Immune checkpoint inhibitors (ICIs) have advanced cancer treatment but are associated with serious cardiovascular side effects, including myocarditis, which is challenging to diagnose due to limited specificity of current biomarkers. Rho-associated kinase 2 (ROCK2) may play a role in myocarditis pathogenesis by mediating inflammation and myocardial remodeling. This study investigates the potential of ROCK2 protein detection as a diagnostic marker for ICIs-associated myocarditis.

To evaluate ROCK2 protein levels in patients with ICIs-associated myocarditis and assess its diagnostic value, providing insights for improved identification and management of this condition.

We conducted a study with 10 ICIs-treated gastric cancer patients diagnosed with myocarditis and a control group of 10 similar ICIs-treated patients without myocarditis. ROCK2 levels and inflammatory markers were measured via ELISA, and clinical assessments included cardiac imaging, electrocardiography, and echocardiography. Statistical analysis of group differences used independent t-tests and chi-square tests.

ROCK2 expression was significantly higher in myocarditis patients compared to controls (p < 0.001), alongside elevated inflammatory markers, specifically hypersensitive C-reactive protein (hs-CRP), interleukins1β (IL-1β) and IL-17. Diagnostic myocardial markers such as N-terminal pro B-type natriuretic peptide (NT-proBNP), and soluble suppression of tumorigenicity 2 (sST2) also showed substantial elevation. Following treatment discontinuation and glucocorticoid administration, both ROCK2 levels and inflammatory indicators declined.

Elevated ROCK2 protein levels could serve as a promising biomarker for ICIs-associated myocarditis. ROCK2 detection, combined with traditional markers, may enhance diagnostic accuracy. Further studies are warranted to explore ROCK2 inhibition as a potential therapeutic strategy for managing ICIs-associated myocarditis.

The etoposide-carboplatin and anti-PD-L1 combination has become the standard-of-care for patients with extensive-stage small cell lung cancer (ES-SCLC). This combinational strategy is well tolerated with manageable immune-related adverse effects (irAEs). In this report, we presented a rare immediate irAE after one course of anti-tumor treatment. The patient with ES-SCLC was treated with first-line etoposide-carboplatin chemotherapy and Durvalumab immunotherapy. After one cycle of indicated treatment, the patient developed persistent high-grade fever with extensive consolidation, surrounding by ground glass opacifications. The lesions did not respond to empirical antibiotics and the results for pathogen testing were negative. Histological analysis of biopsy sample yielded organizing pneumonia that was very likely to associate with Durvalumab treatment. The patient was therefore treated with prednisolone that resulted in a rapid radiological improvement. The reporting of this case is imperative for informing acute onset of irAE in patients with ES-SCLC treated with anti-PD-L1 immunotherapy. Differential diagnosis of infection, tumor progression and exacerbation of underlying illness should be considered before the initiation of prednisolone therapy.

Immune checkpoint inhibitors (ICIs) might increase the risk of major adverse cardiovascular events (MACEs). This study aimed to evaluate the risk of MACE in patients with melanoma after ICI initiation.

We conducted a before-after cohort study using claims data from Optum's deidentified Clinformatics Data Mart Database. We included adult patients with melanoma who received any approved ICI between 2011 and 2021 with a minimum of 12 months of observable data before ICI. The main outcome was time to first MACE (myocardial infarction, coronary revascularization, stroke, heart failure hospitalization) and rate of MACE before and after ICI, ascertained using International Classification of Diseases, 9th/10th Revision diagnostic codes. Hazard ratio (HR) and incidence rate ratio (IRR) were calculated.

We identified 4024 patients with ICI-treated melanoma. Mean age was 67.4 years (SD 14.1), 36% were women; 3066 (76.2%) received monotherapy and 958 (23.8%) combination immunotherapy. A total of 160 (4%) patients had a MACE before ICI and 224 (5.6%) after ICI (HR, 1.76; 95% CI, 1.47-2.12). MACE rate in the year before ICI was 56.16 per 1000 person-years compared with 80.91 per 1000 person-years the year after ICI (IRR, 1.44; 95% CI, 1.21-1.72). Ten cases of myocarditis were observed after ICI, 50% of them had a MACE. Risk factors associated with MACE after ICI were prior MACE, other cardiovascular conditions, hypertension, and older age. Glucocorticoid use was not associated with MACE.

Our results suggest that ICI might increase the risk of MACE in patients with melanoma during the first year after ICI.

The field of cardio-oncology has expanded over the past 2 decades to address the ever-increasing issues related to cardiovascular disease in patients with cancer and survivors. There is increasing recognition that nearly all cancer treatments pose some short- or long-term risk for development of cardiovascular disease and that pediatric patients with cancer may be especially vulnerable to cardiovascular disease because of young age at treatment and expected long life span afterward. Anthracycline chemotherapy and chest-directed radiotherapy are the most well-studied cardiotoxic therapies, and dose reduction, use of cardioprotection for anthracyclines, and modern radiotherapy approaches have contributed to improved cardiovascular outcomes for survivors. Newer treatments such as small-molecule inhibitors, antibody-based cytotoxic therapy, and immunotherapy have expanded options for previously difficult-to-treat cancers but have also revealed new cardiotoxic profiles. Application of effective surveillance strategies in patients with cancer and survivors has been a focus of practitioners and researchers, whereas the prevention and treatment of extant cardiovascular disease is still developing. Incorporation of new strategies in an equitable manner and appropriate transition from pediatric to adult care will greatly influence long-term health-related outcomes in the growing population of childhood cancer survivors at risk for cardiovascular disease.

