Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: A Systematic Review

Immune checkpoint inhibitors (ICIs) are an important advancement in the field of cancer treatment, significantly improving the survival of patients with a series of advanced malignancies, like melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and Hodgkin lymphoma. ICIs act upon T lymphocytes and antigen-presenting cells, targeting programmed cell death protein 1 (PD1), programmed cell death protein ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), breaking the immune tolerance of the T cells against malignant cells and enhancing the body’s own immune response. A variety of cardiac-adverse effects are associated with ICI-based treatment, including pericarditis, arrhythmias, cardiomyopathy, and acute coronary syndrome, with myocarditis being the most studied due to its often-unexpected onset and severity. Overall, Myocarditis is rare but presents an immune-related adverse event (irAE) that has a high fatality rate. Considering the rising number of oncological patients treated with ICIs and the severity of their potential adverse effects, a good understanding and continuous investigation of cardiac irAEs is of the utmost importance. This systematic review aimed to revise recent publications (between 2016–2022) on ICI-induced cardiac toxicities and highlight the therapeutical approach and evolution in the selected cases.


Introduction
Immune checkpoint inhibitors (ICIs) are an important advancement in the field of cancer treatment, significantly improving the survival of patients with a series of advanced malignancies. The most common types of malignancies that benefited from the introduction of ICI-based therapies are melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma, renal cell carcinoma (RCC), and Hodgkin lymphoma [1,2].
Normally, antigens are processed by antigen-presenting cells (APCs) and presented as peptide-major histocompatibility complexes (MHC) to naive lymphocytes in secondary lymphoid organs. This interaction is facilitated by the additional ligand-receptor binding of CD28 (expressed on T cells) and CD80 or CD86 (expressed on APCs). As a consequence, activated lymphocytes clonally proliferate and differentiate towards CD4 + helper or CD8 + cytotoxic phenotypes. These effector cells will further migrate and recognize the antigens in their original location via T cell receptors (TCRs). In physiologic conditions, several mechanisms dampen the activation of T-cells in order to prevent autoimmunity. Therefore, CTLA-4 is upregulated in activated T cells and negatively competes with CD28 in this Several novel checkpoint pathways are also currently under investigation. Lymphocyte activation gene-3 (LAG-3) binds to MHC-II and blocks antigen presentation, while T cell immunoglobulin-3 (TIM-3) and T cell immunoreceptor, with Ig and ITIM domains (TIGIT), are intrinsic inhibitors of T cells. In clinical settings, LAG-3 deficiency was shown to be associated with a proinflammatory state and a higher risk of coronary artery disease [16]. Similarly, TIGIT-positive Tregs possess a protective role regarding atherosclerotic lesions and are severely reduced in acute coronary syndrome [17]. However, TIM-3 expression was correlated with the severity of CHD, suggesting a different effect on lipid metabolism and atherosclerosis formation [18].
Considering the rising number of oncological patients treated with ICIs and the severity of the potential adverse effects, a good understanding and continuous investigation of cardiac irAEs is of the utmost importance. This systematic review aimed to revise recent publications published between January 2016-September 2022 on ICI-induced cardiac toxicities. Furthermore, we highlighted the treatment approach and evolution in selected cases.

ICI-Induced Myocarditis
The most common cardiovascular side effect in ICI-treated oncologic patients is myocarditis. The inflammation of the heart muscle is often associated with arrhythmias, myositis, or myasthenia gravis (MG) ( Table 1, the complete data regarding ICI-induced Regarding acute coronary syndromes, checkpoint blockade seems to be involved in the pathogenesis of atherosclerotic lesions, although the results are contradictory. Therefore, even if PD-1 −/− LDLR −/− mice present an elevated formation of atherosclerosis plaques [14], a retrospective study showed that PD-1 inhibitor, nivolumab, was associated with a favorable course for atherosclerotic lesions [15]. Several novel checkpoint pathways are also currently under investigation. Lymphocyte activation gene-3 (LAG-3) binds to MHC-II and blocks antigen presentation, while T cell immunoglobulin-3 (TIM-3) and T cell immunoreceptor, with Ig and ITIM domains (TIGIT), are intrinsic inhibitors of T cells. In clinical settings, LAG-3 deficiency was shown to be associated with a proinflammatory state and a higher risk of coronary artery disease [16]. Similarly, TIGIT-positive Tregs possess a protective role regarding atherosclerotic lesions and are severely reduced in acute coronary syndrome [17]. However, TIM-3 expression was correlated with the severity of CHD, suggesting a different effect on lipid metabolism and atherosclerosis formation [18].
