Immune checkpoint inhibitors (ICIs) have made important progress in the field of tumor treatment in recent years, and the indications have also been extended from the initial melanoma to non-small cell lung cancer, small cell lung cancer, kidney cell carcinoma, etc., and have achieved good efficacy. While ICIs bring survival benefits to patients with tumors, their immunotoxicity has also become an unavoidable problem in the clinic, of which immune-related cardiotoxicity is a type with low morbidity but high mortality. As ICIs are widely used in the treatment of multiple tumors, the number of cases of immune-related cardiotoxicity is increasing.
ICIs are divided into two categories: cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, programmed cell death protein 1 (PD-1) and ligand PD-L1 inhibitors, CTLA-4 inhibitors include ipilimumab and trimemumab, currently approved PD-1 inhibitors are pambolizumab, navulijumab, cimiprizumab, etc., PD-L1 inhibitors have degrees of vallizumab, atenibizumab and avilumab.
The exact mechanism of ICIs-associated myocarditis is still unclear, but studies have found that there is a common high-frequency T lymphocyte receptor sequence in the myocardium and tumor tissue in such patients, and it is speculated that T lymphocytes activated after the application of ICIs can not only target and recognize tumors, but also may also recognize skeletal muscle and myocardial common antigens, thereby inducing autoimmune lymphocytic myocarditis.
Clinical manifestations of ICIs-associated myocarditis
The symptoms and severity of ICIs myocarditis are diverse and can present as asymptomatic, mild, significant, or fulminant myocarditis. The most common symptoms are dyspnea, which can also be manifested as chest pain, palpitations, and lower extremity puffiness, while in some cases only nonspecific symptoms such as fatigue and general discomfort to nausea are present. Severe cases present with hemodynamically unstable and/or electrophysiologically unstable fulminant myocarditis with cardiogenic shock and death, while mild cases may be asymptomatic with elevated cardiac markers alone.
ECG: ECG abnormalities in 40% to 89% of patients with ICIs-associated myocarditis, no characteristic manifestations, can be sinus bradycardia, sinus tachycardia, bundle branch or atrioventricular block, atrial tachycardia, atrial fibrillation, PR interval prolongation and ST-T changes, etc., in severe cases, complete block, ventricular tachycardia, and ventricular fibrillation. Among them, ST-T changes are the most common, with an incidence of about 39%.
Echocardiography: ICIs-associated myocarditis may present with decreased ejection fraction, chamber size, and ventricular wall movement abnormalities. Left ventricular systolic dysfunction occurred in 40% to 79% of patients, with an average left ventricular ejection fraction of 45%, lower than 55% of patients without myocarditis, and nearly half of patients had a significant decrease in left ventricular ejection fraction. However, ICIs-associated fulminant myocarditis is not necessarily accompanied by a decrease in ejection fraction.
Cardiac enhancement OF MRI: Gadolinium contrast media-enhanced cardiovascular MRI can reveal myocarditis-induced myocardial edema, lymphocyte infiltration, necrosis, and scarring, and can also understand left ventricular function. Myocardial necrosis and fibrosis are characterized by delayed gadolinium intensification, but their incidence in ICIs-associated myocarditis is only 28% to 33%.
In patients with ICIs-related myocarditis, the elevation of cardiac injury markers often precedes the occurrence of clinical symptoms and is positively correlated with the severity of the disease, mainly including troponin, myoglobin, creatine kinase isoenzyme, and creatine kinase, of which troponin has the highest specificity, with a positivity rate of about 90%, often combined with an increase in the level of other biomarkers.
When should myocarditis be suspected and further tests are required?
Patients treated with ICIs should be alert to the possibility of myocarditis if they develop one or more of the following conditions:
(1) New symptoms that cannot be explained by other causes, such as chest pain, dyspnea, palpitations, lower extremity puffiness and unexplained cardiogenic shock;
(2) Compared with the baseline, the biomarkers of cardiac injury were obviously abnormal, such as creatine kinase isoenzyme, lactate dehydrogenase, aspartate aminotransferase, sodium peptide elevation, etc.;
(3) EcG has new various types of conduction block, ST-T changes, QRS wave group widening or tachycardia;
(4) New segmental movement abnormalities, thickening of the left ventricular wall or ventricular dilation or decreased left ventricular ejection fraction on echocardiography;
(5) Chest imaging (X-ray or CT) of the newly appeared cardiac shadow enlargement;
(6) Immune myositis or myasthenia gravis.
When ICIs-related myocarditis is suspected, ICIs treatment is suspended until the diagnosis of myocarditis is ruled out.
