Global Circumferential and Radial Strain Among Patients With Immune Checkpoint Inhibitor Myocarditis

Thiago Quinaglia, Carlos Gongora, Magid Awadalla, Malek Z O Hassan, Amna Zafar, Zsofia D Drobni, Syed S Mahmood, Lili Zhang, Otavio R Coelho-Filho, Giselle A Suero-Abreu, Muhammad A Rizvi, Gagan Sahni, Anant Mandawat, Eduardo Zatarain-Nicolás, Michael Mahmoudi, Ryan Sullivan, Sarju Ganatra, Lucie M Heinzerling, Franck Thuny, Stephane Ederhy, Hannah K Gilman, Supraja Sama, Sofia Nikolaidou, Ana González Mansilla, Antonio Calles, Marcella Cabral, Francisco Fernández-Avilés, Juan José Gavira, Nahikari Salterain González, Manuel García de Yébenes Castro, Ana Barac, Jonathan Afilalo, Daniel A Zlotoff, Leyre Zubiri, Kerry L Reynolds, Richard Devereux, Judy Hung, Michael H Picard, Eric H Yang, Dipti Gupta, Caroline Michel, Alexander R Lyon, Carol L Chen, Anju Nohria, Michael G Fradley, Paaladinesh Thavendiranathan, Tomas G Neilan, Thiago Quinaglia, Carlos Gongora, Magid Awadalla, Malek Z O Hassan, Amna Zafar, Zsofia D Drobni, Syed S Mahmood, Lili Zhang, Otavio R Coelho-Filho, Giselle A Suero-Abreu, Muhammad A Rizvi, Gagan Sahni, Anant Mandawat, Eduardo Zatarain-Nicolás, Michael Mahmoudi, Ryan Sullivan, Sarju Ganatra, Lucie M Heinzerling, Franck Thuny, Stephane Ederhy, Hannah K Gilman, Supraja Sama, Sofia Nikolaidou, Ana González Mansilla, Antonio Calles, Marcella Cabral, Francisco Fernández-Avilés, Juan José Gavira, Nahikari Salterain González, Manuel García de Yébenes Castro, Ana Barac, Jonathan Afilalo, Daniel A Zlotoff, Leyre Zubiri, Kerry L Reynolds, Richard Devereux, Judy Hung, Michael H Picard, Eric H Yang, Dipti Gupta, Caroline Michel, Alexander R Lyon, Carol L Chen, Anju Nohria, Michael G Fradley, Paaladinesh Thavendiranathan, Tomas G Neilan

Abstract

Background: Global circumferential strain (GCS) and global radial strain (GRS) are reduced with cytotoxic chemotherapy. There are limited data on the effect of immune checkpoint inhibitor (ICI) myocarditis on GCS and GRS.

Objectives: This study aimed to detail the role of GCS and GRS in ICI myocarditis.

Methods: In this retrospective study, GCS and GRS from 75 cases of patients with ICI myocarditis and 50 ICI-treated patients without myocarditis (controls) were compared. Pre-ICI GCS and GRS were available for 12 cases and 50 controls. Measurements were performed in a core laboratory blinded to group and time. Major adverse cardiovascular events (MACEs) were defined as a composite of cardiogenic shock, cardiac arrest, complete heart block, and cardiac death.

Results: Cases and controls were similar in age (66 ± 15 years vs 63 ± 12 years; P = 0.20), sex (male: 73% vs 61%; P = 0.20) and cancer type (P = 0.08). Pre-ICI GCS and GRS were also similar (GCS: 22.6% ± 3.4% vs 23.5% ± 3.8%; P = 0.14; GRS: 45.5% ± 6.2% vs 43.6% ± 8.8%; P = 0.24). Overall, 56% (n = 42) of patients with myocarditis presented with preserved left ventricular ejection fraction (LVEF). GCS and GRS were lower in myocarditis compared with on-ICI controls (GCS: 17.5% ± 4.2% vs 23.6% ± 3.0%; P < 0.001; GRS: 28.6% ± 6.7% vs 47.0% ± 7.4%; P < 0.001). Over a median follow-up of 30 days, 28 cardiovascular events occurred. A GCS (HR: 4.9 [95% CI: 1.6-15.0]; P = 0.005) and GRS (HR: 3.9 [95% CI: 1.4-10.8]; P = 0.008) below the median was associated with an increased event rate. In receiver-operating characteristic (ROC) curves, GCS (AUC: 0.80 [95% CI: 0.70-0.91]) and GRS (AUC: 0.76 [95% CI: 0.64-0.88]) showed better performance than cardiac troponin T (cTnT) (AUC: 0.70 [95% CI: 0.58-0.82]), LVEF (AUC: 0.69 [95% CI: 0.56-0.81]), and age (AUC: 0.54 [95% CI: 0.40-0.68]). Net reclassification index and integrated discrimination improvement demonstrated incremental prognostic utility of GRS over LVEF (P = 0.04) and GCS over cTnT (P = 0.002).

