ABSTRACT
BACKGROUND AND OBJECTIVE: There are multiple mechanisms underlying obstructive sleep apnea (OSA) development. However, how classic OSA risk factors such as body mass index (BMI) and sex portend to OSA development have not been fully described. Thus, we sought to evaluate how obesity leads to OSA, and assess how these mechanisms differ between men and women. Methods The San Diego Multi-Outcome OSA Endophenotype (SNOOzzzE) cohort includes 3,319 consecutive adults who underwent a clinical in-laboratory polysomnography at the UCSD sleep clinic between 1/2017-12/2019. Using routine polysomnography signals, we determined OSA endotypes. We then performed mediation analyses stratified by sex to determine how BMI influenced apnea hypopnea index (AHI) using OSA endotypic traits as mediators. Results We included 2,146 patients of whom 919 (43%) were women and 1,227 (57%) were obese. BMI was significantly associated with AHI in both women and men. In men, the effect of BMI on AHI was partially mediated by a reduction in upper airway stiffness (31% of total effect, TE), by a reduction in circulatory delay (16%TE), and by an increase in arousal threshold (7%TE). In women, the effect of BMI on AHI was partially mediated by a reduction in circulatory delay (22%TE). Discussion BMI-related OSA pathogenesis differs by sex. An increase in upper airway collapsibility (in men) is consistent with prior studies. A reduction in circulatory delay may lead to shorter and thus more events per hour (i.e., higher AHI), while the association between a higher arousal threshold and higher AHI may reflect reverse causation.
ABSTRACT
BACKGROUND: Several targeted therapies for cancer have been associated with cardiovascular toxicity. The evidence for this association has not been synthesized systematically nor has the quality of evidence been considered. We synthesized systematic review evidence of cardiovascular toxicity of individual targeted agents. METHODS: We searched MEDLINE, Embase, and the Cochrane Database of Systematic Reviews for systematic reviews with meta-analyses of cardiovascular outcomes for individual agents published to May 2020. We selected reviews according to prespecified eligibility criteria (International Prospective Register of Systematic Reviews CRD42017080014). We classified evidence of cardiovascular toxicity as sufficient, probable, possible, or indeterminate for specific cardiovascular outcomes based on statistical significance, study quality, and size. RESULTS: From 113 systematic reviews, we found at least probable systematic review evidence of cardiovascular toxicity for 18 agents, including high- and all-grade hypertension for bevacizumab, ramucirumab, axitinib, cediranib, pazopanib, sorafenib, sunitinib, vandetanib, aflibercept, abiraterone, and enzalutamide, and all-grade hypertension for nintedanib; high- and all-grade arterial thromboembolism (includes cardiac and/or cerebral events) for bevacizumab and abiraterone, high-grade arterial thromboembolism for trastuzumab, and all-grade arterial thromboembolism for sorafenib and tamoxifen; high- and all-grade venous thromboembolism (VTE) for lenalidomide and thalidomide, high-grade VTE for cetuximab and panitumumab, and all-grade VTE for bevacizumab; high- and all-grade left ventricular ejection fraction decline or congestive heart failure for bevacizumab and trastuzumab, and all-grade left ventricular ejection fraction decline/congestive heart failure for pazopanib and sunitinib; and all-grade corrected QT interval prolongation for vandetanib. CONCLUSIONS: Our review provides an accessible summary of the cardiovascular toxicity of targeted therapy to assist clinicians and patients when managing cardiovascular health.
ABSTRACT
INTRODUCTION: The introduction of targeted therapies for cancer has contributed to dramatic improvements in patient survival. Nevertheless, several targeted therapies have been associated with 'off-target' adverse effects, based on varying levels of evidence. To date, this evidence has not been systematically synthesised. We will synthesise published systematic review evidence of cardiovascular toxicity associated with targeted cancer therapies. METHODS AND ANALYSIS: We will include systematic reviews of randomised controlled trials and observational studies that report on cardiovascular outcomes for individual agents. We will identify systematic reviews by applying predeveloped, standardised search strategies within Embase, Medline and Cochrane Central. Two independent reviewers will identify reviews published up to 31 December 2016 using predefined eligibility criteria. They will resolve ambiguous cases through consensus, arbitrated by a third reviewer if required. The reviewers will extract and report data according to methodological guidelines for overviews provided by the Cochrane Collaboration, Joanna Briggs Institute and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. They will assess the quality of included reviews by applying the Assessment of Multiple Systematic Reviews tool. They will judge the quality of evidence in included reviews based on their assessment of bias and incorporation into the interpretation of findings. In synthesising the evidence, we will classify agents based on systematic review evidence of toxicity (sufficient, probable, possible or indeterminate) for specific cardiovascular outcomes (congestive heart failure, myocardial infarction, ischaemic heart disease, left ventricular ejection fraction decline, cerebrovascular disease, pulmonary embolism, thrombosis and hypertension). This will provide clinicians and patients with an accessible synthesis based on robust methodology. ETHICS AND DISSEMINATION: Ethics approval is not required for overviews. We will conduct the study in collaboration with consumer representatives. We will submit results for peer-review publication, and disseminate them through established clinical and consumer networks. PROSPERO REGISTRATION NUMBER: CRD42017080014.
