Abstract - Imperial College London



Immune checkpoint inhibitors and cardiovascular toxicityAlexander R. Lyon PhD 1,2*, Nadia Yousaf MD 3, Nicolò M.L. Battisti MRCP 3, Javid Moslehi PhD 4 and James Larkin PhD 3Cardio-Oncology Service, Royal Brompton Hospital, London, UKNational Heart and Lung Institute, Imperial College London, UKRoyal Marsden Hospital NHS Foundation Trust, London, UKCardio-Oncology Program, Vanderbilt School of Medicine, Nashville, Tennessee, USA* Corresponding author: Dr. Alexander LyonSenior Lecturer and Honorary Consultant CardiologistRoyal Brompton Hospital London SW3 6NPUKOffice? +44 (0) 207 352 8121 ext 2396Fax???? +44 (0) 207 351 8776AbstractImmune checkpoint inhibitors (ICIs) are a new class of cancer therapies which amplify T cell-mediated immune responses against cancer cells. ICIs have shown important benefits in phase 3 trials and several ICIs have been approved for specific malignancies. Whilst ICI-related adverse events are common, ICI-mediated cardiotoxicity is a rarer complication but can be serious with a relatively high mortality. The majority of cardiotoxicities appear to be inflammatory in nature. As such, clinical assessment in combination with biomarkers, electrocardiography, cardiac imaging and endomyocardial biopsy can be used to confirm the diagnosis. In this article we review the epidemiology of ICI-mediated cardiotoxicity, clinical presentation and subtypes of ICI-mediated cardiotoxicity, risk factors, pathophysiology and clinical management including introduction of a new surveillance strategy. IntroductionA fundamental property of many cancers is the ability to avoid the host immune response and allow cell proliferation and metastasis. Harnessing the immune system to target cancer has been a strategy employed in oncology for many decades.1 A major advance in the last 10 years is the use of immune checkpoint inhibitors (ICIs) to block the inhibitory receptors such at cytotoxic lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) which are expressed by T lymphocytes, 2-5 or programmed cell death ligand 1 (PD-L1) on tumour cells.6-12 When these inhibitory T cell receptors bind to specific ligands such at PD-L1 expressed on host cells, including cancer cells, receptor binding prevents T cell activation and the resulting immune response. Expression of these ligands on cancer cells is a critical mechanism by which cancer cells avoid the host immune response. Therapeutically blocking this inhibitory molecular axis using specific monoclonal antibodies (ICIs) targeted to CTLA-4 (Ipilimumab), PD-1 (Nivolumab, Pembrolizumab) and PD-L1 (Atezolizumab, Avelumab, Durvalumab), either as monotherapy or in combination, activates the immune system to recognise and target cancer cells via a T cell-mediated immune response (see data supplement page 6). The results from the first clinical trials of immunotherapy have been impressive for advanced metastatic cancers, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, head and neck squamous cell carcinoma (SCC), urothelial cancer, refractory Hodgkin’s lymphoma and malignancies with microsatellite instability, and this has resulted in fast track approval by the FDA and EMEA of ICIs for several cancers (see Table 1 and data supplement page 1). In 2017, the US FDA granted accelerated approved for Pembrolizumab for with mismatch repair deficient tumours, marking the first time FDA tissue/site-agnostic approval.13 The benefit of immunotherapy following surgery in the adjuvant setting has recently been reported in melanoma and impressive results after radical chemoradiation in NSCLC,14,15 and both the range of cancers, and the complexity of the treatment strategies is increasing rapidly.16Enhancing immune responses using ICIs causes activation of T cell responses systemically, producing a range of autoimmune toxicities, particularly when dual ICI or a single ICI in combination with another cardiotoxic cancer therapy is prescribed. Over 90% of patients receiving combination immunotherapy with Ipilimumab and Nivolumab had at least one immune-related adverse event (IRAE) in the recent CheckMate 067 phase 3 trial for patients with metastatic melanoma, with ~50% of patients experienced a serious adverse event.3 Most common are fatigue, rashes and gastrointestinal side effects including diarrhoea, colitis and rises in liver transaminases, and these are generally reversible and controlled with steroid therapy. There is emerging evidence that immune responses to the cardiovascular system, and in particular the heart, are observed in patients receiving ICIs.17 Whilst still relatively rare, the cardiovascular toxicity of immunotherapy is serious and potentially fatal, and the true incidence is unknown. In this article we review the latest evidence regarding epidemiology of cardiotoxicity caused by immunotherapy, the clinical presentation and subtypes, the underlying mechanisms for ICI-mediated cardiovascular toxicity and a framework for clinical management. There is a lack of prospective clinical studies in this area of cardiovascular complications of immunotherapy, and the clinical management pathways are the opinions of the authors based upon information currently available. Search strategy and selection criteriaWe systematically reviewed papers published (PubMed, Ovid Medline) using the search words “Checkpoint inhibitor”, “CTLA-4”, “PD-1” or “PD-L1” combined with “cardiotoxicity”, “myocarditis” or “heart block” without date restrictions.Epidemiology of ICI-mediated