Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis

Abstract

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.

Keywords: global longitudinal strain; immune checkpoint inhibitors; major adverse cardiac events; myocarditis.

Figure 1:. Consort Flow Diagram of Cohort.

Consort flow diagram showing the cases from multicenter registry and controls from MGH with available TTE GLS. GLS= global longitudinal strain; ICI= immune checkpoint inhibitors; MGH= Massachusetts General Hospital; TTE= transthoracic echocardiogram.

Figure 2:. GLS among Cases and Controls.

A- Box plot graph of GLS among cases and controls pre-ICI showing lower values among cases compared to controls; B- Spaghetti plot graph of GLS among cases showing the reduction in GLS with the development of myocarditis; C- Spaghetti plot graph of GLS among controls showing no change in GLS among controls on ICI who did not develop myocarditis; D- Box plot graph of GLS among cases during presentation with myocarditis and controls on ICI who did not develop myocarditis, showing lower GLS values among the cases compared to controls; E- Spaghetti plot graph of GLS among cases with follow-up values post discontinuation of ICI-therapy compared to during ICI-myocarditis admission, showing improved GLS post discontinuation of therapy; F- Box plot graph of GLS among cases presenting with both a reduced and preserved EF compared to controls, showing lower GLS among cases compared to controls irrelevant of EF. Box plots summarizing data from minimal values (lowest horizontal line), first quartile (bottom of box), median (horizontal line within the box), third quartile (top of box), and maximum values (highest horizontal line). GLS= global longitudinal strain; ICI=immune checkpoint inhibitors; LVEF= left ventricular ejection fraction.

Figure 3:. Kaplan- Meier survival curves showing the association of MACE and GLS among Cases.

A- Kaplan-Meier curve of MACE free survival among all cases stratified by tertiles of GLS values showing highest MACE free survival among cases with a GLS ≥16% and lowest among cases with a GLS ≤14% (p<0.001). B- Kaplan- Meier curve of MACE free survival among cases with reduced LVEF stratified by GLS values above and below the median value of 13%, showing increased MACE free survival among cases with GLS ≥13% compared to GLS <13% (p<0.001). C- Kaplan- Meier curve of MACE free survival among cases with preserved LVEF stratified by GLS values above and below the median value of 16%, showing increased MACE free survival among cases with GLS ≥16% compared to GLS <16% (p<0.001). GLS= global longitudinal strain; LVEF= left ventricular ejection fraction; MACE= major adverse cardiac event.

Central Illustration:. Global Longitudinal Strain in Immune Checkpoint Inhibitor-myocarditis.

The association of different GLS cut-offs and MACE among cases with reduced and preserved EF. NT-proBNP= N-terminal pro hormone B-type natriuretic peptide; ECG= electrocardiogram; EF= ejection fraction; GLS= global longitudinal strain; ICI= immune checkpoint inhibitors; MACE= major adverse cardiac event.