Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Myocarditis
2021; Lippincott Williams & Wilkins; Volume: 144; Issue: 18 Linguagem: Inglês
10.1161/circulationaha.121.055816
ISSN1524-4539
AutoresJohn R. Power, Joachim Alexandre, Arrush Choudhary, Benay Özbay, Salim S. Hayek, Aarti Asnani, Yuichi Tamura, Mandar A. Aras, Jennifer Cautela, Franck Thuny, Lauren Gilstrap, Dimitri Arangalage, Steven M. Ewer, Shi Huang, Anita Deswal, Nicolas L. Palaskas, Daniel Finke, Lorenz Lehmann, Stéphane Éderhy, Javid J. Moslehi, Joe‐Elie Salem, Baptiste Abbar, Yves Allenbach, Tariq U. Azam, Alan H. Baik, Lauren A. Baldassarre, Barouyr Baroudjian, Pennelope Blakley, Sergey V. Brodsky, Johnny Chahine, Wei-Ting Chan, Amy L. Copeland, Shanthini M. Crusz, Grace K. Dy, Charlotte Fenioux, Kambiz Ghafourian, Arjun K. Ghosh, V. Gounant, Avirup Guha, Manhal Habib, Osnat Itzhaki Ben Zadok, Lily Koo Lin, Michal Laufer‐Perl, Carrie Lenneman, Darryl P. Leong, Matthew Martini, Tyler Meheghan, Elvire Mervoyer, Cecilia Monge, Ryota Morimoto, Anna Narezkina, Martin Nicol, Joseph Nowatzke, Olusola Ayodeji Orimoloye, Milan Patel, Daniel Perry, Nicolas Piriou, Lawrence D. Piro, Tyler B. Moran, Ben Stringer, Kazuko Tajiri, Pankit Vachhani, Ellen Warner, Marie-Claire Zimmer,
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ResumoHomeCirculationVol. 144, No. 18Electrocardiographic Manifestations of Immune Checkpoint Inhibitor Myocarditis Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toSupplementary MaterialsFree AccessLetterPDF/EPUBElectrocardiographic Manifestations of Immune Checkpoint Inhibitor Myocarditis John R. Power, MD, Joachim Alexandre, MD, PhD, Arrush Choudhary, MD, Benay Ozbay, MD, Salim Hayek, MD, PhD, Aarti Asnani, MD, Yuichi Tamura, MD, PhD, Mandar Aras, MD, PhD, Jennifer Cautela, MD, Franck Thuny, MD, PhD, Lauren Gilstrap, MD, Dimitri Arangalage, MD, PhD, Steven Ewer, MD, Shi Huang, PhD, Anita Deswal, MD, MPH, Nicolas L. Palaskas, MD, Daniel Finke, MD, Lorenz Lehmann, MD, Stephane Ederhy, MD, Javid Moslehi, MD and Joe-Elie Salem, MD, PhD John R. PowerJohn R. Power University of California San Diego Health (J.R.P.). , Joachim AlexandreJoachim Alexandre University Caen Normandie, France (J.A.). , Arrush ChoudharyArrush Choudhary Beth Israel Deaconess Medical Center, Boston, MA (A.C., A.A.). , Benay OzbayBenay Ozbay https://orcid.org/0000-0002-2039-5770 Basaksehir Cam and Sakura State Hospital, Istanbul, Turkey (B.O.). , Salim HayekSalim Hayek Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor (S. Hayek). , Aarti AsnaniAarti Asnani https://orcid.org/0000-0003-4967-9918 Beth Israel Deaconess Medical Center, Boston, MA (A.C., A.A.). , Yuichi TamuraYuichi Tamura https://orcid.org/0000-0002-8727-7154 International University of Health and Welfare Mita Hospital, Tokyo, Japan (Y.T.). , Mandar ArasMandar Aras University of California, San Francisco (M.A.). , Jennifer CautelaJennifer Cautela Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Marseille, France (J.C., F.T.). , Franck ThunyFranck Thuny https://orcid.org/0000-0002-8727-7154 Assistance Publique-Hôpitaux de Marseille, Hôpital Nord, Marseille, France (J.C., F.T.). , Lauren GilstrapLauren Gilstrap Dartmouth Hitchcock Medical Center, Lebanon, NH (L.G.). , Dimitri ArangalageDimitri Arangalage https://orcid.org/0000-0002-0898-9090 Hôpital Bichat, Paris, France (D.A.). , Steven EwerSteven Ewer University of Wisconsin Hospital, Madison (S. Ewer). , Shi HuangShi Huang Vanderbilt University Medical Center, Nashville, TN (S. Huang, J.M.). , Anita DeswalAnita Deswal https://orcid.org/0000-0002-6147-9591 University of Texas MD Anderson Cancer Center, Houston (A.D., N.L.P.). , Nicolas L. PalaskasNicolas L. Palaskas https://orcid.org/0000-0001-7565-1797 University of Texas MD Anderson Cancer Center, Houston (A.D., N.L.P.). , Daniel FinkeDaniel Finke University of Heidelberg, Germany (D.F., L.L.). Assistance Publique-Hôpitaux de Paris, University of Paris, France (D.F.). , Lorenz LehmannLorenz Lehmann https://orcid.org/0000-0001-5077-8580 University of Heidelberg, Germany (D.F., L.L.). , Stephane EderhyStephane Ederhy https://orcid.org/0000-0002-0792-2521 Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France (S. Ederhy, J.