Predictors and Risk Score for Immune Checkpoint-Inhibitor-Associated Myocarditis Severity.

Background: Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this "cardiomyotoxicity" are lacking. Methods: A multicenter registry collected data retrospectively from 17 countries between 2014-2023. A multivariable cox regression model (hazard-ratio(HR), [95%confidence-interval]) was used to determine risk factors for the primary composite outcome: severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardio-muscular symptoms, diagnostics, and treatments. Time-dependent covariates were used and missing data were imputed. A point-based prognostic risk score was derived and externally validated. Results: In 748 patients (67% male, age 23-94), 30-days incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17% respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (HR=3.60[1.93-6.72]), presence of cardio-muscular symptoms (HR=2.60 [1.58-4.28]), low QRS-voltage on presenting electrocardiogram (HR for ≤0.5mV versus >1mV=2.08[1.31-3.30]), left ventricular ejection fraction (LVEF) <50% (HR=1.78[1.22-2.60]), and incremental troponin elevation (HR=1.86 [1.44-2.39], 2.99[1.91-4.65], 4.80[2.54-9.08], for 20, 200 and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-days primary outcome incidence increased gradually from 3.9%(risk-score=0) to 81.3%(risk-score≥4). This risk-score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low risk patients who were managed with no immunosuppression resulting in no cardio-myotoxic events. Conclusions: ICI-myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low-QRS voltage, depressed LVEF, and cardio-muscular symptoms. A risk-score incorporating these features performed well. Trial registration number: NCT04294771 and NCT05454527.

Extracorporeal membrane oxygenation (ECMO) during aplasia: A bridge towards myopericarditis recovery after autologous hematopoietic stem cell transplant for systemic sclerosis and recent Coronarovirus disease (COVID-19) vaccination.

Systemic sclerosis (SSc) is a rare autoimmune disease (AD), characterised by early diffuse vasculopathy, activation of the immune response and progressive skin and internal organ fibrosis. In severe progressive diffuse SSc (dSSc), autologous hematopoietic stem cell transplantation (aHSCT) improves survival, despite its own risk of complications and transplant related mortality (TRM). We present herein the case of a dSSc patient undergoing aHSCT with low dose cyclophosphamide conditioning and sudden acute myopericarditis and cardiogenic shock, four weeks after a second mRNA SARS-CoV-2 vaccine (Pfizer) injection. Four days of extracorporeal membrane oxygenation (ECMO) support during the aplasia period, allowed to observe full cardiac function recovery and progressive SSc rehabilitation with sustained disease response at 30 months follow-up. This report illustrates, for the first time to our knowledge, that ECMO can be indicated despite aplasia during aHSCT and successfully used as a bridge towards heart function recovery in highly selected and fragile AD patients. We review the factors that may contribute to endothelial and myocardial stunning and acute reversible cardiac failure in SSc and aggravate intrinsic endothelial injury during the aHSCT procedure. These classically include: cyclophosphamide drug toxicity, viral infections and autoimmune activation with disease flair per se. In the COVID-19 pandemic times, acute myocarditis due to recent viral infection or mRNA vaccine per se, must also be considered.

Prevalence of Pericardial Late Gadolinium Enhancement in Patients After Cardiac Surgery: Clinical and Histological Correlations.

