ICIs-Related Cardiotoxicity in Different Types of Cancer

Immune checkpoint inhibitors (ICIs) are rapidly developing immunotherapy cancer drugs that have prolonged patient survival. However, ICIs-related cardiotoxicity has been recognized as a rare, but fatal, consequence. Although there has been extensive research based on different types of ICIs, these studies have not indicated whether cardiotoxicity is specific to a type of cancer. Therefore, we conducted a systematic review to analyze a variety of ICIs-related cardiotoxicity, focusing on different types of cancer. We found that the incidence of ICIs-related cardiac adverse events (CAEs) and common cardiotoxic manifestations vary with cancer type. This inspired us to explore the underlying mechanisms to formulate targeted clinical strategies for maintaining the cardiovascular health of cancer patients.

With the widespread application of anticancer drugs, the survival of patients has significantly improved, but the related cardiotoxicity affects long-term therapeutic outcomes, and this has attracted considerable attention. Immune checkpoint inhibitors (ICIs), antibodies that target the checkpoints in immune cells, work to activate inhibited T-cells and other cells of the innate and adaptive arms, resulting in the robust activation of the immune system and productive antitumor immune responses. This new type of immunotherapy drug has significantly improved the survival of cancer patients [6][7][8]. ICIs have been widely used in the treatment of melanomas, non-small cell lung cancer (NSCLC), advanced renal cell carcinomas (RCCs), urothelial carcinomas, hepatocellular carcinomas (HCCs), and hematological malignancies [7,[9][10][11][12]. However, their use is associated with adverse side effects involving different organs [13,14]. ICIs-related cardiotoxicity, which may develop even without a history of significant cardiac risk factors, includes myocarditis, pericarditis, heart failure, arrhythmias, and vasculitis [15]. In reported cases of adverse ICIs-related events, 6.2% were cardiac adverse events (CAEs), which can be the main determinants of quality of life and increased mortality [3,16,17]. Recent cohort data from a large healthcare network CAEs were arrhythmia (9.3%) and myocarditis (2.1%) [18]. Cardiotoxicity associated with ICIs is known for its vast array of clinical presentations, which makes it unfavorable for an early diagnosis [19,20]. To date, there has been little agreement on the incidence or specific mechanisms of ICIs-related cardiotoxicity in different types of cancer. We hypothesize that ICIs may exhibit cancer-type-specific cardiotoxicity.

