Preclinical Models of Cancer Therapy-Associated Cardiovascular Toxicity:A Scientific Statement From the American Heart Association

Although cardiovascular toxicity from traditional chemotherapies has been well recognized for decades, the recent explosion of effective novel targeted cancer therapies with cardiovascular sequelae has driven the emergence of cardio-oncology as a new clinical and research field. Cardiovascular toxicity associated with cancer therapy can manifest as a broad range of potentially life-threatening complications, including heart failure, arrhythmia, myocarditis, and vascular events. Beyond toxicology, the intersection of cancer and heart disease has blossomed to include discovery of genetic and environmental risk factors that predispose to both. There is a pressing need to understand the underlying molecular mechanisms of cardiovascular toxicity to improve outcomes in patients with cancer. Preclinical cardiovascular models, ranging from cellular assays to large animals, serve as the foundation for mechanistic studies, with the ultimate goal of identifying biologically sound biomarkers and cardioprotective therapies that allow the optimal use of cancer treatments while minimizing toxicities. Given that novel cancer therapies target specific pathways integral to normal cardiovascular homeostasis, a better mechanistic understanding of toxicity may provide insights into fundamental pathways that lead to cardiovascular disease when dysregulated. The goal of this scientific statement is to summarize the strengths and weaknesses of preclinical models of cancer therapy-associated cardiovascular toxicity, to highlight overlapping mechanisms driving cancer and cardiovascular disease, and to discuss opportunities to leverage cardio-oncology models to address important mechanistic questions relevant to all patients with cardiovascular disease, including those with and without cancer.</p

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning (RIPC), ischemia to one organ protects others organs at a distance. We created mouse models to ask if inhibition of the alpha-ketoglutarate (αKG)-dependent dioxygenase Egln1, which senses oxygen and regulates the hypoxia-inducible factor (HIF) transcription factor, could suffice to mediate local and remote ischemic preconditioning. Using somatic gene deletion and a pharmacological inhibitor, we found that inhibiting Egln1 systemically or in skeletal muscles protects mice against myocardial ischemia-reperfusion (I/R) injury. Parabiosis experiments confirmed that RIPC in this latter model was mediated by a secreted factor. Egln1 loss causes accumulation of circulating αKG, which drives hepatic production and secretion of kynurenic acid (KYNA) that is necessary and sufficient to mediate cardiac ischemic protection in this setting.Broad Institute of MIT and Harvard. SPARC ProgramBurroughs Wellcome Fun

Turning the Oxygen Dial: Balancing the Highs and Lows

Oxygen is both vital and toxic to life. Molecular oxygen is the most used substrate in the human body and is required for several hundred diverse biochemical reactions. The discovery of the PHD-HIF-pVHL system revolutionized our fundamental understanding of oxygen sensing and cellular adaptations to hypoxia. It deepened our knowledge of the biochemical underpinnings of numerous diseases, ranging from anemia to cancer. Cellular dysfunction and tissue pathology can result from a mismatch of oxygen supply and demand. Recent work has shown that mitochondrial disease models display tissue hyperoxia and that disease pathology can be reversed by normalization of excess oxygen, suggesting that certain disease states can potentially be treated by modulating oxygen levels. In this review, we describe cellular and organismal mechanisms of oxygen sensing and adaptation. We provide a revitalized framework for understanding pathologies of too little or too much oxygen

A Hybrid Approach to Estimating the Economic Value of Enhanced Power System Resilience

The costs that power interruptions impose on customers and society have emerged as essential considerations for decision making about power system reliability and resilience. There is well-established literature on the direct costs of localized and relatively short-duration power interruptions. However, far less is known about the costs of widespread and long-duration (WLD) power interruptions, especially the indirect costs and related economy-wide impacts of these events. As a result, utility planning activities generally incorporate these costs incompletely or not at all. This report proposes a new approach to estimating WLD power interruption costs to support utility resilience planning studies. Specifically, the paper describes a hybrid method that integrates: (1) empirical surveys of region- and sector-specific inherent and adaptive customer behaviors during and after power interruptions, and (2) computable general equilibrium (CGE) modeling, which estimates the direct and indirect impacts of WLD power interruptions. The report provides both a rationale for the proposed hybrid approach and a roadmap outlining how it could be implemented

Correction: Osimertinib-induced biventricular cardiomyopathy with abnormal cardiac MRI findings: a case report

Following publication of the original article [1], the authors identified an error in Fig.&nbsp;1, in which Fig. 1A and B were reversed. The correct figure is given below. (Figure presented.) Electrocardiogram (ECG) prior to (A) and after (B) pericardiocentesis. (A) Initial presenting ECG with electrical alternans, in which the direction of electrical activity flips beat-to-beat in lead V3. (B) ECG after pericardiocentesis with resolution of electrical alternans The original article [1] has been updated

Osimertinib-induced biventricular cardiomyopathy with abnormal cardiac MRI findings: a case report

