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Androgen deprivation therapy is a cornerstone of prostate cancer treatment. Pharmacological androgen deprivation includes gonadotropin-releasing hormone agonism and antagonism, androgen receptor inhibition, and CYP17 (cytochrome P450 17A1) inhibition. Studies in the past decade have raised concerns about the potential for androgen deprivation therapy to increase the risk of adverse cardiovascular events such as myocardial infarction, stroke, and cardiovascular mortality, possibly by exacerbating cardiovascular risk factors. In this review, we summarize existing data on the cardiovascular effects of androgen deprivation therapy. Among the therapies, abiraterone stands out for increasing risk of cardiac events in meta-analyses of both randomized controlled trials and observational studies. We find a divergence between observational studies, which show consistent positive associations between androgen deprivation therapy use and cardiovascular disease, and randomized controlled trials, which do not show these associations reproducibly.
Cardio-oncology has emerged as an exciting new field at the intersection of cardiology and oncology. While improved oncology treatment efficacy has increased survival rates in cancer patients, the long-term cardiovascular consequences of this life-saving treatment have become more clinically relevant. Both traditional and newer (targeted) cancer therapies can have cardiovascular and metabolic sequelae, resulting in heart failure, coronary artery disease, myocarditis, pericardial disease, hypertension, and vascular and metabolic perturbations (Moslehi JJ. Cardiovascular toxic effects of targeted cancer therapies. 375: 1457-1467, 2016). Both acute and chronic cardiovascular toxicities have proven challenging for clinicians and patients, significantly contributing to morbidity and mortality. Although chronic cardiovascular disease affects a growing number of cancer survivors (~17 million in the United States in 2019), cardiovascular toxicities associated with cancer and cancer therapies are poorly understood mechanistically. To balance potential damage to the cardiovascular system with effective and efficient cancer treatment, novel strategies are sorely needed. This perspective focuses on an assembly of articles that discuss novel means of counteracting adverse cardiovascular events in response to anticancer therapy. In light of new clinical syndromes in cardiology due to cancer therapies, we hope to highlight promising research opportunities offered by cardio-oncology (Bellinger AM, Arteaga CL, Force T, Humphreys BD, Demetri GD, Druker BJ, Moslehi JJ. Cardio-oncology: how new targeted cancer therapies and precision medicine can inform cardiovascular discovery. 132: 2248-2258, 2015.).
OBJECTIVES - Given the neurocognitive hyperarousal observed in patients with insomnia disorder and associations of nocturnal hot flashes with cardiovascular disease risk, we examined whether women with hot flash-associated insomnia disorder demonstrate exaggerated cardiovascular responsivity to acute stressors, and also a profile of psychological hyperarousal.
METHODS - Peri and postmenopausal women with and without hot flash-associated insomnia disorder underwent assessments of cardiovascular autonomic responsivity to acute stress paradigms and psychological hyperarousal. Hemodynamic responses (heart rate, blood pressure) to nociceptive, social-evaluative, and cognitive stress paradigms were measured in the morning. Psychological hyperarousal was evaluated using questionnaires assessing daytime and presleep hyperarousal, anxiety, and sleep-related cognitions.
RESULTS - Women (25 with and 15 without hot flash-associated insomnia) aged 53.4 ± 4.8 years reported a range of insomnia symptoms. Resting-state hemodynamics were similar between groups. Heart rate and blood pressure responses to stress paradigms did not differ by group nor did they correlate with insomnia severity. Women with insomnia disorder had higher generalized anxiety disorder scores (mean 2.7 ± 3.0 vs 1.0 ± 1.4; P = 0.05) and sleep-related cognitions than those without insomnia (P ≤ 0.05). Insomnia symptom severity was moderately correlated with presleep and daytime hyperarousal, anxiety, and sleep-related cognition (all r ≥ 0.43).
CONCLUSIONS - Though hot flash-associated insomnia is characterized by psychological hyperarousal before sleep and during the daytime, it does not relate to cardiovascular responsiveness to acute stressors. Our findings do not support the hypothesis that altered cardiovascular control is a potential mechanism by which hot flash-associated insomnia confers higher cardiovascular disease risk.