cardiotoxicity The emergence of cardiovascular toxicity secondary to immunotherapy arose initially with single case reports presented at conferences and published from centres enrolling patients in phase 2 and 3 ICI trials.18-21 In 2016 Johnson et al reported two cases of fatal fulminant myocarditis following combination ICI therapy, both occurring after the first dose of therapy.22 Further interrogation of data from the immunotherapy trial database from Bristol Myers Squibb (the manufacturer of Ipilimumab and Nivolumab) revealed 18 cases of myocarditis reported from 20,594 subjects in the pharmacovigilance database (0.09%).22 The incidence of myocarditis was higher in patients receiving combination immunotherapy with two ICIs (0.27 vs 0.06%). Of concern, 50% of ICI-associated myocarditis cases were fatal. A recent meta-analysis of 22 antiPD1 and antiPD-L1 trials in NSCLC patients reported a slightly higher rate of serious cardiovascular events although absolute incidence is still low: cardiorespiratory arrest 1.0%, cardiac failure 2.0%, myocardial infarction 1.0% and stroke 2.0%.23 Cardiotoxicity associated with ICI may extend beyond myocarditis. Heinzeerling and colleagues reported details of 8 cases including ICI-mediated cardiotoxicity, including myocarditis, heart failure with left ventricular dysfunction but without myocarditis on biopsy, myocarditis or fibrosis identified on post-mortem, and a case with cardiac arrest secondary to Takotsubo syndrome. 24Emerging data suggest that myocarditis usually occurs early after exposure to ICI.17,22 Escudier and colleagues reported 30 cases of ICI-mediated cardiotoxicity at their French centres over a 2 year period (n=12) or in the published literature where details were available (n=18).25 The median time to presentation with cardiotoxicity was 65 days (3 ICI cycles), but the range was from 2 days after the first dose to 454 days (range 1-33 ICI infusions). Moslehi and colleagues reviewed 101 cases of ICI-triggered myocarditis from the World Health Organisation’s Vigibase.17 Sixty-four percent (38/59 cases with dosing details available) occurred after the first or second ICI dose, with 76% of cases with timing data available occurring in the first 6 weeks of treatment. 17 The extent of overlap with the cohort published by Escudier is not known. Recently a third cohort of 35 cases from 8 centres was published by Mahmood and colleagues.26 They also report most cases occurred in the first 4 cycles (median time from onset of ICI therapy 34 days), that pre-existing cardiovascular risk factors and disease were common in patients receiving ICI therapy (both cases and controls) and combination ICI therapy was the main risk factor for ICI-mediated myocarditis.26These three reports highlight that most ICI-medicated cardiotoxicity cases occurred early suggesting a potential predisposition, perhaps based on pre-existing risk factors (see table 2) but delayed cardiotoxicity can also occur. In the French series most cases presented with left ventricular systolic dysfunction, which was reversible with high dose steroids in 8 of 12 of cases treated whereas spontaneous recovery was rare.25 Cardiotoxicity also manifested as pericarditis with pericardial effusion, and as ICI-triggered Takotsubo syndrome in 4 cases. Mortality was again high with 8/30 cases (27%) dying from cardiovascular causes, and highest in patients with conduction disease complications and combination immunotherapy (Ipilimumab and Nivolumab),17,22,25 although fatal myocarditis has been reported with Ipilimumab, Nivolumab or Pembrolizumab monotherapy.18,24,27-29Escudier et al reported the results from detailed cardiac investigations with some important learning points: i) left ventricular systolic dysfunction (LVSD) was common but severe LVSD with LVEF <35% was only present in less than half of cases (46%), and therefore ICI-mediated cardiotoxicity should also be considered in new cases with milder LVSD (LVEF 35-55% if new dysfunction is identified compared to baseline); ii) brain natriuretic peptide (BNP) or N-terminus of pro-brain natriuretic peptide (NT-proBNP) levels were increased in 100% cases where measured (14/14) and therefore natriuretic peptides may be a useful screening biomarker; iii) cardiac troponin was not always elevated (46% cases positive), and therefore although useful in the detection of myocarditis troponin was not as sensitive as natriuretic peptide measurement in their cohort. This may reflect the difference between inflammatory mediated cardiotoxicity (BNP and troponin both elevated) versus functional non-inflammatory cardiotoxicity (BNP elevated, troponin normal); iv) cardiac magnetic resonance (CMR) detected myocardial oedema in 33% cases when performed (5/15) and late gadolinium enhancement (reflecting acute myocarditis and/or replacement fibrosis) was present in 3/13 cases. Therefore CMR may lack sensitivity based on this cohort, although details of the specific imaging sequences employed were not provided, and again it may reflect the different subtypes of ICI-mediated left ventricular dysfunction (inflammatory vs functional); v) rescue and recovery of LVSD is possible, with 50% cases who survived (9/18) having complete recovery of LV function.25 Other non-cardiac ICI-related toxicities were common, occurring in approximately half of cases with ICI-mediated myocarditis.26 Concomitant myositis was common (23% cases in French cohort and 25% in WHO cohort) which may reflect a shared antigen profile and immune-phenotype