Considering the rising number of oncological patients treated with ICIs and the severity of the potential adverse effects, a good understanding and continuous investigation of cardiac irAEs is of the utmost importance. This systematic review aimed to revise recent publications published between January 2016-September 2022 on ICI-induced cardiac toxicities. Furthermore, we highlighted the treatment approach and evolution in selected cases.
In approximatively 25% of cases, ICI-induced myocarditis is a part of an overlap syndrome with MG and/or myositis [10,13]. A plausible explanation of this association is the presence of cross-antigens between the tumor and striated muscles [70,71]. Cancers with high-tumor burden (e.g., melanoma, NSCLC) display a higher incidence of irAEs, probably due to antigen spreading [72]. Although, in idiopathic MG, the association with myositis and/or myocarditis is relatively rare, the presence of anti-striational antibodies is correlated with a higher incidence of cardiac involvement [73,74]. Anti-AChR antibodies do not cross-react with heart muscles [75]. In severe myositis, troponin T could reflect the active regeneration of skeletal muscles [76].
Chest X-rays uncovered an abnormal cardiothoracic index with pulmonary congestion [55,83], and pleural effusion [89]. The aforementioned abnormalities were also found with chest computer tomography (CT), which showed pleural and pericardial effusions, pulmonary oedema, and atelectasis [25]. Coronary angiographies ruled out acute coronary syndrome (See Table 1) in those patients with ICI-induced myocarditis.
Cardiac magnetic resonance imaging (cardiac MRI, CMR) was performed in the majority of cases. The most frequent findings associated with ICI-induced myocarditis are represented by oedema of the myocardium (T2-weighted imaging revealed high signal intensities consistent with acute myocarditis) and areas of late gadolinium enhancement (LGE), together with pericardial effusion (See Table 1). Extensive ventricular fibrosis was identified by MRI in some cases [46].
Cardiac catheterization and myocardial biopsies were performed on 23 patients. Endomyocardial biopsy (EMB) represents the gold standard procedure for myocarditis diagnosis [90]. The histopathology, together with the immunochemistry examinations, revealed an admixed interstitial inflammatory infiltration, consisting of T lymphocytes CD3+, CD8+, and macrophages (CD68+) (See Table 1). Furthermore, T lymphocytes expressed PD-1, while the CD68+ macrophages expressed PD-L1 checkpoint proteins [55,87]. The histopathological findings suggest that T lymphocytes play a crucial role in the pathogenesis of ICI-associated myocarditis. Additionally, several animal studies proved that PD-1 [8] and CTLA-4 [91] deficiencies predispose the animal to autoimmune myocarditis with a fatal outcome [8]. Interestingly, a recent study by Xia et al. showed that PD-L1inhibitor treatment is responsible for the upregulation of M1 macrophage populations. An increased population of M1 macrophages has been documented in cardiac inflammation. Additionally, miR-34a expression was found to be higher in the macrophages of PD-L1 inhibitor-treated mice compared to the controls. The M1/M2 polarization of macrophages is regulated by miR-34a via KLF4 [92]. It is noteworthy that miR-34a exacerbates myocardial inflammation via the TGF-β/Smad-signaling pathway [93]. Collagen was also found admixed in with the inflammatory cells in a case reported by Norwood et al. Furthermore, the predominance of CD8+ with few CD4+ lymphocytes in the inflammatory infiltrate was once again established [28]. A case of chronic smoldering myocarditis was diagnosed when the EBM revealed myocardial infiltration by CD4+ and CD8+ T lymphocytes together with a considerable number of histiocytes and macrophages [46]. Neutrophils and eosinophils, together with myocardial necrosis [58,89], were also found in anatomopathological examinations. To better understand the pathophysiology and improve the diagnosis, several authors made use of immunohistochemistry (IHC) or cytokine analysis [55,87,94]. These could provide a better stratification of these entities and identify cell populations and cytokines in order to elect specific immunomodulatory therapies [11]. It is noteworthy that, in several patients, viral serology was positive for influenza [84], Coxsackie B [47], parvovirus B19, and HHV6 [64]. In these cases, it is not clear if the etiology of myocarditis was viral, autoimmune, or a combination of both.