Drug-induced cardiovascular complications are the most common adverse drug events and account for the withdrawal or severe restrictions on the use of multitudinous postmarketed drugs. In this study, we developed new in silico models for systematic identification of drug-induced cardiovascular complications in drug discovery and postmarketing surveillance. Specifically, we collected drug-induced cardiovascular complications covering the five most common types of cardiovascular outcomes (hypertension, heart block, arrhythmia, cardiac failure, and myocardial infarction) from four publicly available data resources: Comparative Toxicogenomics Database, SIDER, Offsides, and MetaADEDB. Using these databases, we developed a combined classifier framework through integration of five machine-learning algorithms: logistic regression, random forest, k-nearest neighbors, support vector machine, and neural network. The totality of models included 180 single classifiers with area under receiver operating characteristic curves (AUC) ranging from 0.647 to 0.809 on 5-fold cross-validations. To develop the combined classifiers, we then utilized a neural network algorithm to integrate the best four single classifiers for each cardiovascular outcome. The combined classifiers had higher performance with an AUC range from 0.784 to 0.842 compared to single classifiers. Furthermore, we validated our predicted cardiovascular complications for 63 anticancer agents using experimental data from clinical studies, human pluripotent stem cell-derived cardiomyocyte assays, and literature. The success rate of our combined classifiers reached 87%. In conclusion, this study presents powerful in silico tools for systematic risk assessment of drug-induced cardiovascular complications. This tool is relevant not only in early stages of drug discovery but also throughout the life of a drug including clinical trials and postmarketing surveillance.
Reactive oxygen species and reactive nitrogen species are biological molecules that play important roles in cardiovascular physiology and contribute to disease initiation, progression, and severity. Because of their ephemeral nature and rapid reactivity, these species are difficult to measure directly with high accuracy and precision. In this statement, we review current methods for measuring these species and the secondary products they generate and suggest approaches for measuring redox status, oxidative stress, and the production of individual reactive oxygen and nitrogen species. We discuss the strengths and limitations of different methods and the relative specificity and suitability of these methods for measuring the concentrations of reactive oxygen and reactive nitrogen species in cells, tissues, and biological fluids. We provide specific guidelines, through expert opinion, for choosing reliable and reproducible assays for different experimental and clinical situations. These guidelines are intended to help investigators and clinical researchers avoid experimental error and ensure high-quality measurements of these important biological species.
© 2016 American Heart Association, Inc.
It is a challenge for the human body to maintain stable blood pressure while standing. The body's failure to do so can lead to dizziness or even fainting. For decades it has been postulated that the vestibular organ can prevent a drop in pressure during a position change--supposedly mediated by reflexes to the cardiovascular system. We show--for the first time--a significant correlation between decreased functionality of the vestibular otolith system and a decrease in the mean arterial pressure when a person stands up. Until now, no experiments on Earth could selectively suppress both otolith systems; astronauts returning from space are a unique group of subjects in this regard. Their otolith systems are being temporarily disturbed and at the same time they often suffer from blood pressure instability. In our study, we observed the functioning of both the otolith and the cardiovascular system of the astronauts before and after spaceflight. Our finding indicates that an intact otolith system plays an important role in preventing blood pressure instability during orthostatic challenges. Our finding not only has important implications for human space exploration; they may also improve the treatment of unstable blood pressure here on Earth.
For most patients with chronic myeloid leukemia, tyrosine kinase inhibitors (TKIs) have turned a fatal disease into a manageable chronic condition. Imatinib, the first BCR-ABL1 TKI granted regulatory approval, has been surpassed in terms of molecular responses by the second-generation TKIs nilotinib, dasatinib, and bosutinib. Recently, ponatinib was approved as the only TKI with activity against the T315I mutation. Although all TKIs are associated with nonhematologic adverse events (AEs), experience with imatinib suggested that toxicities are typically manageable and apparent early during drug development. Recent reports of cardiovascular AEs with nilotinib and particularly ponatinib and of pulmonary arterial hypertension with dasatinib have raised concerns about long-term sequelae of drugs that may be administered for decades. Here, we review what is currently known about the cardiovascular toxicities of BCR-ABL1 TKIs, discuss potential mechanisms underlying cardiovascular AEs, and elucidate discrepancies between the reporting of such AEs between oncology and cardiovascular trials. Whenever possible, we provide practical recommendations, but we concede that cause-directed interventions will require better mechanistic understanding. We suggest that chronic myeloid leukemia heralds a fundamental shift in oncology toward effective but mostly noncurative long-term therapies. Realizing the full potential of these treatments will require a proactive rational approach to minimize long-term cardiovascular and cardiometabolic toxicities.
© 2015 by American Society of Clinical Oncology.
Novel targeted cancer therapies, especially kinase inhibitors, have revolutionized the treatment of many cancers and have dramatically improved the survival of several types of malignancies. Because kinases not only are important in cancer development and progression, but also play a critical role in the cardiovascular (CV) system and metabolic homeostasis, important CV and metabolic sequelae have been associated with several types of kinase inhibitors. This paper reviews the incidences and highlights potential mechanisms of vascular and metabolic perturbations associated with 3 classes of commonly used kinase inhibitors that target the vascular endothelial growth factor signaling pathway, the ABL kinase, and the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathway. We propose preventive, screening, monitoring, and management strategies for CV care of patients treated with these novel agents.
Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.