Androgen Deprivation Therapy/Androgen Receptor Signaling Inhibitor Treatments for Prostate Cancer: Pathophysiology and Review of Effects on Cardiovascular Disease.

Androgen deprivation therapy is the cornerstone of systemic management for prostate cancer but is associated with multiple adverse effects that must be considered during treatment. These effects occur because of the profound hypogonadism that is induced from lack of testosterone or due to the medications used in the treatment or in combination with androgen receptor signaling inhibitors. This article critically reviews the associations between androgen deprivation therapy, androgen receptor signaling inhibitors, and cardiovascular complications such as prolonged QT interval, atrial fibrillation, heart failure, atherosclerosis, coronary heart disease, venous thromboembolism, and peripheral arterial occlusive disease. These unfavorable outcomes reinforce the need for regular cardiovascular screening of patients undergoing androgen deprivation for the management of prostate cancer.

Clonal hematopoiesis and inflammation in the vasculature: CHIVE, a prospective, longitudinal clonal hematopoiesis cohort and biorepository.

ABSTRACT: Clonal hematopoiesis (CH) is an age-associated phenomenon leading to an increased risk of both hematologic malignancy and nonmalignant organ dysfunction. Increasingly available genetic testing has made the incidental discovery of CH clinically common yet evidence-based guidelines and effective management strategies to prevent adverse CH health outcomes are lacking. To address this gap, the prospective CHIVE (clonal hematopoiesis and inflammation in the vasculature) registry and biorepository was created to identify and monitor individuals at risk, support multidisciplinary CH clinics, and refine taxonomy and standards of practice for CH risk mitigation. Data from the first 181 patients enrolled in this prospective registry recapitulate the molecular epidemiology of CH from biobank-scale retrospective studies, with DNMT3A, TET2, ASXL1, and TP53 as the most commonly mutated genes. Blood counts across all hematopoietic lineages trended lower in patients with CH. In addition, patients with CH had higher rates of end organ dysfunction, in particular chronic kidney disease. Among patients with CH, variant allele frequency was independently associated with the presence of cytopenias and progression to hematologic malignancy, whereas other common high-risk CH clone features were not clear. Notably, accumulation of multiple distinct high-risk clone features was also associated with cytopenias and hematologic malignancy progression, supporting a recently published CH risk score. Surprisingly, ∼30% of patients enrolled in CHIVE from CH clinics were adjudicated as not having clonal hematopoiesis of indeterminate potential, highlighting the need for molecular standards and purpose-built assays in this field. Maintenance of this well-annotated cohort and continued expansion of CHIVE to multiple institutions are underway and will be critical to understanding how to thoughtfully care for this patient population.

Primary cardiac sarcoma: demographics, genomic study correlation, and survival benefits of surgery with adjuvant therapy in U.S. population.

BACKGROUND: Cardiac sarcomas are rare and aggressive tumors with little known about the demographics, genetics, or treatment outcomes. OBJECTIVES: The objectives of this study were to characterize the demographics, treatment modality, and survival associated with cardiac sarcomas and evaluate the potential for mutation-directed therapies. METHODS: All cases from 2000 to 2018 of cardiac sarcoma were extracted from the SEER database. Genomic comparison utilized The Cancer Genome Atlas (TCGA) database, as well as reviews and re-analysis of past applicable genomic studies. RESULTS: Cardiac sarcomas occurred most often in White patients, compared with national census data cardiac sarcomas occurred at a significantly higher rate in Asians. The majority of cases were undifferentiated (61.7%) and without distant metastases (71%). Surgery was the most common primary treatment modality and offered survival benefit (HR 0.391 (p = 0.001) that was most pronounced and sustained as compared to patients who received chemotherapy (HR 0.423 (p = 0.001) or radiation (HR 0.826 (p = 0.241) monotherapy. There was no difference in survival when stratified by race or sex; however, younger patients (< 50) had better survival. Genomics data on histologically undifferentiated cardiac sarcomas revealed a significant number were likely poorly differentiated pulmonary intimal sarcomas and angiosarcomas. CONCLUSIONS: Cardiac sarcoma is a rare disease with surgery continuing to be a cornerstone of therapy followed by traditional chemotherapy. Case studies have indicated the potential for therapies directed to specific genetic aberrations to improve survival for these patients and utilization of next-generation sequencing (NGS) will help improve both classification and these therapies for cardiac sarcoma patients.

