Moving towards establishing centres of excellence in cardiac amyloidosis: an International Cardio-Oncology Society statement.

The prevalence of amyloidosis has been increasing, driven by a combination of improved awareness, evolution of diagnostic pathways, and effective treatment options for both transthyretin and light chain amyloidosis. Due to the complexity of amyloidosis, centralised expert providers with experience in delineating the nuances of confirmatory diagnosis and management may be beneficial. There are many potential benefits of a centre of excellence designation for the treatment of amyloidosis including recognition of institutions that have been leading the way for the optimal treatment of this condition, establishing the expectations for any centre who is engaging in the treatment of amyloidosis and developing cooperative groups to allow more effective research in this disease space. Standardising the expectations and criteria for these centres is essential for ensuring the highest quality of clinical care and community education. In order to define what components are necessary for an effective centre of excellence for the treatment of amyloidosis, we prepared a survey in cooperation with a multidisciplinary panel of amyloidosis experts representing an international consortium. The purpose of this position statement is to identify the essential elements necessary for highly effective clinical care and to develop a general standard with which practices or institutions could be recognised as a centre of excellence.

In-Hospital and readmission outcomes of patients with myeloproliferative neoplasms and heart failure: Insights from the National Readmissions Database.

Background: Myeloproliferative neoplasms (MPNs) are chronic leukemias associated with increased risk of cardiovascular (CV) events. Prior studies suggest patients with MPN are at increased risk of HF. Additionally, pre-clinical murine models harboring the JAK2 mutation, the most common driver mutation in MPNs, have shown accelerated adverse cardiac remodeling in myocardial infarction and pressure overload HF models. However, clinical outcomes, including in-hospital and readmission outcomes, of patients with MPN admitted for HF have not been well characterized. Methods: Patients hospitalized for HF with and without MPN were identified using the 2017 and 2018 National Readmission Database. Propensity score matching (PSM) was performed to match 1 MPN with 10 non-MPN controls. Outcomes were in-hospital death, 90-day CV-related, HF-related, and all-cause readmissions. Logistic regression and Cox proportional hazards regression models were used to estimate risk of in-hospital death and 90-day readmission outcomes, respectively. Results: After PSM, 4,626 patients with MPN were matched with 46,260 without. Patients with MPN were associated with increased risk of in-hospital death (OR 1.17, 95% CI 1.00 - 1.35), 90-day CV-related (HR 1.10, 95% CI 1.02 - 1.18) and all-cause (HR 1.24, 95% CI 1.17 - 1.31) but not HF-related (HR 1.05, 95% CI 0.97 - 1.14) readmissions. Conclusion: Among patients hospitalized for HF, MPN was associated with increased risk of in-hospital death, and 90-day CV-related readmissions (driven primarily by thrombotic readmissions). Further investigation is needed in order to improve outcomes in patients with MPN and HF.

Cardiovascular Manifestations From Therapeutic Radiation: A Multidisciplinary Expert Consensus Statement From the International Cardio-Oncology Society.

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.

Role of cardiovascular magnetic resonance in early detection and treatment of cardiac dysfunction in oncology patients.

The purpose of this review is to provide an overview of the essential role that cardiovascular magnetic resonance (CMR) has in the field of cardio-oncology. Recent findings: CMR has been increasingly used for early identification of cancer therapy related cardiac dysfunction (CTRCD) due to its precision in detecting subtle changes in cardiac function and for myocardial tissue characterization. Summary: CMR is able to identify subclinical CTRCD in patients receiving potentially cardiotoxic chemotherapy and guide initiation of cardio protective therapy. Multiparametric analysis with myocardial strain, tissue characterization play a critical role in understanding important clinical questions in cardio-oncology.

Interim Analysis of the Phase II Study: Noninferiority Study of Doxorubicin with Upfront Dexrazoxane plus Olaratumab for Advanced or Metastatic Soft-Tissue Sarcoma.

