Heart Failure With Targeted Cancer Therapies: Mechanisms and Cardioprotection.

Oncology has seen growing use of newly developed targeted therapies. Although this has resulted in dramatic improvements in progression-free and overall survival, challenges in the management of toxicities related to longer-term treatment of these therapies have also become evident. Although a targeted approach often exploits the differences between cancer cells and noncancer cells, overlap in signaling pathways necessary for the maintenance of function and survival in multiple cell types has resulted in systemic toxicities. In particular, cardiovascular toxicities are of important concern. In this review, we highlight several targeted therapies commonly used across a variety of cancer types, including HER2 (human epidermal growth factor receptor 2)+ targeted therapies, tyrosine kinase inhibitors, immune checkpoint inhibitors, proteasome inhibitors, androgen deprivation therapies, and MEK (mitogen-activated protein kinase kinase)/BRAF (v-raf murine sarcoma viral oncogene homolog B) inhibitors. We present the oncological indications, heart failure incidence, hypothesized mechanisms of cardiotoxicity, and potential mechanistic rationale for specific cardioprotective strategies.

Clinical Practice Guidelines in Cardio-Oncology.

Consensus statements on recommended definitions and practice in cardio-oncology have been developed. There is recognition of the potential for anthracyclines, trastuzumab, pertuzumab, immune checkpoint inhibitors, tyrosine kinase inhibitors, cyclophosphamide, and radiotherapy to cause left ventricular dysfunction and heart failure with heterogeneous natural histories. Cardiac function should be evaluated by echocardiography before the initiation of these therapies. For the prevention of cardiotoxicity, there is evidence to support the use of dexrazoxane under specific circumstances; existing research does not support the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or ß-blockers in unselected individuals but should be considered in specific instances.

Cardiac biomarkers and association with subsequent cardiomyopathy and mortality among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort.

BACKGROUND: Survivors of childhood cancer exposed to cardiotoxic therapies are at significant cardiovascular risk. The utility of cardiac biomarkers for identifying the risk of future cardiomyopathy and mortality is unknown. METHODS: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) were assessed in 1213 adults 10 or more years from a childhood cancer diagnosis; 786 were exposed to anthracycline chemotherapy and/or chest-directed radiation therapy (RT). NT-proBNP values above age- and sex-specific 97.5th percentiles were considered abnormal. Generalized linear models estimated cross-sectional associations between abnormal NT-proBNP and anthracycline or chest RT doses as risk ratios with 95% confidence intervals (CIs). A Poisson distribution estimated rates and a Cox proportional hazards model estimated hazard ratios (HRs) for future cardiac events and death. RESULTS: At a median age of 35.5 years (interquartile range, 29.8-42.5 years), NT-proBNP and cTnT were abnormal in 22.5% and 0.4%, respectively. Exposure to chest RT and exposure to anthracycline chemotherapy were each associated with a dose-dependent increased risk for abnormal NT-proBNP (P for trend <.0001). Among exposed survivors with no history of Common Terminology Criteria for Adverse Events-graded cardiomyopathy and with normal systolic function, survivors with abnormal NT-proBNP had higher rates per 1000 person-years of cardiac mortality (2.93 vs 0.96; P < .0001) and future cardiomyopathy (32.10 vs 15.98; P < .0001) and an increased risk of future cardiomyopathy (HR, 2.28; 95% CI, 1.28-4.08) according to a multivariable assessment. CONCLUSIONS: Abnormal NT-proBNP values were prevalent and, among survivors who were exposed to cardiotoxic therapy but did not have a history of cardiomyopathy or current systolic dysfunction, identified those at increased risk for future cardiomyopathy. Further longitudinal studies are needed to confirm this novel finding.

A multi-modal diagnostic model improves detection of cardiac amyloidosis among patients with diagnostic confirmation by cardiac biopsy.