Artificial intelligence modelling to assess the risk of cardiovascular disease in oncology patients.

Aims: There are no comprehensive machine learning (ML) tools used by oncologists to assist with risk identification and referrals to cardio-oncology. This study applies ML algorithms to identify oncology patients at risk for cardiovascular disease for referrals to cardio-oncology and to generate risk scores to support quality of care. Methods and results: De-identified patient data were obtained from Vanderbilt University Medical Center. Patients with breast, kidney, and B-cell lymphoma cancers were targeted. Additionally, the study included patients who received immunotherapy drugs for treatment of melanoma, lung cancer, or kidney cancer. Random forest (RF) and artificial neural network (ANN) ML models were applied to analyse each cohort: A total of 20 023 records were analysed (breast cancer, 6299; B-cell lymphoma, 9227; kidney cancer, 2047; and immunotherapy for three covered cancers, 2450). Data were divided randomly into training (80%) and test (20%) data sets. Random forest and ANN performed over 90% for accuracy and area under the curve (AUC). All ANN models performed better than RF models and produced accurate referrals. Conclusion: Predictive models are ready for translation into oncology practice to identify and care for patients who are at risk of cardiovascular disease. The models are being integrated with electronic health record application as a report of patients who should be referred to cardio-oncology for monitoring and/or tailored treatments. Models operationally support cardio-oncology practice. Limited validation identified 86% of the lymphoma and 58% of the kidney cancer patients with major risk for cardiotoxicity who were not referred to cardio-oncology.

Differentiating pulmonary hypertension associated with protein kinase inhibitors.

Protein kinase inhibitors (PKIs) have been implicated in pulmonary vascular toxicities including risk factors for at least three of the five World Health Organization groups of pulmonary hypertension (PH). These toxicities include direct drug-induced pulmonary arterial hypertension, an increase in cardiomyopathies, and an increase in interstitial lung disease. On- and off-target toxicities are common within multitargeted PKIs leading to cardiopulmonary toxicities. This review highlights the incidence, possible mechanisms, and management strategies for each group of possible PKI-induced PH. Future identification and clarification of protein kinase pathways for both mechanisms of toxicity and pathophysiology for PH could lead to improvements in patient care in oncology and pulmonary vascular diseases.

Emerging cancer therapies and cardiovascular risk.

The cardiovascular (CV) toxicity profiles of traditional cancer therapies such as anthracyclines and radiation therapy are familiar to many cardiologists. With the development and widespread use of additional cancer therapeutics, CV toxicities related to these agents are becoming more common. Cardiovascular specialists are often integrated into the care team for individuals with cancer and knowledge of the CV toxicities of cancer therapeutics has become essential. In this review, we provide a clinically focused summary of the current data regarding CV toxicities of common cancer therapies and identify potential management strategies for the CV specialist.

Bleeding with vascular endothelial growth factor tyrosine kinase inhibitor: A network meta-analysis.

