Immune Checkpoint Inhibitors and Cardiovascular Adverse Events

Abstract

In the last years, we assisted to a tremendous increase in therapeutic options for the management of cancers, with immunotherapy at the forefront of this innovation. Immune checkpoint inhibitors (ICIs) have been developed to enhance the activity of the immune system against cancer cells (1) and the number of approvals for ICIs has rapidly increased. ICIs have also been associated with disinhibited cytotoxic T cells that damage healthy tissue in multiple organs, causing immune‐related adverse events (AEs). Cardiovascular AEs (CVAe) are increasingly reported: myocarditis, Takotsubo syndrome, pericarditis and pericardial effusion, worsening of atherosclerosis, acute coronary syndromes, non‐inflammatory heart failure, and ischaemic stroke. They are classified into five grades, based on presenting symptoms, level of cardiac biomarkers, and imaging. Even though myocarditis occurs more frequently than previously thought, clinically relevant myocarditis is a rare irAE compared to other irAE (0.5–1.2%). The clinical manifestations range from mild symptoms such as to chest pain, heart failure, and cardiogenic shock. The prognosis is severe, with mortality rates ranging from 25% to 50%. It is frequently associated with the concomitant use of combination of checkpoint inhibitors. The treatment strategies are tripartite: (i) holding ICI to prevent further toxicity, (ii) immunosuppression to alleviate inflammatory changes, and (iii) supportive therapy to address cardiac complications. Glucocorticoids represent the first‐line treatment. In hemodynamically unstable patients, treatment with high‐dose steroids should be initiated (intravenous methylprednisolone 1000 or 1250 mg oral methylprednisolone during 4 days). ICI‐associated pericarditis can be accompanied by no/mild pericardial effusion up to cardiac tamponade. The treatment is made of nonsteroidal anti‐inflammatory drugs and colchicine, corticosteroids if needed, and pericardiocentesis for the large effusions. ICIs could be continued for Grade 1 pericarditis, while temporary suspension of ICI is warranted for more severe cases. There is significant potential for accelerated atherosclerosis with ICIs as a long‐term effect, but atherosclerosis‐related CVAEs are not frequent, especially during treatment; increasing evidence associates ICIs with progression of atherosclerosis and increased atherosclerotic cardiovascular disease. ICIs can lead to arrhythmias: atrial fibrillation, supraventricular and ventricular tachycardias. Non‐inflammatory heart failure syndrome have been observed in ICI‐treated patients. Immune checkpoint inhibitors seem to be involved in the development of right ventricular dysfunction and pulmonary arterial hypertension. It is of the outmost importance to improve the collaboration among the different medical figures, such as cardiologists, oncologists, endocrinologists, and immunologists, both in clinical practice and in basic science research, to better recognize these adverse events, to understand their pathophysiological mechanisms, and to improve the overall survival and quality of life of the affected patients.

Introduction

In the last years, we have assisted to a tremendous implementation in therapeutic options for the management of patients suffering from cancers, with immunotherapy at the forefront of this innovation. Immune checkpoint inhibitors (ICIs) have been developed to enhance the activity of the body's immune system against cancer cells. ICIs interact with different co‐stimulatory/co‐inhibitory signalling molecules expressed on T cells, tumour cells, and antigen‐presenting cells, such as cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) and programmed cell death protein (PD1) and its ligand (PDL1). ICIs essentially break the immune tolerance of T cells against cancer cells (Figures 1 and 2 ), which have tremendously so changed the treatment landscape of cancer by achieving unprecedented rates of durable anti‐tumour response. ¹ Given the effectiveness of this therapy mechanism, the number of approvals for ICIs has rapidly increased.

Figure 1.

Spectrum of cardiovascular toxicities.

Figure 2.

Common Terminology Criteria for Adverse Events (CTCAE) and grade of cardiovascular toxicity.

