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The landscape of cancer therapeutics is continually evolving, with successes in improved survivorship and reduced disease progression for many patients with cancer. Improved cancer outcomes expose competing comorbidities, some of which may be exacerbated by cancer therapies. The leading cause of disability and death for many early-stage cancers is cardiovascular disease (CVD), which is often attributed to direct or indirect cardiac injury from cancer therapy. In this review, the authors propose that toxicities related to conventional and novel cancer therapeutics should be considered beyond the heart. The authors provide a framework using the oxygen pathway to understand the impact of cancer treatment on peak oxygen uptake, a marker of integrative cardiopulmonary function and CVD risk. Peripheral toxicities and the impact on oxygen transport are discussed. Consideration for the broad effects of cancer therapies will improve the prediction and identification of cancer survivors at risk for CVD, functional disability, and premature mortality and those who would benefit from therapeutic intervention, ultimately improving patient outcomes.

ABSTRACT: The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell‐based immune therapies including chimeric antigen receptor T lymphocyte (CAR‐T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune‐related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune‐related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI‐related myocarditis with cardiogenic shock to more common complications including less severe ICI‐related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non‐inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR‐T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.

Global collaboration in cardio-oncology is needed to understand the prevalence of cancer therapy-related cardiovascular toxicity in different risk groups, practice settings, and geographic locations. There are limited data on the socioeconomic and racial/ethnic disparities that may impact access to care and outcomes. To address these gaps, we established the Global Cardio-Oncology Registry, a multinational, multicenter prospective registry.We assembled cardiologists and oncologists from academic and community settings to collaborate in the first Global Cardio-Oncology Registry. Subsequently, a survey for site resources, demographics, and intention to participate was conducted. We designed an online data platform to facilitate this global initiative.A total of 119 sites responded to an online questionnaire on their practices and main goals of the registry: 49 US sites from 23 states and 70 international sites from 5 continents indicated a willingness to participate in the Global Cardio-Oncology Registry. Sites were more commonly led by cardiologists (85/119; 72%) and were more often university/teaching (81/119; 68%) than community based (38/119; 32%). The average number of cardio-oncology patients treated per month was 80 per site. The top 3 Global Cardio-Oncology Registry priorities in cardio-oncology care were breast cancer, hematologic malignancies, and patients treated with immune checkpoint inhibitors. Executive and scientific committees and specific committees were established. A pilot phase for breast cancer using Research Electronic Data Capture Cloud platform recently started patient enrollment.We present the structure for a global collaboration. Information derived from the Global Cardio-Oncology Registry will help understand the risk factors impacting cancer therapy-related cardiovascular toxicity in different geographic locations and therefore contribute to reduce access gaps in cardio-oncology care. Risk calculators will be prospectively derived and validated.

Takotsubo syndrome (TTS) occurs more frequently in cancer patients than in the general population, but the effect of specific TTS triggers on outcomes in cancer patients is not well studied.The study sought to determine whether triggering event (chemotherapy, immune-modulators vs. procedural or emotional stress) modifies outcomes in a cancer patient population with TTS.All cancer patients presenting with acute coronary syndrome (ACS) between December 2008 and December 2020 at our institution were enrolled in the catheterization laboratory registry. Demographic and clinical data of the identified patients with TTS were retrospective collected and further classified according to the TTS trigger. The groups were compared with regards to major adverse cardiac events, overall survival and recovery of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) after TTS presentation.Eighty one of the 373 cancer patients who presented with ACS met the Mayo criteria for TTS. The triggering event was determined to be "cancer specific triggers" (use of chemotherapy in 23, immunomodulators use in 7, and radiation in 4), and "traditional triggers" (medical triggers 22, and procedural 18 and emotional stress in 7). Of the 81 patients, 47 died, all from cancer-related causes (no cardiovascular mortality). Median survival was 11.9 months. Immunomodulator (IM) related TTS and radiation related TTS were associated with higher mortality during the follow-up. Patients with medical triggers showed the least recovery in LVEF and GLS while patients with emotional and chemotherapy triggers, showed the most improvement in LVEF and GLS, respectively.Cancer patients presenting with ACS picture have a high prevalence of TTS due to presence of traditional and cancer specific triggers. Survival and improvement in left ventricular systolic function seem to be related to the initial trigger for TTS.

Background and Objectives: Cancer and coronary artery disease (CAD) often coexist. Compared to quantitative coronary angiography (QCA), fractional flow reserve (FFR) has emerged as a more reliable method of identifying significant coronary stenoses. We aimed to assess the specific management, safety and outcomes of FFR-guided percutaneous coronary intervention (PCI) in cancer patients with stable CAD. Materials and Methods: FFR was used to assess cancer patients that underwent coronary angiography for stable CAD between September 2008 and May 2016, and were found to have ≥50% stenosis by QCA. Patients with lesions with an FFR > 0.75 received medical therapy alone, while those with FFR ≤ 0.75 were revascularized. Procedure-related complications, all-cause mortality, nonfatal myocardial infarction, or urgent revascularizations were analyzed. Results: Fifty-seven patients with stable CAD underwent FFR on 57 lesions. Out of 31 patients with ≥70% stenosis as measured by QCA, 14 (45.1%) had an FFR ≥ 0.75 and lesions were reclassified as moderate and did not receive PCI nor DAPT. Out of 26 patients with

