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OBJECTIVE: In obesity and diabetes, myocardial fatty acid utilization and myocardial oxygen consumption (MVo(2)) are increased, and cardiac efficiency is reduced. Mitochondrial uncoupling has been proposed to contribute to these metabolic abnormalities but has not been directly demonstrated. RESEARCH DESIGN AND METHODS: Oxygen consumption and cardiac function were determined in db/db hearts perfused with glucose or glucose and palmitate. Mitochondrial function was determined in saponin-permeabilized fibers and proton leak kinetics and H(2)O(2) generation determined in isolated mitochondria. RESULTS: db/db hearts exhibited reduced cardiac function and increased MVo(2). Mitochondrial reactive oxygen species (ROS) generation and lipid and protein peroxidation products were increased. Mitochondrial proliferation was increased in db/db hearts, oxidative phosphorylation capacity was impaired, but H(2)O(2) production was increased. Mitochondria from db/db mice exhibited fatty acid-induced mitochondrial uncoupling that is inhibitable by GDP, suggesting that these changes are mediated by uncoupling proteins (UCPs). Mitochondrial uncoupling was not associated with an increase in UCP content, but fatty acid oxidation genes and expression of electron transfer flavoproteins were increased, whereas the content of the F1 alpha-subunit of ATP synthase was reduced. CONCLUSIONS: These data demonstrate that mitochondrial uncoupling in the heart in obesity and diabetes is mediated by activation of UCPs independently of changes in expression levels. This likely occurs on the basis of increased delivery of reducing equivalents from beta-oxidation to the electron transport chain, which coupled with decreased oxidative phosphorylation capacity increases ROS production and lipid peroxidation. [ABSTRACT FROM AUTHOR]

Introduction: The shared risk profiles for cancer and heart disease suggest many individuals with cancer may have an implantable cardioverter defibrillator (ICD). ICDs can have dramatic cancer end-of-life care implications including painful and distressing shocks. ICD prevalence and association with aggressive end-of-life care among individuals with breast, colorectal, and pancreatic cancer was evaluated using the Surveillance, Epidemiology, and End Results-Medicare dataset., Methods: A total of 37,306 Medicare beneficiaries aged ≥66 years with stage 3 or 4 cancer who died between 2005 and 2016 were identified. ICD prevalence, ICD-related care utilization that might present opportunities to discuss end-of-life implications and association with aggressive end-of-life care (>1 emergency department visit, intensive care unit admission, >1 hospitalization, terminal hospitalization, chemotherapy, and invasive or life-extending procedures) in the last month of life was assessed using multivariable logistic regression., Results: Among cancer decedents, 6% had an ICD. More individuals with an ICD (31%) died in the hospital than individuals without an ICD (25%; p < .001). Half (46%) of individuals with an ICD had device programming or interrogation visits that could be an opportunity for device discussion. In adjusted models, ICD presence was associated with higher odds of every indicator of aggressive end-of-life care other than chemotherapy., Conclusion: Many older cancer decedents in the United States had an ICD, and those with ICDs received more aggressive care at the end of life. Results suggest there are opportunities to discuss ICD and goals of care, raise awareness and encourage shared decision-making for this population to ensure goal-concordant care, and improve end-of-life care quality., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

The NCCN Guidelines for the Management of Immunotherapy-Related Toxicities are intended to provide oncology practitioners with guidance on how to manage the wide-ranging and potentially fatal toxicities that may occur with cancer immunotherapy. The guidelines address immune-related adverse events related to immune checkpoint inhibitors, CAR T-cell therapies, and lymphocyte engagers (which include T-cell-engaging bispecific antibodies). These NCCN Guidelines Insights highlight recent guideline updates pertaining to the management of emerging toxicities related to cancer immunotherapy.

Introduction: The multidisciplinary American Radium Society Thoracic Committee was assigned to create appropriate use criteria on cardiac toxicity prevention and management for patients undergoing radiotherapy., Methods: A systematic review of the current literature was conducted. Case variants of patients with thoracic malignancies undergoing radiation were created based on presence or absence of cardiovascular risk factors and treatment-related risks assessed by dose exposure to the heart and cardiac substructures. Modified Delphi methodology was used to evaluate the variants and procedures, with less than or equal to three rating points from median defining agreement/consensus., Results: A total of six variants were evaluated. The panel felt that patients with cardiac comorbidities at high risk for radiation-related cardiac toxicity should undergo a prescreening cardiac-focused history and physical (H&P) examination, electrocardiogram, cardiac imaging including an echocardiogram, and referral to a cardiologist/cardio-oncologist. Recommendations for those without cardiac comorbidities at low risk for cardiac toxicity were to undergo a baseline H&P examination only. Conversely, those without cardiac comorbidities but at high risk for radiation-related cardiac toxicity were recommended to undergo a prescreening electrocardiogram, in addition to a H&P examination. For patients with cardiac comorbidities at low risk for cardiac toxicity, the panel felt that prescreening and postscreening tests may be appropriate., Conclusions: The American Radium Society Thoracic appropriate use criteria panel has developed multidisciplinary consensus guidelines for cardiac toxicity prevention, surveillance, and management after thoracic radiotherapy based on cardiac comorbidities at presentation and risk of radiation-related cardiac toxicity., Competing Interests: Disclosure All panelists were required to declare all conflicts of interest for the previous 36 months before initiating work on this document. These complete disclosure forms are retained by the American Radium Society in perpetuity. The American Radium Society Appropriate Use Criteria Steering Committee reviewed these disclosures with the chair and co-chair of this document and approved participation of the panelists before starting development of this work., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

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.