Indeed, there are 10 ICIs already approved by the US FDA: two CTLA‐4‐blocking antibodies (ipilimumab and tremelimumab), four PD‐1‐blocking antibodies (nivolumab, cemiplimab, dostarlimab, and pembrolizumab), three PD‐L1‐blocking antibodies (atezolizumab, avelumab, and durvalumab), and one targeting LAG‐3 (relatlimab). Eight are approved by the European Medicines Agency (EMA): all the above‐mentioned except for cemiplimab and relatlimab. ² Currently, there are approximately 125 indications for ICIs in adjuvant and neoadjuvant settings, including some as first‐line therapy, in more than 20 distinct cancer diseases. This number will increase as multiple ICIs targeting over 300 different proteins are being tested in more than 5600 clinical trials, and it is estimated that approximately 36% of US cancer patients are currently eligible for ICI therapy. ³ Since ICIs also regulate auto‐reactivity, ICIs have been associated with disinhibited cytotoxic T cells that could damage healthy tissue in multiple organs, causing immune‐related adverse events (irAEs). As a matter of fact, above 60–80% of patients experience adverse events such as endocrinopathies, hepatitis, colitis, and pneumonitis ⁴ ; and cardiovascular adverse events (CVAEs) are increasingly reported, although probably under‐represented due to the difficulty in diagnosis and due to their non‐specific clinical manifestations. ⁵ , ⁶ They are emerging as a serious concern and hence the strategies for risk stratification before starting the treatment, as well as the surveillance to enable prompt recognition and treatment of cardiotoxicity are increasingly important recognized. Moreover, with the rapidly rising number of patients with cancer who are eligible for ICI therapy, ⁷ research into ICI‐induced cardiac irAEs is becoming of the outmost importance. The main cardiovascular AEs related to ICIs are myocarditis, Takotsubo syndrome (TTS), pericarditis and pericardial effusion, worsening of atherosclerosis, acute coronary syndromes, non‐inflammatory heart failure (HF), and ischaemic stroke (Figure 1 , ESC Guidelines 2022). They have been classified into 5 grades, based on presenting symptoms, level of cardiac biomarkers and imaging findings (Figure  2 ). We will discuss the most important manifestations in the following review.

Pathogenesis

The systemic augmentation of immune responses by ICIs, especially when used in combination, leads to a range of immune‐related toxicities ⁶ but the exact pathophysiological mechanisms involved in the initiation and propagation of CVAEs remain still now fully understood. ⁸ Robust expansion and clonal expansion of T lymphocytes with highly expressed T‐cell receptor against shared common antigens across tumour cells and affected tissues could be a potential mechanism ⁹ ; for example, frequently expressed T‐cell receptor sequences have been noted in the tumour and in the cardiac muscle, which raises the possibility of a shared antigen target ¹⁰ (Figures 3 and 4 ). Moreover, an association between specific human leucocyte antigen subtypes with increased likelihood of these AEs has been suggested. ¹¹ In fact, the underlying pathophysiology may also involve the unmasking of latent autoimmunity and ICI‐triggered immune dysregulation with over‐activation of pro‐inflammatory pathways and suppression of immune control pathways.

Figure 3.

Pathophysiology: tumour microenvironment without ICI.

Figure 4.

Pathophysiology: immune checkpoints and tumour micro‐environment. Effects of immunotherapy: inhibition of inhibitor signals and T‐cell proliferation and activation.

Myocarditis

Even though myocarditis occurs more frequently than previously thought, clinically relevant myocarditis is a rare irAE compared to other irAE (0.5–1.2%). ¹² , ¹³ The median time of onset is usually 17–34 days, ¹⁴ although late cases have also been described up to several months after starting ICI therapy.

