Immune checkpoint inhibitor therapy can cause immune-related adverse events including myocarditis. Myocarditis associated with immune checkpoint inhibitors has an incidence of 0.04-1.14% but is associated with high mortality of 25-50%. The mechanisms involve unleashing immune responses against cardiomyocytes. Clinical presentation includes symptoms of heart failure, arrhythmias, and elevated troponin and natriuretic peptide levels. Diagnosis is made through cardiac imaging modalities, endomyocardial biopsy, and excluding other causes. Treatment involves high-dose glucocorticoids with monitoring in the ICU due to the high risk of mortality. Further research is still needed to improve diagnosis and guide management of this serious complication.

1. Immune Checkpoint Inhibitor
Myocarditis: Pathophysiological
Characteristics, Diagnosis, and
Treatment
Journal Reading
Sona Andrian
Preseptor : dr. Eifel Faheri, Sp.PD-KHOM
Bagian Ilmu Penyakit Dalam
Ilmu Penyakit Jantung Dan Pembuluh Darah RSUP dr. M. Djamil Padang/ Fakultas Kedokteran
Universitas Andalas
2022

2. Disclosure

3. 1. Introduction
2. Epidemiological Characteristics
3. Mechanisms of Myocardial Toxicity
4. Clinical Presentation of ICI-Associated Myocarditis
5. Establishing the Diagnosis
6. Treatment of ICI-Associated Myocarditis
7. Conclusions
Outline

4. Introduction
• Traditional cytotoxic chemotherapy and novel cancer therapies have
various cardiotoxicities, ranging from heart failure to arrhythmias.
• One of the most exciting developments in cancer treatment is
immunotherapy
• Among the immunotherapy armamentarium are Immune Checkpoint
Inhibitors (ICIs)
• ICIs are monoclonal antibodies that target the host immune negative
regulation receptors, such as CTLA-4 (cytotoxic T- lymphocyte–
associated protein 4), programmed cell death receptor 1 (PD-1), and
programmed cell death ligand 1 (PD- L1)
• The most common fatal IRAE is colitis, but the associated mortality is
low at 2% to 5%
• At the other end of the spectrum is ICI-related myocarditis, which is an
uncom- mon IRAE, but is associated with a high reported mortality

6. Incidence
• ICI-related myocarditis has a
reported incidence of 0.04% to
1.14%, but when compared
with other IRAEs, it has a
significantly higher associated
mortality of 25% to 50%
• The use of combination ICI
therapy has almost twice the
incidence of and mortality
from myocarditis

7. Pathophysiolgy ICI

9. Mechanisms of Myocardial Toxicity
Mechanism by which
checkpoint inhibitors can
promote autoimmune
lymphocytic myocarditis.
PD-L1 is expressed in human
and murine cardiomyocytes,
and its expression can
increase during myocardial
injury. Combination of
checkpoint blockade
(ipilimumab plus nivolumab)
unleashes immune responses
and can cause autoimmune
lymphocytic myocarditis.
Wang DY, Okoye GD, Neilan TG, Johnson DB, Moslehi JJ. Cardiovascular toxicities associated with cancer immunotherapies.

10. Clinical Presentation of ICI-Associated Myocarditis

11. Diagnostic Testing
Laborato
ry
The 2 most common
laboratory factors that may
initially suggest the possibility
of myocarditis are
• Elevated serum troponin
and
• Natriuretic peptide levels
ECG/Telemetr
y• Sinus tachycardia,
• Atrioventricular block,
• Prolonged PR Interval
• ST segment/T-wave abnormalities,
• QRS increased,
• QT increase and prolongation,
• Presence of Q wave,
• Atrial or ventricular arrhythmia or
• Normal

12. Diagnostic Testing
• Reduced left ventricular ejection fraction,
• Increased left ventricular end diastolic
volume,
• Global or focal wall motion abnormalities,
• Diastolic dysfunction,
• Right ventricular dysfunction,
• Pericardial effusion or
• Normal
Echocardiogra
phy
Cardiac Magnetic
Resonance Imaging
Invasive Diagnostics
• Endomyocardial biopsy is
considered the gold standard
diagnostic test for myocarditis
• Coronary Angiography
Presence of late gadolinium enhancement, increased qualitative
T2 signal, left or right ventricular dysfunction, or normal

14. Establishing the Diagnosis
Definite myocarditis
presence of at least one of the following:
• Pathology consistent with myocarditis.
• Diagnostic CMR, clinical syndrome of
myocarditis, and positive biomarker or ECG.
• Echocardiography with wall motion abnormality,
• Clinical syndrome of myocarditis, positive
biomarker, positive ECG, and negative
angiography for CAD.
Probable myocarditis
• Diagnostic CMR without clinical syndrome of
myocarditis, positive ECG, or positive
biomarker, OR
• Suggestive CMR with one of the following:
1. Clinical syndrome of myocarditis.
2. Positive ECG.
3. Positive biomarker, OR
• Echocardiography with wall motion abnormality
and clinical syndrome of myocarditis with
either positive ECG or biomarker, OR
• Clinical syndrome of myocarditis with positron
emission tomography scan evidence and no
alternative diagnosis.
Possible myocarditis
• Suggestive CMR without clinical syndrome of
myocardi- tis, positive ECG, or positive biomarker,
OR
• Echocardiography with wall motion abnormality and
clinical syndrome of myocarditis or positive ECG,
OR
• Elevated biomarker with clinical syndrome of
myocardi- tis or positive ECG and no alternative

15. Algorithm & Treatment of ICI-Associated
Myocarditis

16. Algorithm & Treatment of ICI-Associated
Myocarditis

17. Conclusions
• ICI-related myocarditis is a complex disease that has similarities in
presentation to many other acute cardiac syndromes.
• It is necessary for both the oncologist and cardiologist to have a
high suspicion for this ICI-related cardiac toxicity.
• Studies evaluating multimodality imaging and invasive testing
with endomyocardial biopsy will guide development of better diagnostic
algorithms for this condition
• Current treatment is largely based on glucocorticoids with a possible
role for more targeted immune modulators, depending on the clinical
course of individual patients
• Further research is therefore needed to establish mechanisms and
diagnostic strategies, and to guide treatment of this disease entity

18. Thank you