Discussion
A total of 23,090 subjects from more than 40 studies were analyzed and the major findings were (1) ICIs-related CAEs commonly occur in melanomas, lung cancer, urothelial and renal cell carcinomas, and hematological malignancies. The incidence of ICIs-related CAEs ranged from 0.15 to 10%. The most commonly encountered type of cardiotoxicity in melanomas, renal cell carcinomas, and urothelial carcinomas was hypertension, whereas in lung cancer it was arrhythmia. ICIs-related cardiotoxicities for other cancer types appeared mostly in case reports and presented with myocarditis. (2) Among the abovementioned five cancers, the incidence of grade 3-5 ICIs-related CAEs ranged from 35.7 to 55.4%. Compared with RCCs, the other four types had a higher incidence of CAEs, including sudden cardiac arrest. (3) In different types of cancer, different ICIs had manifested different cardiotoxicities. In melanomas, PD-1/PD-L1 inhibitor use was closely related to a fluctuation in blood pressure. Treatment-related hypertension was linked to lambrolizumab. Nivolumab appeared to have a correlation with ICIs-related hypotension. Abnormal blood pressures might also be caused by the toxic effect of ICIs on other organs (e.g., vasculature). In addition, fatal myocarditis was reported after a single treatment with the combination of nivolumab and ipilimumab [75]. Recent evidence suggests that abatacept, a CTLA-4 agonist, may be used as additional immunosuppression for severe ICI-related myocarditis [76]. In lung cancer, the common cardiotoxic manifestations of durvalumab were acute coronary syndrome, arrhythmia, and heart failure. The common cardiotoxic manifestations of nivolumab and pembrolizumab were arrhythmia, cardiac-related chest pain, cardiomyopathy, myopericardial disease, and pericardial disease. In renal cell carcinomas, nivolumab combined with ipilimumab appeared to cause hypertension. In urothelial carcinoma, atezolizumab was related to hypertension and arrhythmia. (4) In melanomas, we observed that the growing incidence of CAEs correlated with increased dosage [24] and frequency [26] of an ICI application. Regarding the cardiotoxicity of an ICI monotherapy compared with a combination therapy, two studies had inconsistent conclusions [25,30]. In lung cancer, two studies showed contradictory conclusions on the relationship between the ICI dose and ICIs-related cardiotoxicity [37,43]. As different drugs are used for different cancer types, the dosage and therapeutic regimens can also influence toxicity. Therefore, our conclusions require further evidence to be confirmed.
Tumor-intrinsic factors (such as a tumor-associated stroma) [92], patient-intrinsic factors, and environmental factors may be implicated in different cardiotoxicities of ICIs of different cancer types [93]. Tumor-intrinsic factors relating to the genetic, transcriptional, or functional profile of the tumor cells themselves [92,94] appear to be the decisive factors for ICIs-related cardiotoxicity. Patients with tumors having parallel histological and genetic features had a similar incidence of ICIs-related CAEs [92,95]. Tumor-intrinsic factors partook of the tumor-extrinsic mechanisms of ICIs-related cardiotoxicity through their effect on the interaction between the host immune system and the tumor [92,96]. The interval of time required for cardiotoxicity to occur has not yet been precisely indicated [97,98], so further work is required to elucidate this. There are still many unanswered questions about the effect of patient-intrinsic factors on ICIs-related cardiotoxicity because the mechanisms differ, even in patients treated with the same agent. Tumor-intrinsic factors (such as a tumor-associated stroma) [92], patient-intrinsic factors, and environmental factors may be implicated in different cardiotoxicities of ICIs of different cancer types [93]. Tumor-intrinsic factors relating to the genetic, transcriptional, or functional profile of the tumor cells themselves [92,94] appear to be the decisive factors for ICIs-related cardiotoxicity. Patients with tumors having parallel histological and genetic features had a similar incidence of ICIs-related CAEs [92,95]. Tumor-intrinsic factors partook of the tumor-extrinsic mechanisms of ICIs-related cardiotoxicity through their effect on the interaction between the host immune system and the tumor [92,96]. The interval of time required for cardiotoxicity to occur has not yet been precisely indicated [97,98], so further work is required to elucidate this. There are still many unanswered questions about the effect of patient-intrinsic factors on ICIs-related cardiotoxicity because the mechanisms differ, even in patients treated with the same agent.
With a wide range of ICI applications in anticancer therapy, there is growing recognition of a broad spectrum of ICIs-related CAEs. More attention must be paid to cancer-type-specific ICIs-related cardiotoxicity to target high-risk patients so that effective prevention and treatment measures can be applied. For patients treated with ICIs, clinical management-including the observation of clinical symptoms, the detection of cardiac biomarkers, and the performance of electrocardiograms and echocardiograms-are strongly suggested. More importantly, cancer-type-specific clinical management is urgently required. In patients with NSCLC, we suggest that the dynamic monitoring of electrocardiograms be performed after ICI application to evaluate the occurrence of arrhythmias such as atrial fibrillation, conduction blocks, and even malignant arrhythmias. Regarding patients with cancers such as melanomas, renal cell carcinomas, and uroepithelial carcinomas, we suggest that blood pressure be monitored dynamically during ICI therapy.
For ICIs-related cardiac complications, a high dose of steroids a common treatment; however, there are some circumstances in which aggressive therapy may be ineffective [99][100][101]. According to ASCO guidelines, permanent discontinuation of ICIs is recommended for grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement [102]. It is prudent for cardiologists and oncologists to spread With a wide range of ICI applications in anticancer therapy, there is growing recognition of a broad spectrum of ICIs-related CAEs. More attention must be paid to cancertype-specific ICIs-related cardiotoxicity to target high-risk patients so that effective prevention and treatment measures can be applied. For patients treated with ICIs, clinical management-including the observation of clinical symptoms, the detection of cardiac biomarkers, and the performance of electrocardiograms and echocardiograms-are strongly suggested. More importantly, cancer-type-specific clinical management is urgently required. In patients with NSCLC, we suggest that the dynamic monitoring of electrocardiograms be performed after ICI application to evaluate the occurrence of arrhythmias such as atrial fibrillation, conduction blocks, and even malignant arrhythmias. Regarding patients with cancers such as melanomas, renal cell carcinomas, and uroepithelial carcinomas, we suggest that blood pressure be monitored dynamically during ICI therapy.
For ICIs-related cardiac complications, a high dose of steroids a common treatment; however, there are some circumstances in which aggressive therapy may be ineffective [99][100][101]. According to ASCO guidelines, permanent discontinuation of ICIs is recommended for grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement [102]. It is prudent for cardiologists and oncologists to spread awareness about the manifestations of ICIs-related cardiotoxicity for each cancer type and cooperate closely for its successful diagnosis and management. Rigorous follow-ups of patients receiving ICI therapy with cardiac biomarkers, EKGs, and echocardiograms are recommended. It should be borne in mind that different drugs are used for different cancer types, and if a drug causes a different toxicity in a particular cancer type, the composition of each drug should be compared. The dosage and therapeutic regimen should also be compared because they influence toxicity. Further studies focusing on exploring cancer-type-specific ICIs-related car-diotoxic manifestations and potential mechanisms are required and helpful for maintaining the cardiac health of cancer patients treated by chemotherapy. Data Availability Statement: All data can be found in the references.

Conflicts of Interest:
The authors declare no conflict of interest.