BACKGROUND: Pericardial late gadolinium enhancement (LGE) is usually associated with active pericarditis, but it is not infrequently found in patients after cardiac surgery even a long time after the intervention. The clinical relevance of this finding and its histological correlates are unknown. We sought to determine the prevalence of chronic pericardial LGE in patients after cardiac surgery. METHODS: All consecutive patients with previous cardiac surgery, who were referred to cardiovascular magnetic resonance between January 2017 and December 2021 were enrolled in the study. Cardiovascular magnetic resonance examination protocol was adapted to clinical indication but always included standard LGE acquisitions. Two independent observers blinded to clinical data assessed the presence of pericardial enhancement on LGE sequences. Fifteen patients underwent cardiac reintervention and pericardial biopsies were obtained. The primary study end point was to assess the prevalence of pericardial enhancement after cardiac surgery and identify possible determinants. The secondary end point was to correlate pericardial enhancement with clinical symptoms and histopathology. RESULTS: Two hundred four patients were included in the study. The median time between surgery and cardiovascular magnetic resonance was 160 months (35-226 months). Pericardial LGE was observed in 90 patients (44%). All patients were asymptomatic, and no specific treatment for pericarditis was started. All patients remained asymptomatic at a 1-year clinical follow-up. Pericardial LGE was significantly correlated with the number of previous surgeries (P=0.03). Pericardial fibrosis was detected in all 15 pericardial biopsy specimens; pericardial LGE was present in 7 patients (47%) who underwent biopsy. Histological signs of low-grade inflammation were detected in 6 patients (40%) with severe, circumferential pericardial LGE but in no patient without pericardial enhancement. CONCLUSIONS: Pericardial LGE is a frequent finding even several years after cardiac surgery. Its histological correlate is a chronic subclinical post-pericardiotomy inflammation.

Management and outcomes of carcinoid heart disease with liver metastases of midgut neuroendocrine tumours.

OBJECTIVE: Despite recent advances in surgical and interventional techniques, knowledge on the management of carcinoid heart disease (CHD) remains limited. In a cohort of patients with liver metastases of midgut neuroendocrine tumours (NETs), we aimed to describe the perioperative management and short-term outcomes of CHD. METHODS: From January 2003 to June 2022, consecutive patients with liver metastases of midgut NETs and severe CHD (severe valve disease with symptoms and/or right ventricular enlargement) were included at Beaujon and Bichat hospitals. All patients underwent clinical evaluation and echocardiography. RESULTS: Out of 43 (16%) consecutive patients with severe CHD and liver metastases of midgut NETs, 79% presented with right-sided heart failure. Tricuspid valve replacement was performed in 26 (53%) patients including 19 (73%) cases of combined pulmonary valve replacement. The 30-day postoperative mortality rate was high (19%), and preoperative heart failure was associated with worse survival (p=0.02). Epicardial pacemakers were systematically implanted in operated patients and 25% were permanently paced. A postoperative positive right ventricular remodelling was observed (p<0.001). A greater myofibroblastic infiltration was observed in pulmonary versus tricuspid valves (p<0.001), suggesting that they may have been explanted at an earlier stage of the disease than the tricuspid valve, with therefore potential for evolution. CONCLUSIONS: We observed a high postoperative mortality rate and baseline right-sided heart failure was associated with worse outcome. In surviving patients, a positive right ventricular remodelling was observed. Prospective, multicentre studies are warranted to better define the management strategy and to identify biomarkers associated with outcome in CHD.

Carcinoid heart disease in patients with midgut neuroendocrine tumours.

Carcinoid heart disease (CHD) is the main complication of carcinoid syndrome (CS) associated with metastatic small intestine neuroendocrine tumours (NETs). The pathophysiology of CHD is partly understood but vasoactive hormones secreted by NETs, especially serotonin, play a major role, leading to the formation of fibrous plaques. These plaque-like deposits involve the right side of the heart in >90% of cases, particularly the tricuspid and pulmonary valves, which become thickened, retracted and immobile, resulting in regurgitation or stenosis. CHD represents a major diagnostic and therapeutic challenge for patients with NET and CS and is associated with increased risk of morbidity and mortality. CHD often occurs 2-5 years after the diagnosis of metastatic NET, but diagnosis of CHD can be delayed as patients are often asymptomatic for a long time despite severe heart valve involvement. Circulating biomarkers (5HIAA, NT-proBNP) are relevant tools but transthoracic echocardiography is the key examination for diagnosis and follow-up of CHD. However, there is no consensus on the optimal indications and frequency of TTE and biomarker dosing regarding screening and diagnosis. Treatment of CHD is complex and requires a multidisciplinary approach. It relies on antitumour treatment, control of CS and surgical valve replacement in cases of severe CHD. However, cardiac surgery is associated with a high risk of mortality, notably due to perioperative carcinoid crisis and right ventricular dysfunction. Timing of surgery is the most crucial point of CHD management and relies on the case-by-case determination of the optimal compromise between tumour progression, cardiac symptoms and CS control.