between cardiac and skeletal muscle. Surprisingly, myasthenia gravis also occurred concomitantly in 10% of myocarditis cases. The incidence of myocarditis was higher in a small phase 2 trial of Pembrolizumab for recurrent thymic carcinoma (2/41 patients (5%)).30 Cases of ICI-related skeletal myositis should have a cardiac assessment to exclude cardiac involvement.Arrhythmias and cardiac conduction disease were common in cases of cardiotoxicity, including atrial fibrillation (AF - 30%), ventricular tachyarrhythmias (VT, VF - 27%) and conduction disease including heart block (17% cases).25 ICI-mediated conduction disease in the absence of generalised myocarditis is emerging as a more common and potentially serious cause of ICI-mediated sudden death in the absence of generalised myocarditis, and supports the concept of screening ECGs and detailed investigations of patients receiving ICI who present with palpitations, presyncope or syncope e.g. urgent referral to cardio-oncology for clinical assessment, cardiac imaging and 48 hour Holter ECG monitoring.Since the publication by Johnson et al22 and with growing awareness of potentially fatal side effects amongst the oncology and cardiology communities, the incidence of immunotherapy-induced cardiovascular toxicity appears to be rising, with 75% of the WHO series reported in 2017,17 but the true incidence is still unknown. The apparent increase results from a combination of possible factors: higher true incidence, increasing use of combination immunotherapy with multiple checkpoint inhibitors or combination of checkpoint inhibitors with other cardiotoxic cancer therapies in clinical trials e.g. VEGF tyrosine kinase inhibitors, more detailed cardiac assessment detecting evidence of milder cardiovascular toxicity (biomarker rises, asymptomatic LV dysfunction, patterns of late gadolinium enhancement of CMR consistent with previous myocarditis), and increased awareness and reporting from trials and real world practice. Given the relative infrequency of ICI-associated myocarditis, multi-institutional efforts will be necessary to understand the mechanisms of toxicity and to develop preventive and treatment strategies for patient care. One recent effort () uses a web-based platform where physicians who manage acute cases of ICI-associated cardiovascular issues can share ideas for care for these patients and collect a more accurate picture of the range and frequency of ICI-mediated cardiotoxicity.Clinical presentationICI-mediated cardiotoxicity may present to oncology, cardiology, acute medical and community services. In addition, myocarditis in general can be a challenging presentation due to diverse presentations. A number of different forms if ICI-related cardiotoxicity have been reported from the ICI clinical trials and current practice (see Table 3):Myocarditis presenting with acute heart failure, pulmonary oedema and in severe cases cardiogenic shock, multiorgan failure, ventricular arrhythmias and death. Characterised by new left ventricular impairment, elevated serum cardiac troponin and BNP, evidence of active myocardial inflammation on CMR, cardiac FDG18 PET-CT and/or endomyocardial biopsy (EM).19Pericarditis can present in isolation with typical pericardial pain, or in combination with myocardial involvement with peri-myocarditis, and can be complicated by a pericardial effusion and possible cardiac tamponade.20,24 Characterised by presence of a new pericardial effusion on echocardiography, electrocardiography (ECG) changes with PR depression and widespread saddle-shaped ST elevation, atrial and ventricular arrhythmias, elevated serum cardiac troponin (if peri-myocarditis) and evidence of active pericardial inflammation on CMR and/or cardiac FDG18 PET-CT.Atrioventricular conduction disease, heart block, bradycardia and in severe cases sudden cardiac death from complete heart block.31,32 New conduction disease is diagnosed on the 12 lead ECG (e.g. prolonged PR interval, QRS axis deviation, bundle branch block, second degree or complete heart block) or Holter ECG monitoring.Ventricular tachyarrhythmias, including ventricular tachycardia (VT) and ventricular fibrillation (VF).Myocardial infarction (MI) has been reported in a recent trial of the checkpoint inhibitor Atezolizumab and in patients where troponin elevation is detected the differential diagnosis will include acute coronary syndrome. It is not clear if this relates to increased atherosclerotic plaque rupture, ICI-triggered coronary vasculitis or focal myocarditis misdiagnosed as acute MI. Characterised by chest pain, new ischaemic ECG changes e.g. ST elevation, ST depression, T wave inversion, cardiac troponin elevation and usually new regional wall motion abnormalities on echocardiography or CMR. Coronary angiography is diagnostic with percutaneous coronary intervention indicated if a culprit occlusion or severe stenosis is identified. One case of coronary vasospasm secondary to PD-L1 inhibitor with ST elevation also has been reported.33Left ventricular impairment without evidence of myocarditis. This represents a functional impairment and different forms exist, including a dilated cardiomyopathy variant with new global left ventricular impairment and Takotsubo syndrome – presenting with acute heart failure with a typical distribution of regional wall motion abnormalities involving the apical and mid left ventricular myocardium, unobstructed coronary arteries, BNP elevation and acquired long QT syndrome.21,24,34,35 Diagnosis includes exclusion