Abstract Background Osimertinib is a third-generation epidermal growth factor receptor (EGFR) inhibitor that is currently the first-line treatment for metastatic EGFR-mutated non-small-cell lung cancer (NSCLC) due to its favorable efficacy and tolerability profile compared to previous generations of EGFR inhibitors. However, it can cause uncommon, yet serious, cardiovascular adverse effects. Case Presentation We present the case of a 63-year-old man with EGFR-mutated NSCLC treated with osimertinib who developed new-onset non-ischemic cardiomyopathy with biventricular dysfunction and heart failure in the context of an enlarging pericardial effusion. For the first time, we demonstrate cardiac MR imaging findings associated with osimertinib-associated cardiomyopathy, including focal late gadolinium enhancement and myocardial edema. The patient’s biventricular function normalized after initiation of goal-directed medical therapy for heart failure and holding osimertinib. The patient was subsequently started on afatinib, a second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), without recurrence of cardiomyopathy. Conclusions This case highlights the need to better understand osimertinib-induced cardiotoxicity and strategies to optimize oncologic care in patients who develop severe cardiac toxicities from cancer therapy. It further underlines the importance of specialized multidisciplinary care of cancer patients who develop cardiotoxicities to optimize their oncologic outcomes

Power Outage Economics Tool: A Prototype for the Commonwealth Edison Service Territory

Estimates of the economic impact of widespread, long duration (WLD) power interruptions can be used to prioritize and justify significant investments in power system resilience. This report presents estimates of this type for WLDs originating within the Commonwealth Edison (ComEd) service territory. The intended audience for this research includes utility executives and technical staff, regulators, and government agencies. This project involved surveying ComEd customers to understand how they might respond when confronted with a WLD power interruption. The research team used the survey responses to calibrate a state-of-the-art regional economic model (“POET”) to estimate economic impacts to households and 38 industry sectors across 17 impacted micro-regions (individual counties or aggregations of counties) within ComEd’s service territory and beyond. We ran one-day, three-day, and 14-day interruption duration scenarios each with varying geographic extents as well as estimated the benefits of deploying additional backup generation across the service territory. The results were then compared to a “business as usual” scenario assuming that no interruption occurred. There are six key findings from this analysis: -There may be significant losses to gross output (business revenue), gross domestic product, and household consumption during WLD interruptions, especially multi-day interruptions that occur across all of ComEd, Cook county, or the suburbs of Chicago. -The wholesale trade and transportation sectors appear to be highly sensitive to power interruptions—losses to these sectors are large relative to the losses observed across the entire economy. -Several sector-region combinations—e.g., the transportation sector in Cook county—are very sensitive to interruptions. -High-income households experience proportionately larger losses to consumption during a one-day power interruption, but low-income households experience proportionately larger losses during the longest power interruptions. -Increasing the amount of backup generation deployed across ComEd’s service territory provides significant net benefits to system-wide gross domestic product, gross output, and household consumption relative to the existing amount of backup generation already being used. -Some micro-regions (e.g., Dekalb and Kendall counties), sectors (e.g., wholesale trade, transportation), and low-income households in Cook county may especially benefit from targeted resilience interventions. We recommend that decision-makers consider running cost-benefit analyses using each of the economic metrics presented in this report independent of one another to evaluate the robustness of the insights that each of these estimates may provide. In addition to this report, we developed a tool that will allow ComEd staff and other decision-makers to visualize the full suite of results using an easy-to-interpret, user interface. We hope that the findings from this research effort will provide valuable insights to ComEd, policymakers across Illinois, and other stakeholders who have an interest in the resilience of the power system

Equity in Cardio-Oncology Care and Research: A Scientific Statement From the American Heart Association.

Advances in cancer therapeutics have revolutionized survival outcomes in patients with cancer. However, cardiovascular toxicities associated with specific cancer therapeutics adversely affect the outcomes of patients with cancer. Recent studies have uncovered excess risks of these cardiotoxic events, especially in traditionally underrepresented populations. Despite advances in strategies to limit the risks of cardiovascular events among cancer survivors, relatively limited guidance is available to address the rapidly growing problem of disparate cardiotoxic risks among women and underrepresented patient populations. Previously decentralized and sporadic evaluations have led to a lack of consensus on the definitions, investigation, and potential optimal strategies to address disparate cardiotoxicity in contemporary cancer care (eg, with immunotherapy, biologic, or cytotoxic therapies) settings. This scientific statement aims to define the current state of evidence for disparate cardiotoxicity while proposing uniform and novel methodological approaches to inform the identification and mitigation of disparate cardio-oncology outcomes in future clinical trials, registries, and daily clinical care settings. We also propose an evidence-based integrated approach to identify and mitigate disparities in the routine clinical setting. This consensus scientific statement summarizes and clarifies available evidence while providing guidance on addressing inequities in the era of emerging anticancer therapies