Immune checkpoint blockade (ICB) therapies have demonstrated significant clinical efficacy in immune-infiltrated tumors such as melanoma and non-small cell lung cancer. However, "cold tumors"-including ovarian cancer, pancreatic cancer, and gliomas-exhibit insufficient immune infiltration, leading to poor therapeutic responses to ICBs and limited improvement in patient prognosis. Recent studies have shown that tumor-associated tertiary lymphoid structures (TLSs) can induce strong local immune responses within the tumor microenvironment (TME), serving as important biological markers for predicting ICB therapy efficacy. Notably, preclinical and clinical studies on cold tumors have confirmed that TLSs can potently enhance ICB efficacy through TME remodeling-a breakthrough that has attracted considerable attention. Here, we systematically examine the immunological profile of cold tumors and decipher the mechanistic basis for their impaired immune cell infiltration. We further delineate the distinctive features of tumor-associated TLSs in generating antitumor immunity and establish criteria for their identification. Significantly, we emphasize the unique capability of TLSs to reprogram the immunosuppressive tumor microenvironment characteristic of cold tumors. Based on these insights, we evaluate clinical evidence supporting TLS-mediated enhancement of ICB efficacy and discuss emerging strategies for exogenous TLSs induction.

To provide an update on the literature regarding diagnosis and management of immune checkpoint inhibitor myocarditis.

The diagnosis of immune checkpoint inhibitor myocarditis has evolved to include more reliance on performing endomyocardial biopsy to clarify the diagnosis in selected cases. Additionally, there is recognition of a spectrum of disease both clinically and on endomyocardial biopsy suggesting that there is a range of severity from mild to fulminant. The treatment of immune checkpoint inhibitor myocarditis is shifting towards increased use of additional immunosuppressive medications as steroid sparing agents. There are increased studies including two randomized controlled trials evaluating abatacept in the treatment of immune checkpoint inhibitor myocarditis. This review summarizes the latest literature regarding diagnosis and management of immune checkpoint inhibitor myocarditis and provides our experience and approach to this rare but potentially fatal condition.

Immune checkpoint inhibitors (ICI) are the cornerstone of modern oncology; however, side effects such as ICI-related myocarditis (irM) can be fatal. Recently, Bonaca proposed criteria for irM; however, it is unknown if they correlate well with cardiovascular (CV) ICI-related adverse events. Additionally, whether incident irM portends worse long-term CV outcomes remains unclear. We aimed to determine the incidence of long-term CV comorbidities and CV mortality among irM patients.

The ICI-related adverse event (irAE) registry was queried to identify irM patients by using Bonaca criteria. Random controls were selected after excluding patients with other concomitant irAEs. Patients' demographics, comorbidities and myocarditis presenting features were gathered. Outcomes included 2-year freedom from CV comorbidities (composite of atrial fibrillation, stroke, myocardial infarction and heart failure) and freedom from CV death. IrM was treated as a time-varying covariate.

Seventy-six patients developed irM at a median of 167 days (mean age 69, 63.2% male, 47% lung cancer). Majority of patients had new wall motion abnormalities or EKG changes on presentation. Mean LVEF was 43%, median peak TnT was 0.81, and median NTproBNP was 2057 at irM onset. Two-year freedom from CV comorbidities (67% vs 86.8%, P < 0.001) and death (93.4% vs 99.3%, P = 0.003) was lower among irM patients. Incident irM was an independent predictor of CV death (HR 8.28, P = 0.048), but not CV comorbidities (HR 2.21, P = 0.080).

This is the largest case-control study on irM highlighting worse long-term CV outcomes. Future studies are needed to establish appropriate therapeutic strategies and efficient screening strategies for irM survivors.

The most fatal side effect associated with revolutionary immune checkpoint inhibitor (ICI) cancer therapies is myocarditis, a rare and devastating complication with a mortality rate approaching 40%. This review comprehensively examines the limited knowledge surrounding this recently recognized condition, emphasizing the absence of evidence-based therapeutic strategies, diagnostic modalities, and reliable biomarkers that hinder effective management. It explores advancements in preclinical models that are uncovering disease mechanisms and enabling the identification of therapeutic targets. These efforts have informed the design of early clinical trials aimed at reducing mortality. With the growing prevalence of ICI therapies in oncology, addressing critical gaps, such as long-term outcomes and risk stratification, has become increasingly urgent. By synthesizing current evidence, this work seeks to enhance understanding and guide the development of strategies to improve patient outcomes and ensure the continued safe use of ICIs in cancer care.

Immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger myocardial inflammation or myocarditis. Here we leverage genetic mouse models, single-cell sequencing and cell depletion studies to show that an anti-CD40 agonist antibody reshapes the cardiac immune landscape through activation of CCR2+ macrophages and subsequent recruitment of effector memory CD8+ T cells. We identify a positive feedback loop between CCR2+ macrophages (positive for the chemokine receptor CCR2) and CD8+ T cells driven by IL-12b, TNF and IFNγ signaling that promotes myocardial inflammation and show that previous exposure to CD40 agonists sensitizes the heart to secondary insults and accelerates left ventricular remodeling. Collectively, these findings highlight the potential for CD40 agonists to promote myocardial inflammation and potentiate heart failure pathogenesis.

Myocarditis is a dreaded complication of immune-checkpoint inhibitor (ICI) therapy but challenging to diagnose. There are no published data comparing the two leading diagnostic criteria for ICI-related myocarditis (ICIrM) and their association with cardiovascular events.

In this retrospective cohort study, we reviewed all patients who underwent ICI therapy and had cardiac troponin assessment for possible myocarditis across three tertiary institutions from 2011 to 2022. ICIrM was adjudicated by the Bonaca et al. criteria and the ESC-ICOS guidelines. A propensity matched control group was identified of patients treated with ICI without developing myocarditis. Baseline characteristics and long-term outcomes, including cardiac death, MACE (myocardial infarction, TIA/stroke, heart failure), and arrhythmias data were curated, and patients diagnosed with ICIrM by each criteria were compared to controls for cardiovascular events.