of active myocarditis by CMR, cardiac FDG18 PET-CT and/or endomyocardial biopsy (EM).Mechanism(s) of ICI-mediated cardiotoxicityGeneral conceptsPreclinical studies support a critical role for CTLA-4, PD-1 and PD-L1 signalling in cardiac-immune crosstalk with abrogation of this pathway resulting in autoimmune myocarditis and cardiac failure.36,37 T cell mediated responses to cardiac antigens also contribute to acquired disease progression and heart failure in preclinical models in an autoantibody-independent mechanism, with myocardial inflammatory cell infiltration and increasing myocardial fibrosis.38 A PD-1 receptor knockout mouse in a specific genetic background develop spontaneous severe dilated cardiomyopathy with associated premature mortality.39,40 There was evidence for an inflammatory basis of the cardiomyopathy in the PD-1 ko mice with IgG deposition of PD-1 -/- cardiomyocytes and was reported as a model of autoimmune myocarditis. These antibodies were later shown to recognize cardiac troponin I.41 It is interesting that ICI-associated myocarditis in humans appears to be T cell and macrophage mediated and preliminary examination by several groups showed no evidence of B cells or antibody-antigen deposits. CTLA-4 knockout mice also develop and autoimmune myocarditis with CD4+ and CD8+ T lymphocyte infiltration of the myocardium, reinforcing the importance of immune checkpoint signalling in controlling T cell immune responses in the heart.42Cardiomyocyte PD-L1 expression is upregulated in scenarios of cardiac stress and disease including ischaemia-reperfusion and left ventricular hypertrophy in preclinical models.43 In addition to the recognised role of suppressing T lymphocyte-mediated cardiac immune responses, it is not known if PD-L1 on cardiomyocytes also serves an intracellular signalling function independent of T cell suppression as is observed in both cancer cells and other APCs.44 Conceivably PD-L1 signalling may have dual cardioprotective actions, reflecting both the immunomodulatory role to suppress excessive myocardial inflammation and also direct cardioprotective signalling in the setting of cardiac injury e.g. acute ischaemia and myocardial infarction.Pre-existing cardiovascular disease may also be affected by ICIs, and if T cell mediated responses contribute to acquired heart disease progression as demonstrated preclinically,38 then ICIs could cause acceleration or decompensation of pre-existing heart failure in susceptible individuals. Beyond these direct effects on myocardial T cell regulation, heart failure can be accelerated by a general increase systemic inflammation e.g. elevated TNFα which are frequently observed in patients receiving ICI therapy. Furthermore, as survival in patients taking ICIs improves, there could be the potential for amplification of cardiac injury and dysfunction in the setting of de novo cardiac events such as acute myocardial infarction or emergent uncontrolled hypertension, particularly in individuals continuing on ICI treatment. In summary CTLA, PD-1 and PD-L1 inhibition may result in autoimmune T cell-mediated myocarditis, conduction disease, ventricular arrhythmias and acute myocardial infarction, and direct PD-L1 inhibition may also accelerate pre-existing heart disease, and also potentially cause non-inflammatory cardiomyocyte dysfunction in diseased hearts even in the absence of an immune response.MyocarditisThe pathophysiology of ICI-induced myocarditis is incompletely understood. Post mortem assessment in fatal cases has confirmed myocarditis with a significant inflammatory cell infiltrate, increased extracellular space volume and loss of cardiomyocytes. In one study evaluation of the inflammatory cell component confirmed the presence of both CD4+ and CD8+ T cells and macrophages, but not B cells.22 This would align with the known mechanism of ICI action and can be considered an ‘on target’ toxicity. T cell receptor sequencing in 2 cases from the heart, skeletal muscle and tumour revealed similar clones of T cells in all tissues. Transcriptome analysis (via RNA sequencing) of the tumour (in these cases melanoma) revealed expression cardiac-specific genes (e.g. cardiac troponin and myosin heavy chain);22 it is conceivable that the tumour itself activates clonal expansion of a T cell population which will cross react with the same cardiac antigens presented on MHC class 1 complexes on cardiomyocytes within the heart. Secondly, after immunotherapy there was evidence of T cells from the same clones in both the tumour and in the inflamed myocardium, also supporting the hypothesis that the same T cell response which is therapeutic against the tumour is responsible for the ‘on target’ myocarditis. Phenotyping the tumour antigen profile and pre-treatment T cell clone is a rapid and timely manner could contribute to baseline risk prediction.22 One study also reported myocarditis, cardiogenic shock and death in the first two patients infused with engineered T cells targeting the immune checkpoint protein MAGE-A3.45 The engineered T cells had an ‘off target’ cross reactivity to the cardiac myofilament protein titin in in vitro studies which may explain the inflammatory response in the heart.ArrhythmiasA number of different arrhythmias have been reported in patients receiving immunotherapy as summarised in Table 3. The most severe are complete atrioventricular block (3rd degree heart block) and ventricular tachyarrhythmias (VT and VF), both of which can be fatal. The potential mechanisms