Cardiovascular and cancer outcomes intersect within the realm of cardio-oncology survivorship care, marked by disparities across ethnic, racial, social, and geographical landscapes. Although the clinical community is increasingly aware of this complex issue, effective solutions are trailing. To attain substantial public health impact, examinations of cancer types and cardiovascular risk mitigation require complementary approaches that elicit the patient's perspective, scale it to a population level, and focus on actionable population health interventions. Adopting such a multidisciplinary approach will deepen our understanding of patient awareness, motivation, health literacy, and community resources for addressing the unique challenges of cardio-oncology. Geospatial analysis aids in identifying key communities in need within both granular and broader contexts. In this review, we delineate a pathway that navigates barriers from individual to community levels. Data gleaned from these perspectives are critical in informing interventions that empower individuals within diverse communities and improve cardio-oncology survivorship., Competing Interests: The research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under award number UL1 TR003163. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH (National Institutes of Health). Dr Hong has received support from the Texas Health Resources Clinical Scholars program, American Cancer Society Clinician Scientist Development Grant, CSDG-20-023-01-CPHPS. Drs Smith-Morris and Zaha have received support from the Harold C. Simmons Comprehensive Cancer Center and the Cancer Center Support Grant (P30CA142543). Dr Zaha has received support from the Cancer Prevention Research Institute of Texas, award RP180404. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Hematopoietic stem cell transplantation can cure various disorders but poses cardiovascular risks, especially for elderly patients and those with cardiovascular diseases. Cardiovascular evaluations are crucial in pretransplantation assessments, but guidelines are lacking. This American Heart Association scientific statement summarizes the data on transplantation-related complications and provides guidance for the cardiovascular management throughout transplantation. Hematopoietic stem cell transplantation consists of 4 phases: pretransplantation workup, conditioning therapy and infusion, immediate posttransplantation period, and long-term survivorship. Complications can occur during each phase, with long-term survivors facing increased risks for late effects such as cardiovascular disease, secondary malignancies, and endocrinopathies. In adults, arrhythmias such as atrial fibrillation and flutter are the most frequent acute cardiovascular complication. Acute heart failure has an incidence ranging from 0.4% to 2.2%. In pediatric patients, left ventricular systolic dysfunction and pericardial effusion are the most common cardiovascular complications. Factors influencing the incidence and risk of complications include pretransplantation therapies, transplantation type (autologous versus allogeneic), conditioning regimen, comorbid conditions, and patient age. The pretransplantation cardiovascular evaluation consists of 4 steps: (1) initial risk stratification, (2) exclusion of high-risk cardiovascular disease, (3) assessment of cardiac reserve, and (4) optimization of cardiovascular reserve. Clinical risk scores could be useful tools for the risk stratification of adult patients. Long-term cardiovascular management of hematopoietic stem cell transplantation survivors includes optimizing risk factors, monitoring, and maintaining a low threshold for evaluating cardiovascular causes of symptoms. Future research should prioritize refining risk stratification and creating evidence-based guidelines and strategies to optimize outcomes in this growing patient population.

Quantitative PET attenuation correction (AC) for cardiac PET/CT and PET/MR is a challenging problem. We propose and evaluate an AC approach that uses coincidences from a relatively weak and physically fixed sparse external source, in combination with that from the patient, to reconstruct μ -maps based on physics principles alone. The low 30 cm3 volume of the source makes it easy to fill and place, and the method does not use prior image data or attenuation map assumptions. Our supplemental transmission aided maximum likelihood reconstruction of attenuation and activity (sTX-MLAA) algorithm contains an attenuation map update that maximizes the likelihood of terms representing coincidences originating from tracer in the patient and a weighted expression of counts segmented from the external source alone. Both external source and patient scatter and randoms are fully corrected. We evaluated performance of sTX-MLAA compared to reference standard CT-based AC with FDG PET/CT phantom studies; including modeling a patient with myocardial inflammation. Through an ROI analysis we measured ≤ 5 % bias in activity concentrations for PET images generated with sTX-MLAA and a TX source strength ≥ 12.7 MBq, relative to CT-AC. PET background variability (from noise and sparse sampling) was substantially reduced with sTX-MLAA compared to using counts segmented from the transmission source alone for AC. Results suggest that sTX-MLAA will enable quantitative PET during cardiac PET/CT and PET/MR of human patients.

Preclinical data strongly suggest that myocardial steatosis leads to adverse cardiac remodelling and left ventricular dysfunction. Using 1 H cardiac magnetic resonance spectroscopy, similar observations have been made across the spectrum of health and disease. The purpose of this brief review is to summarize these recent observations. We provide a brief overview of the determinants of myocardial triglyceride accumulation, summarize the current evidence that myocardial steatosis contributes to cardiac dysfunction, and identify opportunities for further research., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Competing Interests: Declaration of Competing Interest Dr. Grodin receives consultancy fees from Alnylam, AstraZeneca, Pfizer (New York, New York), Eidos/BridgeBio, and Sarepta. Dr. de Lemos has received grant support from Roche Diagnostics and Abbott Diagnostics and consulting fees from Siemen's Health Care Diagnostics, Beckman Coulter, and Quidel. Dr. Cutrell was an unpaid co-investigator on COVID-19 clinical trials sponsored by the NIH, Gilead and Regeneron. Dr. Zaha was supported by a research grant from the Hammon Center for Regenerative Medicine, UT Southwestern Medical Center. Dr. Hendren has received research grant support from Tricog Health. The remaining authors have no competing interests to declare.

