Immune checkpoint inhibitor-associated sick sinus syndrome and cardiogenic shock

Abstract

Immune checkpoint inhibitors (ICI) represent a major advance in the treatment of cancer. Most studies of ICI have underestimated their cardiotoxicity; however, an increasing number of cases of cardiotoxicity are being reported. Herein we discussed a 67-year-old, male, Japanese patient who presented with cardiogenic shock accompanied by sick sinus syndrome 4 days into his second course of ipilimumab plus nivolumab combination therapy. A temporary transvenous pacemaker was subsequently placed, and a permanent pacemaker was implanted for persistent, symptomatic, intermittent bradycardia. The permanent implantation of the pacemaker improved his symptoms and allowed him to continue his ICI therapy.

Introduction

Immune checkpoint inhibitors (ICI) represent a major advance in the treatment of cancer. However, they can also induce a wide variety of immune-related adverse events (irAE) [1]. Most studies of ICI have underestimated their cardiotoxicity [2]; however, cases of ICI-related cardiotoxicity are apparently on the rise [3]. Although cardiotoxicity occurs less frequently than other side effects, it is an important consideration for cardiologists and oncologists because it can be lethal and often results in treatment discontinuation [4].

We herein discussed the case of a 67-year-old, male patient who presented with cardiogenic shock accompanied by sick sinus syndrome (SSS) during ICI therapy. The patient was treated successfully by permanent pacemaker implantation and continues to receive immunotherapy.

Case report

A 67-year-old Japanese male presented with a dry cough to the Department of Respiratory Medicine at the study center in November 2013. Chest X-ray revealed an abnormal shadow in the left lung field. Enhanced thoracic-abdominal computed tomography revealed a tumor in the left upper lobe and enlarged mediastinal lymph nodes. Bronchoscopy was performed, and lung adenocarcinoma was diagnosed on the basis of the findings. Gadolinium-enhanced brain magnetic resonance imaging and bone scintigraphy denied any other metastases. The tumor was T4N2M0 stage IIIB according to the TNM classification of the Union of International Cancer Control (UICC), 6th edition.

Two cycles of cisplatin/S-1 therapy and radiotherapy 60 Gy were administered from February 2014, after which the patient was recurrence-free for seven years. However, the primary lesion progressed, and the patient experienced a relapse in October 2021. Combination immunotherapy consisting of cisplatin 75 mg/m2, pemetrexed 500 mg/m2, ipilimumab 1 mg/kg, and nivolumab 360 mg was begun in November 2021.

The patient received a second course of chemotherapy with pemetrexed 500 mg/m2, ipilimumab 1 mg/kg, and nivolumab 360 mg. On day 5 of the therapy, the patient complained of progressive fatigue and fading consciousness. At the initial examination, he was afebrile, had good oxygen saturation on room air in the lying position, and had bradycardia 25 beats/min, and blood pressure 78/42 mmHg. Apart from the bradycardia, the examination revealed no murmurs, rubs or gallops. The patient had a history of paroxysmal atrial fibrillation, and his daily medication included bisoprolol 2.5 mg and pilsicainide 100 mg. He had no history of bradyarrhythmia or had ever experienced these symptoms previously. Electrocardiography (ECG) revealed sinus arrest with a junctional escape rhythm (Fig. 1). ECG readings obtained three weeks earlier during a medical check-up were unremarkable (Fig. 2). A transthoracic echocardiogram (TTE) revealed no pericardial effusion or abnormality of the left ventricular systolic function. The initial laboratory data revealed no evidence of myocarditis (the blood level of troponin-T and CK was 0.025 ng / ml and 85 U/L, respectively). The troponin-T and CK did not significantly increase during hospitalization (Fig. 3). The patient was later admitted to the cardiovascular intensive care unit for further management. A temporary transvenous pacemaker was inserted via the right jugular vein for symptomatic bradycardia with sinus arrest (back-up low rate: 60 beats / minute). The sinus arrest resolved without treatment within three hours after the temporary pacemaker was placed. The N-terminal pro-B-type natriuretic peptide (NT-proBNP) level was 2,028 pg / ml at the onset of the sinus arrest, then dropped to 1,268 pg / ml after pacemaker placement (Fig. 4). A permanent pacemaker was implanted on hospital day 8 because symptomatic, intermittent sinus arrest and a slow escape rhythm were observed.

Fig. 1.

12-lead ECG revealed sinus arrest with a narrow junctional escape rhythm

Fig. 2.

Normal 12-lead ECG

Fig. 3.

Time-series changes in blood tests. SSS, sick sinus syndrome

Fig. 4.

Time-series changes in NT-proBNP. SSS, sick sinus syndrome; NT-proBNP, N-terminal pro-brain natriuretic peptide

Two cycles of chemo-IO achieved stable disease status. Nivolumab and ipilimumab were continued instead of chemotherapy or observation because the performance status declined to 2 and the patient asked that the therapy be continued. After one cycle of nivolumab and ipilimumab therapy, a grade 2 skin rash developed, and the patient chose to stop the therapy. After three and a half years, the tumor has shown no sign of progression.

Discussion

ICI act on inhibitory pathways by stimulating the immune response to exert anti-tumor effects via monoclonal antibodies acting on programmed cell death protein-1 (PD-1), programmed cell-death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) [5]. Several studies have shown that the myocardium, pericardium, vascular system, and electrical conduction system can be adversely affected by ICI [6]. Conduction abnormalities have been widely reported in the context of immune-mediated myocarditis. The diagnosis of cardiac complications can be quite challenging and requires a very high index of clinical suspicion.