for the arrhythmias are unknown but include the following:Ventricular myocarditis with inflammation and fibrosis forming the arrhythmia substrate for triggered activity and/or re-entry arrhythmias.Inflammation of the His-Purkinje conduction system, either via direct T cell-Purkinje interactions or via activation of local macrophages resident in the Purkinje system resulting in triggered activity and/or re-entry arrhythmias. Atrial and ventricular arrhythmias due to the increased systemic inflammatory state but without myocarditisAtrial and ventricular arrhythmias arising from left ventricular impairment due to non-inflammatory functional cardiotoxicity, particularly in patients receiving immunotherapy combined with other cardiotoxic cancer therapiesInflammation of myocardial metastases (if present) as part of the therapeutic effect, although this is rare.Other causes of arrhythmias in cancer patients e.g. QT prolonging drugs, electrolyte imbalances, pulmonary emboli, pre-existing cardiovascular diseaseNon-inflammatory left ventricular dysfunctionThe majority of cases of immunotherapy-induced left ventricular dysfunction have been secondary to myocarditis. However, there are an emerging subgroup where active myocarditis appears absent based on the lack of a rise in circulating cardiac troponin, CMR or cardiac PET-CT evidence of myocardial inflammation, and lack of inflammatory cell infiltrate on EM biopsy or at post mortem.25 This could explain the cases with ‘false negative’ results (normal serum troponin, lack of oedema on CMR), with a global functional impairment of ventricular function in the absence of inflammation or conduction disease consistent with a dilated cardiomyopathy. Another form of acute left ventricular dysfunction observed is Takotsubo syndrome.21,34,46,47 This is classically an acute heart failure syndrome triggered by stress, and where high catecholamine levels are believed to play a role. Whether this reflects a direct effect of checkpoint inhibitors on the myocardium, the coronary vasculature or an indirect effect via sudden release of high levels of epinephrine from the adrenal glands and/or norepinephrine from postganglionic sympathetic nerves in the heart remains to be determined.Lessons from inflammatory cardiac diseasesThere are several systemic inflammatory disorders associated with cardiac involvement including polymyositis, rheumatoid arthritis, systemic lupus erythematosus (SLE) and sarcoidosis. Each have different immunological pathophysiology, but may present with acute myocarditis, isolated conduction disease or chronic heart failure following subclinical myocarditis. These systemic autoimmune diseases which cause myocardial inflammation teach us that their cardiac involvement can vary widely, and there is no single gold standard diagnostic test, with biomarkers, MRI and cardiac PET-CT imaging, Holter ECG monitoring and endomyocardial biopsy all having variable diagnostic value. This appears to also hold true for ICI-mediated cardiotoxicity, and applying an appropriate range of diagnostic tools integrated with clinical opinion is key, and not relying on one single modality.Although no cases have been reported, the phenomenon of autoimmune valvular inflammation is recognised in conditions such as rheumatic fever and SLE. Individuals who have previously experienced inflammatory heart valve disease should be reviewed to ensure reactivation of valvulitis or endocarditis does not occur when taking ICI, and this diagnosis should be considered in the setting of acute deterioration of valvular function. Interaction with other cardiotoxic cancer treatments leading to left ventricular impairmentCancer treatment pathways are frequently characterised by sequential treatment protocols, with progression to the next stage triggered by evidence of disease resistance and cancer progression on current treatment. Many cancer patients have received multiple treatments prior to starting ICIs in the metastatic setting, some of which may be cardiotoxic e.g. Raf and MEK inhibitors for melanoma, VEGF-TKIs for renal carcinoma, anthracyclines and radiotherapy involving the heart in the treatment field in Hodgkin’s lymphoma. These treatments, by damaging the heart muscle, may lead to the exposure of cardiac antigens and development of cardiac-specific immune responses which are initially subclinical, but can become amplified in the setting of ICI therapy. As an example, a recent trial for RCC where a PD-L1 inhibitor was combined with a TKI reported fatal myocarditis in 1/50 patients (2%).6 A recent preclinical model has reported amplification of acute radiation-induced cardiotoxicity by anti-PD-1 blockade highlighting the interaction between known cardiotoxic cancer therapies and ICIs.48Whilst ICI therapy is effective in up to 58% patients, a significant proportion who have resistant disease, or intolerable side effects, will progress to further treatments after immunotherapy. One example is the use of Raf and MEK inhibitors for BRAF-mutant metastatic melanoma. These drugs have potential cardiotoxicity via inhibition of the Raf-MEK pathway in cardiomyocytes which is a protective signalling pathway. Immunotherapy-mediated cardiotoxicity may lead to a subclinical cardiac injury, and subsequent use of Raf and MEK inhibitors can cause significant LVSD and heart failure. This ‘synergistic’ cardiotoxicity has been observed with other drug combinations e.g. anthracyclines and trastuzumab, and the principles are the same. One therapy (ICI, anthracycline) causes myocardial injury and this is amplified by the concomitant or subsequent use of a molecular cancer therapy targeting a survival pathway expressed in both the cancer cell and the cardiomyocyte (e.g. ErbB2, Raf, MEK, PD-L1).iv Myocardial infarctionMany common cardiovascular diseases including atherosclerosis are characterised by low grade chronic inflammation. Atherosclerotic plaque rupture, the fundamental event underlying acute myocardial infarction (MI) and thromboembolic stroke in the majority of cases, results from plaque inflammation and erosion of the fibrosis cap separating the lipid core from the arterial blood. It is well recognised in clinical cardiology that chronic inflammatory diseases including psoriasis, SLE and rheumatoid arthritis accelerate atherosclerosis and plaque rupture. These chronic inflammatory diseases are included in contemporary primary prevention cardiovascular risk calculators.49 Furthermore acute inflammatory conditions such as acute infections (e.g. pneumonia) are known to trigger acute plaque rupture and myocardial infarction.50 This may explain the emerging signal of acute MI in some ICI trials, with ICI activating inflammation in pre-existing atherosclerotic coronary plaques and triggering fibrous cap rupture, acute coronary thrombosis and MI. An alternative explanation for ICI-mediated acute MI is the direct activation of a T cell mediated coronary vasculitis in the absence of atherosclerosis, but this has yet to be reported.With the increasing use of immunotherapy in a wider range of cancer patients, including older patients who frequently have overt or subclinical cardiovascular disease, the potential for ICIs to destabilise pre-existing atherosclerotic plaques and trigger acute events, and/or accelerate the development of new vascular disease in the growing number of cancer survivors, remains to be determined. For cancer survivors where the immune system is chronically activated by immunotherapy, could this increase long term CV inflammation? Is a transient acute activation of inflammation by immunotherapy associated with a change in atherosclerotic plaque inflammatory activity and a potential to increase future acute atherothrombotic events and MI? How does the acute inflammatory reaction to the tumour, and non-cardiac autoimmune toxicities, contribute to cardiovascular toxicity, including activation of platelets and the coagulation cascade? These important pathophysiological questions remain to be answered. Clinical management of cardiotoxicityManagement of the acute cardiac complications of immunotherapy requires three complimentary approaches and will depend upon the severity of the cardiotoxicity, ranging from asymptomatic laboratory abnormalities (cardiac biomarker elevation, ECG changes) through to fulminant myocarditis, cardiogenic shock, complete heart block, ventricular arrhythmias and cardiac arrest (see Table 3). Diagnostic test including cardiac biomarkers, ECG and cardiac imaging are appropriate. If myocarditis is suspected then CMR with inflammatory sequences and late gadolinium enhancement is advisable, even in cases of normal left ventricular function on echocardiography. If CMR is not available or contraindicated then cardiac 18FDG PET-CT with appropriate fasting is helpful to detect myocardial inflammation. In equivocal or uncertain cases endomyocardial biopsy may be helpful.The first is to consider stopping the ICI depending upon the severity of the cardiotoxicity. This requires discussion between the oncologist and cardio-oncology specialist. ICIs have a long functional half-life and stopping will not lead to an immediate reversal of the biological effect. As safety is paramount, temporarily interrupting ICI until clarity is certain regarding possible cardiotoxicity is a reasonable approach in most cases.The second are conventional cardiac treatments for the complications including treatment of acute heart failure and pulmonary oedema with intravenous nitrates and diuretics, cardiac pacemakers for complete heart block, and beta blockers and/or amiodarone for ventricular tachyarrhythmias with external cardioversion/defibrillation for haemodynamically unstable VT and VF. In cases of cardiogenic shock inotropic support and consideration for advanced mechanical support e.g. extracorporeal membrane oxygenation or a temporary left ventricular assist device will depend on the clinical context, response to ICI treatment at the time of presentation, co-morbidities and prognosis from cardiac and non-cardiac complications and cancer. Pericardiocentesis for large pericardial effusions with cardiac tamponade is recommended. Admission to coronary care unit or level 2 high dependency unit for continuous ECG and haemodynamic monitoring is recommended for patients receiving ICI therapy presenting with acute chest pain with troponin elevation, clinical heart failure, arrhythmias or tamponade. Even in milder cases diagnosed by surveillance (see below) e.g. new BNP or troponin rise, new asymptomatic mild LVSD on echocardiography or a new mild conduction abnormality on ECG then specialist cardio-oncology review is recommended. Cardiology management strategies include closer monitoring of cardiac status whilst continuing ICI treatment, or if indicated introduction of treatments for LVSD. To date there is no evidence that cardiac medication such as ACE inhibitors or beta blockers can prevent ICI-mediated cardiotoxicity, but in the setting of new LVSD they are indicated, and they may