Preclinical studies have shown the possible physiopathological mechanisms of the disease: The lymphocytic infiltration in knockout mice deficient in CTLA‐4 and PD‐1 and disruption of PD‐1 gene leads to severe HF and dilated cardiomyopathy, ¹⁵ with histopathological evidence of cardiomyocyte necrosis with significant rise of serum biomarkers. The clinical manifestations range from mild aspecific symptoms to chest pain, dyspnoea, HF, and cardiogenic shock. Tachyarrhythmias such as atrial fibrillation, supraventricular and ventricular tachycardias, and bradyarrhytmias such as atrioventricular block can also be a manifestation of myocarditis; however, they are not pathognomonic of the disease. They can be also associated with ICI‐related thyroiditis or severe systemic inflammatory syndromes. There is a high prevalence of electrical conduction diseases, probably due to infiltration of the conduction system by T cells, and therefore, it is important to assure close monitoring for early referral for to cardiac pacing implantation. As compared with other forms of myocarditis, the prognosis of ICI‐related myocarditis is significantly worse, with mortality rates ranging from 25% to 50%. It is more severe and frequently associated with the concomitant use of a combination of checkpoint inhibitors, ¹⁶ which is the most well‐established risk factor and also predicts a more severe course of the disease. Other negative prognostic factors are the co‐existence of cardiovascular disease, especially coronary artery disease, and the occurrence of other IrAEs, especially those involving skeletal muscle and/or the neuromuscular junction: myositis and/or myasthenia gravis (Figure 5 A,B ). ¹⁷

Figure 5.

(A) Risk factors for development of immune‐related adverse events. (B) Risk factors for poor prognosis in ICI‐related myocarditis.

A recent study found also that obesity is associated with ICI‐related systolic dysfunction in both sexes, possibly due to obesity related T‐cell exhaustion, highlighting the importance of considering the metabolic conditions when evaluating the risk of cardiotoxicity. ¹⁸

Myocarditis may frequently (40%) co‐occur with myositis/myasthenia gravis (the so‐called overlap syndrome), with a fulminant (after first ICI infusion) and usually fatal (75%) outcome. In a multicentre observational study from eight sites in the period 2013–2017, myocarditis was noted in 1.1% of the patients, who suffered more frequently from diabetes, obesity, and sleep apnoea as compared with controls, ¹⁹ and 15% of them developed fulminant myocarditis. Nearly all myocarditis cases had troponin elevation and abnormal ECG. The degree of troponin elevation seems useful in predicting adverse cardiac outcomes. ²⁰ , ²¹ Given that the initial presentation may be non‐specific and rapid progression with fulminant course is possible, a high degree of suspicion is key. Prompt initial evaluation should include ECG, measurement of cardiac biomarkers (NT‐pro‐BNP, troponin T or I in ultrasensitive assays), and transthoracic echocardiography. ²² , ²³ The peptides are markers of myocardial stretch/damage; however, they are sensible but not specific enough to reach the diagnosis without any further clinical element.

To establish the diagnosis, according to the ESC guidelines 2022 diagnostic criteria, there must be a significative change in troponin values associated with one major or two minor (clinical and/or iconographic) criteria (Figure  6 ). ¹⁷ Of note, current guidelines do not give any priority to either hs‐TnI or hs‐TnT, ¹⁷ but there are some evidences that suggest that hs‐TnI might represent a more reliable, heart‐specific biomarker for diagnosing, risk‐stratifying, and monitoring ICI‐related myocarditis. Indeed, Hs‐TnI has been associated with early signs of left ventricular dysfunction, as shown by reduced left ventricular longitudinal strain in patients under ICI therapy. ²⁴ Moreover, hs‐TnI has a shorter plasma half‐life than hs‐TnT, while TnT elevation might persist for a longer time beyond the healing of myocarditis, making more difficult to recognize the healing, and therefore, the decision to re‐challenge with ICI therapies. ²⁵ Particularly, in ICI‐related myocarditis, hs‐TnT was found to be persistently elevated for up to 60 days. ²¹ Moreover, there is evidence of TnT expression in the skeletal muscle, which can also be enhanced in the setting of both non‐inflammatory myopathies and myositis, likely related to an overexpression of the TNNT2 gene. ²⁶ Hence, it will be important to investigate whether the overall extra‐cardiac expression of TnT can make the TnI as a more specific marker, especially in the case of simultaneous suspicion of myocarditis and myositis. It is also important to underline that generally accepted cut‐offs and reference values of CV biomarkers have not been established for patients with cancer or for those who receive cancer therapies.

Figure 6.

Diagnosis and severity classification of ICI‐related myocarditis.

However, a recent study ²⁷ pointed out that also TnT is associated with MACE and is sensitive for diagnosis and surveillance in patients with ICI myocarditis, especially a cTnT:URL ratio <32 within 72 h of diagnosis is associated with a subgroup at low risk for MACE.

Emerging data show that global longitudinal strain obtained together with 2‐D echocardiography may be helpful both for diagnosis and for prognosis. ²⁴ CMR can be more effective in demonstration of myocardial inflammation and necrosis in T1and T2 sequences and on late gadolinium enhancement. ²⁸ Endomyocardial biopsy represents the gold standard diagnostic modality and provides a definitive diagnosis, although the myocardial involvement is usually patchy, making biopsy less sensitive. Histology shows typically lymphocyte and macrophage infiltration with myocardial fibrosis. ²⁹ Endomyocardial biopsy should be reserved for patients who do not respond to initial treatment or in cases of doubtful diagnosis, in patients with severe cardiac impairment and/or serious ventricular arrhythmias or atrioventricular blocks, fulminant myocarditis, and cardiogenic shock. EMB can be repeated in the case of unexplained progression of HF or to monitor response to treatment. ³⁰

Cardiac fluorodeoxyglucose positron emission tomography (18‐FDGPET‐CT) may be considered but has low sensitivity and requires a strict 18‐h fasting. ³¹ Of increasing interest is the utilization of the 68Ga‐DOTATOC PET/CT, which showed promising results as an imaging modality for the diagnosis of ICI‐related myocarditis. ³² It is characterized by high sensitivity, and it might be of value at the early stage of the disease in patients with suggestive clinical symptoms who may not yet present myocardial damage on CMR imaging. Its value is supported by a good concordance with serum levels of hs troponin I and the inflammatory IL‐6/Th1 cytokine markers. ³² These results need to be confirmed in a larger population of patients and validated against a histological gold standard, if available.

ESC guidelines recommend that timing and frequency of monitoring should be individualized based on patients' baseline cardiovascular risk profile and therapy received (Figure  7 ). ¹⁷ They recommend cardiac detection of biomarkers (troponin and natriuretic peptides) and ECG at baseline and before and after administration of each of the first three cycles of ICI administration. Transthoracic echocardiogram is also recommended at baseline in high‐risk patients (Figure  7 ). ¹⁷ Of note, among 272 recommendations in the 2022 ESC guidelines, only 3% were supported by Level of Evidence (LoE) A, whereas 76% by LoE C (expert opinion, small or retrospective studies, or registries), underlining the lack of randomized clinical trials or high‐quality scientific evidence in this domain. ³³

Figure 7.

Imaging modalities and biomarker strategies for monitoring.

With respect to management modalities, the treatment strategies are tripartite: (i) holding ICI to prevent further toxicity, (ii) immunosuppression to alleviate inflammatory changes, and (iii) supportive therapy to address cardiac complications. ⁵ ICIs should be discontinued and permanent discontinuation should be discussed for those with more severe presentation, while in mildly symptomatic patients, resumption of ICI therapy under close monitoring may be considered ³⁴ after multidisciplinary discussion, considering various factors such as severity of ICI‐CVAE, alternative oncology treatment options, and metastatic versus adjuvant/neoadjuvant indication and after reducing from dual ICI to single ICI treatment.

Initial management if ICI myocarditis should be based on clinical likelihood and severity of the clinical presentation, with a low threshold for starting high‐dose steroids in the absence of an alternative diagnosis (such as coronary artery disease/acute coronary syndrome). Glucocorticoids represent the first‐line treatment, but guidelines vary significantly in terms of initial dose and treatment strategies. According to the recent retrospective study of Zhang and Neilan, ³⁵ patients who received steroids within the first 24 h were less likely to have persistent troponin elevation at discharge and had a lower rate of major adverse cardiovascular events (MACE). There was moreover an inverse relationship between initial dose and re‐occurrence of MACE. In haemodynamically unstable patients, treatment with high‐dose methylprednisolone should be promptly initiated ¹⁹ : 1000 mg intravenous methylprednisolone or 1250 mg oral methylprednisolone during 4 days. Corticosteroid tapering should be done according to ESC guidelines: Based on biomarkers and cardiac imaging, tapering should be done, whereas biomarkers are down‐trending, and in the absence of worsening LVEF, and not waiting to wean after normalization of these parameters. Indeed, biomarkers may remain mildly elevated (of unknown significance) even after successful treatment of ICI myocarditis. Tapering should be done slowly, over 4–6 weeks after having reached complete normalization of cardiac function and biomarkers. ¹⁷ Patients unresponsive to glucocorticoids should be evaluated for second‐line immunosuppressive therapy options, such as plasmapheresis, intravenous immunoglobulins, anti‐thymocyte globulin, mycophenolatemofetil, tocilizumab, tacrolimus, and infliximab. ²³ , ³⁶ However, the available data are still insufficient to recommend a specific second‐line immunosuppression regimen, and multidisciplinary discussion is recommended. ³⁷ Patients should be managed as inpatient with telemetry and deserve immediate consultation with cardio‐oncologist and multidisciplinary approach. ¹ In unstable patients, mechanical circulatory support may need to be considered. A summary of recommendations suggested by the 2022 ESC guidelines is shown in Figure 8 .

Figure 8.

ESC guidelines' suggested therapies.

Other cardiovascular manifestations

ICIs have been also associated with other cardiovascular adverse events: pericarditis and pericardial effusion, worsening of atherosclerosis and acute coronary syndromes, vasculitis (mainly giant cell arteritis [GCA] ³⁸ ) with 28% of cases severe enough to cause vision impairment, arrhythmias, TTS, non‐inflammatory HF, thrombotic events, pulmonary vascular disease, and ischaemic stroke. ¹⁷

ICI‐associated pericarditis can be accompanied by no or mild pericardial effusion until to cardiac tamponade and can be associated with myocarditis. ³⁹ There are no available estimates of the whole incidence, but haemodynamically significant pericardial effusions were reported in 0.38% of patients treated with ICI. ⁴⁰ The fatality rate was estimated about 21.1% according to a 95‐patient WHO database registry, ⁴¹ although it remains difficult to assess the direct contribution of pericardial disease to this fatality rate. No specific studies are available that clarify with certainty the mechanism of ICI‐associated pericardial disease. It is thought that it results from ICI stimulation of T cells against the pericardium, leading to inflammation. ⁴¹ The majority of these cases are associated with lung cancer patients. The hypothesis behind this disproportionately high incidence of pericardial disease in lung cancer patients is the previous exposure to radiotherapy. Theoretically, radiotherapy might expose the pericardial antigens leading to enhanced T‐cell binding and, consequently, pericardial inflammation. ⁴² , ⁴³ The highest prevalence so far has been documented with nivolumab (0.61%), followed by pembrolizumab (0.19%) and atezolizumab (0.32%). ⁴⁴ An international database of patient case reports showed that the average time to manifestation of ICI‐associated pericarditis was about 30 days. ⁴⁰ Clinical presentation ranged from cardiac symptoms like chest pain and dyspnea to non‐specific ones such as myalgia and asthenia. ECG findings are usually non‐specific, and TTE and MRI may demonstrate pericardial effusion and inflammation, respectively. Severity of the disease is distinguished according to five different grades (G1–G5; Figure 2 ). ⁴⁵ The treatment consists in the use of non‐steroidal anti‐inflammatory drugs (NSAIDs) and colchicine, corticosteroids if needed, and pericardiocentesis for the large effusions. ⁴⁴ Based on the available evidence, ICIs could be continued for G1 pericarditis, while temporary suspension of ICI is recommended for G2 to G4. For the steroid‐resistant cases, successful results were reported with other treatments like mycophenolate and TNF‐alpha inhibitors. It is also important to differentiate pericarditis and pericardial effusion from pseudo‐progression, ⁴⁶ which is a condition with transient worsening of the underlying cancer disease before resolution. This pseudo‐progression likely arises from the extensive inflammation generated from activated T cells against the tumour, leading to pericardial effusion. ⁴⁷ , ⁴⁸

Atherosclerosis‐related CVAEs are emerging as one of the most frequent immune‐related cardiovascular adverse events. Increasing preclinical and clinical data associate ICIs with progression of atherosclerosis and increased atherosclerotic cardiovascular disease, although the potential for accelerated atherosclerosis should be separated from the acute atherosclerosis related CVAEs. ² A meta‐analysis has shown a significant association between ICIs and worsening of dyslipidaemia, leading to clinical sequelae such as manifest atherosclerosis and myocardial infarction. ¹² A single‐centre retrospective study found a 3‐fold higher risk of aortic plaque progression and coronary atherosclerosis leading to myocardial infarction, ischaemic stroke, and coronary revascularization during and after ICI therapy. ⁴⁹ Another study demonstrated enhanced FDG‐PET uptake in large arteries after ICI treatment, confirming the pro‐inflammatory hypothesis. ⁵⁰ Multiple basic cellular, animal, and human studies have demonstrated that PD‐1, PD‐L1, and CTLA‐4 are down‐regulators of atherosclerosis. ⁵¹ , ⁵² , ⁵³ , ⁵⁴ Thus, their blockade may lead to accelerated atherosclerosis by enhancing T‐cell responses and inflammation, by limiting regulatory T‐cell function, and by infiltrating the vascular endothelium. ⁵⁴ It is very important to find treatment options to reduce this emerging CV risk. Drobni et al. could demonstrate a reduction of the progression of aortic plaque while on ICI treatment, through the administration of statin. ⁵⁵ In addition to lipid lowering effect, statins have been associated with plaque stabilization, endothelial dysfunction reversal, and inflammation reduction, thus counteracting on the second postulated mechanism of ICI‐induced atherosclerosis acceleration. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are an increasingly popular class of monoclonal antibodies that reduce serum low‐density lipoprotein (LDL) and atherosclerotic events in higher risk patients. Statins and PCSK9 inhibitors have shown preliminary evidence of synergistic benefit when paired with ICI therapy independently of their cholesterol‐lowering effects. Several clinical studies in patients with advanced NSCLC and malignant pleural mesothelioma treated with ICIs demonstrated that statins were associated with increased response rate, improved time to treatment failure, and progression‐free and overall survival. ⁵⁶ , ⁵⁷ Liu et al. found that PCSK9 inhibition with evolocumab synergized with anti‐PD‐1 therapy to suppress tumour growth by increasing the expression of MHC I proteins and enhancing lymphocyte proliferation into the tumour. ⁵⁷ These findings demonstrate that statins and PCSK9 inhibitors have the potential to both enhance ICI efficacy and treat ICI‐related atherosclerosis. However, Drobni et al. revealed an increased risk of myopathy in patients treated concurrently with statins and ICIs, ⁵⁸ Indeed, these growing clinical findings invite to pay better attention to pharmacotherapies to reduce cardiovascular events in this specific population. Thus, further studies are needed to confirm the safety of existing therapies and eventually identify novel therapeutics in the treatment of atherosclerotic cardiovascular disease in the context of ICI use.

ICIs can lead to cardiac arrhythmias such as atrial fibrillation, supraventricular tachycardias, ventricular tachycardia, and atrioventricular blocks. It is important to note that these arrhythmias may arise due to various factors, such as concurrent myocarditis, pericarditis, endocrinopathies, and electrolyte abnormalities or also as isolated manifestation of ICI therapy. ⁴⁴

Non‐inflammatory heart failure syndromes

Non‐inflammatory HF syndromes have also been observed in patients treated with ICI.

These include TTS, non‐inflammatory HF or left ventricular disease (LVD), ⁵⁵ and post‐MI HF. ⁵⁶ Clinical studies from the past 5 years suggest that HF after ICI therapy is a more common phenomenon (0.5–7%) than previously thought, ⁵⁹ as early or late presentation, and the mechanisms of this association remain unclear. In the literature, pro‐inflammatory cytokine release, autoantibodies, disruption of myocardial homeostasis, and the role of the thymus have been suggested as one of the potential mechanisms for cardiac dysfunction without myocarditis. ⁵⁷ Given that inflammation has been associated with the development and progression of HF, inhibiting the immune checkpoints responsible for preventing pro‐inflammatory responses might put the heart at risk of dysfunction and eventually HF ⁶ and needs proper HF treatment according to current guidelines. ⁵⁷ Interruption versus continuation of ICI therapy depends on the severity of the HF syndrome, and each case should be reviewed by a multidisciplinary team (multidisciplinary meeting [MDM]). ¹⁹

Pulmonary vascular disease

Finally, ICIs seem involved, by means of endothelial dysfunction and development of pulmonary vascular disease, right ventricular dysfunction, and pulmonary arterial dilatation and hypertension. A recent retrospective study by Mylvaganam et al. ⁶⁰ demonstrated after a median of 59 days of ICI therapy, a worsening in the pulmonary artery to aorta ratio, and a decrease in right ventricular free wall strain, raising concerns that T cells potentially play a role in the pathogenesis of pulmonary vascular injury.

Conclusions

ICIs are associated with cardiovascular toxicities such as myocarditis, pericardial disease, arrhythmias, or disturbances of the conduction system and progression of the atherosclerosis. These immune‐related adverse effects require prompt ICI discontinuation and sometimes immunosuppressive treatment, particularly considering the high fatality rates of some of them. There are an increasing number of patients suffering from cancer disease who may be eligible for ICI therapy so that their use is projected to rapidly arise in the next coming years. Recognizing patients at risk, monitoring these patients during ICI therapy, detecting rapidly adverse events, and evaluating reintroduction of immunotherapy after its suspension represent all significant challenges for clinicians and patients, particularly for those who did benefit in terms of cancer treatment. The evidence supporting the re‐administration of ICIs for patients who experienced cardiac toxicity is scarce, and there is a lack of expert guidance in this area. It is of the outmost importance to improve the collaboration among the different medical figures who face with these clinical challenges scenarios, such cardiologists, oncologists, endocrinologists, and immunologists, both in clinical practice and in basic science research, in order to improve knowledge (some of the most significant studies to date are shown in Table 1 ) and expertise to further enhance overall survival and quality of life of the affected patients.

Table 1.