Multidisciplinary recommendations for essential baseline functional and laboratory tests to facilitate early diagnosis and management of immune-related adverse events among cancer patients.

Immune checkpoint inhibitors (ICIs) have fundamentally changed the treatment landscape of various cancers. While ICI treatments result in improved survival, quality of life and are cost-effective, the majority of patients experience at least one immune-related adverse event (irAE). Many of these side effects cause little discomfort or are asymptomatic; however, irAEs can affect any organ and are potentially life-threatening. Consequently, early diagnosis and appropriate treatment of irAEs are critical for optimizing long-term outcomes and quality of life in affected patients. Some irAEs are diagnosed according to typical symptoms, others by abnormal findings from diagnostic tests. While there are various guidelines addressing the management of irAEs, recommendations for the early recognition of irAEs as well as the optimal extent and frequency of laboratory tests are mostly lacking. In clinical practice, blood sampling is usually performed before each ICI administration (i.e., every 2-3 weeks), often for several months, representing a burden for patients as well as health care systems. In this report, we propose essential laboratory and functional tests to improve the early detection and management of irAEs and in cancer patients treated with ICIs. These multidisciplinary expert recommendations regarding essential laboratory and functional tests can be used to identify possible irAEs at an early time point, initiate appropriate interventions to improve patient outcomes, and reduce the burden of blood sampling during ICI treatment.

Coronary artery disease and revascularization associated with immune checkpoint blocker myocarditis: Report from an international registry.

PURPOSE: Immune checkpoint blocker (ICB) associated myocarditis (ICB-myocarditis) may present similarly and/or overlap with other cardiac pathology including acute coronary syndrome presenting a challenge for prompt clinical diagnosis. METHODS: An international registry was used to retrospectively identify cases of ICB-myocarditis. Presence of coronary artery disease (CAD) was defined as coronary artery stenosis >70% in patients undergoing coronary angiogram. RESULTS: Among 261 patients with clinically suspected ICB-myocarditis who underwent a coronary angiography, CAD was present in 59/261 patients (22.6%). Coronary revascularization was performed during the index hospitalisation in 19/59 (32.2%) patients. Patients undergoing coronary revascularization less frequently received steroids administration within 24 h of admission compared to the other groups (p = 0.029). Myocarditis-related 90-day mortality was 9/17 (52.7%) in the revascularised cohort, compared to 5/31 (16.1%) in those not revascularized and 25/156 (16.0%) in those without CAD (p = 0.001). Immune-related adverse event-related 90-day mortality was 9/17 (52.7%) in the revascularized cohort, compared to 6/31 (19.4%) in those not revascularized and 31/156 (19.9%) in no CAD groups (p = 0.007). All-cause 90-day mortality was 11/17 (64.7%) in the revascularized cohort, compared to 13/31 (41.9%) in no revascularization and 60/158 (38.0%) in no CAD groups (p = 0.10). After adjustment of age and sex, coronary revascularization remained associated with ICB-myocarditis-related death at 90 days (hazard ratio [HR] = 4.03, 95% confidence interval [CI] 1.84-8.84, p < 0.001) and was marginally associated with all-cause death (HR = 1.88, 95% CI, 0.98-3.61, p = 0.057). CONCLUSION: CAD may exist concomitantly with ICB-myocarditis and may portend a poorer outcome when revascularization is performed. This is potentially mediated through delayed diagnosis and treatment or more severe presentation of ICB-myocarditis.

