Faculty Bibliography

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.

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.

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.

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/OBJECTIVE: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.

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.

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.

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.

Serum- and glucocorticoid-induced kinase 1 is a ubiquitous kinase that regulates diverse processes such as ion transport and cell survival. We report that a single SGK1 mRNA produces isoforms with different N-termini owing to alternative translation initiation. The long isoforms, 49 and 47 kDa, are the most abundant, localize to the ER membrane, exhibit rapid turnover, their expression is decreased by ER stress, activate the epithelial sodium channel (ENaC) and translocate FoxO3a transcriptional factors from the nucleus to the cytoplasm. The short isoforms, 45 and 42 kDa, localize to the cytoplasm and nucleus, exhibit long half-life and phosphorylate glycogen synthase kinase-3beta. The data indicate that activation of Sgk1 in different cellular compartments is key to providing functional specificity to Sgk1 signaling pathways. We conclude that the distinct properties and functional specialization of Sgk1 given by the N-terminus confer versatility of function while maintaining the same core kinase domain.