BACKGROUND: Targeted therapies like vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are the first-choice treatment in several types of cancers. We aim to determine the comparative risk of bleeding events associated with the VEGFR-TKIs through a network meta-analysis. METHODS: Published data search up to November 2018 reporting bleeding in cancer patients treated with VEGFR-TKIs was performed. The primary outcome was presence of hemorrhagic events at the end of the trial. Bleeding as a side-effect profile was examined for eleven VEGFR-TKIs (Apatinib, Brivanib, Cabozantinib, Lenvatinib, Motesanib, Nintedanib, Pazopanib, Regorafenib, Sorafenib, Sunitinib and Vandetanib). Network meta-analysis based on random effects model estimating Odds Ratio (OR) with 95 % confidence interval (CI), compared the risk of bleeding events among the VEGFR-TKIs with respect to placebo control conditions. RESULTS: Fifty Randomized Clinical Trials (RCTs) including 16,753 cancer patients were included in this analysis. Twenty studies compared VEGFR-TKIs with placebo, the remaining studies compared VEGFR-TKIs with the standard chemotherapeutic regimen. VEGFR-TKIs were associated with increased incidence of all-grade hemorrhagic events in comparison to control (standard chemotherapy and/or placebo) (OR = 1.79; 95 % CI 1.50-2.13, p-value <0.0001) and placebo (OR = 1.50; 95 % CI 1.16-1.93, p-value = 0.1). However, there was no difference in high-grade bleeding in patients treated with VEGFR-TKI in comparison to control (OR = 1.22; 95 % CI 0.87-1.71, p-value 0.74) or placebo alone (OR = 1.05; 95 % CI 0.65-1.70, p-value 0.73). Among individual VEGFR-TKIs, Sunitinib (OR = 3.31, 95 % CI 2.34-4.69) and Regorafenib (OR = 2.92, 95 % CI 1.50-5.71) were associated with higher risk of hemorrhagic events in comparison to placebo. CONCLUSION: VEGR-TKIs, particularly Sunitinib and Regorafenib appear to be associated with increased risk of bleeding incidence. TRIAL REGISTRATION NUMBER: PROSPERO CRD42017056406.

Cardiovascular Complications of Chimeric Antigen Receptor T-Cell Therapy: The Cytokine Release Syndrome and Associated Arrhythmias.

In recent years, cancer treatment has evolved, and new therapies have been introduced with significant improvement in prognosis. The immunotherapies stand out owing to their efficacy and remission rate. Chimeric antigen receptor (CAR) T-cell therapy is a part of this new era of therapies. Chimeric antigen receptor T-cell therapy is a form of adoptive cellular therapy that uses a genetically encoded CAR in modified human T cells to target specific tumor antigens in a nonconventional, non-major histocompatibility complex (MHC) protein presentation. Chimeric antigen receptor T-cell therapy successfully identifies tumor antigens and through activation of T cells destroys tumoral cells. It has been found to efficiently induce remission in patients who have been previously treated for B-cell malignancies and have persistent disease. As the use of this novel therapy increases, its potential side effects also have become more evident, including major complications like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cytokine release syndrome is a major systemic inflammatory process as a result of massive cytokine production by the proliferating and activated CAR T cells in which multiple interleukins and immune cells contribute to the inflammatory response. Cytokine release syndrome has been associated with cardiovascular life-threatening complications including hypotension, shock, tachycardia, arrhythmias, left ventricular dysfunction, heart failure, and cardiovascular death. Arrhythmias, among its major complications, vary from asymptomatic prolonged corrected QT interval (QTc) to supraventricular tachycardia, atrial fibrillation, flutter, and ventricular arrhythmias like Torsade de pointes. This article focuses on the cardiovascular complications and arrhythmias associated with CRS and CAR T-cell therapy.

Valvular Heart Disease in Cancer Patients: Etiology, Diagnosis, and Management.

OPINION STATEMENT: Cardiac valvular disease as consequence of radiation and chemotherapy during treatment for malignancy is growing in its awareness. While the overwhelming emphasis in this population has been on the monitoring and preservation of left ventricular systolic function, we are now developing a greater appreciation for the plethora of cardiac sequelae beyond this basic model. To this end many institutions across the country have developed cardio-oncology programs, which are collaborative practices between oncologists and cardiologists in order to minimize a patient's cardiovascular risk while allowing them to receive the necessary treatment for their cancer. These programs also help to recognize early nuanced treatment complications such as valvular heart disease, and provide consultation for the most appropriate course of action. In this article we will discuss the etiology, prevalence, diagnosis, and current treatment options of valvular heart disease as the result of chemotherapy and radiation.

Cardiovascular Risk and Level of Statin Use Among Women With Breast Cancer in a Cardio-Oncology Clinic.

BACKGROUND: Because of the improvements in survival rates, patients with breast cancer are now more likely to die from cardiovascular disease than from cancer. Thus, providing appropriate preventive cardiovascular care to patients with cancer is of the utmost importance. METHODS: We retrospectively compared the cardiovascular risk and management of 146 women treated at the Cardio-Oncology (Cardio-Onc) and the Obstetrics and Gynecology (Ob-Gyn) clinics. We calculated cardiovascular risk using the American College of Cardiology (ACC)/American Heart Association (AHA) atherosclerotic cardiovascular disease (ASCVD) risk calculator and the Framingham Risk Score Calculator. We also determined the prevalence of appropriate statin use according to both the 2013 ACC/AHA and the 2002 Adult Treatment Panel (ATP) III lipid guidelines. RESULTS: The 10-year ASCVD risk score was not significantly different between the 2 cohorts. More patients in the Ob-Gyn cohort with an ASCVD risk score >7.5% were already appropriately on statins compared to patients in the Cardio-Onc cohort (60.9% vs 31.0%, respectively, P=0.003), but after the first Cardio-Onc visit, 4 additional patients with breast cancer were prescribed statins (44.8% total). Fourteen (19.2%) Cardio-Onc patients had a high Framingham Risk Score compared to 6 (8.2%) Ob-Gyn patients. CONCLUSION: We demonstrated that the ASCVD risk is similar between women with breast cancer attending the Cardio-Onc clinic and the women without breast cancer attending the Ob-Gyn clinic, but the Cardio-Onc cohort had significantly more patients with a high Framingham Risk Score. Both clinics had similarly poor rates of appropriate statin prescribing rates according to the ATP III guidelines.

Cardio-Oncology: A Focused Review of Anthracycline-, Human Epidermal Growth Factor Receptor 2 Inhibitor-, and Radiation-Induced Cardiotoxicity and Management.

BACKGROUND: Cardio-oncology is a collaborative approach between cardiologists and oncologists in the treatment of patients with cancer and heart disease. Radiation and chemotherapy have played a major role in the decreased cancer-related mortality achieved in the past 2 decades. However, anthracycline-, tyrosine kinase-, and radiation-based therapies are each associated with independent cardiovascular (CV) risks, and these risks are cumulative when these therapies are used in combination. METHODS: We analyzed several published articles, studies, and guidelines to provide a focused review of cardiotoxicity associated with anthracyclines, human epidermal growth factor receptor 2 inhibitors, and radiation therapy and its management. RESULTS: The focus on CV risk among individuals being treated with cardiotoxic agents is important because once the cancer is cured, CV disease becomes the number 1 cause of death among cancer survivors. Cardio-oncology focuses on assessing CV risk prior to starting therapy, optimizing modifiable risk factors, and providing surveillance and treatment for any early signs of cardiotoxicity in patients undergoing radiation and chemotherapy. A collaborative approach between oncologists and cardiologists is integral to the optimal care of patients with cancer. Although radiation and chemotherapy treatments have evolved with the aim of targeting cancer cells while having minimal effect on the heart, the increased risk of cardiomyopathy in patients receiving these treatments remains significant. CONCLUSION: Proper screening and treatment of cardiotoxicity are essential for patients with cancer. As cardiac diseases and cancer remain the first and second causes of mortality in developed nations, respectively, cardio-oncology is the answer to this group of individuals who are especially vulnerable to both causes of mortality.

Cardiovascular Effects of Exposure to Cigarette Smoke and Electronic Cigarettes: Clinical Perspectives From the Prevention of Cardiovascular Disease Section Leadership Council and Early Career Councils of the American College of Cardiology.

Cardiovascular morbidity and mortality as a result of inhaled tobacco products continues to be a global healthcare crisis, particularly in low- and middle-income nations lacking the infrastructure to develop and implement effective public health policies limiting tobacco use. Following initiation of public awareness campaigns 50 years ago in the United States, considerable success has been achieved in reducing the prevalence of cigarette smoking and exposure to secondhand smoke. However, there has been a slowing of cessation rates in the United States during recent years, possibly caused by high residual addiction or fatigue from cessation messaging. Furthermore, tobacco products have continued to evolve faster than the scientific understanding of their biological effects. This review considers selected updates on the genetics and epigenetics of smoking behavior and associated cardiovascular risk, mechanisms of atherogenesis and thrombosis, clinical effects of smoking and benefits of cessation, and potential impact of electronic cigarettes on cardiovascular health.