Conclusions: GCS and GRS are lower in ICI myocarditis, and the magnitude of reduction has prognostic significance.

Keywords: cardiovascular risk stratification; immune checkpoint inhibitors; myocarditis; strain modalities survival analysis.

Conflict of interest statement

Funding Support and Author Disclosures This work was supported by the National Institutes of Health (P30CA008748 to DG and CLC; R01HL137562, R01HL130539; and T32HL007208-39 to DAZ). Dr Mahmood has received consultancy fees from Health and Wellness Partners, OMR Globus, Alpha Detail, and Opinion Research Team. Dr Zhang is consultant for MERCK. Dr Sullivan has served as a consultant for Merck and Novartis. Dr Heinzerling has received consultancy, advisory board, and speaker fees from Merck Sharp & Dohme, BMS, Roche, Novartis, Amgen, Sun Pharma, Pierre Fabre, and CureVac. Dr Gavira has received research support from Amgen. Dr Zubiri has served as a consultant to Merck and is supported by a SEOM (Sociedad Española de Oncología Médica) grant. Dr Yang has received research funding from CSL Behring. Dr Nohria has received research support from Amgen and has been a consultant for Takeda Oncology, Boehringer Ingelheim, and AstraZeneca; and he has received support from the Catherine Geoff Fitch fund and Gelb Master Clinician Fund. Dr Fradley has received consulting fees from AstraZeneca and Abbott and has received a research grant from Medtronic. Dr Neilan is supported by a gift from A. Curt Greer and Pamela Kohlberg and from Christina and Paul Kazilionis, the Michael and Kathryn Park Endowed Chair in Cardiology, and a Hassenfeld Scholar Award; has received advisory fees from AbbVie, Amgen, C4 Therapeutics, H3-Biomedicine, Genentech, Roche, BMS, and Intrinsic Imaging; has received grant funding from AstraZeneca; and he is also supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL130539, R01HL137562, K24HL150238). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Copyright © 2022 American College of Cardiology Foundation. All rights reserved.

Figures

Figure 1:. Consort Flow Diagram of Cohort.
Figure 1:. Consort Flow Diagram of Cohort.
Consort flow diagram showing the cases from multicenter registry and controls from MGH with available TTE GCS. Cases are patients treated with an ICI and who developed myocarditis and controls are defined as patients on ICI who did not develop myocarditis. GLS= global longitudinal strain; GCS= global circumferential strain GRS= global radial strain; ICI= immune checkpoint inhibitors; MGH= Massachusetts General Hospital; TTE= transthoracic echocardiogram.
Figure 2:. Echocardiographic Strain Measures before and…
Figure 2:. Echocardiographic Strain Measures before and after ICI start among Myocarditis Cases and Controls.
A) Box-and-whisker plot showing the reduction in GCS during myocarditis compared to controls; B) Box-and-whisker plot showing the reduction in GRS during myocarditis compared to controls. Sample sizes vary according to time point (Pre-ICI: 10 cases and 39 controls; On-ICI: 75 cases and 49 controls). Minimal values (lowest horizontal line or dot) and maximum values (highest horizontal line or dot) are presented, as well as, first quartile (bottom of box), median (horizontal line within the box) and third quartile. GCS= global circumferential strain GRS= global radial strain; ICI= immune checkpoint inhibitors; * p

Figure 3.. Kaplan-Meier curve comparing those with…

Figure 3.. Kaplan-Meier curve comparing those with a GCS above and below the median (absolute…

Figure 3.. Kaplan-Meier curve comparing those with a GCS above and below the median (absolute values).
Dashed line indicates the median survival time.

Figure 4.. Kaplan-Meier curve comparing those with…

Figure 4.. Kaplan-Meier curve comparing those with a GRS above and below the median.

Dashed…

Figure 4.. Kaplan-Meier curve comparing those with a GRS above and below the median.
Dashed line indicates the median survival time.

Figure 5:. Receiver-operating characteristic (ROC) curves for…

Figure 5:. Receiver-operating characteristic (ROC) curves for prediction of MACE in ICI myocarditis.