A total of 59 patients (mean age was 73.1 ± 10.2 years, 60.1% male) were identified as having a diagnosis of ICIrM by Bonaca criteria (16 definite, 13 probable and 30 possible myocarditis). Forty-seven of these patients met the ESC-ICOS guidelines criteria, and all patients meeting either set of ICIrM criteria were treated with steroid therapy. At 3-year follow up, patients diagnosed with ICIrM by the Bonaca criteria had a high risk of cardiac mortality (HR 17.84, 95%CI 2.36-134.62, p = 0.005), MACE (HR 4.90, 95%CI 2.40-10.02, p < 0.001) and arrhythmias (HR 3.33, 95%CI 1.78-6.21, p < 0.001) when compared to matched controls. ICIrM by ESC-ICOS criteria was similarly predictive of cardiac mortality, MACE, and arrhythmias (HR 15.01, 95%CI 1.96-114.76, p = 0.009, HR 5.18, 95%CI 2.33-11.53, p < 0.001, and HR 3.41, 95%CI 1.73-6.70, p < 0.001 respectively).

The ESC-ICOS guidelines were more restrictive than the Bonaca et al. criteria for the diagnosis of ICIrM but similar in terms of prognostic value.

Immune checkpoint inhibitors (ICIs) have revolutionized treatment for advanced lung cancer, yet their cardiotoxicity, particularly immune checkpoint inhibitor-related myocarditis, poses significant clinical challenges. This study aims to create a predictive model using cardiac biomarkers to identify patients prone to myocarditis during treatment, thereby enhancing clinical decision-making and patient outcomes.

In this retrospective cohort study, 1,838 patients with locally advanced and metastatic lung cancer and abnormal baseline cardiac parameters receiving immunotherapy from June 2018 to August 2024 were analyzed, with a follow-up date cutoff of September 20, 2024. Patients were randomly divided into training (70%) and validation (30%) cohorts. Logistic regression analysis was conducted on demographic information, clinical characteristics, treatments, and cardiac parameters of these patients prior to immunotherapy. A nomogram was constructed via multivariable logistic regression, and AUC and Hosmer-Lemeshow tests were performed to verify the accuracy of the model.

Among 1,838 patients, 89 (4.84%) developed myocarditis. Independent predictors included α-HBDH > 910 U/L (OR = 10.57, 95%CI: 2.47-45.22, P = 0.001), CK-MB > 15 ng/mL (OR = 3.87, 95%CI: 1.06-14.11, P = 0.040), hs-cTnT elevation (14-28 pg/mL: OR = 4.19; 28-42 pg/mL: OR = 13.10; >42 pg/mL: OR = 25.43, P < 0.001), NT-proBNP > 3× age-adjusted upper limit (OR = 9.72, 95%CI: 1.09-86.73, P = 0.042), and Caprini score ≥ 4 (OR = 4.49, 95%CI: 2.26-8.90, P < 0.001). The nomogram demonstrated strong discrimination ability, with an AUC of 0.831 in the training cohort (sensitivity: 0.842, specificity: 0.717) and an AUC of 0.844 in the validation cohort.

This study establishes a validated risk assessment model integrating cardiac biomarkers (α-HBDH, CK-MB, hs-cTnT, NT-proBNP) and Caprini risk score to predict ICI-related myocarditis in lung cancer patients with cardiac abnormalities. The tool facilitates early identification of high-risk patients, enabling tailored monitoring and preemptive management. These findings underscore the critical role of baseline cardiac profiling in optimizing immunotherapy safety.

Cardio-oncology is an emerging interdisciplinary field concerned with cancer treatment-related cardiovascular toxicities (CTR-CVT) and concomitant cardiovascular diseases (CVD) in patients with cancer. Inflammation and immune system dysregulation are common features of tumors and cardiovascular disease (CVD). In addition to the mutual exacerbating effect through inflammation, tumor treatments, including immunotherapy, chemotherapy, radiation therapy, and targeted therapy, may induce immune inflammatory reactions leading to cardiovascular damage. Cancer immunotherapy is currently a new method of cancer treatment. Immunotherapeutic agents, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptor T cell immunotherapy (CAR-T), mRNA vaccines, etc., can induce anti-tumor effects by enhancing the host immune response to eliminate tumor cells. They have achieved remarkable therapeutic efficacy in clinical settings but lead to many immune-related adverse events (irAEs), especially CTR-CVT. Establishing specific evaluation, diagnostic, and monitoring criteria (e.g., inflammatory biomarkers) for both immunotherapy and anti-inflammatory therapy-related cardiovascular toxicity is vital to guide clinical practice. This article explores the role of immune response and inflammation in tumor cardiology, unravels the underlying mechanisms, and provides improved methods for monitoring and treating in CTR-CVT in the field of cardio-oncology.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by modulating immune responses, leading to enhanced anti-tumor activity. ICIs, including agents targeting cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and programmed cell death ligand, are now widely used in various malignancies, either as monotherapy or in combination with chemotherapy, radiotherapy, or targeted therapies. However, ICIs are associated with immune-related adverse events, affecting multiple organ systems, with myocarditis emerging as a rare but potentially fatal complication. We present a 67-year-old man with a history of prostate and renal cell carcinoma treated with pembrolizumab and lenvatinib, who developed myocarditis secondary to ICI therapy. The patient initially presented with generalized fatigue and bradycardia, later progressing to more severe symptoms, including sinus bradycardia and elevated troponin levels. An electrocardiogram revealed a sinus rhythm with first-degree atrioventricular block, non-specific intraventricular conduction delay, and elevated high-sensitivity troponin levels progressively increasing to 50,000 pg/mL. A comprehensive diagnostic workup ruled out ischemic causes, leading to the diagnosis of ICI-induced myocarditis. The patient was treated with high-dose corticosteroids, intravenous immunoglobulin, and temporary pacemaker insertion, resulting in clinical improvement. This case highlights the need for vigilance and prompt intervention in patients receiving ICI therapy, as early recognition and treatment of myocarditis are crucial to optimizing patient outcomes in this high-risk population.

