0 2 0Repeat Remote Ischemic Conditioning and Doxorubicin Cardiotoxicity M A R C H 2 0 2 0 : 5 3 – 554limb RIC remain unclear, but involve the release ofcytoprotective factor(s) into the systemic circulation,and the activation of prosurvival signaling pathwaysin the heart, that target the detrimental effects ofacute IRI, including oxidative stress, apoptosis,inflammation, and mitochondrial dysfunction (3). Thefact that many of these factors have also been impli-cated as mediators of DOX cardiotoxicity, raised thepossibility that limb RIC may be cardioprotective inpatients undergoing anthracycline chemotherapy.In this regard, Gertz et al. (7) recently reported thepotential cardioprotective effects of limb RIC againstDOX cardiotoxicity. Using a mouse model, theydemonstrated that a single-limb RIC stimulus (three5-min cycles of femoral artery ligation and reflow)reduced mortality, preserved left ventricular (LV)mass, decreased myocardial fibrosis and apoptosis,and upregulated autophagy signaling. However, nobeneficial effects were observed on either mitochon-drial or cardiac function, and so the mechanismsunderlying the observed improvement in survivalwith RIC remain unclear. The findings from this studysuggested that a single-limb RIC stimulus has thetherapeutic potential to prevent or attenuate DOXcardiotoxicity, and provide a low-cost and noninva-sive cardioprotective strategy for testing in patientsundergoing anthracycline chemotherapy. In this re-gard, the ongoing ERIC-ONC study (Effect of RemoteIschemic Conditioning in Oncology Patients;NCT02471885) is currently investigating the car-dioprotective effects of a single-limb RIC stimulus(four 5-min inflations and deflations of a pneumaticcuff placed on the upper arm) applied immediatelybefore each chemotherapy cycle in adult oncologypatients newly referred for anthracycline chemo-therapy, with the primary endpoint being myocardialinjury (measured by high-sensitive troponin T at 6and 24 h) (8).Interestingly, emerging data have suggested thatrepeated daily episodes of limb RIC for 28 days,termed repeated RIC (rRIC) or chronic remoteischemic conditioning (9), may have beneficial effectsover and above a single-limb RIC stimulus in experi-mental small animal models of AMI in terms of pre-venting adverse post-AMI LV remodeling viapotential anti-apoptotic, anti-inflammatory, auto-phagic effects, and exosome-mediated improvementsin intercellular communication (10,11). Furthermore,in patients with intracranial arterial stenosis, rRICadministered for 365 days was shown to reduce therisk of stroke (12), and rRIC applied for 7 to 28 dayshas been shown to have vascular and cytoprotectiveeffects that may benefit patients with endothelialdysfunction, hypertension, chronic heart failure, andpost-AMI LV remodeling (9).In this issue of JACC: CardioOncology, a study byHe et al. (13) tested the cardioprotective efficacy ofrRIC in a mouse model of doxorubicin-induced car-diotoxicity. They found that limb RIC (four 5-mincycles of limb ischemia and reperfusion using atourniquet placed on the hindlimb), initiated 30 minbefore DOX administration and applied daily for5 days, had the following beneficial effects: it reducedDOX-induced myocardial apoptosis, myocardialinjury (measured by troponin release), myocardialinflammation, and interstitial fibrosis; it enhancedcellular autophagy and maintained cardiomyocytesize and heart weight; and it partially attenuated theDOX-induced depression in cardiac function,although the effect was modest (assessed by echo-determined LV ejection fraction [DOX 47.5% vs.DOX þ rRIC 51.6%] and fractional shortening). As nosham limb RIC group was included in the study, thepotential confounding effects of daily episodes ofanesthesia over 5 days (which would be required toadminister the limb RIC stimulus) on the observedeffects of rRIC, cannot be excluded. Given that thesalutary effects on cardiac function of rRIC weremodest, perhaps a more prolonged course of rRIC(as used in the studies demonstrating less post-AMIadverse LV remodeling with rRIC applied for28 days [10,11]) may have had a greater car-dioprotective effect against DOX cardiotoxicity.However, a prolonged rRIC protocol would raise is-sues of patient compliance in future clinical studies.Interestingly, the authors also demonstrated thatrRIC had cytoprotective effects in other organs, suchas the kidney, spleen, and liver, in terms of preser-ving organ weight and function (13). The multiorganbenefits of rRIC may be explained by the release intothe systemic circulation of, so far unidentified, cyto-protective factor(s) by the limb RIC stimulus (3). Infuture studies, it would be important to determinewhether rRIC can protect mitochondrial respiratoryfunction against the damaging effects of DOX in theheart and other organs, although a single RIC stim-ulus did not have any mitoprotective effects againstDOX cardiotoxicity in a recent study (7). Furthermore,studies of rRIC in a tumor-bearing animal model areneeded before clinical testing to ensure rRIC does notattenuate the cytotoxic potency and anticancer effi-cacy of DOX.In summary, recent studies have demonstratedpotential cardioprotective effects of limb rRIC againstJ A C C : C A R D I O O N C O L O G Y , V O L . 