GLS= global…

Figure 5:. Receiver-operating characteristic (ROC) curves for prediction of MACE in ICI myocarditis.
GLS= global circumferential strain; GRS= global radial strain; ICI= immune checkpoint inhibitors; LVEF= left ventricular ejection fraction; cTnT= cardiac Troponin T; TTE= transthoracic echocardiogram

Central Illustration:. Event rate stratification in ICI…

Central Illustration:. Event rate stratification in ICI myocarditis.

Event rate stratification using strain modalities from…

Central Illustration:. Event rate stratification in ICI myocarditis.
Event rate stratification using strain modalities from echocardiography and circulating troponin T in a retrospective ICI myocarditis cohort. GCS= global circumferential strain; GRS= global radial strain; GLS= global longitudinal strain; ICI= immune checkpoint inhibitors; LVEF= left ventricular ejection fraction; cTnT= Troponin T.
Figure 3.. Kaplan-Meier curve comparing those with…
Figure 3.. Kaplan-Meier curve comparing those with a GCS above and below the median (absolute values).
Dashed line indicates the median survival time.
Figure 4.. Kaplan-Meier curve comparing those with…
Figure 4.. Kaplan-Meier curve comparing those with a GRS above and below the median.
Dashed line indicates the median survival time.
Figure 5:. Receiver-operating characteristic (ROC) curves for…
Figure 5:. Receiver-operating characteristic (ROC) curves for prediction of MACE in ICI myocarditis.
GLS= global circumferential strain; GRS= global radial strain; ICI= immune checkpoint inhibitors; LVEF= left ventricular ejection fraction; cTnT= cardiac Troponin T; TTE= transthoracic echocardiogram
Central Illustration:. Event rate stratification in ICI…
Central Illustration:. Event rate stratification in ICI myocarditis.
Event rate stratification using strain modalities from echocardiography and circulating troponin T in a retrospective ICI myocarditis cohort. GCS= global circumferential strain; GRS= global radial strain; GLS= global longitudinal strain; ICI= immune checkpoint inhibitors; LVEF= left ventricular ejection fraction; cTnT= Troponin T.