This investigation aims to identify and evaluate the most common and critical drugs associated with the risk of noninfectious myocarditis utilizing the US Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Data pertaining to noninfectious myocarditis from 2004 Q1 to 2024 Q2 were extracted. Following data standardization, multiple signal quantification techniques, including Reporting Odds Ratio (ROR) and Proportional Reporting Ratio, were employed for analysis.

The study identified a total of 10,763 adverse event reports associated with noninfectious myocarditis. Disproportionality analysis revealed that the top 5 drugs by ROR were phendimetrazine tartrate (ROR 104.64), trimethoprim + sulfamethoxazole (ROR 67.65), aldesleukin (ROR 52.67), mesalazine (ROR 49.73), and balsalazide disodium (ROR 45.26). Notably, among the 30 drugs with the strongest ROR signals, 8 drugs lacked myocarditis risk information in their package inserts.

Through comprehensive analysis of the FAERS database, our study identified drugs with a strong signal for myocarditis that are not currently indicated on their labels. The findings suggest that the potential risk of myocarditis associated with these medications is significant and warrants close monitoring in clinical practice.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, significantly improving survival across various malignancies. However, these therapies are associated with various types of immune-related adverse events (irAEs), including cardiotoxicity, a spectrum of rare but potentially life-threatening complications impacting significantly morbidity and mortality. Cardiovascular imaging has become key in cardio-oncology, providing essential diagnostic tools for early detection and monitoring. This review synthesizes current evidence and underlines the pivotal role of early and tailored imaging strategies in managing ICI-induced cardiotoxicity. By bridging the knowledge gap, it aims to provide targetable insights to optimize the clinical management in patients undergoing immunotherapy.

The field of cardio-oncology has traditionally focused on the impact of cancer and its therapies on cardiovascular health. Mounting clinical and preclinical evidence, however, indicates that the reverse may also be true: cardiovascular disease can itself influence tumor growth and metastasis. Numerous epidemiological studies have reported that individuals with prevalent cardiovascular disease have an increased incidence of cancer. In parallel, studies using preclinical mouse models of myocardial infarction, heart failure, and cardiac remodeling support the notion that cardiovascular disorders accelerate the growth of solid tumors and metastases. These findings have ushered in a new and burgeoning field termed reverse cardio-oncology that investigates the impact of cardiovascular disease pathophysiology on cancer emergence and progression. Recent studies have begun to illuminate the mechanisms driving this relationship, including shared risk factors, reprogramming of immune responses, changes in gene expression, and the release of cardiac factors that result in selective advantages for tumor cells or their local milieu, thus exacerbating cancer pathology. Here, we review the evidence supporting the relationship between cardiovascular disease and cancer, the mechanistic pathways enabling this connection, and the implications of these findings for patient care.

Immune checkpoint inhibitors (ICIs) are successful in treating many cancers but may cause immune-related adverse events. ICI-mediated myocarditis has a high fatality rate with severe cardiovascular consequences. Targeted therapies for ICI myocarditis are currently limited.

We used a genetic mouse model of PD1 deletion (MRL/Pdcd1-/-) along with a novel drug-treated ICI myocarditis mouse model to recapitulate the disease phenotype. We performed single-cell RNA-sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes on immune cells isolated from MRL and MRL/Pdcd1-/- mice at serial time points. We assessed the impact of macrophage deletion in MRL/Pdcd1-/- mice, then inhibited CXCR3 (C-X-C motif chemokine receptor 3) in ICI-treated mice to assess the therapeutic effect on myocarditis phenotype. Furthermore, we delineated the functional and mechanistic effects of CXCR3 blockade on T-cell and macrophage interactions. We then correlated the results in human single-cell multiomics data from blood and heart biopsy data from patients with ICI myocarditis.

Single-cell multiomics demonstrated expansion of CXCL (C-X-C motif chemokine ligand) 9/10+CCR2+ macrophages and CXCR3hi (C-X-C motif chemokine receptor 3 high-expressing) CD8+ (cluster of differentiation) effector T lymphocytes in the hearts of MRL/Pdcd1-/- mice correlating with onset of myocarditis development. Both depletion of CXCL9/10+CCR2+ (C-C motif chemokine receptor) macrophages and CXCR3 blockade, respectively, led to decreased CXCR3hi CD8+ T-cell infiltration into the heart and significantly improved survival. Transwell migration assays demonstrated that the selective blockade of CXCR3 and its ligand, CXCL10, reduced CXCR3+CD8+ T-cell migration toward macrophages, implicating this interaction in T-cell cardiotropism toward cardiac macrophages. Furthermore, cardiomyocyte apoptosis was induced by CXCR3hi CD8+ T cells. Cardiac biopsies from patients with confirmed ICI myocarditis demonstrated infiltrating CXCR3+ T cells and CXCL9+/CXCL10+ macrophages. Both mouse cardiac immune cells and patient peripheral blood immune cells revealed expanded TCRs (T-cell receptors) correlating with CXCR3hi CD8+ T cells in ICI myocarditis samples.

These findings bring forth the CXCR3-CXCL9/10 axis as an attractive therapeutic target for ICI myocarditis treatment, and more broadly as a druggable pathway in cardiac inflammation.