2 , N O . 1 , 2 0 2 0 Hausenloy et al.M A R C H 2 0 2 0 : 5 3 – 5 Repeat Remote Ischemic Conditioning and Doxorubicin Cardiotoxicity55DOX cardiotoxicity, providing a low-cost noninvasivetreatment strategy for improving cardiac outcomes inoncology patients undergoing anthracycline chemo-therapy. Further work is needed to determine theoptimal rRIC protocol for cardioprotection in terms ofthe duration of the rRIC protocol (as this will haveimplications for patient compliance); the number ofischemia and reperfusion cycles that make up theoptimum limb RIC stimulus (this has not beenadequately defined); whether it is efficacious in pa-tients with cardiovascular morbidities such as dia-betes, hypertension, and obesity, factors that mayconfound RIC-induced cardioprotection; and itssafety (in relation to whether it interferes with thecytotoxic actions of DOX). Identification of thecirculating cytoprotective factor(s) released by limbRIC, and the elucidation of the molecular pathwaysunderlying RIC-induced multiorgan protection, mayresult in the discovery of novel therapeutic targetsand treatments for improving clinical outcomes inoncology patients at risk of DOX cardiotoxicity.ADDRESS FOR CORRESPONDENCE: Dr. Derek J.Hausenloy, Cardiovascular and Metabolic DisordersProgram, Duke-National University of Singapore, 8College Road, Singapore 169857. E-mail: derek.hausenloy@duke-nus.edu.sg. Twitter: @dukenus.RE F E RENCE S1. McGowan JV, Chung R, Maulik A, Piotrowska I,Walker JM, Yellon DM. Anthracycline chemo-therapy and cardiotoxicity. Cardiovasc Drugs Ther2017;31:63–75.2. Hayek SS, Ganatra S, Lenneman C, et al. Pre-paring the cardiovascular workforce to care foroncology patients: JACC Review Topic of theWeek. J Am Coll Cardiol 2019;73:2226–35.3. Sivaraman V, Pickard JMJ, Hausenloy DJ.Remote ischaemic conditioning: cardiac protectionfrom afar. Anaesthesia 2015;70:732–48.4. Kharbanda RK, Mortensen UM, White PA, et al.Transient limb ischemia induces remote ischemicpreconditioning in vivo. Circulation 2002;106:2881–3.5. Chong J, Bulluck H, Yap EP, Ho AF, Boisvert WA,Hausenloy DJ. Remote ischemic conditioning inST-segment elevation myocardial infarction - anupdate. Cond Med 2018;1:13–22.6. Hausenloy DJ, Kharbanda RK, Moller UK, et al.Effect of remote ischaemic conditioning on clinicaloutcomes in patients with acute myocardialinfarction (CONDI-2/ERIC-PPCI): a single-blindrandomised controlled trial. Lancet 2019;394:1415–24.7. Gertz ZM, Cain C, Kraskauskas D, et al. Remoteischemic pre-conditioning attenuates adversecardiac remodeling and mortality following doxo-rubicin administration in mice. J Am Coll CardiolCardioOnc 2019;1:221.8. Chung R, Maulik A, Hamarneh A, et al. Effect ofRemote ischaemic conditioning in oncology pa-tients undergoing chemotherapy: rationale anddesign of the ERIC-ONC study–a single-center,blinded, randomized controlled trial. Clin Cardiol2016;39:72–82.9. Chong J, Bulluck H, Ho AFW, Boisvert WA.Hausenloy DJ Chronic remote ischemic condition-ing for cardiovascular protection. Cond Med 2019;2:164–9.10. Yamaguchi T, Izumi Y, Nakamura Y, et al.Repeated remote ischemic conditioning attenu-ates left ventricular remodeling via exosome-mediated intercellular communication on chronicheart failure after myocardial infarction. Int JCardiol 2015;178:239–46.11. Wei M, Xin P, Li S, et al. Repeated remoteischemic postconditioning protects againstadverse left ventricular remodeling and improvessurvival in a rat model of myocardial infarction.Circ Res 2011;108:1220–5.12. Meng R, Asmaro K, Meng L, et al. Upper limbischemic preconditioning prevents recurrentstroke in intracranial arterial stenosis. Neurology2012;79:1853–61.13. He Q, Wang F, Ryan TD, Chalasani M,Redington AN. Repeated remote ischemicconditioning reduces doxorubicin-induced car-diotoxicity. J Am Coll Cardiol CardioOnc 2020;2:41–52.KEY WORDS anthracycline cardiotoxicity,cardioprotection, chronic remote ischemicconditioning, repeat remote ischemic conditioning

Repeated Remote Ischemic Conditioning Protects Against Doxorubicin Cardiotoxicity Never Too Much of a Good Thing

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Repeated Remote Ischemic Conditioning Protects Against Doxorubicin Cardiotoxicity Never Too Much of a Good Thing

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