References

    1. Robert C.A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun 2020;11:3801.
    1. Xin Yu J, Hubbard-Lucey VM, Tang J. Immuno-oncology drug development goes global. Nat Rev Drug Discov 2019;18:899–900.
    1. Zhang L, Jones-O’Connor M, Awadalla M et al. Cardiotoxicity of Immune Checkpoint Inhibitors. Curr Treat Options Cardiovasc Med 2019;21:32.
    1. Ganatra S, Neilan TG. Immune Checkpoint Inhibitor-Associated Myocarditis. Oncologist 2018;23:879–886.
    1. Ma R, Wang Q, Meng D, Li K, Zhang Y. Immune checkpoint inhibitors-related myocarditis in patients with cancer: an analysis of international spontaneous reporting systems. BMC Cancer 2021;21:38.
    1. Awadalla M, Mahmood SS, Groarke JD et al. Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis. J Am Coll Cardiol 2020;75:467–478.
    1. Stoodley PW, Richards DA, Hui R et al. Two-dimensional myocardial strain imaging detects changes in left ventricular systolic function immediately after anthracycline chemotherapy. Eur J Echocardiogr 2011;12:945–52.
    1. Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 2014;63:2751–68.
    1. Stokke TM, Hasselberg NE, Smedsrud MK et al. Geometry as a Confounder When Assessing Ventricular Systolic Function: Comparison Between Ejection Fraction and Strain. J Am Coll Cardiol 2017;70:942–954.
    1. Lang RM, Bierig M, Devereux RB et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–63.
    1. Lang RM, Badano LP, Mor-Avi V et al.. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1–39 e14.
    1. Zhang L, Awadalla M, Mahmood SS et al. Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis. Eur Heart J 2020;41:1733–1743.
    1. Thavendiranathan P, Zhang L, Zafar A et al. Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor-Associated Myocarditis. J Am Coll Cardiol 2021;77:1503–1516.
    1. Aretz HT, Billingham ME, Edwards WD et al. Myocarditis. A histopathologic definition and classification. Am J Cardiovasc Pathol 1987;1:3–14.
    1. Leone O, Veinot JP, Angelini A et al. 2011 consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology. Cardiovasc Pathol 2012;21:245–74.
    1. Caforio AL, Pankuweit S, Arbustini E et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013;34:2636–48, 2648a-2648d.
    1. Mahmood SS, Fradley MG, Cohen JV et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol 2018;71:1755–1764.
    1. Sundstrom J, Byberg L, Gedeborg R, Michaelsson K, Berglund L. Useful tests of usefulness of new risk factors: tools for assessing reclassification and discrimination. Scand J Public Health 2011;39:439–41.
    1. Yingchoncharoen T, Agarwal S, Popovic ZB, Marwick TH. Normal ranges of left ventricular strain: a meta-analysis. J Am Soc Echocardiogr 2013;26:185–91.
    1. Tuzovic M, Wu PT, Kianmahd S, Nguyen KL. Natural history of myocardial deformation in children, adolescents, and young adults exposed to anthracyclines: Systematic review and meta-analysis. Echocardiography 2018;35:922–934.
    1. Cheung YF, Hong WJ, Chan GC, Wong SJ, Ha SY. Left ventricular myocardial deformation and mechanical dyssynchrony in children with normal ventricular shortening fraction after anthracycline therapy. Heart 2010;96:1137–41.
    1. Yu W, Li SN, Chan GC, Ha SY, Wong SJ, Cheung YF. Transmural strain and rotation gradient in survivors of childhood cancers. Eur Heart J Cardiovasc Imaging 2013;14:175–82.
    1. Mincu RI, Pohl J, Mrotzek S et al. Left ventricular global longitudinal strain reduction in patients with melanoma and extra-cardiac immune-related adverse events during immune checkpoint inhibitor therapy. European Heart Journal 2020;41.
    1. Faron A, Isaak A, Mesropyan N et al. Cardiac MRI Depicts Immune Checkpoint Inhibitor-induced Myocarditis: A Prospective Study. Radiology 2021:210814.
    1. Gruner C, Verocai F, Carasso S et al. Systolic myocardial mechanics in patients with Anderson-Fabry disease with and without left ventricular hypertrophy and in comparison to nonobstructive hypertrophic cardiomyopathy. Echocardiography 2012;29:810–7.
    1. Higgins AY, Arbune A, Soufer A et al. Left ventricular myocardial strain and tissue characterization by cardiac magnetic resonance imaging in immune checkpoint inhibitor associated cardiotoxicity. PLoS One 2021;16:e0246764.
    1. Kawel-Boehm N, Hetzel SJ, Ambale-Venkatesh B et al.. Reference ranges (“normal values”) for cardiovascular magnetic resonance (CMR) in adults and children: 2020 update. J Cardiovasc Magn Reson 2020;22:87.
    1. Taylor RJ, Moody WE, Umar F et al. Myocardial strain measurement with feature-tracking cardiovascular magnetic resonance: normal values. Eur Heart J Cardiovasc Imaging 2015;16:871–81.
    1. Michel L, Helfrich I, Hendgen-Cotta UB et al. Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. European Heart Journal 2021.
    1. Suerken CK, D’Agostino RB Jr., Jordan JH et al. Simultaneous Left Ventricular Volume and Strain Changes During Chemotherapy Associate With 2-Year Postchemotherapy Measures of Left Ventricular Ejection Fraction. J Am Heart Assoc 2020;9:e015400.
    1. Kang Y, Xu X, Cheng L et al. Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during epirubicine-based chemotherapy. Eur J Heart Fail 2014;16:300–8.
    1. Tschope C, Ammirati E, Bozkurt B et al. Myocarditis and inflammatory cardiomyopathy: current evidence and future directions. Nat Rev Cardiol 2021;18:169–193.
    1. Ammirati E, Cipriani M, Moro C et al. Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis: Multicenter Lombardy Registry. Circulation 2018;138:1088–1099.
    1. Ammirati E, Veronese G, Cipriani M et al. Acute and Fulminant Myocarditis: a Pragmatic Clinical Approach to Diagnosis and Treatment. Curr Cardiol Rep 2018;20:114.
    1. Grani C, Eichhorn C, Biere L et al. Prognostic Value of Cardiac Magnetic Resonance Tissue Characterization in Risk Stratifying Patients With Suspected Myocarditis. J Am Coll Cardiol 2017;70:1964–1976.
    1. Aquaro GD, Perfetti M, Camastra G et al.. Cardiac MR With Late Gadolinium Enhancement in Acute Myocarditis With Preserved Systolic Function: ITAMY Study. J Am Coll Cardiol 2017;70:1977–1987.
    1. Hsiao JF, Koshino Y, Bonnichsen CR et al. Speckle tracking echocardiography in acute myocarditis. Int J Cardiovasc Imaging 2013;29:275–84.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever