Cardiotoxicity of Immune Checkpoint Inhibitors: Beyond Myocarditis

To the Editor:

We read with great interest the review article on cancer immunotherapy published in the Journal of Medical Toxicology by Chhabra and Kennedy [1]. As physicians who often care for these patients, we acknowledge the many valid points in this thorough review and hope to provide additional insight, specifically with regards to immune checkpoint inhibitor (ICI)–related cardiotoxicity.

ICI-related cardiotoxicity carries a high mortality rate [2]. Recognition and adequate management are of utmost importance. The authors do a great job of describing ICI-associated myocarditis; however, there are other cardiac conditions the medical toxicologist should be aware of. Namely, a newly emerging overlap syndrome that includes myocarditis, myositis, and myasthenia gravis [3, 4], cardiac dysrhythmias, Takotsubo cardiomyopathy, and acute coronary syndrome (ACS).

Clinically, ICI-related myocarditis will be difficult to diagnose in the emergency department (ED). Clinicians should consider using Bonaca’s criteria [2] for defining myocarditis to help guide initial management. According to Bonaca et al. [2], suspected myocarditis can be categorized into three groups, which include definite myocarditis, probable myocarditis, or possible myocarditis. Definite myocarditis is a diagnosis that cannot be made clinically and requires either tissue pathology, cardiac magnetic resonance imaging, or negative angiography, none of which are feasible to obtain in the ED. A diagnosis of probable myocarditis can be made in the ED if the clinical syndrome is consistent with myocarditis and findings are not explained by another diagnosis, as well as if there are new wall motion abnormalities on echocardiogram with either elevated cardiac biomarker, or electrocardiogram consistent with myopericarditis. Finally, possible myocarditis should be considered if there is a new wall motion abnormality on echocardiogram with either the clinical syndrome of myocarditis or electrocardiogram evidence of myopericarditis. Additionally, if there are new elevated cardiac biomarkers and clinical syndrome or EKG evidence of myopericarditis, this is also sufficient for possible myocarditis [2].

While a normal electrocardiogram, lack of symptoms, and a normal ejection fraction are not enough to rule out ICI-related myocarditis, the degree of troponin elevation has been associated with development of a major adverse cardiovascular event (MACE) [5, 6]. However, as more EDs begin to use the high sensitivity troponin T assay, it is important to keep in mind that due to high rates of concurrent myositis, and the potential cross-reactivity of high sensitivity troponin T and creatine kinase, the preferred cardiac biomarker is troponin I as it is more specific for myocardial injury [2]. Additionally, there have been several reported cases of myocarditis occurring concurrently with myositis and myasthenia gravis [3, 4]. This syndrome has high mortality and will often require treatment beyond glucocorticoids [3, 4]. It should be suspected when patients present with nonspecific and bulbar symptoms.

Other conditions such as dysrhythmias are often associated with myocarditis as the authors correctly mention; however, there have been reports of isolated dysrhythmias as the initial presentation of ICI-related cardiotoxicity. Similarly, there have been cases of sudden cardiac death due to complete heart block [7]. The most encountered dysrhythmias were ventricular dysrhythmias (17%), atrioventricular conduction delay (13%), and atrial fibrillation (3%) [8].

Patients with signs and symptoms of heart failure, chest pain, dyspnea, syncope, or cardiogenic shock should also be evaluated for Takotsubo cardiomyopathy as there have been several reports in the literature [9]. The approach to diagnosis is as usual, and will require assessment of left ventricular systolic function as well as coronary angiography.

Finally, ACS and acute myocardial infarction have also been reported [7, 10]. Patients on ICI have increased rates of atherosclerotic events as well as the inflammatory state leading to destabilization of atherosclerotic lesions resulting in ACS [11]. Since there are many similarities in presentation and laboratory findings between ACS and ICI-related myocarditis, we advocate for early diagnostic invasive workup, including coronary angiography. However, as non-invasive imaging has limited sensitivity and specificity for myocarditis, we advocate for endomyocardial biopsy at the time of diagnostic coronary angiography, as this is the gold standard for the diagnosis of ICI-related myocarditis [12]. Early invasive workup also allows for the right heart catheterization to evaluate for filling pressures that can help guide management.

We agree with the authors that treatment with glucocorticoids is the first line for ICI-related cardiotoxicity. Some authors advocate for initial treatment with pulse dose steroids of 500–1000 mg of intravenous methylprednisolone for 3 days as the first line, instead of 1–2 mg/kg of prednisone or equivalent [12]. This is due to higher steroid doses being associated with a lower rate of MACE. Others advocate for additional immunosuppressive therapy with infliximab or mycophenolate if the patient has grade 4 cardiotoxicity [2]. As the authors mention, these decisions should not be made without discussion with the cardiologist. However, if consultants are not immediately available, and the patient is stable, we recommend 1–2mg/kg of prednisone or equivalent, until cardiology can be consulted.

In summary, the review by Chhabra and Kennedy adds to our understanding of novel cancer therapies. Cardiac toxicities, although rare, have a high mortality rate, and familiarization with these conditions will potentially improve the care of the patient with cancer.