Rituximab-Induced Acute ST Elevation Myocardial Infarction.

BACKGROUND: Rituximab has rarely been associated with acute coronary syndrome (ACS). We report the case of a patient in whom rituximab, a monoclonal antibody used to treat lymphomas of B-cell origin, induced ST elevation myocardial infarction. CASE REPORT: A 46-year-old male patient diagnosed with stage II non-Hodgkin lymphoma presented to the emergency department with acute crushing, substernal chest pain that radiated to his back 1 day after a chemotherapy infusion with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. An electrocardiogram revealed normal sinus rhythm with ST elevations in the inferior leads. The patient underwent primary percutaneous coronary intervention (PCI) of his right coronary artery and first diagonal artery with placement of drug-eluting stents. He did well postprocedure and resumed therapy with rituximab under close monitoring by the cardiology and oncology departments without any further cardiac events. CONCLUSION: In patients with ACS because of chemotherapy, complete revascularization during PCI should be considered.

Risk assessment and management of anthracycline and HER2 receptor inhibitor-induced cardiomyopathy.

With the advent and increased use of chemotherapeutic agents and radiation therapy, cancer survival rates have increased. With increased survival, both acute and chronic cardiotoxic adverse effects have emerged. The growing need for managing the treatment of individuals with chemotherapy-induced cardiotoxicity has led to the formation of cardio-oncology programs throughout the United States. These programs concentrate on many aspects of cardiac disease in the oncology patient. Of these, the cardiotoxic effects (particularly cardiomyopathy) of anthracyclines and HER2 receptor inhibitors are a large focus of cardio-oncology practice. Despite the increasing availability of these programs, no consensus guidelines have been established to provide a framework for treating these patients. This review describes the initial evaluation, risk assessment, and management of individuals receiving anthracycline and HER2 receptor inhibitor therapy for cardiomyopathy. These recommendations are supported by the current literature in this field.

Smoking, sex, risk factors and abdominal aortic aneurysms: a prospective study of 18†782 persons aged above 65 years in the Southern Community Cohort Study.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a leading cause of death in the USA. We evaluated the incidence and predictors of AAA in a prospectively followed cohort. METHODS: We calculated age-adjusted AAA incidence rates (IR) among 18 782 participants aged ≥65 years in the Southern Community Cohort Study who received Medicare coverage from 1999-2012, and assessed predictors of AAA using multivariable Cox proportional hazards models, overall and stratified by sex, adjusting for demographic, lifestyle, socioeconomic, medical and other factors. HRs and 95% CIs were calculated for AAA in relation to factors ascertained at enrolment. RESULTS: Over a median follow-up of 4.94 years, 281 cases were identified. Annual IR was 153/100,000, 401, 354 and 174 among blacks, whites, men and women, respectively. AAA risk was lower among women (HR 0.48, 95% CI 0.36 to 0.65) and blacks (HR 0.51, 95% CI 0.37 to 0.69). Smoking was the strongest risk factor (former: HR 1.91, 95% CI 1.27 to 2.87; current: HR 5.55, 95% CI 3.67 to 8.40), and pronounced in women (former: HR 3.4, 95% CI 1.83 to 6.31; current: HR 9.17, 95% CI 4.95 to 17). A history of hypertension (HR 1.44, 95% CI 1.04 to 2.01) and myocardial infarction or coronary artery bypass surgery (HR 1.9, 95% CI 1.37 to 2.63) was negatively associated, whereas a body mass index ≥25 kg/m(2) (HR 0.72; 95% CI 0.53 to 0.98) was protective. College education (HR 0.6, 95% CI 0.37 to 0.97) and black race (HR 0.44, 95% CI 0.28 to 0.67) were protective among men. CONCLUSIONS: Smoking is a major risk factor for incident AAA, with a strong and similar association between men and women. Further studies are needed to evaluate benefits of ultrasound screening for AAA among women smokers.