Treatment of ICI-Induced Myocarditis
The first therapeutic intervention in ICI myocarditis cases was the cessation of the incriminated drug. Steroid therapy is the main treatment for ICI-induced myocarditis. The efficacy of high doses of systemic corticosteroids, such as intravenous methylprednisolone, was documented in several studies (See Table 1). However, steroids could promote a transient myasthenic crisis in half of MG patients [49,95], and for that reason, it is recommended to associate it with intravenous immunoglobulin (IVIG) or plasmapheresis in these patients [96]. IVIG and plasmapheresis reduce autoantibodies in neuromuscular AEs [97]. Even if IVIG presents a relatively safer profile compared to other immunomodulatory strategies [94], it should be restricted in patients with high thromboembolic risk [85].
Additionally, plasma exchange (PLEX) is considered more suitable for MG patients with positive anti-MuSK antibodies [98].

Evolution of ICI-Induced Myocarditis
ICI myocarditis was lethal in 23 of the cases included in the present review. An anti-PD-1 antibody was administered in most of the fatal cases, namely pembrolizumab [55,89,99] or nivolumab [45,59,87]. Fatal outcomes saw myocarditis patients treated with an association of ICI (anti-PD-1 + anti-CTLA-4 inhibitors) [27,31]. In the present review, myocarditis onset presented large temporal variations in relation to ICI administration. Thus, it developed as early as 1 week after the first ipilimumab + nivolumab infusion [29], but it was also diagnosed after long-lasting treatment with pembrolizumab (8 cycles, 1 year) [57].
It is noteworthy that there is a lack of medical history documentation in the majority of ICI-associated myocarditis patients. Special consideration should have been attributed to the previously diagnosed cardiovascular pathologies and autoimmune diseases. Another critical aspect that should be cautiously taken into consideration is represented by the infectious ethology of myocarditis. Additionally, several patients had a history of thymoma (See Table 1). The association between thymoma, myocarditis [100], MG, and myositis [101,102] is well known. Thus, thymoma-induced autoimmunity is also plausible in patients with thymic tumors treated with ICI [35].

ICI-Induced Pericarditis
ICIs have been associated with the development of other various cardiovascular toxicities, including pericarditis. Regarding pericardial diseases associated with ICI-based therapy, we analyzed several case reports and the time to onset of pericarditis was 5 to 340 days; most of the cases were reported in male subjects with an average age of 60 years. Moreover, at particular intervals of time, the patients developed clinical manifestations, like dyspnea, thoracic pain, fatigue, and general malaise (See Table 2). Furthermore, a patient presented dyspnea with tachycardia and a low-grade fever [103], limb oedema, and increased body weight [104], while others developed severe hypotension due to cardiogenic shock [105]. With regard to the associated comorbidities with ICI-related pericarditis, only asthma and hypertension were mentioned [106]. It is also noteworthy that previous immune toxicity, characterized by thyroiditis [103,107], autoimmune hepatitis [104,107], generalized pruriginous rash, [106,107], colitis, and MG [106], may show a predisposition to autoimmune toxicity with these drugs. After the initial clinical evaluation, for a complete diagnosis, the management of ICIrelated pericarditis included an ECG, echocardiogram, CT, and MRI. The ECG findings ranged from normal ECGs [103,104,108,109] to new T-wave inversions in anterolateral leads and prolonged QT intervals [107,110], sinus tachycardia and decreased QRS voltage [105,107], atrial fibrillation with a high heart rate and an ST segment elevation [96,111], and in some cases, non-specific repolarisation anomalies [106].