Immune checkpoint inhibitors (ICIs) therapy has revolutionized cancer treatment. However, it is important to acknowledge that ICI therapy can lead to immune-related adverse events (irAEs), including myocarditis. While early-onset myocarditis is well-documented, late-onset cases are increasingly recognized. This case series presents four cases of late-onset ICI-associated myocarditis, emphasizing the need for long-term surveillance of this potentially fatal complication. Patients exhibited a range of cardiac symptoms, including chest pain, shortness of breath, and arrhythmias. The diagnosis was confirmed through cardiac magnetic resonance imaging (MRI) and elevated cardiac biomarkers. Treatment involved the immediate discontinuation of ICI therapy and the initiation of high-dose corticosteroids. In cases with an inadequate response, additional immunosuppressive agents were considered. This case series underscores the importance of prolonged monitoring for late-onset ICI-associated myocarditis. Further research is needed to establish optimal treatment strategies and long-term management approaches for this complex condition.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by unleashing the power of the immune system against malignant cells. However, their use is associated with a spectrum of adverse effects, including cardiovascular complications, which can pose significant clinical challenges. Several mechanisms contribute to cardiovascular toxicity associated with ICIs. First, the dysregulation of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein-1 (PD-1) and its ligand (PD-L1), and molecular mimicry with cardiac autoantigens, leads to immune-related adverse events, including myocarditis and vasculitis. These events result from the aberrant activation of T cells against self-antigens within the myocardium or vascular endothelium. Second, the disruption of immune homeostasis by ICIs can lead to autoimmune-mediated inflammation of cardiac tissues, manifesting as cardiac dysfunction and heart failure, arrhythmias, or pericarditis. Furthermore, the upregulation of inflammatory cytokines, particularly tumor necrosis factor-alpha, interferon-γ, interleukin-1β, interleukin-6, and interleukin-17 contributes to cardiac and endothelial dysfunction, plaque destabilization, and thrombosis, exacerbating cardiovascular risk on the long term. Understanding the intricate mechanisms of cardiovascular side effects induced by ICIs is crucial for optimizing patient care and to ensure the safe and effective integration of immunotherapy into a broader range of cancer treatment protocols. The clinical implications of these mechanisms underscore the importance of vigilant monitoring and early detection of cardiovascular toxicity in patients receiving ICIs. Future use of these key pathological mediators as biomarkers may aid in prompt diagnosis of cardiotoxicity and will allow timely interventions.

Heart failure and cancer remain 2 of the leading causes of morbidity and mortality, and the 2 disease entities are linked in a complex manner. Patients with cancer are at increased risk of cardiovascular complications related to the cancer therapies. The presence of cardiomyopathy or heart failure in a patient with new cancer diagnosis portends a high risk for adverse oncology and cardiovascular outcomes. With the rapid growth of cancer therapies, many of which interfere with cardiovascular homeostasis, heart failure practitioners need to be familiar with prevention, risk stratification, diagnosis, and management strategies in cardio-oncology. This Heart Failure Society of America statement addresses the complexities of heart failure care among patients with active cancer diagnoses and cancer survivors. Risk stratification, monitoring and management of cardiotoxicity are presented across stages A through D heart failure, with focused discussion on heart failure with preserved ejection fraction and special populations, such as survivors of childhood and young-adulthood cancers. We provide an overview of the shared risk factors between cancer and heart failure, highlighting heart failure as a form of cardiotoxicity associated with many different cancer therapeutics. Finally, we discuss disparities in the care of patients with cancer and cardiac disease and present a framework for a multidisciplinary-team approach and critical collaboration among heart failure, oncology, palliative care, pharmacy, and nursing teams in the management of these complex patients.

Immune checkpoint inhibitor (ICI)-associated myocarditis is a rare but potentially fatal immune-related adverse event. Previously, we reported a case of ICI-associated myocarditis with elevated autoantibodies to 4E-binding protein 3 (4E-BP3). Recent studies have suggested that 4E-BP3 may play an important role in tumor development. However, its role in cardiac diseases including myocarditis is unknown. We investigated the role of 4E-BP3 in an autoimmune myocarditis mouse model. Myocarditis was induced in wild-type and 4E-BP3 knockout mice by immunization with murine α-myosin peptide. 4E-BP3 gene expression was upregulated in the heart of myocarditis mouse. We found that genetic deletion of 4E-BP3 attenuated myocardial inflammation, reduced fibrosis area, and improved cardiac function in myocarditis mice. Studies in bone marrow-chimeric mice demonstrated that immune cell-derived 4E-BP3 plays a pivotal role in the pathogenesis of myocarditis. Immune cell transfer experiments revealed that 4E-BP3 deficiency in dendritic cells and CD4+ T cells decreased disease severity in recipient mice. Furthermore, dendritic cells that were deficient in 4E-BP3 exhibited a diminished capacity to produce IL-6 and IL-1β. Naive CD4+ T cells lacking 4E-BP3 had a reduced ability to differentiate into T-helper (Th)1 and Th17 cells. These findings suggest that 4E-BP3 in dendritic cells and CD4+ T cells may be critically involved in the pathogenesis of α-myosin-specific T cell-mediated myocarditis. Thus, 4E-BP3 could be a possible therapeutic target for myocarditis.

Immune checkpoint inhibitors (ICIs), such as pembrolizumab, have revolutionized cancer treatment by enhancing the immune system's response to malignancies. However, these therapies are associated with immune-related adverse events (irAEs), including neuromuscular complications such as myasthenia gravis, myositis, and myocarditis. We describe two male patients, aged 67 and 68, with small cell and non-small cell lung cancers, who developed progressive neuromuscular symptoms, including ptosis, diplopia, and generalized weakness, after receiving pembrolizumab. Clinical, biochemical, imaging, and electrophysiological findings confirmed the diagnosis of myositis with myastheniform features, with one case also involving myocarditis. Both patients underwent treatments with intravenous immunoglobulin (IVIg), pyridostigmine, and corticosteroids. The first patient, despite aggressive treatment including plasma exchange and rituximab, succumbed to complications from aspiration pneumonia. The second patient showed partial response to pyridostigmine and IVIg but later died due to metastatic cancer progression. A literature review revealed 52 cases of pembrolizumab-associated myositis with myastheniform symptoms, emphasizing its high morbidity and the need for vigilant monitoring. Pembrolizumab-associated myositis with myastheniform symptoms, especially when accompanied by myocarditis, presents a significant clinical challenge with high mortality. Early recognition and aggressive management of these irAEs are crucial to improving outcomes in cancer patients receiving ICIs.