be effective against functional non-inflammatory LVSD. Coronary angiography (invasive or CT coronary angiography) should be considered in patients with angina, acute ischaemic ECG changes (ST elevation, ST depression, T wave inversion) and cardiac troponin elevation if an acute coronary syndrome is suspected.The third arm of treatment is immunosuppression. The intensity depends on the severity of the cardiotoxicity (see Table 4). For severe cases with confirmed (or suspected with a high degree of clinical suspicion) myocarditis, symptomatic heart failure, pericarditis or serious arrhythmias (2nd degree or complete heart block, ventricular tachycardia or ventricular fibrillation) high intensity immunosuppression is indicated e.g. daily intravenous methylprednisolone (500mg-1g daily) until clinical stability is achieved followed by oral prednisolone initially at 1mg/kg per day before tapering according to response. The steroid weaning protocol will be dependent on the severity of the complication and the rate of clinical response to the initial immunosuppression treatment. Objective markers of toxicity including troponin, inflammation on CMR, and LV dysfunction on echocardiography and conduction disease on the ECG can be used in addition to clinical status to evaluate response to immunosuppression and guide the speed of weaning. Appropriate prophylactic antibiotics should be considered. If first line immunosuppression with intravenous methylprednisolone is unsuccessful with a lack of clinical response after 48 hours then second line immunosuppression with mycophenolate motefil or infliximab should be considered. If still refractory then the diagnosis should be reviewed, and other possible options including anti-thymocyte globulin (ATG)51 and intravenous immunoglobulin (IVIG) which may be considered in extreme cases, and IVIG would be appropriate if a positive auto-antibody result was detected. If milder cases occur then less intense immunosuppression and close monitoring may be appropriate.The decision to stop versus continue with ICI therapy depends on the nature and severity of the new cardiac abnormality and the clinical certainty that it is an ICI-related cardiac complication versus an unrelated event. In milder ICI-mediated cardiotoxicity cases e.g. uncomplicated pericarditis or subclinical myocardial dysfunction without conduction disease, after appropriate immunosuppression and resolution of the cardiotoxicity it may be appropriate to restart ICI with close surveillance for recurrence. There are risks of rechallenging and we do not advise restarting in cases of ICI-mediated myocarditis as this has been associated with fatal recurrence.52 These decisions regarding continuing versus stopping ICI, and restarting ICI after an interruption for cardiac causes, are frequently challenging and require close collaboration between the oncology and cardiology teams. A specialist cardio-oncology review is recommended if available.Surveillance strategies for ICI-mediated cardiotoxicityAn interesting and challenging clinical question is whether surveillance has a role to detect early immunotherapy-mediated cardiotoxicity before the severe and life threatening complications develop, analogous to surveillance for other cardiotoxic cancer therapies such as doxorubicin and trastuzumab. Currently no evidence-based algorithm exists, and the clinical context is that severe ICI-mediated cardiotoxicity is still relatively rare, but the consequences are serious and frequently fatal. If surveillance is to be considered then the strategy proposed in Figure 1 is the opinion of the authors as there are no prospective trials to guide formal surveillance. Several important principles should be considered and adhered to when considering surveillance for cardiac complications in patients receiving immunotherapy. The most important is that the benefits of immunotherapy can be significant, and therefore the ICI treatment should not be stopped for prolonged periods unless definite evidence of clinically significant ICI-mediated cardiotoxicity is present e.g. myocarditis, new left ventricular impairment or arrhythmias. Secondly non-toxicity related cardiac abnormalities, including increased cardiac biomarkers and atrial or ventricular ectopy, is a common finding in patients with advanced and metastatic cancer, particularly if they have pre-existing cardiovascular disease or cardiotoxic cancer therapies. Therefore any strategy for surveillance must incorporate a baseline measurement of cardiac function using the modalities used for surveillance. In our proposed schema BNP, cardiac troponin and ECG are chosen as cases to date have been characterised consistently by BNP elevation or conduction disease, and we suggest measurement at baseline and before cycles 2-4 in higher risk patients (see figure 1). Addition of cardiac troponin should also be considered as it is more specific for myocarditis, which is the most important ICI-triggered cardiotoxicity. However it may be normal in other ICI-mediated cardiotoxicities, and therefore combined troponin and BNP will be most sensitive. Thirdly a clear protocol must be in place, agreed by both oncologists and cardio-oncologists, for the action if a new abnormality is detected during surveillance. This must be tailored to the magnitude and severity of the new abnormality, and not always result in cessation of ICI therapy. Fourthly the biomarkers should be serially measured by the same laboratory with the same assays to limit the