A single chest X-ray showed moderate bilateral pleural effusions and an enlarged heard silhouette [107]; in most of the cases, for better accuracy, CT scans were performed, which confirmed the pericardial effusion [103,104,107,109]. For a better investigation, the cardiac MRI showed a marked pericardial hyperintensity in T2-weighted sequences as a sign of active inflammation [109]. Cardiac MRI proved the presence of pericardial thickening, although without evidence of myocardial oedema or marked late godalinium enhancement in the pericardium [104].
What is more, the cardiac enzymes, such as troponin levels and BNP, remained within the normal range in patients with ICI-related pericarditis [105,107,110,111], except for one case where the serum troponin-T level was high, but there was no evidence of active myocarditis from the endomyocardial biopsy. Elevated serum troponin indicated myocardial inflammation that was associated with severe inflammation of the pericardium [104]. In some cases of ICI-pericarditis, the histopathologic evaluation showed only non-specific chronic inflammation with extensive fibrosis and lymphocyte infiltration, with no evidence of malignancy or microorganisms [103,105,107].
Regarding the treatment of ICI, pericardiocentesis remains the preferred procedure for the acute management of massive pericardial effusions by either mechanism [103][104][105]107,108,110]. Corticosteroids are a prefered treatment, needing only a prompt initiation. [96] In our reviewed cases, corticosteroids were administered to all the patients with ICI-related pericardial effusions (See Table 2). The treatment starts with high doses of prednisone (1-2 mg/kg) with a tapering off of at least 4 weeks in selected cases. Transplant rejection doses must be administered in unresponsive cases, which means 1 g methylprednisolone given daily in association with mycophenolate mofetil, infliximab [104], or anti thymocyte globulin [110].
In the present review, the majority of ICI-induced pericarditis has not developed any other immune-related adverse events (See Table 2). These case reports highlight the importance of prompt diagnosis and high-dose corticosteroid treatment for immune-related pericarditis. Nevertheless, in one case (of a 54-year-old patient diagnosed with lung adenocarcinoma who was treated with ICI), it was discovered that the patient had moderate paraneoplastic pericarditis; a tapering scheme of prednisone was administered (10 mg/day, every 2 weeks) in combination with colchicine for 6 months to prevent another pericardial effusion. His cardiac condition was evaluated again by echocardiogram, which was substantially stable compared to the previous one. Thus, a second cycle of chemotherapy was initiated without administering pembrolizumab (given the high doses of prednisone ongoing). Unfortunately, the patient experienced acute dyspnea and succumbed to sudden death after less than two months after the first cycle of chemotherapy. No autopsy was conducted as per the family's wish [111].
To stratify the patient risk before starting ICI treatment, it is recommended that complete blood tests be performed, including troponin and brain natriuretic peptide (BNP), ECG, and echocardiogram, besides the usual clinical follow-up. The echocardiogram, cardiac biomarkers, and/or cardiac MRI are useful investigations for diagnosing late-onset cardiotoxicity, both in the initial and later phases of ICI therapy [96].
After a period (running from two weeks to five months) following the initiation of ICI therapy, the patients met the definition of ICI-induced arrhythmias. They tended to be older and more likely to have a history of hypertension, diabetes mellitus [112,115,117], and hyperlipidemia [117]. It is noteworthy that a single patient with pre-existing atrial fibrillation underwent three prior ablations in the past [112]. Regarding the anamnesis and clinical examination in patients with arrhythmias, some patients remained asymptomatic [112,116]. Most of them developed manifestations, like increased fatigue, generalized malaise, dizziness, or syncope [112,113,118,119], while others experienced palpitations [119] or worsening dyspnea [115].