BACKGROUND: Timely recognition of cardiac amyloidosis is clinically important, but the diagnosis is frequently delayed. OBJECTIVES: We sought to identify a multi-modality approach with the highest diagnostic accuracy in patients evaluated by cardiac biopsy, the diagnostic gold standard. METHODS: Consecutive patients (N = 242) who underwent cardiac biopsy for suspected amyloidosis within an 18-year period were retrospectively identified. Cardiac biomarker, ECG, and echocardiography results were examined for correlation with biopsy-proven disease. A prediction model for cardiac amyloidosis was derived using multivariable logistic regression. RESULTS: The overall cohort was characterized by elevated BNP (median 727 ng/mL), increased left ventricular wall thickness (IWT; median 1.7 cm), and reduced voltage-to-mass ratio (median 0.06 mm/[g/m2]). One hundred and thirteen patients (46%) had either light chain (n = 53) or transthyretin (n = 60) amyloidosis by cardiac biopsy. A prediction model including age, relative wall thickness, left atrial pressure by E/e', and low limb lead voltage (<0.5 mV) showed good discrimination for cardiac amyloidosis with an optimism-corrected c-index of 0.87 (95% CI 0.83-0.92). The diagnostic accuracy of this model (79% sensitivity, 84% specificity) surpassed that of traditional screening parameters, such as IWT in the absence of left ventricular hypertrophy on ECG (98% sensitivity, 20% specificity) and IWT with low limb lead voltage (49% sensitivity, 91% specificity). CONCLUSION: Among patients with an advanced infiltrative cardiomyopathy phenotype, traditional biomarker, ECG, and echocardiography-based screening tests have limited individual diagnostic utility for cardiac amyloidosis. A prediction algorithm including age, relative wall thickness, E/e', and low limb lead voltage improves the detection of cardiac biopsy-proven disease.

Cardiovascular Events in Men with Prostate Cancer Receiving Hormone Therapy: An Analysis of the FDA Adverse Event Reporting System (FAERS).

PURPOSE: The comparative cardiovascular risk profiles of available hormone therapies for the treatment of prostate cancer is not known. MATERIALS AND METHODS: We queried the U.S. Food and Drug Administration Adverse Event Reporting System, a retrospective, pharmacovigilance database, for cardiovascular adverse event reports in men with prostate cancer receiving gonadotropin releasing hormone (GnRH) agonists, GnRH antagonists, androgen receptor antagonists, and/or androgen synthesis inhibitors from January 2000 to April 2020. RESULTS: Cardiovascular adverse events accounted for 6,231 reports (12.6%) on hormone monotherapy and 1,793 reports (26.1%) on combination therapy. Arterial vascular events were reported most commonly, followed by arrhythmias, heart failure, and venous thromboembolism. Compared to GnRH agonists, GnRH antagonists were associated with fewer cardiovascular adverse event reports as monotherapy (adjusted reporting odds ratio [ROR]=0.70 [95% CI 0.59-0.84], p <0.001) and as combination therapy (ROR=0.47 [0.34-0.67], p <0.0001), driven by reductions in arterial vascular events. Second generation androgen receptor antagonists and abiraterone were associated with more reports of hypertension requiring hospitalization (ROR=1.21 [1.03-1.41], p=0.02 and ROR=1.19 [1.01-1.40], p=0.03, respectively), and more heart failure events when used in combination with GnRH antagonists (ROR=2.79 [1.30-6.01], p=0.009 and ROR=2.57 [1.12-5.86], p=0.03). CONCLUSIONS: In this retrospective analysis of a pharmacovigilance database, arterial vascular events were the most commonly reported cardiovascular adverse events in men on hormone therapy for prostate cancer. GnRH antagonists were associated with fewer reports of overall cardiovascular events and arterial vascular events than GnRH agonists. Additional study is needed to identify optimal strategies to reduce cardiovascular morbidity among men with prostate cancer receiving hormone therapy.

Hypertension in the Cardio-Oncology Clinic.

As cancer therapies improve, the population of survivors of cancer has increased, and the long-term effects of cancer treatments have become more apparent. Cardiotoxicity is a well-established adverse effect of many antineoplastic agents. Hypertension is common in survivors of cancer, can be caused or worsened by certain agents, and has been shown to increase the risk of other cardiovascular diseases including heart failure. Pretreatment risk assessment and careful monitoring of blood pressure during therapy is essential. Aggressive management of preexisting or incident hypertension in survivors of cancer is paramount to decrease the risk of heart failure and other cardiovascular diseases in these patients.

Recurrent cardiotoxicity potentiated by the interaction of proteasome inhibitor and immunomodulatory therapy for the treatment of multiple myeloma.

Patients with multiple myeloma (MM) have improved treatment options, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Despite their efficacy, increased rates of cardiovascular (CV) complications occur in patients exposed to some of these therapies. While previous research has focused on identifying the toxicities inherent to each specific agent, the CV side effects may be potentiated by the combination of PIs and IMiDs plus dexamethasone. We present a patient with MM with recurrent cardiotoxicity only when exposed to combination PI and IMiD-based therapy. We also review the literature in this context, and propose a potential algorithm for cardiotoxicity prevention in this population.

Effects of endogenous serum neuregulin-1ß on morbidity and mortality in patients with heart failure and left ventricular systolic dysfunction.