Competing Interests: Disclosures None.

Advances in cancer therapeutics have led to dramatic improvements in survival, now inclusive of nearly 20 million patients and rising. However, cardiovascular toxicities associated with specific cancer therapeutics adversely affect the outcomes of patients with cancer. Advances in cardiovascular imaging have solidified the critical role for robust methods for detecting, monitoring, and prognosticating cardiac risk among patients with cancer. However, decentralized evaluations have led to a lack of consensus on the optimal uses of imaging in contemporary cancer treatment (eg, immunotherapy, targeted, or biological therapy) settings. Similarly, available isolated preclinical and clinical studies have provided incomplete insights into the effectiveness of multiple modalities for cardiovascular imaging in cancer care. The aims of this scientific statement are to define the current state of evidence for cardiovascular imaging in the cancer treatment and survivorship settings and to propose novel methodological approaches to inform the optimal application of cardiovascular imaging in future clinical trials and registries. We also propose an evidence-based integrated approach to the use of cardiovascular imaging in routine clinical settings. This scientific statement summarizes and clarifies available evidence while providing guidance on the optimal uses of multimodality cardiovascular imaging in the era of emerging anticancer therapies.

T-cell therapies, such as chimeric antigen receptor (CAR) T-cell, bispecific T-cell engager (BiTE) and tumor-infiltrating lymphocyte (TIL) therapies, fight cancer cells harboring specific tumor antigens. However, activation of the immune response by these therapies can lead to a systemic inflammatory response, termed cytokine release syndrome (CRS), that can result in adverse events, including cardiotoxicity. Retrospective studies have shown that cardiovascular complications occur in 10% to 20% of patients who develop high-grade CRS after CAR T-cell therapy and can include cardiomyopathy, heart failure, arrhythmias, and myocardial infarction. While cardiotoxicities have been less commonly reported with BiTE and TIL therapies, systematic surveillance for cardiotoxicity has not been performed. Patients undergoing T-cell therapies should be screened for cardiovascular conditions that may not be able to withstand the hemodynamic perturbations imposed by CRS. Generalized management of CRS, including the use of the interleukin-6 antagonist, tocilizumab, for high-grade CRS, is used to mitigate the risk of cardiotoxicity., Competing Interests: Dr Nohria is supported by the Catherine Fitch Fund and the Gelb Master Clinician Fund at Brigham and Women’s Hospital; and is a consultant for AstraZeneca, Boehringer Ingelheim, Bantam Pharmaceuticals, and Takeda Oncology. Dr Zaha has received support from the Cancer Prevention Research Institute of Texas (RP180404). Dr Yang has received research funding from CSL Behring, Boehringer Ingelheim, and Eli Lilly; and has received consulting fees from Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Objective: The primary objectives of this pilot study were to assess cognition and cerebral metabolic rate of oxygen (CMRO 2 ) consumption in people with severe obesity before (baseline), and again, 2- and 14-weeks after sleeve gastrectomy bariatric surgery., Methods: Six people with severe/class 3 obesity (52 ± 10 years, five females, body mass index (BMI) = 41.9 ± 3.9 kg/m 2 ), and 10 normal weight sex- and age-matched healthy controls (HC) (48 ± 6 years, eight females, 22.8 ± 1.9 kg/m 2 ). Global CMRO 2 was measured non-invasively using MRI and cognition using the Integneuro testing battery., Results: Following a sleeve gastrectomy induced weight loss of 6.4 ± 2.5 kg (% total-body-weight-lost = 5.4) over two-weeks, cognition total scores improved by 0.8 ± 0.5 T-scores (p=0.03, 15.8% improvement from baseline). Weight loss over 14-weeks post-surgery was 15.4 ± 3.6 kg (% total-body-weight-lost = 13.0%) and cognition improved by 1.1 ± 0.4 (p=0.003, 20.6% improvement from baseline). At 14-weeks, cognition was 6.4 ± 0.7, comparable to 6.0 ± 0.6 observed in the HC group. Baseline CMRO 2 was significantly higher compared to the HC (230.4 ± 32.9 vs. 177.9 ± 33.9 µmol O 2 /100 g/min, p=0.02). Compared to baseline, CMRO 2 was 234.3 ± 16.2 µmol O 2 /100 g/min at 2-weeks after surgery (p=0.8, 1.7% higher) and 217.3 ± 50.4 at 14-weeks (p=0.5, 5.7% lower) after surgery. 14-weeks following surgery, CMRO 2 was similar to HC (p=0.17)., Conclusion: Sleeve gastrectomy induced weight loss was associated with an increase in cognition and a decrease in CMRO 2 observed 14-weeks after surgery. The association between weight loss, improved cognition and CMRO 2 decrease should be evaluated in larger future studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Anwar, Tucker, Puzziferri, Samuel, Zaha, Lingvay, Almandoz, Wang, Gonzales, Brothers, Nelson and Thomas.)