A combination of ECGs, echocardiograms, cardiac catheterizations, and biomarkers was used to identify cases of ICI-induced arrhythmias after the initiation of immune checkpoint inhibitor therapy. Twelve-lead ECGs were recorded with the presence of atrial fibrillation with rapid ventricular response [112], sinus tachycardia associated with firstdegree atrioventricular block, right bundle branch block, and left anterior fascicular block, then accelerated junctional rhythm with complete heart block [113], symptomatic sinus bradycardia of 40 bpm [112,118], a new first-degree AV block [116], Mobitz type 2 s-degree AV block of 30 bpm followed by complete heart block with a ventricular rate of 22 bpm after 3 h [117], a third-degree AV block with a bradycardia of 44 bpm [115], and complete AV block with wide QRS complexes [119].
Furthermore, QT dispersion (QTd) is measured as the difference between the longest and the shortest QT intervals within a 12-lead ECG. Prolongation of corrected QT interval (QTc) is an important indicator of arrhythmogenesis [116]. In this review, there was one study that mentioned a significant increase in QTd after treatment initiation with a combination of ICI, while no significant difference was observed in patients treated with PD-1i monotherapy [116].
In 90% of the cases with ICI-induced arrhythmias, the transthoracic echocardiogram did not reveal abnormalities in wall motion, with the preservation of the ejection fraction of the left ventricle. Nevertheless, an unusual case of progressive conduction abnormalities after the initiation of checkpoint inhibitors, anti-PD-L1 and anti-CTL4, showed a moderate decrease in the left ventricle ejection fraction (30-35%), associated with kinetic disorders (anteroseptal hypokinesis and apical akinesis with septal motion consistent with conduction abnormality) in the setting of a normally sized left ventricle. The systolic function and contractility of the right ventricle were reduced in spite of no significant valvular disease or pericardial effusion [113].
Laboratory results were negative for elevations in troponin or BNP in half of the cases [116][117][118], but increased myoglobin, creatin-kinase, and troponin were detected in the rest of them [113,115,119]. Cardiac catheterization was also performed in three cases of ICI-induced arrhythmias, which did not reveal any significant stenosis [115,119] or there were minor luminal irregularities in the coronary arteries [113].  The evaluation for the immune-related effects, like hyperthyroidism, was notable in only one case, which was felt to possibly be drug-induced toxicity from the ICIs, treated with methimazole and steroids [112]. A suggested approach to the management of a patient with suspected ICI-induced arrhythmias is outlined following the guidelines for the management of patients presenting different arrhythmias. Self-limited AF resolved spontaneously after about 48 h [112], persistent AF managed with an echocardiogram (TEE)guided cardioversion, anticoagulation and beta blockers and antiarrhythmic drugs [112], implantation of a temporary pacemaker, then permanent pacemaker for the heart conduction disorders [113,115,119] and association of cortisone in immune-mediated sinoatrial node dysfunction with immediate improvement of symptoms and bradycardia without relapsing-symptoms [118] None of the ICI-induced arrhythmias cases required stopping treatment with the ICIs, and in most instances, the arrhythmias could be managed in a relatively straightforward manner with positive evolution, except for one case where pembrolizumab was discontinued due to the progressive status of his HCC. Unfortunately, one patient 26 days after beginning anti-PD-1treatment. Considering the metastatic malignant underlying disease, and the worsening hemodynamic and respiratory situation, the relatives made the decision to reduce medical care with an unfavorable prognosis.

Takotsubo Cardiomyopathy and Acute Heart Failure
ICIs have also been associated with the development of other various cardiovascular toxicities, such as acute heart failure, cardiomyopathies, Takotsubo syndrome, and acute coronary syndromes. Concerning cardiomyopathies, including Takotsubo syndrome, we analyzed several case reports and the time to onset of cardiomyopathy is 4 to 112 days; most of the cases were reported in male subjects with an average age of 64 yo, the youngest being 42 yo and the oldest 79 yo.