PURPOSE: To report the interim analysis of the phase II single-arm noninferiority trial, testing the upfront use of dexrazoxane with doxorubicin on progression-free survival (PFS) and cardiac function in soft-tissue sarcoma (STS). PATIENTS AND METHODS: Patients with metastatic or unresectable STS who were candidates for first-line treatment with doxorubicin were deemed eligible. An interim analysis was initiated after 33 of 65 patients were enrolled. Using the historical control of 4.6 months PFS for doxorubicin in the front-line setting, we tested whether the addition of dexrazoxane affected the efficacy of doxorubicin in STS. The study was powered so that a decrease of PFS to 3.7 months would be considered noninferior. Secondary aims included cardiac-related mortality, incidence of heart failure/cardiomyopathy, and expansion of cardiac monitoring parameters including three-dimensional echocardiography. Patients were allowed to continue on doxorubicin beyond 600 mg/m2 if they were deriving benefit and were not demonstrating evidence of symptomatic cardiac dysfunction. RESULTS: At interim analysis, upfront use of dexrazoxane with doxorubicin demonstrated a PFS of 8.4 months (95% confidence interval: 5.1-11.2 months). Only 3 patients were removed from study for cardiotoxicity, all on > 600 mg/m2 doxorubicin. No patients required cardiac hospitalization or had new, persistent cardiac dysfunction with left ventricular ejection fraction remaining below 50%. The median administered doxorubicin dose was 450 mg/m2 (interquartile range, 300-750 mg/m2). CONCLUSIONS: At interim analysis, dexrazoxane did not reduce PFS in patients with STS treated with doxorubicin. Involvement of cardio-oncologists is beneficial for the monitoring and safe use of high-dose anthracyclines in STS.See related commentary by Benjamin and Minotti, p. 3809.

Cardiac Amyloidosis for the Primary Care Provider: A Practical Review to Promote Earlier Recognition of Disease.

Cardiac amyloidosis is increasingly recognized as an underdiagnosed cause of heart failure. Diagnostic delays of up to 3 years from symptom onset may occur, and patients may be evaluated by more than 5 specialists prior to receiving the correct diagnosis. Newly available therapies improve clinical outcomes by preventing amyloid fibril deposition and are usually more effective in early stages of disease, making early diagnosis essential. Better awareness among primary care providers of the clinical presentation and modern treatment landscape is essential to improve timely diagnosis and early treatment of this disease. In this review, we provide practical guidance on the epidemiology, clinical manifestations, diagnostic evaluation, and treatment of transthyretin and light chain cardiac amyloidosis to promote earlier disease recognition among primary care providers.

Plasma Hepatocyte Growth Factor for Diagnosis and Prognosis in Light Chain and Transthyretin Cardiac Amyloidosis.

BACKGROUND: Delays in diagnosis of cardiac amyloidosis are common, usually resulting from nonspecific findings on clinical examination and testing. A discriminatory plasma biomarker could result in earlier diagnosis and improve prognosis assessment. OBJECTIVES: To determine the diagnostic and prognostic utility of hepatocyte growth factor (HGF) in light chain and transthyretin cardiac amyloidosis. METHODS: 188 patients with cardiac amyloidosis, amyloidosis without cardiac involvement, or symptomatic heart failure with left ventricular hypertrophy (LVH) or reduced ejection fraction (HFrEF) were enrolled prospectively. Serum biomarkers were measured at study enrollment, and all patients with amyloidosis were followed for all-cause mortality, cardiac transplant, or left ventricular assist device implant. Multinomial logistic regression and Kaplan-Meier survival estimates tested the association of biomarker levels with cardiac amyloidosis and clinical outcomes, respectively. Harrell's C-statistic and the likelihood ratio test compared the prognostic accuracy of plasma biomarkers. RESULTS: HGF was significantly higher in patients with cardiac amyloidosis (p<0.001). An HGF level of 205 pg/mL discriminated cardiac amyloidosis from LVH and HFrEF with 86% sensitivity, 84% specificity, and an area under the curve of 0.88 (95% CI 0.83-0.94). In patients with amyloidosis, elevated HGF levels were associated with worse event-free survival over a median follow-up period of 2.6 years (p<0.001) with incremental prognostic accuracy over NT-proBNP and troponin-T (p<0.001). CONCLUSIONS: HGF discriminates light chain and transthyretin cardiac amyloidosis from patients with symptomatic HF with LVH or HFrEF, and is associated with worse cardiac outcomes. Confirmation of these findings in a larger, multi-center study enrolling confirmed and suspected cases of cardiac amyloidosis is underway.

Cardio-Oncology Education and Training: JACC Council Perspectives.

The innovative development of cancer therapies has led to an unprecedented improvement in survival outcomes and a wide array of treatment-related toxicities, including those that are cardiovascular in nature. Aging of the population further adds to the number of patients being treated for cancer, especially those with comorbidities. Such pre-existing and developing cardiovascular diseases pose some of the greatest risks of morbidity and mortality in patients with cancer. Addressing the complex cardiovascular needs of these patients has become increasingly important, resulting in an imperative for an intersecting discipline: cardio-oncology. Over the past decade, there has been a remarkable rise of cardio-oncology clinics and service lines. This development, however, has occurred in a vacuum of standard practice and training guidelines, although these are being actively pursued. In this council perspective document, the authors delineate the scope of practice in cardio-oncology and the proposed training requirements, as well as the necessary core competencies. This document also serves as a roadmap toward confirming cardio-oncology as a subspecialty in medicine.