-E.S.). , Javid MoslehiJavid Moslehi Correspondence to: Javid Moslehi, MD, Section of Cardio-Oncology & Immunology, Division of Cardiology and the Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Blvd South, Box 3118, San Francisco, CA 94143-3118; Email E-mail Address: [email protected] Vanderbilt University Medical Center, Nashville, TN (S. Huang, J.M.). and Joe-Elie SalemJoe-Elie Salem Joe-Elie Salem, MD, PhD, Center d'Investigation Clinique Paris-Est, Hôpital Pitié-Salpêtrière, Bâtiment Antonin Gosset, 47-83 Bld de l'hôpital, 75013 Paris, France. Email E-mail Address: [email protected] https://orcid.org/0000-0002-0331-3307 Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France (S. Ederhy, J.-E.S.). and on behalf of the International ICI-Myocarditis Registry† Originally published1 Nov 2021https://doi.org/10.1161/CIRCULATIONAHA.121.055816Circulation. 2021;144:1521–1523is corrected byCorrection to: Electrocardiographic Manifestations of Immune Checkpoint Inhibitor MyocarditisOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 1, 2021: Previous Version of Record Immune checkpoint inhibitors (ICIs) have transformed oncology care by unleashing T-cells to achieve antitumor effects but can cause inflammatory adverse events including myocarditis.1 ICI-myocarditis is highly arrhythmogenic, but specific electrocardiographic manifestations and their prognostic significance are poorly understood.2A retrospective multicenter registry including 49 institutions and 11 countries was built using a Research Electronic Data Capture web-based platform with Institutional Review Board approval (Institutional Review Board No. 181337; URL: http://www.clinicaltrials.gov; Unique identifier: NCT04294771). Through January 2020, 147 cases of ICI-myocarditis were collected. Presenting ECG, defined as ECG obtained within 3 days of admission, was available in 125 cases for independent analysis by 2 cardiologists (blinded to each case) who interpreted 24 prespecified ECG features. To allow for complete ECG measurement, presenting ECGs were excluded if they only showed paced rhythms or sustained ventricular arrhythmias. Baseline ECG was defined as the most recent ECG obtained before ICI exposure and was available for independent interpretation in 52 cases. Data are available on request. Paired t test and McNemar's test were used to compare features of presenting ECG with baseline ECG. A Cox proportional-hazards model adjusted for age and sex determined association of ECG features with all-cause mortality within 30 days of presentation. The proportional hazard assumption was verified and met for each predictor using the score test on the basis of the Schoenfeld residuals.Median (interquartile range) age was 67 years (58–77), and 92/147 (62.6%) were male. Median time from first ICI dose to myocarditis presentation was 38 days (21–83). Presenting ECG showed elevated heart rate (93.9 versus 80.4 bpm; P=0.009), prolonged QRS (95.3 versus 93.2 ms; P=0.02), and prolonged QT corrected for heart rate (441.8 versus 421.0 ms; P=0.03; Fridericia's) compared with baseline ECG (n=52). Sokolow-Lyon Index (sum of S wave in V1 and R wave in V5 or V6) showed a significant decrease in voltage from baseline (1.39 versus 1.69 mV; P=0.006). The incidence of left bundle-branch block (10/52 [19%] versus 3/52 [6%]; P=0.046) and sinus tachycardia (25/52 [48%] versus 15/52 [29%]; P=0.02) was increased versus baseline. In