Herein, we present a case of severe immune-related adverse events (irAEs), myocarditis with myositis, and myasthenia gravis overlap syndrome (IM3OS) in a patient receiving an immune checkpoint inhibitor (ICI), as adjuvant therapy after surgery for muscle-invasive bladder cancer. An 80-year-old woman who had undergone a total cystectomy for bladder cancer presented with ptosis, diplopia, and paralysis 18 days after receiving nivolumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody, as adjuvant therapy for the first time. Initial testing revealed positive findings on the ice pack test; elevated troponin, creatine kinase, and aldolase levels; and an abnormal electrocardiogram, suggesting that the patient had developed ICI-related myocarditis, myositis, and myasthenia gravis. Despite treatment with intravenous immunoglobulin (IVIG) and high-dose corticosteroids, her condition worsened, leading to a complete atrioventricular block. After cardiac pacemaker insertion and intensive treatment with repeated high-dose corticosteroids, IVIG, plasma exchange, and tacrolimus, left ventricular function and myositis symptoms improved. However, the patient developed a respiratory infection and renal failure, leading to death on day 99. Although ICIs are considered relatively safe with few side effects, they can cause serious complications and lead to death. In particular, when severe irAEs occur in multiple organs, such as IM3OS, the prognosis is poor. Although IM3OS has no specific diagnostic biomarker, making early detection difficult, clinicians should always pay attention to patient symptoms when using ICI and evaluate other pathologies with IM3OS when conditions such as myositis or myocarditis are suspected. Further research is needed to elucidate the pathophysiology and risk factors of IM3OS.

Immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy have revolutionized cancer treatment but can cause life-threatening cardiovascular toxicities through immune-related adverse events. Myocarditis is the most common and potentially fatal toxicity with immune checkpoint inhibitors. T-cell therapies can potentially lead to cytokine release syndrome. Diagnosis of ICI-myocarditis requires a multimodal approach, including biomarkers, imaging, and endomyocardial biopsy, while CRS is characterized by a clinical syndrome resembling distributive shock. Management involves discontinuing the offending therapy, immunosuppression with corticosteroids for ICI-myocarditis, and interleukin-6 antagonists for CRS. Collaboration between oncologists and cardiologists is crucial for early recognition and prompt treatment.

Immune-checkpoint-inhibitors (ICI) target key regulators of the immune system expressed by cancer cells that mask those from recognition by the immune system. They have improved the outcome for patients with various cancer types, such as melanoma. ICI-based therapy is frequently accompanied by immune-related adverse side effects (IRAEs). The reversible melanoma cancer mouse model (B16F10 cells stably expressing a ganciclovir (GCV)-inducible suicide gene in C57BL/6N mice: B16F10-GCV) allows chemotherapy-free tumor elimination in advanced disease stage and demonstrates almost complete recovery of the mouse heart from cancer-induced atrophy, molecular impairment and heart failure. Thus, enabling the study of anti-cancer-therapy effects. Here, we analyzed potential cardiac side effects of antibody-mediated PD-L1 inhibition in the preclinical B16F10-GCV mouse model after tumor elimination and 2 weeks recovery (50 days after tumor inoculation). Anti-PD-L1 treatment was associated with improved survival as compared to isotype control (Ctrl) treated mice. Surviving anti-PD-L1 and Ctrl mice showed similar cardiac function, dimensions and the expression of cardiac stress and hypertrophy markers. Although anti-PD-L1 treatment was associated with increased troponin I type 3 cardiac (TNNI3) blood levels, cardiac mRNA expression of macrophage markers and elevated cardiac levels of secreted inflammatory factors compared to Ctrl treatment, both groups showed a comparable density of inflammatory cells in the heart (using CXCR4-ligand 68Ga-Pentixafor in PET-CT and immunohistochemistry). Thus, anti-PD-L1 therapy improved survival in mice with advanced melanoma cancer with no major cardiac phenotype or inflammation 50 days after tumor inoculation. Without a second hit that triggers the inflammatory response, anti-PD-L1 treatment appears to be safe for the heart in the preclinical melanoma mouse model.

Breast cancer (BC) survivors are at increased risk for cardiovascular disease (CVD) and require their primary care physicians to manage their long-term general medical care, including cardiovascular (CV) health. Yet, evidence exists that some primary care physicians possess insufficient knowledge about survivorship care. With the goal of bridging these knowledge gaps, a PubMed review was conducted from July 7, 2020, through October 2, 2020, with an updated PubMed review from January 3, 2024, through April 28, 2024, focusing on CV health considerations in the primary care of BC survivors. Search terms included variations of "breast cancer survivors" and "cardiovascular." In total, 152 publications were included. Breasts cancer survivors may have increased CVD risk because some anticancer therapies are cardiotoxic and risk factors for BC often also increase the risk for CVD. Multiple risk factors overlap for BC and CVD such as older age, Western diet, early menarche, physical inactivity, high body mass index, and smoking. In this review, results are summarized from studies that report the presence of CV risk factors and CVD in BC survivors. Also described are the CV effects of BC therapies (chemotherapy, hormonal agents, targeted therapies, and radiotherapy) and the type of CV evaluation (cardiac imaging and measurement of biomarkers) that these patients may need. Primary care physicians have an important role in managing the CV health of BC survivors from preventing, assessing, and managing CV risk factors to referring patients to appropriate specialists when needed.