variability. Finally not all patients have the same risk, and personalising the approach to different patients based on their baseline risk assessment may be relevant.The risk factors for developing ICI-mediated cardiotoxicity from the cohorts and cases published to date as summarised in Table 2 and Figure 2B. At this point, the most direct evidence for any risk factor is the use of combination ICI or ICI with another cardiotoxic drug. A limited baseline assessment should be considered for all patients, and a limited surveillance protocol offered to patients with risk factors focussing on the first 12 weeks (4 cycles) which appears to be the highest risk time window. What is less clear is whether a history of previous myocardial injury such as myocardial infarction or viral myocarditis, where cardiac antigens have been exposed to the immune system, is a risk factor for immunotherapy-mediated cardiotoxicity. The presence of pre-existing autoimmune conditions including polymyalgia rheumatica, rheumatoid arthritis, SLE and sarcoidosis who may be at higher risk of autoimmune disease, and particularly if they have had prior cardiac involvement.Cases of ICI-related skeletal myositis should have a cardiac assessment to exclude cardiac involvement e.g. ECG, serum natriuretic peptide and cardiac troponin measurement and echocardiography. This may also allow earlier identification of patients with ICI-mediated myocarditis if they present with ICI-related skeletal myositis.Genetic factors and analysis for the expression of cardiac antigens in tumour samples, or the presence of T cell clones active against cardiac antigens are interesting but are not routinely available in clinical practice or in a clinically relevant timeline.Conclusions and future directions ICIs are having a major impact on several malignancies, including long term cancer free survival in some patients with previously incurable disease, and are now licensed for various cancer types. ICI-mediated cardiotoxicity is currently considered to be relatively rare, but serious and potentially fatal. Myocarditis, conduction disease with heart block and ventricular arrhythmias are the most common reported toxicities, but acute myocardial infarction, non-inflammatory LVSD, Takotsubo syndrome and pericarditis may also occur. Treatment requires careful coordination between oncology and cardiology and includes immunosuppression and appropriate cardiac therapies. Baseline cardiac assessment is advised for all patients scheduled to receive ICIs, and surveillance strategies may be considered for individuals at higher risk based on their ICI treatment strategy and past medical history (cardiovascular and autoimmune). The complexity of this field is growing rapidly, with trials in a wide range of solid and haematological malignancies, increasing permutations of treatment combinations with more than one ICI and with other cancer therapies, including those with known cardiotoxicity, and cell-based immune strategies e.g. CAR-T therapies. The raising awareness of cardiotoxicity is important given the possible consequences, but should not be exaggerated as to date the incidence of severe complications is low. More research is required to clarify many unanswered questions: 1. the true incidence of ICI-mediated cardiotoxicity; 2. the different manifestations and clinical subtypes, and their various levels of severity; 3. the underlying pathophysiology of the different subtypes; 4. the appropriate treatment interventions to rescue and ideally to prevent ICI-mediated cardiotoxicity; 5. the appropriate surveillance strategies and best biomarkers to detect early toxicity; 6. appropriate scenarios where ICI can be restarted following ICI-cardiotoxicity; 7. the long term implications for cancer survivors if they develop new myocardial disease e.g. myocardial infarction; and 8. how to provide coordinated care for these patients and the growing demand for specialist cardio-oncology services. Further understanding of ICI-mediated cardiotoxicity will also offer new insights into cardiovascular biology which may be transferrable to the understanding of other cardiac diseases, particularly cardiac autoimmune diseases where current understanding is limited. It is an exciting time to be involved in oncology, cardiology and cardio-oncology. ICI-mediated cardiotoxicity is a new clinical problem which is challenging now and physicians will continue to face in the coming years with the growth of immunotherapies. Web-based platforms such as??may allow multi-institutional efforts to better understand these new clinical entities. Combining knowledge and expertise in this new field of modern medicine will help oncologists and cardiologists come together with the common goal to improve the survival and outcomes for cancer patients receiving ICI.DisclosuresARL has received speaker, advisory board or consultancy fees and/or research grants from Pfizer, Novartis, Servier, Amgen, Clinigen Group, Takeda, Roche, Eli Lily, Eisai, Bristol Myers Squibb, Ferring Pharmaceuticals and Boehringer Ingelheim. NY has received speaker fees from Astra Zeneca and travel grant from MSD. JM has received advisory board fees or research grants from Pfizer, Novartis, Bristol Myers Squibb, Daiichi Sankyo, Takeda, Pharmacyclis and Regeneron. JL has received consultancy fees from Eisai, Bristol Myers Squibb, MSD, Glaxo Smith Kline, Kymab, Pfizer, Novartis, Roche/Genentech, Secarna, Pierre Fabre and EUSA Pharma. 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