aggregate, conduction disorders (35/52 [67%] versus 23/52 [44%]; P=0.01) and repolarization abnormalities (27/52 [52%] versus 13/52 [25%]; P=0.008) were significantly increased (Table).Table. Presenting ECG of ICI-Myocarditis Compared With Baseline and as Predictors of All-Cause Mortality Using Survival Analyses Adjusting for Age and Sex*ICI-myocarditis, presenting ECG; median (IQR) N; n/N (%)ICI-myocarditis, baseline ECG; median (IQR) N; n/N (%)P valueCox proportional hazards model for 30-day all-cause mortality; adjusted HR (95% CI), P value; NHeart rate, bpm93.9 (72.6–114.7) N=5280.4 (68.1–94.8) N=520.009†1.01 (0.99–1.02), P=0.40; N=125PR length, ms‡162.8 (136.0–186.0) N=42154.1 (136.0–187.6) N=460.10†1.00 (0.99–1.01), P=0.55; N=107QTcF length, ms§441.8 (414.9–462.6) N=49421.0 (399.2–440.4) N=510.03†1.00 (1.00–1.01), P=0.36; N=122QRS length, ms95.3 (85.7–118.2) N=5293.2 (82.7–102.5) N=520.02†1.00 (0.99–1.01), P=0.90; N=125Sokolow-Lyon Index, mV∥1.39 (0.85–2.03) N=521.69 (1.28–2.26) N=520.006†0.57 (0.34–0.94), P=0.03; N=124Conduction disorders¶35/52 (67%)23/52 (44%)0.01#1.56 (0.69–3.53), P=0.29; N=125 Bundle-branch block, left bundle10/52 (19%)3/52 (6%)0.05#1.00 (0.38–2.62), P=0.99; N=125 Bundle-branch block, right bundle14/52 (27%)9/52 (17%)0.18#1.48 (0.71–3.06), P=0.29; N=125 Fascicular block, left anterior10/52 (19%)5/52 (10%)0.23#0.85 (0.32–2.25), P=0.75; N=125 Fascicular block, left posterior6/52 (12%)2/52 (4%)0.22#1.34 (0.47–3.85), P=0.59; N=125 Heart block, first-degree9/52 (17%)7/52 (13%)0.72#0.83 (0.28–2.40), P=0.72; N=125ECG findings of pericarditis4/52 (8%)1/52 (2%)0.25#0.75 (0.22–2.51), P=0.64; N=125 ST-segment–elevation, diffuse3/52 (6%)1/52 (2%)0.62#0.83 (0.25–2.81), P=0.76; N=125Premature ventricular complex (all types)9/52 (17%)3/52 (6%)0.08#1.01 (0.37–2.75), P=0.99; N=125 Premature ventricular complex9/52 (17%)3/52 (6%)0.08#0.77 (0.26–2.30), P=0.64; N=125Sinus mechanism42/52 (81%)46/52 (88%)0.29#0.76 (0.31–1.89), P=0.56; N=125 Normal sinus rhythm17/52 (33%)31/52 (60%)0.002#0.50 (0.23–1.09), P=0.08; N=125 Sinus tachycardia25/52 (48%)15/52 (29%)0.02#1.67 (0.80–3.49), P=0.17; N=125Repolarization abnormalities27/52 (52%)13/52 (25%)0.008#1.52 (0.74–3.12), P=0.26; N=125 ST-segment depression, diffuse5/52 (10%)1/52 (2%)0.22#1.60 (0.48–5.30), P=0.44; N=125 ST-segment depression, regional4/52 (8%)0/52 (0%)NA0.53 (0.07–3.90), P=0.53; N=125 T wave inversions21/52 (40%)12/52 (23%)0.07#1.49 (0.71–3.12), P=0.29; N=125Supraventricular arrhythmia7/52 (13%)6/52 (12%)1.00#2.21 (0.84–5.79), P=0.11; N=125 Atrial fibrillation6/52 (12%)5/52 (10%)1.00#1.83 (0.63–5.27), P=0.27; N=125Uncategorized Premature atrial complex5/52 (10%)3/52 (6%)0.68#1.59 (0.47–5.38), P=0.46; N=125 Left ventricular hypertrophy12/52 (23%)16/52 (31%)0.34#0.49 (0.15–1.61), P=0.24; N=125 Low QRS voltage4/52 (8%)1/52 (2%)0.37#3.27 (0.95–11.23), P=0.06; N=125 P wave abnormality suggestive of left atrial enlargement11/52 (21%)9/52 (17%)0.75#1.10 (0.46–2.63), P=0.83; N=125 Q waves, pathological8/52 (15%)4/52 (8%)0.22#5.98 (2.8–12.79), P 2 are shown.† P values were determined using the paired t test.‡ PR intervals are unmeasurable in supraventricular arrhythmia.§ QT intervals are unmeasurable in paced ventricular complexes. QT was corrected for heart rate by Fridericia's method (QTcF).∥ Sokolow-Lyon Index is unmeasurable without precordial leads.¶ When multiple eligible ECGs were available, ECGs without complete heart block or supraventricular arrhythmias were preferentially selected for this analysis focusing on PR, QRS, and QTc measurements.