The population of patients with cancer is rapidly expanding, and the diagnosis and monitoring of cardiovascular complications greatly rely on imaging. Numerous advances in the field of cardio-oncology and imaging have occurred in recent years. This review presents updated and practical approaches for multimodality cardiovascular imaging in the cardio-oncology patient and provides recommendations for imaging to detect the myriad of adverse cardiovascular effects associated with antineoplastic therapy, such as cardiomyopathy, atherosclerosis, vascular toxicity, myocarditis, valve disease, and cardiac masses. Uniquely, we address the role of cardiovascular imaging in patients with pre-existing cardiomyopathy, pregnant patients, long-term survivors, and populations with limited resources. We also address future avenues of investigation and opportunities for artificial intelligence applications in cardio-oncology imaging. This review provides a uniform practical approach to cardiovascular imaging for patients with cancer., Competing Interests: Funding Support and Author Disclosures Dr Baldassarre has received research funding from the American Heart Association (18CDA34110361) and the National Center for Advancing Translational Science (NCATS), a component of the National Institute of Health (UL1 TR001863). Dr Yang has received research funding from CSL Behring, Boehringer Ingelheim, and Eli Lilly; and has received consultation fees from Pfizer. Dr Zaha is supported by the Cancer Prevention Research Institute of Texas (RP180404). Dr Dent has received research funding and honoraria from Novartis. Dr Deswal is supported in part by the Ting Tsung and Wei Fong Chao Distinguished Chair. Dr Liu has received research funding from Johnson and Johnson; has received consultation fees from Caption Health and Phillips; and has served on the DMSB for Caelum Biosciences. Dr Scherrer-Crosbie is supported by the National Heart, Lung, and Blood Institute (R01HL130539). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor T-cell (CAR T) therapy is a revolutionary personalized therapy that has significantly impacted the treatment of patients with hematologic malignancies refractory to other therapies. Cytokine release syndrome (CRS) is a major side effect of CAR T therapy that can occur in 70-90% of patients, with roughly 40% of patients at grade 2 or higher. CRS can cause an intense inflammatory state leading to cardiovascular complications, including troponin elevation, arrhythmias, hemodynamic instability, and depressed left ventricular systolic function. There are currently no standardized guidelines for the management of cardiovascular complications due to CAR T therapy, but systematic practice patterns are emerging. In this review, we contextualize the history and indications of CAR T cell therapy, side effects related to this treatment, strategies to optimize the cardiovascular health prior to CAR T and the management of cardiovascular complications related to CRS. We analyze the existing data and discuss potential future approaches., Competing Interests: Author FA has provided consultancy to: Genentech, Astrazeneca, Abbvie, Janssen, Pharmacyclics, Gilead sciences, Kite pharma, Celgene, Karyopharm, MEI Pharma, Verastem, Incyte, Beigene, Johnson and Johnson, Dava Oncology, BMS, Merck, Cardinal Health, ADCT therapeutics, and Epizyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rao, Stewart, Eljalby, Ramakrishnan, Anderson, Awan, Chandra, Vallabhaneni, Zhang and Zaha.)

Gender differences exist throughout the medical field and significant progress has been made in understanding the effects of gender in many aspects of healthcare. The field of cardio-oncology is diverse and dynamic with new oncologic and cardiovascular therapies approved each year; however, there is limited knowledge regarding the effects of gender within cardio-oncology, particularly the impact of gender on cardiotoxicities. The relationship between gender and cardio-oncology is unique in that gender likely affects not only the biological underpinnings of cancer susceptibility, but also the response to both oncologic and cardiovascular therapies. Furthermore, gender has significant socioeconomic and psychosocial implications which may impact cancer and cardiovascular risk factor profiles, cancer susceptibility, and the delivery of healthcare. In this review, we summarize the effects of gender on susceptibility of cancer, response to cardiovascular and cancer therapies, delivery of healthcare, and highlight the need for further gender specific studies regarding the cardiovascular effects of current and future oncological treatments.

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Cardiovascular imaging is an evolving component in the care of cancer patients. With improved survival following prompt cancer treatment, patients are facing increased risks of cardiovascular complications. While currently established imaging modalities are providing useful structural mechanical information, they continue to develop towards increased specificity. New modalities, emerging from basic science and oncology, are being translated, targeting earlier stages of cardiovascular disease. Besides these technical advances, matching an imaging modality with the patients' individual risk level for a specific pathological change is part of a successful imaging strategy. The choice of suitable imaging modalities and time points for specific patients will impact the cardio-oncological risk stratification during surveillance and follow-up monitoring. In addition, future imaging tools are poised to give us important insights into the underlying cardiovascular molecular pathology associated with cancer and oncological therapies. This review aims at giving an overview of the novel imaging technologies that have the potential to change cardio-oncological science and clinical practice in the near future., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: The development of Brutons Tyrosine Kinase (BTK) inhibitors has transformed the treatment of B-cell malignancies and other non-malignant conditions. Management of the unique cardiotoxic profile of these agents requires prompt recognition and a multi-disciplinary approach., Areas Covered: The increasing indications and addition of newer agents to clinical practice and emergence of BTK inhibitor-related cardiac adverse events have complicated the management decisions for utilization of this class of therapy. We review the incidence, mechanisms, and management approaches for BTK inhibitor-related atrial fibrillation, hypertension, and ventricular arrhythmias., Expert Opinion: The newer BTK inhibitor acalabrutinib represents a new standard of care in front-line chronic lymphocytic leukemia (CLL) given the results of the ELEVATE-RR trial demonstrating comparable efficacy and a more favorable toxicity profile especially with regard to cardiac adverse events as compared to ibrutinib. Often not recognized by clinicians, BTK inhibitor-induced hypertension is common and can be severe, requiring prompt recognition and initiation or adjustment of anti-hypertensive medications to prevent major adverse cardiac outcomes. Novel BTK inhibitors in development are being designed to overcome the patterns of resistance from first-generation agents and to minimize off-target kinase activity, with promising toxicity profiles in early trials.