CONTEXT: Improved left ventricular ejection fraction (LVEF) following administration of recombinant human Neuregulin-1ß (NRG), epidermal growth factor (EGF) involved in cardiomyocyte repair/survival, has been observed in patients with systolic heart failure (HF). METHODS: Serum NRG was measured by ELISA in 248 patients with NYHA class I-IV HF. RESULTS: NRG exhibited a marginally significant effect on LVEF trajectory over 11 months (p = 0.07). There is no apparent level of NRG that predicts improved survival. CONCLUSIONS: There is a potential relationship between serum NRG and improved LVEF, indicating the need to investigate the utility of NRG in predicting HF outcomes, including LVEF maintenance.

Management of Cancer Therapeutics-Related Cardiac Dysfunction.

Improvements in detection and treatment of cancer have resulted in a significant increase in cancer survivors. However, cancer survivorship comes with long-term risk of adverse effects of cancer therapies, including cardiomyopathy, heart failure, arrhythmias, ischemic heart disease, atherosclerosis, thrombosis, and hypertension. There is a renewed interest in understanding the pathophysiology of cancer therapeuticserelated cardiac dysfunction. In recent years, efforts have been directed to the management of cancer therapeuticserelated cardiac dysfunction. This article discusses the pathophysiology and molecular mechanisms that contribute to cancer therapeutics-related cardiac dysfunction and presents an napproach to the evaluation and treatment of these patients.

Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults.

BACKGROUND: Anthracyclines are important chemotherapeutic agents, but their use is limited by cardiotoxicity. Candidate gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity and heart failure, but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular (LV) function. The purpose of this study was to identify genetic factors influencing changes in LV function after anthracycline chemotherapy. METHODS: We conducted a genome-wide association study (GWAS) of change in LV function after anthracycline exposure in 385 patients identified from BioVU, a resource linking DNA samples to de-identified electronic medical record data. Variants with P values less than 1×10 were independently tested for replication in a cohort of 181 anthracycline-exposed patients from a prospective clinical trial. Pathway analysis was performed to assess combined effects of multiple genetic variants. RESULTS: Both cohorts were middle-aged adults of predominantly European descent. Among 11 candidate loci identified in discovery GWAS, one single nucleotide polymorphism near PR domain containing 2, with ZNF domain (PRDM2), rs7542939, had a combined P value of 6.5×10 in meta-analysis. Eighteen Kyoto Encyclopedia of Gene and Genomes pathways showed strong enrichment for variants associated with the primary outcome. Identified pathways related to DNA repair, cellular metabolism, and cardiac remodeling. CONCLUSION: Using genome-wide association we identified a novel candidate susceptibility locus near PRDM2. Variation in genes belonging to pathways related to DNA repair, metabolism, and cardiac remodeling may influence changes in LV function after anthracycline exposure.

ERBB signaling attenuates proinflammatory activation of nonclassical monocytes.

Immune activation in chronic systolic heart failure (HF) correlates with disease severity and prognosis. Recombinant neuregulin-1 (rNRG-1) is being developed as a possible therapy for HF, based on the activation of ERBB receptors in cardiac cells. Work in animal models of HF led us to hypothesize that there may be direct effects of NRG-1 on immune system activation and inflammation. We investigated the expression of ERBB receptors and the effect of rNRG-1 isoform glial growth factor 2 (GGF2) in subpopulations of peripheral blood mononuclear cells (PB MNCs) in subjects with HF. We found that human monocytes express both ERBB2 and ERBB3 receptors, with high interindividual variability among subjects. Monocyte surface ERBB3 and TNF-α mRNA expression were inversely correlated in subjects with HF but not in human subjects without HF. GGF2 activation of ERBB signaling ex vivo inhibited LPS-induced TNF-α production, specifically in the CD14lowCD16+ population of monocytes in a phosphoinositide 3-kinase-dependent manner. GGF2 suppression of TNF-α correlated directly with the expression of ERBB3. In vivo, a single dose of intravenous GGF2 reduced TNF-α expression in PB MNCs of HF subjects participating in a phase I safety study of GGF2. These results support a role for ERBB3 signaling in the regulation of TNF-α production from CD14lowCD16+ monocytes and a need for further investigation into the clinical significance of NRG-1/ERBB signaling as a modulator of immune system function.NEW & NOTEWORTHY This study identified a novel role of neuregulin-1 (NRG-1)/ERBB signaling in the control of proinflammatory activation of monocytes. These results further improve our fundamental understanding of cardioprotective effects of NRG-1 in patients with heart failure.

Validation of an automated electronic algorithm and "dashboard" to identify and characterize decompensated heart failure admissions across a medical center.