# P values were determined using the McNemar test.Throughout hospitalization (median, 11 days [interquartile range, 7–24]), 101/147 (68.7%) patients experienced conduction disorders defined as fascicular, bundle, and/or heart blocks with second-degree heart block in 11/147 (7.5%) and complete heart block in 25/147 (17.0%). Supraventricular arrhythmias including atrial fibrillation, atrial flutter, and multifocal atrial tachycardia had a cumulative incidence of 35/147 (23.8%), 31/147 (21.1%), 2/147 (1.4%), and 2/147 (2.1%), respectively. A total of 22/147 (15.0%) patients experienced 1 or more life-threatening ventricular arrhythmia episodes, including 16/147 (10.9%) sustained ventricular tachycardia, 4/147 (2.7%) ventricular fibrillation, and 2/147 (1.4%) torsade de pointes. Complete heart block and life-threatening ventricular arrhythmia co-occurred in 11/147 (7.5%) patients.Immunomodulating treatments were given to 121/147 (82.3%) patients, of whom 118/121 (97.5%) received corticosteroids and 51/121 (42.1%) received plasmapheresis or nonsteroidal immunomodulators. Electrophysiology devices were placed in 21/146 (14.4%) patients within 30 days of presentation including 20/21 (95%) pacemakers for high-grade atrioventricular block and 3/21 (14%) defibrillators for secondary prevention of ventricular arrhythmia. In 146 patients with 30-day surveillance, 39/146 (26.7%) died within 30 days of presentation, of which 24/39 (62%) were attributable to myocarditis. Other causes of death included cancer progression, 6/39 (15%); sepsis, 6/39 (15%); and noncardiac immune-related adverse events, 7/39 (18%); of which 6 were attributable to noncardiac myotoxicities (eg, myositis).Patients with ICI-myocarditis were more likely to experience all-cause mortality within 30 days if they developed complete heart block (12/25 [48%] versus 27/122 [22.1%]; hazard ratio, 2.62 [95% CI, 1.33–5.18]; P=0.01) or life-threatening ventricular arrhythmias (12/22 [55%] versus 27/125 [21.6%]; hazard ratio, 3.10 [95% CI, 1.57–6.12]; P=0.001).All-cause mortality was associated with pathological Q waves (12/19 [63%] versus 18/106 [17.0%]; hazard ratio, 5.98 [95% CI, 2.8–12.79]; P<0.001, adjusted for age and sex) and inversely associated with Sokolow-Lyon Index (hazard ratio/mV=0.57 [95% CI, 0.34–0.94]; P=0.03). Other ECG features were not associated with mortality (Table). Both low-voltage and pathological Q waves signify a loss of electromotive force and are intuitive markers for the extent of inflammatory infiltrate and cardiomyocyte damage. ICI-myocarditis is histologically characterized by lymphocyte and macrophage infiltrates that affect both the myocardium and the conduction system.3,4 The finding that low-voltage and pathological Q waves predict mortality suggests that suppressing the underlying inflammatory infiltrate may be a greater priority than antiarrhythmic drugs or devices.5This study's multicenter approach introduced variability in data collection and interpretation. To mitigate this, clear adjudication criteria were provided, and submissions were subjected to a bi-institutional review process. Self-reporting allowed for assembly of an ICI-myocarditis cohort of this size but likely selected for more clinically severe cases. The comparison with baseline ECG was limited by availability of baseline ECG, which likely enriched for patients with preexisting cardiac disease, thereby underestimating ECG changes caused by ICI-myocarditis.This study shows that ICI-myocarditis is highly arrhythmogenic, presenting with new conduction blocks, decreased voltage, and repolarization abnormalities that frequently degenerate to malignant arrhythmias. Further studies are needed to evaluate how these ECG changes can facilitate screening, prognostication, and monitoring strategies in ICI-myocarditis.Article InformationAcknowledgmentsThis study would not have been possible without the many contributors who participated in the International ICI-Myocarditis Registry.Sources of FundingThis study was supported by grant UL1 TR000445 from the National Center for Advancing Translational Sciences/National Institutes of Health. J.M. was supported by National Institutes of Health grants R01HL141466, R01HL155990, and R01HL156021.Supplemental MaterialsInvestigators in the International ICI-Myocarditis Registry.Disclosures Dr Salem has participated on Bristol Myers Squibb advisory boards and consulted for AstraZeneca. Dr Moslehi has served on advisory boards for Bristol Myers Squibb, Takeda, Regeneron, Audentes, Deciphera, Ipsen, Janssen, ImmunoCore, Boston Biomedical, Amgen, Myovant, Triple Gene/Precigen, Cytokinetics, and AstraZeneca and is supported by National Institutes of Health grants (R01HL141466, R01HL155990, R01HL156021). Dr Finke received speakers' honoraria from Bristol Myers Squibb. Dr Lehmann has served on the advisory board for Daiichi Sankyio, Senaca, and Servier, and as an external expert for Astra Zeneca, and received speakers' honoraria from Novartis and Merck Sharpe & Dohme.Footnotes*J. Moslehi and J.-E. Salem contributed equally.†A complete list of the investigators in the International ICI-Myocarditis Registry is provided in the Data Supplement.https://www.ahajournals.org/journal/circThe Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.121.055816.For Sources of Funding and Disclosures, see page 1523.Correspondence to: Javid Moslehi, MD, Section of Cardio-Oncology & Immunology, Division of Cardiology and the Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Blvd South, Box 3118, San Francisco, CA 94143-3118; Email javid.[email protected]eduJoe-Elie Salem, MD, PhD, Center d'Investigation Clinique Paris-Est, Hôpital Pitié-Salpêtrière, Bâtiment Antonin Gosset, 47-83 Bld de l'hôpital, 75013 Paris, France. Email joe-elie.[email protected]frReferences1. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL, et al.. Fulminant myocarditis with combination immune checkpoint blockade.N Engl J Med. 2016; 375:1749–1755. doi: 10.1056/NEJMoa1609214CrossrefMedlineGoogle Scholar2. Zlotoff DA, Hassan MZO, Zafar A, Alvi RM, Awadalla M, Mahmood SS, Zhang L, Chen CL, Ederhy S, Barac A, et al.. Electrocardiographic features of immune checkpoint inhibitor associated myocarditis.J Immunother Cancer. 2021; 9:e002007. doi: 10.1136/jitc-2020-002007CrossrefMedlineGoogle Scholar3. Champion SN, Stone JR. Immune checkpoint inhibitor associated myocarditis occurs in both high-grade and low-grade forms.Mod Pathol. 2020; 33:99–108. doi: 10.1038/s41379-019-0363-0CrossrefMedlineGoogle Scholar4. Hulsmans M, Clauss S, Xiao L, Aguirre AD, King KR, Hanley A, Hucker WJ, Wülfers EM, Seemann G, Courties G, et al.. Macrophages facilitate electrical conduction in the heart.Cell. 2017; 169:510–522.e20. doi: 10.1016/j.cell.2017.03.050CrossrefMedlineGoogle Scholar5. Wei SC, Meijers WC, Axelrod ML, Anang NAS, Screever EM, Wescott EC, Johnson DB, Whitley E, Lehmann L, Courand PY, et al.. A genetic mouse model recapitulates immune checkpoint inhibitor-associated myocarditis and supports a mechanism-based therapeutic intervention.Cancer Discov. 2021; 11:614–625. doi: 10.1158/2159-8290.CD-20-0856CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByWilcox N, Rotz S, Mullen M, Song E, Ky Hamilton B, Moslehi J, Armenian S, Wu J, Rhee J and Ky B (2022) Sex-Specific Cardiovascular Risks of Cancer and Its Therapies, Circulation Research, 130:4, (632-651), Online publication date: 18-Feb-2022.Related articlesCorrection to: Electrocardiographic Manifestations of Immune Checkpoint Inhibitor MyocarditisCirculation. 2021;144:e490-e490 November 2, 2021Vol 144, Issue 18Article InformationMetrics Download: 723 © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.055816PMID: 34723640 Originally publishedNovember 1, 2021 Keywordsmyocarditiscardio-oncologyimmunotherapyelectrophysiologyPDF download Advertisement
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