The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.

Purpose: Previous cardiac imaging studies using hyperpolarized (HP) [1- 13 C]pyruvate were acquired at end-diastole (ED). Little is known about the interaction between cardiac cycle and metabolite content in the myocardium. In this study, we compared images of HP pyruvate and products at end-systole (ES) and ED., Methods: A dual-phase 13 C MRI sequence was implemented to acquire two sequential HP images within a single cardiac cycle at ES and ED during successive R-R intervals in an interleaved manner. Each healthy volunteer (N = 3) received two injections of HP [1- 13 C]pyruvate for the dual-phase imaging on the short-axis and the vertical long-axis planes. Spatial distribution of HP 13 C metabolites at each cardiac phase was correlated to multiphase 1 H MRI to confirm the mechanical changes. Ratios of myocardial HP metabolites were compared between ES and ED. Segmental analysis was performed on the midcavity short-axis plane., Results: In addition to mechanical changes, metabolic profiles of the heart detected by HP [1- 13 C]pyruvate differed between ES and ED. The myocardial signal of [ 13 C]bicarbonate relative to [1- 13 C]lactate was significantly smaller at ED than the ratio at ES (p < .05), particularly in mid-anterior and mid-inferoseptal segments. The distinct metabolic profiles in the myocardium likely reflect the technical aspects of the imaging approach such as the coronary flow in addition to the cyclical changes in metabolism., Conclusion: The study demonstrates that metabolic profiles of the heart, measured by HP [1- 13 C]pyruvate, are affected by the cardiac cycle in which that the data are acquired., (© 2021 International Society for Magnetic Resonance in Medicine.)

Improving cancer survival represents the most significant effect of precision medicine and personalized molecular and immunologic therapeutics. Cardiovascular health becomes henceforth a key determinant for the direction of overall outcomes after cancer. Comprehensive tissue diagnostic studies undoubtedly have been and continue to be at the core of the fight against cancer. Will a systemic approach integrating circulating blood-derived biomarkers, multimodality imaging technologies, strategic panomics, and real-time streams of digitized physiological data overcome the elusive cardiovascular tissue diagnosis in cardio-oncology? How can such a systemic approach be personalized for application in day-to-day clinical work, with diverse patient populations, cancer diagnoses, and therapies? To address such questions, this scientific statement approaches a broad definition of the biomarker concept. It summarizes the current literature on the utilization of a multitude of established cardiovascular biomarkers at the intersection with cancer. It identifies limitations and gaps of knowledge in the application of biomarkers to stratify the cardiovascular risk before cancer treatment, monitor cardiovascular health during cancer therapy, and detect latent cardiovascular damage in cancer survivors. Last, it highlights areas in biomarker discovery, validation, and clinical application for concerted efforts from funding agencies, scientists, and clinicians at the cardio-oncology nexus.

