TY - JOUR
T1 - Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis
AU - Awadalla, Magid
AU - Mahmood, Syed S.
AU - Groarke, John D.
AU - Hassan, Malek Z.O.
AU - Nohria, Anju
AU - Rokicki, Adam
AU - Murphy, Sean P.
AU - Mercaldo, Nathaniel D.
AU - Zhang, Lili
AU - Zlotoff, Daniel A.
AU - Reynolds, Kerry L.
AU - Alvi, Raza M.
AU - Banerji, Dahlia
AU - Liu, Shiying
AU - Heinzerling, Lucie M.
AU - Jones-O'Connor, Maeve
AU - Bakar, Rula B.
AU - Cohen, Justine V.
AU - Kirchberger, Michael C.
AU - Sullivan, Ryan J.
AU - Gupta, Dipti
AU - Mulligan, Connor P.
AU - Shah, Sachin P.
AU - Ganatra, Sarju
AU - Rizvi, Muhammad A.
AU - Sahni, Gagan
AU - Tocchetti, Carlo G.
AU - Lawrence, Donald P.
AU - Mahmoudi, Michael
AU - Devereux, Richard B.
AU - Forrestal, Brian J.
AU - Mandawat, Anant
AU - Lyon, Alexander R.
AU - Chen, Carol L.
AU - Barac, Ana
AU - Hung, Judy
AU - Thavendiranathan, Paaladinesh
AU - Picard, Michael H.
AU - Thuny, Franck
AU - Ederhy, Stephane
AU - Fradley, Michael G.
AU - Neilan, Tomas G.
N1 - Funding Information:
Dr. Mahmood provided cardiovascular event adjudication for PIVOT-2 clinical trials of anticancer therapy; has received a Glorney-Raisbeck Fellowship Award in Cardiovascular Diseases from the New York Academy of Medicine; and has received consultancy fees from Medicure, OMR Globus, Alpha Detail, and Opinion Research Team. Dr. Groarke has received research support from Amgen. Dr. Nohria has received research support from Amgen; and has been a consultant for Takeda Oncology and Triple Gene Therapy. Dr. Heinzerling has received consultancy, advisory board, and speaker fees from Merck Sharp and Dohme, Bristol-Myers Squibb, Roche, Novartis, Amgen, and Curevac; has received research funding from Novartis; and has performed clinical studies for Bristol-Myers Squibb, Merck Sharp & Dohme, Merck, Roche, Amgen, GlaxoSmithKline, Curevac, Iovance, and Novartis. Dr. Cohen has served as a consultant for Sanofi Genzyme and Bristol-Myers Squibb. Dr. Sullivan has served as a consultant to Merck, Novartis, and Bristol-Myers Squibb. Dr. Tocchetti was funded by a “Riceca di Ateneo/Federico II University” grant. Dr. Devereux provided consultation for 1 day in 2018 for Acer Pharmaceuticals about unrelated application to the U.S. Food and Drug Administration for celiprolol for vascular Ehlers-Danlos syndrome. Dr. Lyon has received speaker, advisory board, or consultancy fees and/or research grants from Pfizer, Novartis, Servier, Amgen, Takeda, Roche, Janssens-Cilag Ltd., Clinigen Group, Eli Lily, Eisai, Bristol-Myers Squibb, Ferring Pharmaceuticals, and Boehringer Ingelheim. Dr. Chen’s research was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748. Dr. Barac has received honoraria from Bristol-Myers Squibb; and has served on the Data Safety and Monitoring Board of CTI Biopharma. Dr. Fradley has received research grant support from Medtronic; and has served as a consultant for Novartis. Dr. Neilan has received advisory fees from H3 Biomedicine, Parexel, Aprea Therapeutics, Bristol-Myers Squibb, and Intrinsic Imaging. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Funding Information:
Dr. Mahmood provided cardiovascular event adjudication for PIVOT-2 clinical trials of anticancer therapy; has received a Glorney-Raisbeck Fellowship Award in Cardiovascular Diseases from the New York Academy of Medicine; and has received consultancy fees from Medicure, OMR Globus, Alpha Detail, and Opinion Research Team. Dr. Groarke has received research support from Amgen. Dr. Nohria has received research support from Amgen; and has been a consultant for Takeda Oncology and Triple Gene Therapy. Dr. Heinzerling has received consultancy, advisory board, and speaker fees from Merck Sharp and Dohme, Bristol-Myers Squibb, Roche, Novartis, Amgen, and Curevac; has received research funding from Novartis; and has performed clinical studies for Bristol-Myers Squibb, Merck Sharp & Dohme, Merck, Roche, Amgen, GlaxoSmithKline, Curevac, Iovance, and Novartis. Dr. Cohen has served as a consultant for Sanofi Genzyme and Bristol-Myers Squibb. Dr. Sullivan has served as a consultant to Merck, Novartis, and Bristol-Myers Squibb. Dr. Tocchetti was funded by a ?Riceca di Ateneo/Federico II University? grant. Dr. Devereux provided consultation for 1 day in 2018 for Acer Pharmaceuticals about unrelated application to the U.S. Food and Drug Administration for celiprolol for vascular Ehlers-Danlos syndrome. Dr. Lyon has received speaker, advisory board, or consultancy fees and/or research grants from Pfizer, Novartis, Servier, Amgen, Takeda, Roche, Janssens-Cilag Ltd., Clinigen Group, Eli Lily, Eisai, Bristol-Myers Squibb, Ferring Pharmaceuticals, and Boehringer Ingelheim. Dr. Chen's research was funded in part through the National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748. Dr. Barac has received honoraria from Bristol-Myers Squibb; and has served on the Data Safety and Monitoring Board of CTI Biopharma. Dr. Fradley has received research grant support from Medtronic; and has served as a consultant for Novartis. Dr. Neilan has received advisory fees from H3 Biomedicine, Parexel, Aprea Therapeutics, Bristol-Myers Squibb, and Intrinsic Imaging. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
PY - 2020/2/11
Y1 - 2020/2/11
N2 - Background: There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis. Objectives: This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis. Methods: This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death. Results: Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8). Conclusions: GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.
AB - Background: There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis. Objectives: This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis. Methods: This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death. Results: Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8). Conclusions: GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.
KW - global longitudinal strain
KW - immune checkpoint inhibitors
KW - major adverse cardiac events
KW - myocarditis
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U2 - 10.1016/j.jacc.2019.11.049
DO - 10.1016/j.jacc.2019.11.049
M3 - Article
C2 - 32029128
AN - SCOPUS:85078237903
VL - 75
SP - 467
EP - 478
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 5
ER -