Most significative studies/case report/meta‐analysis of the past years

Authors	Year	Major knowledge gained	Title
Laubli H, Balmelli C, Bossard M, et al.	2015	First time an autoimmune myocarditis under pembrolizumab treatment was reported	Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer; 3:11
Roth ME, Muluneh B, Jensen BC, Madamanchi C, Lee CB	2016	First described case report of ipilimumab‐related heart failure, without myocarditis. 4 months after completing a second course of treatment for metastatic melanoma	Left ventricular dysfunction after treatment with ipilimumab for metastatic melanoma. Am J Ther;23: e1925–e1928.
Mahmood SS, Frsdley MG, Cohen JV, et al.	2018	After observation of sporadic ICI‐associated myocarditis cases, the authors created a multicenter registry with eight sites. From November 2013 to July 2017, there were 35 patients with ICI‐associated myocarditis, who were compared to a random sample of 105 ICI‐treated patients without myocarditis. The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI, has a malignant course, and responds to higher steroid doses	Myocarditis in patients treated with immune checkpoint inhibitors. JACC; 71: 1755–1764
Omori M, Okuma Y, Hakozaki T, Hosomi Y	2019	A total of 67 patients treated with nivolumab for NSCLC from 2016 to 2017 were prospectively investigated. NSCLC patients previously treated with nivolumab who were administered statins exhibited an increased response rate and longer time to treatment failure	Statins improve survival in patients previously treated with nivolumab for advanced non‐small cell lung cancer: an observational study. Mol Clin Oncol 10(1):137–143. doi:10.3892/mco.1765
Calabretta R, Hoeller C, Pichler V, Mitterhauser M, Karanikas G, Haug A, et al.	2020	Activated T cells produce large amounts of proatherogenic cytokines that may contribute to both the growth and destabilization of atherosclerotic plaques	Checkpoint inhibitor therapy induces inflammatory activity in large arteries. Circulation 2020;142(24):2396–2398. doi:10.1161/circulationaha.120.048708
Droni ZD, Alvi RM, Taron J, Zafar A, Murphy SP, Rambarat PK, et al.	2020	Cardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk, prior to, during and after treatment, should be considered among patients on an ICI	Association between immune checkpoint inhibitors with cardiovascular events and atherosclerotic plaque. Circulation 142(24):2299–311. doi:10.1161/circulationaha.120.049981
Zhang L, Awadalla M, Mahmood SS, Nohria A, Hassan MZO, et al.	2020	LGE is present in >80% of patients with non‐ICI myocarditis; in contrast, LGE is present in <50% of patients with ICI‐associated myocarditis. Increased time between clinical presentation and CMR is associated with greater detection of LGE; however, delays in diagnosis are not recommended as delayed treatment in ICI‐associated myocarditis may be associated with bad prognosis. These data suggest caution if using an LGE or qualitative T2‐weighted STIR imaging‐only approach to diagnose or exclude ICI associated myocarditis, especially among the majority of patients who have a normal LVEF, and suggest that when there is a clinical suspicion of myocarditis, a biopsy be strongly considered in those with a negative	Cardiovascular magnetic resonance in immune checkpoint inhibitor‐associated myocarditis. Eur Heart J. 2020;41(18):1733–1743. doi: 10.1093/eurheartj/ehaa051
Dolladille C, Akroun J, Morice PM, Dompmartin A, Ezine E, Sassier M, et al.	2021	The authors systematically reviewed all randomized clinical trials including at least one ICI containing arm and available CV adverse event (CVAE) data in cancer patients in the ClinicalTrials.gov registry, Medline, and the Cochrane CENTRAL Register of Controlled Trials, up to 31 August 2020. The primary outcome was the summary risk of 16 different CVAEs associated with ICI exposure versus controls (placebo and non‐placebo). The incidence of these CVAEs ranged from 3.2 (95% CI 2.0–5.1) to 19.3 (6.7–54.1) per 1000 patients, in studies with a median follow‐up ranging from 3.2 to 32.8 months	Cardiovascular immunotoxicities associated with immune checkpoint inhibitors: a safety meta‐analysis. Eur Heart J 42(48):4964–4977
Tamura Y, Tamura Y, Takemura R, Yamada K, Taniguchi H, Iwasawa J, Yada H, Kawamura A	2022	The authors conducted a retrospective cohort study with 129 patients who received ICIs. Age‐ and sex‐adjusted Cox regression analysis was used to evaluate the association between LS and elevations in hsTnI and myocarditis. An early worsening in the global and regional LS was associated with increased hsTnI in patients receiving ICIs	Longitudinal strain and troponin I elevation in patients undergoing immune checkpoint inhibitor therapy. JACC CardioOncol; 4: 673–685
Vasbinder A, Chen Y, Procureur A, Gradone A, Azam TU, Perry D, Shadid H, Anderson E, Catalan T, et al.	2022	In a large cohort of patients receiving ICI therapy for cancer, myocarditis was commonly preceded by a rise in non‐cardiac biomarkers, notably AST, ALT, and CPK. Elevations in these biomarkers during ICI therapy should prompt clinicians to screen for myocarditis using high‐sensitivity troponin and consider further diagnostic evaluation	Biomarker trends, incidence, and outcomes of immune checkpoint inhibitor‐induced myocarditis. JACC CardioOncol; 4: 689–700
Laenens, D., et al.	2022	The incidence of MACE was 10.3% during a median follow‐up of 13 (interquartile range, 6–22) months. In multivariable analysis, cumulative incidence rates were significantly higher in the ICI group compared with the cancer cohort not exposed to ICI and the population controls, mainly driven by a higher risk of HF events	Incidence of cardiovascular events in patients treated with immune checkpoint inhibitors. J Clin Oncol 40, 3430–3438

Conflict of interest

G.M. has received advisory board or speaker's fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Gebro Pharma, Novartis, and Vifor, all outside of the submitted work. M.L.D.P. received advisory board fee from Boehringer Ingelheim, outside of the submitted work. The other authors have no conflicts of interest.

De Perna, M. L. , Rigamonti, E. , Zannoni, R. , Espeli, V. , and Moschovitis, G. (2025) Immune Checkpoint Inhibitors and Cardiovascular Adverse Events. ESC Heart Failure, 12: 2404–2416. 10.1002/ehf2.15281.