Figure 1. Examination and diagnostic procedures for suspected ICIs-associated myocarditis
Diagnosis of ICIs-associated myocarditis
Due to the lack of specificity of the symptoms, signs, ECG, laboratory tests, and imaging tests associated with ICIs, clinical diagnosis is difficult, and can be divided into definitive myocarditis, more likely myocarditis, possible myocarditis, and subclinical myocardial injury, and the corresponding diagnostic criteria are as follows.
Early diagnosis of myocarditis focuses on proactive monitoring, including pre-drug baseline evaluation and post-medication monitoring. Baseline assessment includes the collection of an underlying medical history, clinical presentation, physical examination, and improvement of biomarkers of cardiac injury, natriuretic peptides, D-dimers, ECG, and echocardiography. Closely follow the patient's symptoms and signs within 3 months of medication, review the biomarkers of cardiac injury within 7 days after the first dose of treatment, if similar to the baseline, then ICI will check the biomarkers of cardiac injury and electrocardiogram before each medication. After 3 months, monitor the symptoms and signs, electrocardiogram, and check the biomarkers of heart injury and echocardiography when there are suspicious indications.
Cardiotoxicity grading and treatment measures
G1: Subclinical myocardial injury, only elevated biomarkers of cardiac injury, no cardiovascular symptoms, no ECG, echocardiographic changes. If the biomarkers of cardiac injury are mildly abnormal and stable, ICIs therapy may be continued, and if progressively elevated, ICIs therapy should be suspended and glucocorticoid therapy given if necessary.
For G1 patients, guidelines recommend active monitoring, cardiovascular consultation, and improvement of cardiac injury biomarkers, natriuretic peptides (BNP or NT-proBNP), D-dimers, inflammatory markers, viral titers, electrocardiograms, echocardiography, etc., and cardiac magnetic resonance imaging (grade I) in those with conditions.
If asymptomatic myocarditis diagnosis is established, methylprednisolone is given immediately at an initial dose of 1 to 4 mg/kgd▪for 3 to 5 days, after which the dose is tapered gradually, and hormone therapy is continued for 2 to 4 weeks after cardiac injury biomarkers return to baseline levels. ICIs can be continued after cardiac injury biomarkers have returned to baseline levels, but enhanced surveillance (level II) is required.
G2: Mild cardiovascular symptoms with cardiac injury biomarkers and/or ECG abnormalities. IcIs treatment was discontinued and glucocorticoid therapy was given.
CSCO guidelines recommend immediate discontinuation of ICIs, bed rest, cardiovascular consultation, ECG monitoring, improvement of biomarkers of heart injury, natriuretic peptides, ELECTROCardiogram, echocardiography, cardiac magnetic resonance imaging if possible, and endocardial biopsy if necessary. Methylprednisolone is given immediately at an initial dose of 1 to 4 mg/kgd▪for 3 to 5 days, after which the dose is tapered gradually, and hormone therapy is continued for 2 to 4 weeks (grade I) after returning to baseline levels.
If glucocorticoid therapy is not sensitive, other immunosuppressants are used as appropriate. Careful restart of ICIs treatment (grade II) after returning to baseline levels.
G3-G4: Patients with significant cardiovascular symptoms or life-threatening conditions who require emergency treatment in hospitalization should be given immediately with shock doses of glucocorticoids.
CSCO guidelines recommend permanent discontinuation of ICIs, bed rest, and multidisciplinary consultations in cardiovascular and critical care medicine. Improve cardiac injury biomarkers, natriuretic peptides, electrocardiogram, echocardiography, cardiac magnetic resonance imaging, and if necessary, endocardial myocardial biopsy. In terms of treatment, methylprednisolone shock therapy is given immediately, 500 to 1000 mg/day for 3 to 5 days, then gradually reduced, and after cardiac function returns to baseline levels, continue hormone therapy for about 4 weeks. Pacemakers are installed when necessary in patients with arrhythmias, and circulatory and respiratory support is given in critically ill patients (Grade I) in a timely manner.
If there is no improvement in hormonal therapy for 24 hours, measures such as other immunosuppressants± plasmapheresis, or life support (grade II) are added.
Figure 2. IcIs-related myocarditis management process
Author: Tian Xinfang
Source: Cardiovascular Frontline of the Health Community
Resources
1. 2021 CSCO Guidelines for Toxicity Management Related to Immune Checkpoint Inhibitors
2.ZHU Yan, GONG Yanjun, WU Shikai. Research advances in cardiotoxic reactions associated with immune checkpoint inhibitors. Journal of Clinical Oncology. 2021; 26(4): 373-379.
3. Chinese Expert Consensus on Monitoring and Management of Immune Checkpoint Inhibitor-related Myocarditis (2020 Edition). Chinese Oncology Clinic. 2020; 47(20):1027-1038.