Patients with cancer have elevated cardiovascular risks compared to those without cancer. As cancer incidence increases and cancer-related mortality decreases, cardiovascular diseases in patients with a history of cancer will become increasingly important. This in turn is reflected by the exponentially increasing amount of cardio-oncology research in recent years. This narrative review aims to summarize the key existing literature in several main areas of cardio-oncology, including the epidemiology, natural history, prevention, management, and determinants of the cardiovascular health of patients with cancer, and identify relevant gaps in evidence for further research.

Neoplastic transformation reprograms tumor and surrounding host cell metabolism, increasing nutrient consumption and depletion in the tumor microenvironment. Tumors uptake nutrients from neighboring normal tissues or the bloodstream to meet energy and anabolic demands. Tumor-induced chronic inflammation, a high-energy process, also consumes nutrients to sustain its dysfunctional activities. These tumor-related metabolic and physiological changes, including chronic inflammation, negatively impact systemic metabolism and physiology. Furthermore, the adverse effects of antitumor therapy and tumor obstruction impair the endocrine, neural, and gastrointestinal systems, thereby confounding the systemic status of patients. These alterations result in decreased appetite, impaired nutrient absorption, inflammation, and shift from anabolic to catabolic metabolism. Consequently, cancer patients often suffer from malnutrition, which worsens prognosis and increases susceptibility to secondary adverse events. This review explores how neoplastic transformation affects tumor and microenvironment metabolism and inflammation, leading to poor prognosis, and discusses potential strategies and clinical interventions to improve patient outcomes.

As the understanding of immune-related mechanisms in the development and progression of cancer advances, immunotherapies, notably Immune Checkpoint Inhibitors (ICIs), have become integral in comprehensive cancer treatment strategies. ICIs reactivate T-cell cytotoxicity against tumors by blocking immune suppressive signals on T cells, such as Programmed Death-1 (PD-1) and Cytotoxic T-lymphocyte Antigen-4 (CTLA-4). Despite their beneficial effects, ICIs are associated with immune-related adverse events (irAEs), manifesting as autoimmune side effects across various organ systems. A particularly alarming irAE is life-threatening myocarditis. This rare but severe side effect of ICIs leads to significant long-term cardiac complications, including arrhythmias and heart failure, and has been observed to have a mortality rate of up to 50% in affected patients. This greatly limits the clinical application of ICI-based immunotherapy. In this review, we provide a comprehensive summary of the current knowledge regarding the diagnosis and management of ICI-related myocarditis. We also discuss the utility of preclinical mouse models in understanding and addressing this critical challenge.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of several malignancies, with improved survival. These monoclonal antibodies target immune checkpoints, including cytotoxic T-lymphocyte-associated protein 4 (ipilimumab and tremelimumab), programmed death 1 (nivolumab, pembrolizumab, cemiplimab, and dostarlimab), programmed death ligand 1 (atezolizumab, avelumab, and durvalumab), and lymphocyte activation gene 3 (relatlimab), and effectively augment the immune response against tumor cells. Releasing the brakes on the immune system has consequences, however, in the form of immune-related adverse events (irAEs), which may affect any organ. Neurologic irAEs represent 1%-3% of all irAEs, with immune-mediated myopathy (ICI myopathy) being the most common manifestation. Recent large patient series and systematic reviews have established the key features and highlighted new insights into ICI myopathy. ICI myopathy is characterized by an acute or subacute onset of oculobulbar and/or proximal limb weakness, with or without associated respiratory insufficiency and myocarditis. Creatine kinase elevation is common. Oculobulbar presentations with or without respiratory failure may be misattributed to neuromuscular junction disorders, particularly because acetylcholine receptor antibodies are present in up to 40% of patients; however, an electrodiagnostic evidence of a defect of neuromuscular transmission is often absent even in patients with severe weakness, highlighting that the myopathic process is the driving force behind these presentations. Muscle histopathology commonly demonstrates a unique signature of multifocal clusters of necrotic and regenerating fibers, differentiating ICI myopathy from other autoimmune myopathies. Transcriptomic analysis has uncovered distinct subgroups within ICI myopathy, revealing varying degrees of type 1 and type 2 interferon pathway activation alongside notable upregulation of the interleukin (IL)-6 pathway in affected muscle tissue. This discovery presents a promising avenue for intervention through the use of therapies that suppress the interferon pathway and target IL-6 or its receptor. Despite clinical improvements with immunomodulatory therapy, with corticosteroids the mainstay of treatment, mortality remains high, particularly in those with associated myocarditis or respiratory failure requiring intubation, where mortality occurs in up to 50%. ICI withdrawal can lead to cancer progression and death, highlighting a need for improved approaches to ICI rechallenge, performed in limited patients with variable success to date.

There is an urgent need to better understand the diverse presentations, risk factors, and outcomes of immune checkpoint inhibitor (ICI)-associated cardiovascular toxicity. There remains a lack of consensus surrounding cardiovascular screening, risk stratification, and clinical decision-making in patients receiving ICIs.

We conducted a single center retrospective cohort study including 2165 cancer patients treated with ICIs between 2013 and 2020. The primary outcome was adverse cardiovascular events (ACE): a composite of myocardial infarction, coronary artery disease, stroke, peripheral vascular disease, arrhythmias, heart failure, valvular disease, pericardial disease, and myocarditis. Secondary outcomes included all-cause mortality and the individual components of ACE. We additionally conducted an imaging substudy examining imaging characteristics from echocardiography (echo) and cardiac magnetic resonance (CMR) imaging.