In regard to the diagnosis, most of the patients presented ECG changes, such as sinus tachycardia [123], atrial flutter [126], ST elevation [121,126], or T wave changes [120,122]. A TTE was performed in all the cases and was always abnormal. In patients diagnosed with Takotsubo syndrome, TTE revealed apical akinesis with apical ballooning, hyperdynamic basal LV segments, and a reduced cardiac ejection fraction [120][121][122]127,129]. One case of atypical Takotsubo cardiomyopathy was also described whereby the TTE revealed hypokinesia of the mid inferior and mid anterior septum, mid inferolateral, mid anterolateral, mid inferior and mid anterior wall, sparing the apical and basal segments [123]. In acute heart failure cases, the wall motion abnormalities were not systematized [125,126].  Chest X-rays uncovered pulmonary congestion, pulmonary effusion, and cardiac dilation, but these were performed only in a few cases [123,126]. A CMR was obtained in the majority of cases, mainly to rule out the diagnosis of ICI-induced myocarditis. It is noteworthy that one patient had concomitant myopericarditis and Takotsubo syndrome following ICI therapy. In this case, the CMR revealed mid-myocardial to subepicardial delayed enhancement (MDE) in the inferior lateral walls, as well as in the apex [127].
The laboratory analyses (TnI, CK, CK-MB, BNP, and NT-proBNP) were determined in the majority of cases and were almost always elevated, which raised the question of an acute coronary syndrome [120][121][122][123]125,127,129]. Subsequently, a coronary angiography was performed in the majority of the cases and an acute myocardial infarction was ruled out [121][122][123][125][126][127]129]. Cardiac catheterization and myocardial biopsies were performed in two patients, which excluded a possible myocarditis [120,126].
The first therapeutic intervention (when ICI-induced side effects were suspected) was the cessation of the incriminated drug. Immunosuppressive therapy with intravenous corticosteroids was initiated and continued with oral prednisone taper when myocarditis was diagnosed [127] or suspected [122,125,127,129]. In all cases, guideline-directed heart failure treatment was started with betablockers, ACE inhibitors, and diuretics, as well as IV dopamine and tolvaptan in one severe acute heart failure case [126]. After the ICI treatment was discontinued and heart failure treatment was initiated, the evolution was favorable in all the cases, with an improvement in the symptoms and the left ventricular ejection fraction [120][121][122][123][125][126][127]129].

Acute Coronary Syndrome
We analyzed the case reports of acute coronary syndromes (ACS) related to ICI administration, and the time to onset of ACS is 2-365 days, and most of the cases were reported in male subjects with an average age of 67 years, the youngest being 52 yo and the oldest 87 yo. Concerning underlying oncological disease, the cases were reported in patients diagnosed with lung cancer [130][131][132][133][134], melanoma [135], and renal cell carcinoma [136], as we have presented in Table 5.
More than 70% of the cases were described as non-ST elevation myocardial infarction (NSTEMI), but ST-elevation myocardial infarction (STEMI) [133] and vasospastic angina were also described [136][137][138]. The main clinical manifestations of ICI-associated ACS were chest pain and dyspnea; only one case reported no symptoms, and the diagnosis was based on the elevated cardiac biomarkers [131]. Concerning concomitant autoimmune diseases, one patient developed grade five colitis while being hospitalized for ICI-related myocardial infarction [134]. Another patient presented related concomitant autoimmune manifestations, namely erythema multiforme, thyroid dysfunction, and interstitial pneumonia [131], while another case with associated ICI-induced hepatitis was also reported [131]. The concomitant autoimmune diseases were treated with high-dose intravenous corticosteroids, followed by oral corticosteroids taper.
Most of the patients underwent a percutaneous coronary intervention with implantation of drug-eluting stents [112][113][114][115][116]. However, one patient with underlying severe CAD was surgically treated with coronary artery bypass grafts (CABG) for the affected arteries [135]. The patient diagnosed with vasospastic angina was treated with calcium channel blockers and nitrates, and the symptoms gradually disappeared [136]. All the patients were discharged with chronic myocardial infarction treatment, namely dual antiplatelet therapy, ACE inhibitors, beta-blockers, and statins, except for the patient diagnosed with vasospastic angina [136]. The evolution of the patients was almost always favorable [130][131][132][133][134][135][136], except for one patient who died 16 days after stenting due to refractory shock without ACS recurrence [134].