Association of early electrical changes with cardiovascular outcomes in immune checkpoint inhibitor myocarditis.

BACKGROUND: Immune-checkpoint inhibitor-associated myocarditis (ICI-myocarditis) often presents with arrhythmias, but the prognostic value of early electrocardiogram findings is unclear. Although ICI-myocarditis and acute cellular rejection (ACR) following cardiac transplantation use similar treatment strategies, differences in arrhythmia burden are unknown. OBJECTIVE: To evaluate the association of electrocardiogram findings in ICI-myocarditis with myocarditis-related mortality and life-threatening arrhythmia. METHODS: A total of 125 cases of ICI-myocarditis were identified retrospectively across 49 hospitals worldwide; 50 cases of grade 2R or 3R ACR were included as comparators. Two cardiologists blinded to clinical data interpreted electrocardiograms. Associations between electrocardiogram features, myocarditis-related mortality and the composite of myocarditis-related mortality and life-threatening arrhythmias were examined. Adjusted hazard ratios (aHRs) were calculated. RESULTS: The cohort had 78 (62.4%) men; median (interquartile range) age was 67 (58-76) years. At 30 days, myocarditis-related mortality was 20/124 (16.1%), and 28/124 (22.6%) met the composite endpoint. Patients who developed complete heart block (aHR by subdistribution hazards model [aHR(sh)] 3.29, 95% confidence interval [CI] 1.24-8.68; P=0.02) or life-threatening cardiac arrhythmias (aHR(sh) 6.82, 95% CI: 2.87-16.21; P<0.001) had a higher risk of myocarditis-related mortality. Pathological Q waves (aHR(sh) 3.40, 95% CI: 1.38-8.33; P=0.008), low QRS voltage (aHR(sh) 6.05, 95% CI: 2.10-17.39; P<0.001) and Sokolow-Lyon index (aHR(sh)/mV 0.54, 95% CI: 0.30-0.97; P=0.04) on admission electrocardiogram were also associated with increased risk of myocarditis-related mortality. These associations were mirrored in the composite outcome analysis. Compared with ACR, ICI-myocarditis had a higher incidence of life-threatening cardiac arrhythmias (15/125 [12.0%] vs 1/50 [2%]; P=0.04) and third-degree heart block (19/125 [15.2%] vs 0/50 [0%]; P=0.004). CONCLUSIONS: Electrocardiograms in ICI-myocarditis with ventricular tachycardias, heart block, low-voltage and pathological Q waves were associated with myocarditis-related mortality and life-threating arrhythmia. Arrhythmia burden in ICI-myocarditis exceeds that of ACR after heart transplant.

Feasibility of adenosine stress cardiovascular magnetic resonance perfusion imaging in patients with MR-conditional transvenous permanent pacemakers and defibrillators.

BACKGROUND: The use of stress perfusion-cardiovascular magnetic resonance (CMR) imaging remains limited in patients with implantable devices. The primary goal of the study was to assess the safety, image quality, and the diagnostic value of stress perfusion-CMR in patients with MR-conditional transvenous permanent pacemakers (PPM) or implantable cardioverter-defibrillators (ICD). METHODS: Consecutive patients with a transvenous PPM or ICD referred for adenosine stress-CMR were enrolled in this single-center longitudinal study. The CMR protocol was performed using a 1.5 T system according to current guidelines while all devices were put in MR-mode. Quality of cine, late-gadolinium-enhancement (LGE), and stress perfusion sequences were assessed. An ischemia burden of ≥ 1.5 segments was considered significant. We assessed the safety, image quality and the occurrence of interference of the magnetic field with the implantable device. In case of ischemia, we also assessed the correlation with the presence of significant coronary lesions on coronary angiography. RESULTS: Among 3743 perfusion-CMR examinations, 66 patients had implantable devices (1.7%). Image quality proved diagnostic in 98% of cases. No device damage or malfunction was reported immediately and at 1 year. Fifty patients were continuously paced during CMR. Heart rate and systolic blood pressure remained unchanged during adenosine stress, while diastolic blood pressure decreased (p = 0.007). Six patients (9%) had an ischemia-positive stress CMR and significant coronary stenoses were confirmed by coronary angiography in all cases. CONCLUSION: Stress perfusion-CMR is safe, allows reliable ischemia detection, and provides good diagnostic value.