Objectives: The aim of this study was to define the variability of maximal wall thickness (MWT) measurements across modalities and predict its impact on care in patients with hypertrophic cardiomyopathy (HCM)., Background: Left ventricular MWT measured by echocardiography or cardiovascular magnetic resonance (CMR) contributes to the diagnosis of HCM, stratifies risk, and guides key decisions, including whether to place an implantable cardioverter-defibrillator (ICD)., Methods: A 20-center global network provided paired echocardiographic and CMR data sets from patients with HCM, from which 17 paired data sets of the highest quality were selected. These were presented as 7 randomly ordered pairs (at 6 cardiac conferences) to experienced readers who report HCM imaging in their daily practice, and their MWT caliper measurements were captured. The impact of measurement variability on ICD insertion decisions was estimated in 769 separately recruited multicenter patients with HCM using the European Society of Cardiology algorithm for 5-year risk for sudden cardiac death., Results: MWT analysis was completed by 70 readers (from 6 continents; 91% with >5 years' experience). Seventy-nine percent and 68% scored echocardiographic and CMR image quality as excellent. For both modalities (echocardiographic and then CMR results), intramodality inter-reader MWT percentage variability was large (range -59% to 117% [SD ±20%] and -61% to 52% [SD ±11%], respectively). Agreement between modalities was low (SE of measurement 4.8 mm; 95% CI 4.3 mm-5.2 mm; r = 0.56 [modest correlation]). In the multicenter HCM cohort, this estimated echocardiographic MWT percentage variability (±20%) applied to the European Society of Cardiology algorithm reclassified risk in 19.5% of patients, which would have led to inappropriate ICD decision making in 1 in 7 patients with HCM (8.7% would have had ICD placement recommended despite potential low risk, and 6.8% would not have had ICD placement recommended despite intermediate or high risk)., Conclusions: Using the best available images and experienced readers, MWT as a biomarker in HCM has a high degree of inter-reader variability and should be applied with caution as part of decision making for ICD insertion. Better standardization efforts in HCM recommendations by current governing societies are needed to improve clinical decision making in patients with HCM., Competing Interests: Funding Support and Author Disclosures This program was funded by Barts Charity grant 1107/2356/MRC0140 to Dr Captur. Dr Captur is supported by British Heart Foundation Special Programme Grant MyoFit46 (SP/20/2/34841), the National Institute for Health Research (NIHR) Rare Diseases Translational Research Collaboration, and the NIHR UCL Hospitals Biomedical Research Center. Dr Petersen has received support from the Barts Biomedical Research Centre, funded by the NIHR. Dr Moon is directly and indirectly supported by the UCL Hospitals NIHR BRC and Biomedical Research Unit at Barts Hospital, respectively. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Radiation therapy is a cornerstone of cancer therapy, with >50% of patients undergoing therapeutic radiation. As a result of widespread use and improved survival, there is increasing focus on the potential long-term effects of ionizing radiation, especially cardiovascular toxicity. Radiation therapy can lead to atherosclerosis of the vasculature as well as valvular, myocardial, and pericardial dysfunction. We present a consensus statement from the International Cardio-Oncology Society based on general principles of radiotherapy delivery and cardiovascular risk assessment and risk mitigation in this population. Anatomical-based recommendations for cardiovascular management and follow-up are provided, and a priority is given to the early detection of atherosclerotic vascular disease on imaging to help guide preventive therapy. Unique management considerations in radiation-induced cardiovascular disease are also discussed. Recommendations are based on the most current literature and represent a unanimous consensus by the multidisciplinary expert panel., Competing Interests: Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002345 as well as by the National Institutes of Health grant R01 HL147884. Dr Mitchell has received research funding from Pfizer, Longer Life Foundation, and Children’s Discovery Institute; and is a consultant for Pfizer (modest). Dr Bergrom has received research support from the Susan G. Komen Foundation and Innovation Pathways. Dr Ferencik has received research support from the National Institutes of Health and the American Heart Association; and is a consultant for Biograph, Inc (unrelated to current work). Dr Szmit has received personal fees from Amgen, Angelini, AstraZeneca, Bayer, Berlin-Chemie, Bristol Myers Squibb, Clinigen, Janssen-Cilag, Pfizer, Polpharma, Roche, and TEVA. Dr Zaha has received support from the Cancer Prevention Research Institute of Texas (RP180404). Dr Herrmann was supported by the National Cancer Institute of the National Institutes of Health (CA233610), the Miami Heart Foundation, and the Mayo Clinic. Dr Nohria has received research funding from Amgen, Inc; and is a consultant for Takeda Oncology and AstraZeneca. Dr Lenihan has received research funding from Myocardial Solutions; and is a consultant for Lilly, Prothena, AstraZeneca, Roche, Clementia, and Eidos (all consultancy renumeration is modest). Dr Dent has received research funding from Novartis; and is a consultant for Novartis and Eli Lilly. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Purpose: Noninvasive imaging with hyperpolarized (HP) pyruvate can capture in vivo cardiac metabolism. For proper quantification of the metabolites and optimization of imaging parameters, understanding MR characteristics such as T 2 ∗ s of the HP signals is critical. This study is to measure in vivo cardiac T 2 ∗ s of HP [1- 13 C]pyruvate and the products in rodents and humans., Methods: A dynamic 13 C multi-echo spiral imaging sequence that acquires [ 13 C]bicarbonate, [1- 13 C]lactate, and [1- 13 C]pyruvate images in an interleaved manner was implemented for a clinical 3 Tesla system. T 2 ∗ of each metabolite was calculated from the multi-echo images by fitting the signal decay of each region of interest mono-exponentially. The performance of measuring T 2 ∗ using the sequence was first validated using a 13 C phantom and then with rodents following a bolus injection of HP [1- 13 C]pyruvate. In humans, T 2 ∗ of each metabolite was calculated for left ventricle, right ventricle, and myocardium., Results: Cardiac T 2 ∗ s of HP [1- 13 C]pyruvate, [1- 13 C]lactate, and [ 13 C]bicarbonate in rodents were measured as 24.9 ± 5.0, 16.4 ± 4.7, and 16.9 ± 3.4 ms, respectively. In humans, T 2 ∗ of [1- 13 C]pyruvate was 108.7 ± 22.6 ms in left ventricle and 129.4 ± 8.9 ms in right ventricle. T 2 ∗ of [1- 13 C]lactate was 40.9 ± 8.3, 44.2 ± 5.5, and 43.7 ± 9.0 ms in left ventricle, right ventricle, and myocardium, respectively. T 2 ∗ of [ 13 C]bicarbonate in myocardium was 64.4 ± 2.5 ms. The measurements were reproducible and consistent over time after the pyruvate injection., Conclusion: The proposed metabolite-selective multi-echo spiral imaging sequence reliably measures in vivo cardiac T 2 ∗ s of HP [1- 13 C]pyruvate and products., (© 2021 International Society for Magnetic Resonance in Medicine.)