BACKGROUND: We aim to validate the diagnostic performance of the first fully automatic, electronic heart failure (HF) identification algorithm and evaluate the implementation of an HF Dashboard system with 2 components: real-time identification of decompensated HF admissions and accurate characterization of disease characteristics and medical therapy. METHODS: We constructed an HF identification algorithm requiring 3 of 4 identifiers: B-type natriuretic peptide >400 pg/mL; admitting HF diagnosis; history of HF International Classification of Disease, Ninth Revision, diagnosis codes; and intravenous diuretic administration. We validated the diagnostic accuracy of the components individually (n = 366) and combined in the HF algorithm (n = 150) compared with a blinded provider panel in 2 separate cohorts. We built an HF Dashboard within the electronic medical record characterizing the disease and medical therapies of HF admissions identified by the HF algorithm. We evaluated the HF Dashboard's performance over 26 months of clinical use. RESULTS: Individually, the algorithm components displayed variable sensitivity and specificity, respectively: B-type natriuretic peptide >400 pg/mL (89% and 87%); diuretic (80% and 92%); and International Classification of Disease, Ninth Revision, code (56% and 95%). The HF algorithm achieved a high specificity (95%), positive predictive value (82%), and negative predictive value (85%) but achieved limited sensitivity (56%) secondary to missing provider-generated identification data. The HF Dashboard identified and characterized 3147 HF admissions over 26 months. CONCLUSIONS: Automated identification and characterization systems can be developed and used with a substantial degree of specificity for the diagnosis of decompensated HF, although sensitivity is limited by clinical data input.

Current Concepts of Cardiac Amyloidosis: Diagnosis, Clinical Management, and the Need for Collaboration.

Cardiac amyloidosis is a complex and vexing clinical condition that requires a high degree of suspicion for the diagnosis with a substantial amount of discipline to discern the extent of disease and the best available therapy. There is a complex interplay between multiple organ systems, and the clinical presentation may involve a myriad of confusing clinical symptoms. The diagnosis of cardiac amyloidosis can be confirmed with a combination of physical findings, cardiac biomarkers, noninvasive testing, and, if necessary, myocardial biopsy. Genetic testing is critical to establish the type of amyloidosis.

The Utility of Point-of-Care Biomarkers to Detect Cardiotoxicity During Anthracycline Chemotherapy: A Feasibility Study.

BACKGROUND: Anthracycline chemotherapy is associated with an increased risk of developing heart failure (HF). The current standard for detecting HF or cardiotoxicity during chemotherapy involves episodic cardiac imaging typically at prescribed intervals and there are limited studies examining techniques beyond measuring left ventricular (LV) function. This study explores whether cardiac biomarkers troponin I (TnI) and B-type natriuretic peptide (BNP) could be part of a screening strategy for early detection of the development of cardiotoxicity in patients undergoing anthracycline chemotherapy. METHODS AND RESULTS: Patients were enrolled from a single medical center. Cardiac biomarkers (TnI, BNP) were measured before and within 24 hours after completion of anthracycline administration for each cycle of therapy. Cardiac imaging was obtained at baseline and at completion of chemotherapy (commonly at 6 or 12 months) or based on clinical suspicion of a cardiac event. Of the enrolled 109 patients, 11 (10.1%) experienced cardiac events; all of these patients had at least 1 BNP value >100 pg/mL before the cardiac event. Significant reduction in LV ejection fraction as defined for cardiotoxicity occurred in only 3 of 10 patients (30%) with a cardiac event. CONCLUSIONS: The use of cardiac biomarkers, particularly BNP, may allow early detection of cardiotoxicity related to anthracycline chemotherapy.

Clinical and Research Considerations for Patients With Hypertensive Acute Heart Failure: A Consensus Statement from the Society of Academic Emergency Medicine and the Heart Failure Society of America Acute Heart Failure Working Group.

Management approaches for patients in the emergency department (ED) who present with acute heart failure (AHF) have largely focused on intravenous diuretics. Yet, the primary pathophysiologic derangement underlying AHF in many patients is not solely volume overload. Patients with hypertensive AHF (H-AHF) represent a clinical phenotype with distinct pathophysiologic mechanisms that result in elevated ventricular filling pressures. To optimize treatment response and minimize adverse events in this subgroup, we propose that clinical management be tailored to a conceptual model of disease based on these mechanisms. This consensus statement reviews the relevant pathophysiology, clinical characteristics, approach to therapy, and considerations for clinical trials in ED patients with H-AHF.

Cardio-Oncology Training: A Proposal From the International Cardioncology Society and Canadian Cardiac Oncology Network for a New Multidisciplinary Specialty.