Acute cardiac manifestations under immune checkpoint inhibitors-beware of the obvious: a case report.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized the management of many cancer types by drastically improving the median survival rate of patients. However, this efficiency comes at the cost of a high rate of immune-related adverse events, including lethal cardiac manifestations. Rapidly fatal cases of ICI-induced myocarditis have been reported and drawn considerable attention over the past years. However, it is essential to bear in mind that not all cardiac events occurring under ICI therapy are necessarily myocarditis. CASE SUMMARY: A 61-year-old female treated with pembrolizumab for a stage IV melanoma was admitted for chest pain leading to the diagnosis of ICI-related myocarditis based on the description of a discrete left ventricular subepicardial late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging. ICI were suspended and intravenous methylprednisolone initiated. A second line anti-MEK therapy was initiated. After a month of treatment, similar chest pain occurred. CMR revealed a midventricular stress cardiomyopathy and no LGE was detected. A posteriori interrogation revealed emotional stressors preceding both episodes. Review of the first CMR, performed 2 weeks after symptom onset, indicated a pattern compatible with the recovery phase of a stress cardiomyopathy and the presence of LGE was questioned. ICI were reintroduced without recurrence of cardiac events. DISCUSSION: Not all cardiac manifestations occurring under ICI therapy are drug-related adverse events, therefore differential diagnoses must systematically be considered as the contraindication of ICI may have a major impact on patient prognosis. Cardiac imaging should be performed early and plays a key role in the management strategy.

Pathophysiology, diagnosis and management of cardiac toxicity induced by immune checkpoint inhibitors and BRAF and MEK inhibitors.

Immune checkpoint inhibitors (ICIs) and BRAF and MEK inhibitors (BRAFi/MEKi) have drastically improved the outcome of melanoma patients. ICIs can induce myocarditis, a rare immune related adverse event (irAE) with an estimated lethality of 50%. BRAFi/MEKi may induce left ventricular ejection fraction decrease, hypertension or QT interval prolongation. While the BRAFi/MEKi induced cardiotoxicity is often reversible upon treatment discontinuation or dose adaptation and symptomatic therapy is often sufficient to restore cardiac function, the treatment of ICI-induced myocarditis mainly relies on high dose corticosteroids. There is no established therapy for steroid resistant myocarditis, yet various drugs have been reported to improve outcome. Shared epitopes between melanoma cells and cardiac tissue are thought to underlie the development of ICIs induced myocarditis. The mechanism of BRAFi/MEKi induced cardiotoxicity appears to be related to the Ras-Raf-MEK-ERK pathway in cardiomyocyte repair, survival and proliferation. With the emerging application of ICI-BRAFi/MEKi combinations, so called triplet therapies, differentiating between these two types of cardiotoxicity will become important for appropriate patient management. In this article we provide a summary of the existing literature on the pathophysiology, diagnosis and management of cardiotoxicity of melanoma therapies.

Prognostic Value of Peak Exercise Systolic Pulmonary Arterial Pressure in Asymptomatic Primary Mitral Valve Regurgitation.