Purpose: This study aimed to investigate the role of regional f 0 inhomogeneity in spiral hyperpolarized 13 C image quality and to develop measures to alleviate these effects., Methods: Field map correction of hyperpolarized 13 C cardiac imaging using spiral readouts was evaluated in healthy subjects. Spiral readouts with differing duration (26 and 45 ms) but similar resolution were compared with respect to off-resonance performance and image quality. An f 0 map-based image correction based on the multifrequency interpolation (MFI) method was implemented and compared to correction using a global frequency shift alone. Estimation of an unknown frequency shift was performed by maximizing a sharpness objective based on the Sobel variance. The apparent full width half at maximum (FWHM) of the myocardial wall on [ 13 C]bicarbonate was used to estimate blur., Results: Mean myocardial wall FWHM measurements were unchanged with the short readout pre-correction (14.1 ± 2.9 mm) and post-MFI correction (14.1 ± 3.4 mm), but significantly decreased in the long waveform (20.6 ± 6.6 mm uncorrected, 17.7 ± 7.0 corrected, P = .007). Bicarbonate signal-to-noise ratio (SNR) of the images acquired with the long waveform were increased by 1.4 ± 0.3 compared to those acquired with the short waveform (predicted 1.32). Improvement of image quality was observed for all metabolites with f 0 correction., Conclusions: f 0 -map correction reduced blur and recovered signal from dropouts, particularly along the posterior myocardial wall. The low image SNR of [ 13 C]bicarbonate can be compensated with longer duration readouts but at the expense of increased f 0 artifacts, which can be partially corrected for with the proposed methods., (© 2021 International Society for Magnetic Resonance in Medicine.)

Background: Professional society guidelines are emerging for cardiovascular care in cancer patients. However, it is not yet clear how effectively the cancer survivor population is screened and treated for cardiomyopathy in contemporary clinical practice. As electronic health records (EHRs) are now widely used in clinical practice, we tested the hypothesis that an EHR-based cardio-oncology registry can address these questions., Objective: The aim of this study was to develop an EHR-based pragmatic cardio-oncology registry and, as proof of principle, to investigate care gaps in the cardiovascular care of cancer patients., Methods: We generated a programmatically deidentified, real-time EHR-based cardio-oncology registry from all patients in our institutional Cancer Population Registry (N=8275, 2011-2017). We investigated: (1) left ventricular ejection fraction (LVEF) assessment before and after treatment with potentially cardiotoxic agents; and (2) guideline-directed medical therapy (GDMT) for left ventricular dysfunction (LVD), defined as LVEF<50%, and symptomatic heart failure with reduced LVEF (HFrEF), defined as LVEF<50% and Problem List documentation of systolic congestive heart failure or dilated cardiomyopathy., Results: Rapid development of an EHR-based cardio-oncology registry was feasible. Identification of tests and outcomes was similar using the EHR-based cardio-oncology registry and manual chart abstraction (100% sensitivity and 83% specificity for LVD). LVEF was documented prior to initiation of cancer therapy in 19.8% of patients. Prevalence of postchemotherapy LVD and HFrEF was relatively low (9.4% and 2.5%, respectively). Among patients with postchemotherapy LVD or HFrEF, those referred to cardiology had a significantly higher prescription rate of a GDMT., Conclusions: EHR data can efficiently populate a real-time, pragmatic cardio-oncology registry as a byproduct of clinical care for health care delivery investigations., (©Alvin Chandra, Steven T Philips, Ambarish Pandey, Mujeeb Basit, Vaishnavi Kannan, Evan J Sara, Sandeep R Das, Simon J C Lee, Barbara Haley, DuWayne L Willett, Vlad G Zaha. Originally published in JMIR Cardio (https://cardio.jmir.org), 12.05.2021.)

In response to the coronavirus disease 2019 (COVID-19) pandemic, the Cardio-Oncology and Imaging Councils of the American College of Cardiology offers recommendations to clinicians regarding the cardiovascular care of cardio-oncology patients in this expert consensus statement. Cardio-oncology patients-individuals with an active or prior cancer history and with or at risk of cardiovascular disease-are a rapidly growing population who are at increased risk of infection, and experiencing severe and/or lethal complications by COVID-19. Recommendations for optimizing screening and monitoring visits to detect cardiac dysfunction are discussed. In addition, judicious use of multimodality imaging and biomarkers are proposed to identify myocardial, valvular, vascular, and pericardial involvement in cancer patients. The difficulties of diagnosing the etiology of cardiovascular complications in patients with cancer and COVID-19 are outlined, along with weighing the advantages against risks of exposure, with the modification of existing cardiovascular treatments and cardiotoxicity surveillance in patients with cancer during the COVID-19 pandemic., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Heart failure with preserved ejection fraction (HFpEF) is now the dominant form of heart failure and one for which no efficacious therapies exist. Obesity and lipid mishandling greatly contribute to HFpEF. However, molecular mechanism(s) governing metabolic alterations and perturbations in lipid homeostasis in HFpEF are largely unknown. Here, we report that cardiomyocyte steatosis in HFpEF is coupled with increases in the activity of the transcription factor FoxO1 (Forkhead box protein O1). FoxO1 depletion, as well as over-expression of the Xbp1s (spliced form of the X-box-binding protein 1) arm of the UPR (unfolded protein response) in cardiomyocytes each ameliorates the HFpEF phenotype in mice and reduces myocardial lipid accumulation. Mechanistically, forced expression of Xbp1s in cardiomyocytes triggers ubiquitination and proteasomal degradation of FoxO1 which occurs, in large part, through activation of the E3 ubiquitin ligase STUB1 (STIP1 homology and U-box-containing protein 1) a novel and direct transcriptional target of Xbp1s. Our findings uncover the Xbp1s-FoxO1 axis as a pivotal mechanism in the pathogenesis of cardiometabolic HFpEF and unveil previously unrecognized mechanisms whereby the UPR governs metabolic alterations in cardiomyocytes.