The frequency of irAE was substantially higher in patients treated with a combination of ICI [7]. ICI-related myocarditis is associated with a high mortality rate of 50% [3] while ipilimumab–nivolumab combination therapy is associated with cardiovascular mortality and conduction abnormalities [8]. In the present case, the escape rhythm progressively slowed to 15–25 beats/min and was followed by cardiogenic shock requiring transvenous pacing at 3 h after the first syncope episode. All life-support measures were implemented simultaneously because the symptoms occurred during hospitalization. Syncope occurring outside a properly equipped healthcare facility or at home has the potential to be fatal.

A previous study demonstrated that nearly all cases of myocarditis had elevated troponin and abnormal ECG at presentation [9]. In the present case, transthoracic echocardiography revealed normal left ventricular function and no muscle edema or pericardial effusion. Further, the troponin-T and CK levels did not significantly increase during hospitalization. Kumar et al. [10] reported indirect cardiotoxicity via severe hypothyroidism leading to sinus arrest with subsequent cardiogenic shock. The present patient, however, did not demonstrate any endocrine deficiencies. Myocarditis and pericardial disease were excluded by the cardiac enzyme levels and echocardiographic findings. Thus, the present case possibly demonstrated the existence of a hitherto unknown pathway by which the ICI directly affected the sinus node.

ICI-related cardiotoxicity is classified into four grades based on the presenting symptoms, degree of cardiac biomarker elevation, and echocardiographic findings [11]. ICI administration should be halted immediately in all patients with ICI-related cardiotoxicity, and permanent discontinuation should be considered if the severity is greater than grade 1.

The onset of intermittent SSS without elevated cardiac enzymes ruled out a presumptive diagnosis of myocarditis. Glucocorticoid, including both oral prednisone and intravenous methylprednisolone [11], is generally used to treat ICI-associated myocarditis. However, in the present case, the sinus arrest resolved without treatment within 3 h of temporary pacemaker implantation. The decision was made not to administer immunosuppressants, given the apparent absence of cardiomyopathy.

There are few reports of cisplatin-induced bradycardia in the medical literature. It may be induced by various factors, including cellular interference in electrolyte concentrations caused by cisplatin, or by the accumulation of cisplatin in the electrical conduction system of the heart, which may lead to conduction disturbances [12].

A potential cause of the bradyarrhythmia in the present patient was his daily medications. However, bisoprolol 2.5 mg and pilsicainide 100 mg/day were below the maximum dose, and his liver and renal function were normal when he received his second course of therapy. When the SSS developed, creatinine increased 1.6-fold (Fig. 3) but returned to baseline after pacemaker implantation. The patient’s renal failure was due to low cardiac output. Although it was difficult completely to exclude the involvement of factors other than ICI as the cause of the bradyarrhythmia, a permanent pacemaker implanted for symptomatic bradyarrhythmia improved the symptoms. In the absence of effective alternatives, pacemaker implantation (class I indication) was performed after discussion with a cardiologist to treat the SSS caused by the clinically necessary therapy.

The introduction of immunotherapy has led to a paradigm shift in how clinicians view the treatment of advanced stage malignancies [13]. Thanks to ICI therapy, survival outcomes have improved markedly in patients with previously fatal, advanced stage non-small-cell lung cancer [14]. Furthermore, a long-term responder to immunotherapy is expected to survive for a long period of time, and irAE have been associated with ICI efficacy in patients with non-small-cell lung cancer [15]. However, the discontinuation of immunotherapy cannot be ruled out in the event of a serious adverse event. The criteria for the resumption of ICI therapy in cases of cardiac irAE have not been established, and the decision to resume ICI therapy should be made carefully. Including cardiac disease that can be resolved by pacemaker implantation as an irAE would force discontinuation of treatment even in cases that could have benefited from ICI. The patient may benefit from a resumption of immunotherapy if the cardiac dysfunction can be controlled by implanting a pacemaker.

In the present case, no new arrhythmias were detected after pacemaker implantation, and no myocardial injury or heart failure has occurred. ICI therapy is currently being continued under close monitoring. SSS developed during immunotherapy, but the patient was able to continue the treatment thanks to the implantation of the pacemaker.

Abbreviations

ICI

Immune checkpoint inhibitors

irAE

Immune-related adverse events

UICC

Union of International Cancer Control

ECG

Electrocardiography

TTE

Transthoracic echocardiogram

NT-proBNP

N-terminal pro-B-type natriuretic peptide

PD-1

Programmed cell death protein-1

PD-L1

Programmed cell-death ligand 1

CTLA-4

Cytotoxic T lymphocyte-associated protein 4

SSS

Sick sinus syndrome

Data availability

The data in this report are available on reasonable request from the corresponding author.

Declarations

Conflict of interest

Y. H. received honoraria (lecture fees) from AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda, Eisai, Novartis, Pfizer and MSD. M.Y. received honoraria (lecture fees) from AstraZeneca, Takeda, MSD, Chugai Pharmaceutical, Ono Pharmaceutical, and Bristol-Myers Squibb. M. K. received honoraria (lecture fees) from Chugai Pharmaceutical. The other authors declare that they have no conflicts of interest.

Ethical approval

Formal consent was not required for this study.

Informed consent

Informed consent was obtained from the participant.