BACKGROUND: The contribution of exercise echocardiography in primary asymptomatic mitral regurgitation (MR) remains debated. The aim of this study was to gain evidence regarding its usefulness in this setting and to investigate the prognostic value of peak exercise systolic pulmonary artery pressure (SPAP). METHODS: One hundred seventy-seven patients (mean age, 56 ± 13 years; 69% men) with moderate to severe (grade 3+) or severe (grade 4+) degenerative MR and preserved left ventricular ejection fraction, in sinus rhythm, referred for clinically indicated exercise echocardiography were identified. The end point, MR-related events, was a composite of all-cause death or occurrence of symptoms, heart failure, atrial fibrillation, left ventricular ejection fraction < 60%, left ventricular end-systolic diameter ≥ 45 mm, or resting SPAP > 50 mm Hg. RESULTS: At rest, effective regurgitant orifice area was 48 ± 16 mm2, regurgitant volume 74 ± 26 mL, and SPAP 32 ± 7 mm Hg, and MR was severe in 138 patients (78%). Peak exercise SPAP was 55 ± 10 mm Hg. Positive results on exercise testing motivated surgery in 26 patients, 11 underwent prophylactic surgery, 10 were lost to follow-up, and 130 were included in the outcome analysis. During a follow-up period of 19 ± 7 months, 31 MR-related events (24%) were reported. Peak exercise SPAP was predictive of outcomes in univariate analysis (P = .01) and after adjustment for age, gender, MR severity, and resting SPAP (P < .05). Peak exercise SPAP ≥ 50 mm Hg was associated with worse event-free survival (hazard ratio, 5.24; 95% CI, 1.77-15.53; P = .003), but not the threshold of ≥60 mm Hg proposed in previous guidelines (hazard ratio, 1.70; 95% CI, 0.71-4.03; P = .24). CONCLUSIONS: The present findings support the use of exercise echocardiography for risk stratification in patients with asymptomatic primary MR and suggest a lower peak exercise SPAP threshold (50 mm Hg) than previously recommended to define the timing of intervention. Prospective studies are needed to confirm these findings.

[Cardiotoxicity of immune checkpoint inhibitors used in cancer treatment]. / Cardiotoxicité des inhibiteurs de points de contrôle immunitaire utilisés dans le traitement des cancers.

Immune checkpoint inhibitors (ICI) have revolutionized the field of oncology, by reshaping the prognosis of many cancers and are progressively becoming the standard of care. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), of which cardiovascular irAEs are particularly feared. ICI-induced myocarditis is often a diagnostic challenge because of the vast heterogeneity of clinical presentations, and it is associated with a high mortality rate of around 50%. The present article summarizes the cardiac manifestations, the diagnostic strategy and the therapeutic management of patients with ICI-induced myocarditis used in the treatment of cancer.

Les inhibiteurs de points de contrôle immunitaire (ICI), ou immune checkpoint inhibitors (ICI), ont révolutionné la prise en charge de nombreux cancers en améliorant significativement la survie des patients et en devenant progressivement la norme de soins. Cette efficacité a néanmoins pour prix un taux élevé d'effets indésirables immunomédiés avec un large spectre d'organes touchés. Les toxicités cardiaques, dominées par la myocardite induite par les ICI, sont particulièrement redoutées du fait des difficultés diagnostiques et du risque d'évolution rapidement défavorable associée à une mortalité élevée, de l'ordre de 50 %. Le présent article s'intéresse aux manifestations cardiaques, à la stratégie diagnostique ainsi qu'à la prise en charge des patients présentant une myocardite induite par les ICI utilisés dans le traitement du cancer.

Epicardial adipose tissue volume is associated with left ventricular remodelling in calcific aortic valve stenosis.