IrAEs Reported in Clinical Trials
Between 2017 and January 2022, there were published trials that reported cardiac irAEs following the administration of ICIs, the most common AE being myocarditis. Maio et al. [139] conducted a double-blind placebo-controlled trial, evaluating the use of tremelimumab as second-or third-line treatment in patients with relapsed malignant melanoma, reporting a multitude of cardiac AE. In the treatment group, one case of myocardial infarction (vs. none in the placebo group) was identified, along with one case of cardiac failure (vs. one in the placebo group) and twelve cases of pericardial effusion (vs. six in the placebo group). A dose-finding and dose-expansion phase 1b trial conducted by Choueiri et al. [140], regarding the use of avelumab, a PD-L1 inhibitor, in association with axitinib, a tyrosine kinase inhibitor (TKi), in patients with clear-cell renal-cell carcinoma reported one case of myocarditis diagnosed before the first evaluation of the patients, resulting in the death of the patient. Among the six deaths reported in this study, this was the only one caused by irAEs, with the other five being a result of disease progression. Juergens et al. [141] assessed the efficacy of durvalumab with or without tremelimumab in combination with platinum-doublet based chemotherapy in several types of malignancies, the most common being NSCLC. There was one reported case of myocarditis, which was confirmed using post-mortem. The ESCORT trial assessed the efficacy of camrelizumab vs. the investigator's choice chemotherapy regime in advanced or metastatic esophageal squamous cell carcinoma. A total of 10 treatment-related deaths were reported, 7 of them for camrelizumab (one with myocarditis) [142].
Hasson et al. [143] assessed the safety of reintroducing immunotherapy in patients that survived ICI-induced myocarditis. Three patients were chosen from a total of seven and ICIs were reintroduced under close surveillance and in combination with low dose PO prednisone and cardio-protective therapy (angiotensin-converting-enzyme inhibitors, betablockers, or mineralocorticoid receptor antagonists). One of the three patients exhibited heart failure symptoms which required the cessation of the ICI regiment, while the other two continued treatment with durvalumab and pembrolizumab without irAEs at the time of data cut-off.

Limitations of the Study
For the moment, a lot of information is emerging from daily clinical practice but must be treated with caution. Considering the lack of full data about patients' profiles (regarding their cardiovascular and non-cardiovascular history and associated risk factors), further research is needed to fully assess the relationship between ICI and cardiotoxicity.

Conclusions
ICI-induced cardiac toxicity comprises a large field of morphological and functional abnormalities, including myocarditis, pericarditis, Takotsubo cardiomyopathy, and acute coronary syndrome. Despite only a few reports from the first clinical trials involving ICI, many cases were documented in later years. For this review, we identified and collected relevant data from the last five years in the literature in order to highlight the clinical and paraclinical patterns, as well as any therapeutic approaches. Although rare, these adverse events can lead to fatal outcomes, especially in the case of myocarditis. The precise mechanisms are not yet fully elucidated, and consequently, the treatment lacks standardization. Further research is needed for the better stratification of these pathological entities and the proper design for early diagnosis and treatment strategies.
Supplementary Materials: The supporting information can be downloaded at:

Conclusions
ICI-induced cardiac toxicity comprises a large field of morphological and functional abnormalities, including myocarditis, pericarditis, Takotsubo cardiomyopathy, and acute coronary syndrome. Despite only a few reports from the first clinical trials involving ICI, many cases were documented in later years. For this review, we identified and collected relevant data from the last five years in the literature in order to highlight the clinical and paraclinical patterns, as well as any therapeutic approaches. Although rare, these adverse events can lead to fatal outcomes, especially in the case of myocarditis. The precise mechanisms are not yet fully elucidated, and consequently, the treatment lacks standardization. Further research is needed for the better stratification of these pathological entities and the proper design for early diagnosis and treatment strategies.