What are the cardiotoxicities of immunotherapy? How is it treated?

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Immune checkpoint inhibitors (ICIs) have been widely used in oncology patients, but their wide range of immune-related adverse events (IRAEs) cannot be ignored

This paper summarizes the clinical manifestations of cardiovascular toxicity of PD-1/PD-L1 inhibitors, as well as the potential pathological mechanisms and current diagnosis and treatment methods

1

Clinical manifestations of ICI-associated cardiotoxicity

Currently, ICI clinical trial results and current clinical practice reports suggest multiple manifestations of ICI-associated cardiotoxicity, such as myocarditis, pericardial disease, arrhythmias, myocardial infarction, and even non-inflammatory left ventricular dysfunction such as Tako-Tsubo cardiomyopathy [1] (Figure 1

Figure 1 Clinical manifestations of ICI-related cardiotoxic damage

1.

ICI-associated myocarditis, characterized by acute and fulminant, is the predominant early ICI-associated cardiovascular adverse event (CAEs), in which the onset time is approximately 30 days

2.

ICI-associated pericardial disorders include pericarditis, pericardial effusion, and pericardial tamponade

3.
Arrhythmias and conduction diseases

ICI treatment can also lead to cardiac conduction disorders, including atrial fibrillation, ventricular arrhythmias (ventricular tachycardia or ventricular fibrillation), and AV block (second-degree or complete AV block).


The highest incidence of ICI-related arrhythmias is supraventricular arrhythmias, including sinus tachycardia, frequent atrial premature beats, atrial tachycardia, atrial flutter, and even atrial fibrillation
.

ICI-related conduction disorders may present with prolonged PR intervals, bundle branch block, and in severe cases, complete AV block or even cardiac arrest
.

4.
Myocardial infarction

Patients using ICI have been reported to present with stable angina and acute coronary syndrome
.

Myocardial infarction is characterized by sudden chest pain, ischemic changes on ECG (e.
g.
, ST-segment elevation, ST-segment depression, or T-wave inversion), elevated myocardial troponin, and echocardiography or cardiac MRI suggesting new-onset local wall movement abnormalities
.

5.
Non-inflammatory left ventricular dysfunction

ICI treatment can also result in non-myocardiallytic left ventricular dysfunction, i.
e.
, no inflammatory manifestations, presenting only as functional impairment
.

ICI-associated left ventricular dysfunction has a variety of manifestations, such as dilated cardiomyopathy with left ventricular dysfunction and Tako-Tsubo cardiomyopathy
.

6.
ICI-associated valve dysfunction

ICI has been reported to cause valvular dysfunction such as moderate to severe aortic valve, mitral valve, and tricuspid regurgitation
.

In addition, most of these lesions are accompanied by myocardial lesions, such as myocarditis or dilated cardiomyopathy
.

2

Diagnosis and treatment of ICI-related cardiotoxicity

1.
Diagnosis and evaluation of ICI-related cardiotoxicity:

Management of ICI-associated cardiac injury first requires determining and assessing the severity of cardiotoxicity [5
].

The severity of ICI-related cardiotoxicity can currently be divided into 4 grades (see Table 1
).

It is recommended that the clinical team of the oncology department include a cardiovascular system specialist in addition to the oncology specialist in order to detect cardiovascular disease early before the oncology treatment begins, in order to provide the best treatment plan
for oncology patients.

Table 1 Severity of ICI-related cardiotoxicity

Diagnostic tests including ECG, chest x-ray, echocardiography, cardiac biomarkers (including creatine kinase and troponin), inflammatory-related indicators (including ESR, CRP, and WBC counts), and BNP, NT pro-BNP, and anti-rhabdomyometric antibody levels
are recommended in patients with suspected ICI-related cardiotoxicity.

In addition, cardiac ¹⁸ F-FDG PET/CT can also help detect myocarditis
.

In cases where it is unclear or uncertain, endocardial myocardial biopsy is necessary
.

2.
Therapeutic strategies for ICI-related cardiotoxicity:

Treatment strategies for ICI-related cardiovascular complications are divided into three areas:

(1) stop using ICI to prevent further toxicity;

(2) Supportive treatment of cardiac complications;

(3) Application of immunosuppression inflammatory overreaction
.

Due to the long functional half-life of ICI, stopping ICI may not immediately reverse its cardiotoxicity
.

Deciding whether ICI treatment can be discontinued requires a comprehensive discussion between oncologists and cardiovascular specialists
.

Some current guidelines recommend discontinuation of ICI treatment
when patients develop grade 3 or 4 ICI-related toxicity.

Patients with ICI heart injury may receive effective supportive care
if necessary.

Patients with heart failure should receive medications recommended by guidelines including β-blockers and ACEI/ARB
.

Immunosuppressive therapy can also be used against overactive T cell responses
.

The first-line immunosuppressive agent for ICI-associated myocarditis is currently considered corticosteroids, and current ASCO guidelines recommend oral or intravenous high-dose corticosteroids
.