BACKGROUND: The severity of left ventricular (LV) remodelling is only partially related to the severity of aortic valve stenosis; additional factors, including diabetes, insulin resistance, obesity and metabolic syndrome, may play important roles. Epicardial adipose tissue (EAT), now considered as a metabolically active organ, is also linked to these factors. AIM: To analyse the association between EAT volume measured using computed tomography and LV remodelling in a prospective cohort of patients with aortic stenosis. METHODS: Consecutive asymptomatic patients with at least mild degenerative aortic stenosis enrolled in a prospective cohort that aimed to assess the determinants of aortic stenosis occurrence and progression constituted our population. RESULTS: We enrolled 143 patients (78±5 years; 65% men). Mean LV mass and EAT volume were 219±64g and 134±56mL, respectively. LV hypertrophy was diagnosed in 86 patients (60%), and concentric hypertrophy (32%) was the main remodelling pattern. EAT was associated with body mass index (P<0.001) and body surface area (P<0.001), but not with age (P=0.33) or aortic stenosis severity (all P>0.10). EAT was correlated with LV mass (r=0.41; P<0.0001), and after adjustment for age, sex, body mass index/body surface area, hypertension, waist circumference, low-density lipoprotein cholesterol and aortic stenosis severity, EAT was independently associated with LV mass (P=0.01/P=0.02). Similar results were found when EAT and LV mass index (adjusted for body surface area) were considered instead of absolute values (P=0.04). CONCLUSIONS: In this prospective cohort of patients with aortic stenosis, EAT volume was independently associated with LV mass. Further studies are warranted to elucidate the underlying mechanisms of this link.

Relationship of Iron Deposition to Calcium Deposition in Human Aortic Valve Leaflets.

BACKGROUND: Intraleaflet hematomas are associated with advanced stages of aortic valve calcification and suspected to be involved in disease progression. However, the mechanism by which the entry of blood cells into the valves affects the biology of aortic valvular interstitial cells (VICs) remains to be elucidated. OBJECTIVES: This study sought to evaluate the putative link between intraleaflet hematoma and aortic valve calcification and to assess its pathophysiological implications. METHODS: The spatial relationship between calcium deposits and intraleaflet hematomas was analyzed by whole-mount staining of calcified and noncalcified human aortic valves, obtained in the context of heart transplantation and from patients who underwent surgical valve replacement. Endothelial microfissuring was evaluated by en face immunofluorescence and scanning electron microscopic analyses of the fibrosa surface. Red blood cell (RBC) preparations were used in vitro to assess, by immunofluorescence microscopy and Alizarin red staining, the potential impact of intraleaflet hematomas on phenotypic changes in VICs. RESULTS: Intraleaflet hematomas, revealed by iron deposits and RBCs into the fibrosa, secondary to endothelial microfissuring, were consistently found in noncalcified valves. The contact of primary VICs derived from these valves with RBCs resulted in a global inflammatory and osteoblastic phenotype, reflected by the up-regulation of interleukin-6, interleukin-1ß, bone sialoprotein, osteoprotegerin, receptor activator of nuclear factor kappa B, bone morphogenic protein 2, and muscle segment homeobox 2, the production of osteocalcin, and the formation of calcium deposits. CONCLUSIONS: The acquisition of an osteoblastic phenotype in VICs that come into contact with the senescent RBCs of intraleaflet hematomas may play a critical role in the initiation of calcium deposition into the fibrosa of human aortic valves.

Management of immune-related adverse events resulting from immune checkpoint blockade.

INTRODUCTION: Immune checkpoint inhibitors (ICI) are now a standard of care in the treatment of many cancers leading to durable responses in patients with metastatic disease. These agents are generally well tolerated but may lead to the occurrence of immune-related adverse events (irAEs). As any organ may be affected, clinicians should be aware of the broad range of clinical manifestations and symptoms and keep in mind that toxicities may occur late, at any point along a patient's treatment course. Although the most common irAEs are rarely severe, some of them may be associated with great morbidity and even become life-threatening. The rate of occurrence, type and severity of irAEs may vary with the type of ICI; thus, grade 3 and 4 irAEs are reported in more than 55% of patients treated with the combination of ipilimumab 3 mg/kg and nivolumab 1 mg/kg. Area covered: This review presents the management of irAEs resulting from checkpoint blockade, with a focus on rare irAEs. Expert commentary: With the development of immuno-oncology and the expanding role of ICI, physicians have learnt to diagnose and treat most of the irAEs that can occur. This review provides an overview of current guidelines, previously published studies and our multidisciplinary team based practices.