In our cohort, 44% (n = 962/2165) of patients experienced ACE. In a multivariable analysis, dual ICI therapy (hazard ratio [HR] 1.23, confidence interval [CI] 1.04-1.45), age (HR 1.01, CI 1.00-1.01), male sex (HR 1.18, CI 1.02-1.36), prior arrhythmia (HR 1.22, CI 1.03-1.43), lung cancer (HR 1.17, CI 1.01-1.37), and central nervous system (CNS) malignancy (HR 1.23, CI 1.02-1.47), were independently associated with increased ACE. ACE was independently associated with a 2.7-fold increased risk of mortality (P<0.001). Dual ICI therapy was also associated with a 2.0-fold increased risk of myo/pericarditis (P = 0.045), with myo/pericarditis being associated with a 2.9-fold increased risk of mortality (P<0.001). However, the cardiovascular risks of dual ICI therapy were offset by its mortality benefit, with dual ICI therapy being associated with a ~25% or 1.3-fold decrease in mortality. Of those with echo prior to ICI initiation, 26% (n = 115/442) had abnormal left ventricular ejection fraction or global longitudinal strain, and of those with echo after ICI initiation, 28% (n = 207/740) had abnormalities. Of those who had CMR imaging prior to ICI initiation, 43% (n = 9/21) already had left ventricular dysfunction, 50% (n = 10/20) had right ventricular dysfunction, 32% (n = 6/19) had left ventricular late gadolinium enhancement, and 9% (n = 1/11) had abnormal T2 imaging.

Dual ICI therapy, prior arrhythmia, older age, lung and CNS malignancies were independently associated with an increased risk of ACE, and dual ICI therapy was also independently associated with an increased risk of myo/pericarditis, highlighting the utmost importance of cardiovascular risk factor optimization in this particularly high-risk population. Fortunately, the occurrence of myo/pericarditis was relatively uncommon, and the overall cardiovascular risks of dual ICI therapy appeared to be offset by a significant mortality benefit. The use of multimodal cardiac imaging can be helpful in stratifying risk and guiding preventative cardiovascular management in patients receiving ICIs.

Immunotherapy has become a pillar of modern oncological management but is associated with significant immunotherapy-related adverse events (IRAEs). While myocarditis is a prominent IRAE which clinicians are increasingly aware of, immunotherapy-related coronary vasospasm is far less appreciated and can be especially difficult to elucidate in pre-existing coronary artery disease. This case demonstrates the approach to diagnosis and management of multiple cardiovascular and non-cardiovascular IRAEs.

A 57-year-old male with a history of metastatic melanoma on combined immunotherapy and ischaemic heart disease with multiple previous percutaneous coronary interventions presented with typical chest pain and troponin rise. Differential diagnoses for this presentation included a non-ST elevation myocardial infarction, myocarditis, and coronary vasospasm. Coronary angiogram did not reveal any new significant obstructive coronary artery disease while cardiac MRI did not reveal any radiological features consistent with myocarditis. However, empirical treatment for IRAEs resulted in both clinical and biochemical improvement and ability to discharge the patient on steroids and coronary vasodilators, having been GTN-infusion dependent as an inpatient.

Cardiovascular IRAEs are important to be aware of when managing patients on immunotherapy and more than one IRAE can occur concurrently. Given the caveats of non-invasive imaging and invasive nature of endomyocardial biopsy, the clinical history is key in establishing these crucial diagnoses which will significantly impact ongoing oncological management.

Immune checkpoint inhibitors are widely used anticancer therapies1 that can cause morbid and potentially fatal immune-related adverse events such as immune-related myocarditis (irMyocarditis)2-5. The pathogenesis of irMyocarditis and its relationship to antitumour immunity remain poorly understood. Here we sought to define immune responses in heart, tumour and blood in patients with irMyocarditis by leveraging single-cell RNA sequencing coupled with T cell receptor (TCR) sequencing, microscopy and proteomics analyses of samples from 28 patients with irMyocarditis and 41 unaffected individuals. Analyses of 84,576 cardiac cells by single-cell RNA sequencing combined with multiplexed microscopy demonstrated increased frequencies and co-localization of cytotoxic T cells, conventional dendritic cells and inflammatory fibroblasts in irMyocarditis heart tissue. Analyses of 366,066 blood cells revealed decreased frequencies of plasmacytoid dendritic cells, conventional dendritic cells and B lineage cells but an increased frequency of other mononuclear phagocytes in irMyocarditis. Fifty-two heart-expanded TCR clones from eight patients did not recognize the putative cardiac autoantigens α-myosin, troponin I or troponin T. Additionally, TCRs enriched in heart tissue were largely nonoverlapping with those enriched in paired tumour tissue. The presence of heart-expanded TCRs in a cycling blood CD8 T cell population was associated with fatal irMyocarditis case status. Collectively, these findings highlight crucial biology driving irMyocarditis and identify putative biomarkers.

Immunotherapy has revolutionized cancer treatment in the last decade and has significantly improved patient survival. However, immunotherapy is associated with serious cardiac adverse events including myocarditis and conduction disturbances. In the literature, the mortality rate in patients with immunotherapy-associated myocarditis and complete AV block is reported to be approximately 60%. Current cardio-oncology guidelines provide a series of recommendations for the management of immune myocarditis (IM). However, there is no recommendation on whether or when pacemaker implantation should be performed in the setting of complete AV block associated with myocarditis. This gap in the literature has led to a trend in cardio-oncology practice to implant permanent pacemakers (PPMs) in a significant proportion of patients without waiting for a response to immunosuppressive therapy. However, in a significant proportion of patients undergoing PPM implantation, complete AV block resolves after immunosuppressive therapy. This suggests that in cases of complete AV block in the setting of IM, more robust clues are needed for PPM implantation. This review aims to present algorithms for the management of myocarditis and complete AV block, one of the most lethal complications of immunotherapy, to help fill this gap in the literature.