Electrocardiographic features of immune checkpoint inhibitor associated myocarditis

Abstract

Background: Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis.

Methods: From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested.

Results: Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39).

Conclusions: The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.

Keywords: autoimmunity; immune tolerance; immunotherapy; inflammation; self tolerance.

Figure 1

Changes in ECG parameters with ICI myocarditis. (A) PR interval, (B) QRS duration, and (C) QTc-F interval values were derived from ECGs obtained pre-ICI therapy (“baseline or pre-ICI”), after initiating ICI therapy (“on-ICI”), or at the time of myocarditis (for cases only; “myocarditis”). Shown are box-and-whisker plots with the central line indicating the median value, the margins of the box indicating the 25th/75th percentiles, and the whiskers indicating the 5th/95th percentiles. ICI, immune checkpoint inhibitor.

Figure 2

Relationship between ECG parameters, ejection fraction, and left ventricular volumes. (A) Scatter-plots of QRS duration (left) or QTc-F interval (right) versus echocardiographic left ventricular EF. Shown are the linear regression lines with their 95% CI. (B) Scatter-plots of QRS duration (left) or QTc-F interval (right) versus EF. (C) Scatter-plots of QRS duration (left) or QTc-F interval (right) versus LVEDV. EF, ejection fraction; LVEDV, left ventricular end-diastolic volume.

Figure 3

Association between QRS duration or QTc-F interval and MACE. (A) Kaplan-Meier curves indicate the occurrence of MACE over 120 days from time of diagnosis for myocarditis patients stratified by QRS duration. Similar analyses were performed for male (B) and female (C) myocarditis patients stratified by QTc-F interval as indicated. P value obtained from the log-rank test. MACE, major adverse cardiac events.

Figure 4

Frequency of MACE components. Frequencies of the indicated outcome among all myocarditis patients stratified by QRS duration are shown. Numbers at the end of each bar indicate the fraction of patients in each stratum with the indicated event. MACE, major adverse cardiac events.