While pre-existing cardiovascular disease (CVD) appears to be associated with poor outcomes in patients with Coronavirus Disease 2019 (COVID-19), data on patients with CVD and concomitant cancer is limited. The purpose of this study is to evaluate the effect of underlying CVD and CVD risk factors with cancer history on in-hospital mortality in those with COVID-19.Data from symptomatic adults hospitalized with COVID-19 at 86 hospitals in the US enrolled in the American Heart Association's COVID-19 CVD Registry was analyzed. The primary exposure was cancer history. The primary outcome was in-hospital death. Multivariable logistic regression models were adjusted for demographics, CVD risk factors, and CVD. Interaction between history of cancer with concomitant CVD and CVD risk factors were tested.Among 8222 patients, 892 (10.8%) had a history of cancer and 1501 (18.3%) died. Cancer history had significant interaction with CVD risk factors of age, body mass index (BMI), and smoking history, but not underlying CVD itself. History of cancer was significantly associated with increased in-hospital death (among average age and BMI patients, adjusted odds ratio [aOR] = 3.60, 95% confidence interval [CI]: 2.07-6.24; p

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

BACKGROUND: The National Comprehensive Cancer Network and American Society of Clinical Oncology recommend consideration of the use of echocardiography 6 to 12 months after completion of anthracycline-based chemotherapy in at-risk populations. Assessment of BNP (B-type natriuretic peptide) has also been suggested by the American College of Cardiology/American Heart Association/Heart Failure Society of America for the identification of Stage A (at risk) heart failure patients. The real-world frequency of the use of these tests in patients after receipt of anthracycline therapy, however, has not been studied previously. METHODS AND RESULTS: In this retrospective study, using administrative claims data from the OptumLabs Data Warehouse, we identified 31 447 breast cancer and lymphoma patients (age ≥18 years) who were treated with an anthracycline in the United States between January 1, 2008 and January 31, 2018. Continuous medical and pharmacy coverage was required for at least 6 months before the initial anthracycline dose and 12 months after the final dose. Only 36.1% of patients had any type of cardiac surveillance (echocardiography, BNP, or cardiac imaging) in the year following completion of anthracycline therapy (29.7% echocardiography). Surveillance rate increased from 37.5% in 2008 to 42.7% in 2018 (25.6% in 2008 to 40.5% echocardiography in 2018). Lymphoma patients had a lower likelihood of any surveillance compared with patients with breast cancer (odds ratio, 0.79 [95% CI, 0.74-0.85]; P50% rate of surveillance. CONCLUSIONS: The majority of survivors of breast cancer and lymphoma who have received anthracycline-based chemotherapy do not undergo cardiac surveillance after treatment, including those with a history of cardiovascular comorbidities, such as heart failure.

The increased risk for cardiovascular events in aging cancer survivors and those undergoing certain chemotherapeutic treatments has raised concern for more rigorous screening and surveillance methods above that of the general population. At this time, there are limited guidelines for how to best manage this vulnerable cohort. Questions regarding timing of screening, choice of imaging modality and risk reduction strategies-especially in those patients with known atherosclerotic disease-remain to be elucidated. Over a decade of case series, retrospective studies and clinical trials have shed light on the evolving role of cardiac computed tomography (CT) in this population, of which there is a relative paucity of data regarding its potential utility in the specific cardio-oncology population. Focusing on ability of cardiac CT to evaluate multiple cardiac and vascular structures, provide diagnostic and prognostic information, as well as assist interventional and surgical colleagues in surgical/percutaneous valve replacement and revascularization strategies is the premise for this review.

Cardio-oncology has organically developed as a new discipline within cardiovascular medicine as a result of the cardiac and vascular adverse sequelae of the major advances in cancer treatment. Patients with cancer and cancer survivors are at increased risk of vascular disease for a number of reasons. First, many new cancer therapies, including several targeted therapies, are associated with vascular and metabolic complications. Second, cancer itself serves as a risk factor for vascular disease, especially by increasing the risk for thromboembolic events. Finally, recent data suggest that common modifiable and genetic risk factors predispose to both malignancies and cardiovascular disease. Vascular complications in patients with cancer represent a new challenge for the clinician and a new frontier for research and investigation. Indeed, vascular sequelae of novel targeted therapies may provide insights into vascular signaling in humans. Clinically, emerging challenges are best addressed by a multidisciplinary approach in which cardiovascular medicine specialists and vascular biologists work closely with oncologists in the care of patients with cancer and cancer survivors. This novel approach realizes the goal of providing superior care through the creation of cardio-oncology consultative services and the training of a new generation of cardiovascular specialists with a broad understanding of cancer treatments.

Targeting NLRP3 inflammasome has been recognized as a promising therapeutic strategy for the treatment of numerous common diseases. UK5099, a long‐established inhibitor of mitochondrial pyruvate carrier (MPC), is previously found to inhibit macrophage inflammatory responses independent of MPC expression. However, the mechanisms by which UK5099 inhibit inflammatory responses remain unclear. Here, it is shown that UK5099 is a potent inhibitor of the NLRP3 inflammasome in both mouse and human primary macrophages. UK5099 selectively suppresses the activation of the NLRP3 but not the NLRC4 or AIM2 inflammasomes. Of note, UK5099 retains activities on NLRP3 in macrophages devoid of MPC expression, indicating this inhibitory effect is MPC‐independent. Mechanistically, UK5099 abrogates mitochondria‐NLRP3 interaction and in turn inhibits the assembly of the NLRP3 inflammasome. Further, a single dose of UK5099 persistently reduces IL‐1β production in an endotoxemia mouse model. Importantly, structure modification reveals that the inhibitory activities of UK5099 on NLRP3 are unrelated to the existence of the activated double bond within the UK5099 molecule. Thus, this study uncovers a previously unknown molecular target for UK5099, which not only offers a new candidate for the treatment of NLRP3‐driven diseases but also confounds its use as an MPC inhibitor in immunometabolism studies. [ABSTRACT FROM AUTHOR]