Competing Interests: All authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: People with human immunodeficiency virus (PWH) face increased risks for heart failure and adverse heart failure outcomes. Myocardial steatosis predisposes to diastolic dysfunction, a heart failure precursor. We aimed to characterize myocardial steatosis and associated potential risk factors among a subset of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) participants., Methods: Eighty-two PWH without known heart failure successfully underwent cardiovascular magnetic resonance spectroscopy, yielding data on intramyocardial triglyceride (IMTG) content (a continuous marker for myocardial steatosis extent). Logistic regression models were applied to investigate associations between select clinical characteristics and odds of increased or markedly increased IMTG content., Results: Median (Q1, Q3) IMTG content was 0.59% (0.28%, 1.15%). IMTG content was increased (> 0.5%) among 52% and markedly increased (> 1.5%) among 22% of participants. Parameters associated with increased IMTG content included age (P = .013), body mass index (BMI) ≥ 25 kg/m2 (P = .055), history of intravenous drug use (IVDU) (P = .033), and nadir CD4 count < 350 cells/mm³ (P = .055). Age and BMI ≥ 25 kg/m2 were additionally associated with increased odds of markedly increased IMTG content (P = .049 and P = .046, respectively)., Conclusions: A substantial proportion of antiretroviral therapy-treated PWH exhibited myocardial steatosis. Age, BMI ≥ 25 kg/m2, low nadir CD4 count, and history of IVDU emerged as possible risk factors for myocardial steatosis in this group., Clinical Trials Registration: NCT02344290; NCT03238755., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Tremendous progress in cancer detection and therapy has improved survival. However, cardiovascular complications are a major source of morbidity in cancer survivors. Cardiotoxicity is currently defined by structural myocardial changes and cardiac injury biomarkers. In many instances, such changes are late and irreversible. Therefore, diagnostic modalities that can identify early alterations in potentially reversible biochemical and molecular signaling processes are of interest. This review is focused on emerging translational metabolic imaging modalities. We present in context relevant mitochondrial biology aspects that ground the development and application of these technologies for detection of cancer therapy-related cardiac dysfunction (CTRCD). The application of these modalities may improve the assessment of cardiovascular risk when anticancer treatments with a defined cardiometabolic toxic mechanism are to be used. Also, they may serve as screening tools for cardiotoxicity when novel lines of cancer therapies are applied.

Background: Bariatric surgery is an effective long-term weight loss strategy yielding improvements in neurocognitive function; however, the mechanism(s) responsible for these improvements remains unclear. Here, we assessed the feasibility of using magnetic resonance imaging (MRI) to evaluate whether cerebral vascular reactivity (CVR) is impaired in severely obese bariatric surgery candidates compared with normal weight healthy controls and whether CVR improves following bariatric surgery. We also investigated whether changes in CVR were associated with changes in cognitive function., Methods: Bariatric surgery candidates ( n = 6) were compared with normal weight healthy controls of a similar age ( n = 10) at baseline, and then reassessed 2 weeks and 14 weeks following sleeve gastrectomy bariatric surgery. Young reference controls ( n = 7) were also studied at baseline to establish the range of normal for each outcome measure. Microvascular and macrovascular CVR to hypercapnia (5% CO 2 ) were assessed using blood-oxygen-level-dependent (BOLD) MRI, and changes in the middle cerebral artery (MCA) cross-sectional area, respectively. Cognitive function was assessed using a validated neurocognitive software., Results: Compliance with the CVR protocol was high. Both macro- and micro-cerebrovascular function were highest in the young reference controls. Cognitive function was lower in obese bariatric surgery candidates compared with normal weight controls, and improved by 17% at 2 weeks and 21% by 14 weeks following bariatric surgery. To our surprise, whole-brain CVR BOLD did not differ between obese bariatric surgery candidates and normal weight controls of similar age (0.184 ± 0.101 vs. 0.192 ± 0.034 %BOLD/mmHgCO 2 ), and did not change after bariatric surgery. In contrast, we observed vasoconstriction of the MCA during hypercapnia in 60% of the obese patients prior to surgery, which appeared to be abolished following bariatric surgery. Improvements in cognitive function were not associated with improvements in either CVR BOLD or MCA vasodilation after bariatric surgery., Conclusions: Assessing CVR responses to a hypercapnic challenge with MRI was feasible in severely obese bariatric patients. However, no changes in whole-brain BOLD CVR were observed following bariatric surgery despite improvements in cognitive function. We recommend that future large trials assess CVR responses to cognitive tasks (rather than hypercapnia) to better define the mechanisms responsible for cognitive function improvements following bariatric surgery., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)