Cardio-oncology care in the era of the coronavirus disease 2019 (COVID-19) pandemic: An International Cardio-Oncology Society (ICOS) statement.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has given rise to a pandemic of unprecedented proportions in the modern era because of its highly contagious nature and impact on human health and society: coronavirus disease 2019 (COVID-19). Patients with cardiovascular (CV) risk factors and established CV disease (CVD) are among those initially identified at the highest risk for serious complications, including death. Subsequent studies have pointed out that patients with cancer are also at high risk for a critical disease course. Therefore, the most vulnerable patients are seemingly those with both cancer and CVD, and a careful, unified approach in the evaluation and management of this patient population is especially needed in times of the COVID-19 pandemic. This review provides an overview of the unique implications of the viral outbreak for the field of cardio-oncology and outlines key modifications in the approach to this ever-increasing patient population. These modifications include a shift toward greater utilization of cardiac biomarkers and a more focused CV imaging approach in the broader context of modifications to typical practice pathways. The goal of this strategic adjustment is to minimize the risk of SARS-CoV-2 infection (or other future viral outbreaks) while not becoming negligent of CVD and its important impact on the overall outcomes of patients who are being treated for cancer.

Clinical Practice and Research in Cardio-Oncology: Finding the "Rosetta Stone" for Establishing Program Excellence in Cardio-oncology.

The burgeoning field of cardio-oncology (C-O) is now necessary for the delivery of excellent care for patients with cancer. Many factors have contributed to this increasing population of cancer survivors or those being treated with novel and targeted cancer therapies. There is a tremendous need to provide outstanding cardiovascular (CV) care for these patients; however, current medical literature actually provides a paucity of guidance. C-O therefore provides a novel opportunity for clinical, translational, and basic research to advance patient care. This review aims to be a primer for cardio-oncologists on how to develop a vibrant and comprehensive C-O program, use practical tools to assist in the construction of C-O services, and to proactively incorporate translational and clinical research into the training of future leaders as well as enhance clinical care.

Anthracycline Cardiotoxicity: It Is Possible to Teach an Old Dog Some New Tricks.

Anthracyclines have proved to be one of the most effective chemotherapeutic agents in the treatment of numerous solid tumors and hematologic malignancies in both adult and pediatric patients. Their clinical benefit, however, is sometimes hampered by the development of cardiotoxicity, a process that still remains elusive despite decades of investigation. It has been postulated that anthracycline-induced cardiotoxicity is mediated in part by reactive oxygen species and redox cycling. This article reviews anthracycline cardiotoxicity in terms of historical significance, epidemiology, current detection strategies, prevention strategies, and patient care after anthracycline-based chemotherapy.

Vascular Toxicity in Patients with Cancer: Is There a Recipe to Clarify Treatment? CME.

The acknowledgement of cardiovascular disease as one of the leading causes of mortality and morbidity among cancer survivors is the cornerstone of the growing field of cardio-oncology. Although standardizing treatment for any given disease is often considered ideal, it is important to recognize the value of pursuing a practical and personalized approach when caring for an oncology patient to minimize the risk of treatment-related cardiotoxicity. We hereby discuss a series of cases that illustrate the ways vascular toxicity can manifest in patients with cancer and, when appropriate, provide scientific evidence that supports clinical decision making. We also raise questions about the complex management of these patients while shedding light on future research in this growing field.

Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions.

Recent studies have demonstrated that kynurenic acid (KYNA), a compound produced endogenously by the interferon-gamma-induced degradation of tryptophan by indoleamine 2,3-dioxygenase, activates the previously orphaned G protein-coupled receptor, GPR35. This receptor is expressed in immune tissues, although its potential function in immunomodulation remains to be explored. We determined that GPR35 was most highly expressed on human peripheral monocytes. In an in vitro vascular flow model, KYNA triggered the firm arrest of monocytes to both fibronectin and ICAM-1, via beta(1) integrin- and beta(2) integrin-mediated mechanisms, respectively. Incubation of monocytes with pertussis toxin prior to use in flow experiments significantly reduced the KYNA-induced monocyte adhesion, suggesting that adhesion is triggered by a G(i)-mediated process. Furthermore, KYNA-triggered adhesion of monocytic cells was reduced by short hairpin RNA-mediated silencing of GPR35. Although GPR35 is expressed at slightly lower levels on neutrophils, KYNA induced firm adhesion of these cells to an ICAM-1-expressing monolayer as well. KYNA also elicited neutrophil shedding of surface L-selectin, another indicator of leukocyte activation. Taken together, these data suggest that KYNA could be an important early mediator of leukocyte recruitment.