There is an increasing awareness and clinical interest in cardiac safety during cancer therapy as well as in optimally addressing cardiac issues in cancer survivors. Although there is an emerging expertise in this area, known as cardio-oncology, there is a lack of organization in the essential components of contemporary training. This proposal, an international consensus statement organized by the International Cardioncology Society and the Canadian Cardiac Oncology Network, attempts to marshal the important ongoing efforts for training the next generation of cardio-oncologists. The necessary elements are outlined, including the expectations for exposure necessary to develop adequate training. There should also be a commitment to local, regional, and international education and research in cardio-oncology as a requirement for advancement in the field.

Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma.

Carfilzomib is a novel irreversible proteasome inhibitor (PI) used with increasing frequency to treat patients with relapsed and/or refractory multiple myeloma (RRMM). This agent is an effective treatment for this challenging population, but proteasome inhibition has the potential of significant cardiac toxicity via the accumulation of intracellular protein aggregates. Although large clinical trials have not suggested an excess of heart failure with PI therapy, nonhuman animal studies and case reports in humans with the PI bortezomib have suggested otherwise. We describe the clinical presentation and management of 6 patients with RRMM who experienced significant cardiac toxicity associated with carfilzomib treatment. A common clinical syndrome of dyspnea associated with left ventricular systolic and/or diastolic dysfunction was identified. These abnormalities were largely reversible with prompt cessation of PI therapy and initiation of traditional heart failure treatments. Safe readministration of carfilzomib with dose modification was possible in some cases.

Early management of patients with acute heart failure: state of the art and future directions. A consensus document from the society for academic emergency medicine/heart failure society of America acute heart failure working group.

Heart failure (HF) afflicts nearly 6 million Americans, resulting in one million emergency department (ED) visits and over one million annual hospital discharges. An aging population and improved survival from cardiovascular diseases is expected to further increase HF prevalence. Emergency providers play a significant role in the management of patients with acute heart failure (AHF). It is crucial that emergency physicians and other providers involved in early management understand the latest developments in diagnostic testing, therapeutics and alternatives to hospitalization. Further, clinical trials must be conducted in the ED in order to improve the evidence base and drive optimal initial therapy for AHF. Should ongoing and future studies suggest early phenotype-driven therapy improves in-hospital and post-discharge outcomes, ED treatment decisions will need to evolve accordingly. The potential impact of future studies which incorporate risk-stratification into ED disposition decisions cannot be underestimated. Predictive instruments that identify a cohort of patients safe for ED discharge, while simultaneously addressing barriers to successful outpatient management, have the potential to significantly impact quality of life and resource expenditures.

Cardio-oncology: a tremendous opportunity to improve patient care.

A cardiologist at Vanderbilt University (TN, USA), Daniel J Lenihan is President of the International CardiOncology Society-North America. In 1988, Daniel graduated from the University of Tennessee College of Medicine at Memphis and did his residency at Wright-Patterson Air Force Base in Dayton (OH, USA). Ultimately, he gained a cardiology fellowship from the University of Cincinnati (OH, USA) and went on to become Professor and Director of Cardiovascular Research in the Department of Cardiology at The University of Texas MD Anderson Cancer (TX, USA). He now works as Professor of Medicine and Director of Clinical Research in the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville (TN, USA) specializing in advanced heart failure medicine and cardio-oncology. For over 20 years, he has been active in clinical research in heart failure, and the main focuses of his work have included hemodynamic assessments, angiogenic growth factor response, novel cardiac biomarkers and optimal methods to prevent or detect heart failure at the earliest stage possible in patients undergoing treatment for cancer.

Cardiotoxicity due to Chemotherapy: the Role of Biomarkers.

An ever-increasing array of chemotherapeutic agents is being used in the treatment of solid organ or hematologic malignancies. The success of many of these agents has led to an increasing survival of patients with cancer. However, many of these agents, particularly anthracyclines and trastuzumab, are associated with the development of cardiotoxicity. The current standard for the evaluation of chemotherapy-associated cardiotoxicity typically involves the use of serial measurements of left ventricular (LV) function by echocardiogram (Echo) and radionuclide ventriculogram (MUGA). Unfortunately, this time-honored method offers low sensitivity to the early prediction or detection of cardiac events. Frequently, by the time cardiotoxicity is detected, significant LV dysfunction has occurred and ultimately this may not respond to standard cardioprotective treatment. Cardiac biomarkers, troponin I and B-type natriuretic peptide, may allow a more accurate and timely monitoring strategy. The current data and a summarized understanding of how to utilize cardiac biomarkers for the prevention and early detection of cardiac dysfunction during chemotherapy are presented.