Mechanisms underlying secondhand smoke-induced cardiovascular dysfunction

二手烟诱发心血管功能障碍的机制

基本信息

批准号：
8861949
负责人：
CHAO-YIN CHEN
金额：
$ 42.94万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8861949
关键词：
Action Potentials Acute Adverse effects Age Air Pollution Arrhythmia Attention Attenuated Autonomic Dysfunction Autonomic nervous system Benzoic Acids Brain Stem Cardiac Cardiovascular system Cell Nucleus Cells Cessation of life Chronic Complex Computer software Conscious Data Data Analyses Disease Electrocardiogram Environmental Tobacco Smoke Epoxide hydrolase Exposure to Functional disorder Goals Heart Heart Block Heart Diseases Inflammation Inflammatory Inflammatory Response Iron Lung Lung Inflammation Mediating Microsomal Epoxide Hydrolase Morbidity - disease rate Mus Muscarinic M2 Receptor Muscarinics Myocardial Myocarditis Neuronal Plasticity Neurons Outcome Patch-Clamp Techniques Pharmaceutical Preparations Play Policies Predisposition Process Property Protocols documentation Public Health Recovery Risk Risk Assessment Risk Factors Slice Smoking Soot Stress Telemetry Testing Time Uncertainty Ventricular Water air filter atherogenesis base cardiovascular health cardiovascular risk factor electrical property environmental tobacco smoke exposure heart rate variability improved in vivo indexing inhibitor/antagonist killings mortality neuronal excitability neuroregulation non-smoker novel therapeutics optical imaging particle public health relevance receptor response sudden cardiac death

项目摘要

DESCRIPTION (provided by applicant): Secondhand smoke (SHS) has significant detrimental cardiovascular effects, including sudden cardiac death and cardiac arrhythmias that kill more than any other disease. Reducing SHS exposure with smoking bans in public places has been shown to improve cardiovascular health in non-smokers. However, exposure to SHS continues to be a major public health concern. While there is no doubt that SHS exposure poses a significant cardiovascular health risk, the challenges are to resolve the causes and mechanisms. The objectives of this project are to systematically investigate 1) the concentration- and time-dependent changes in neuroplasticity of cardiac vagal neurons and cardiac electrical properties underlying SHS exposure-induced cardiovascular dysfunction; and 2) the contribution of inflammation, cardiac autonomic nervous system, and cardiac remodeling in SHS exposure-induced cardiovascular dysfunction. Aim 1 will determine concentration- and time-dependent SHS exposure-induced decreased heart rate variability (HRV) and increased arrhythmia burdens using telemetry ECG recordings in conscious mice and specialized data analysis software. Aim 2 will determine the extent to which reduced neuronal intrinsic excitability in anatomically identified cardiac vagal neurons in the nucleus ambiguous contributes to the SHS-induced concentration- and time-dependent changes in HRV using whole-cell patch-clamp technique in brainstem slices. Aim 3 will determine the extent to which direct remodeling of cardiac electrical properties contributes to the SHS-induced concentration- and time-dependent increase in arrhythmia susceptibility using optical imaging of electrophysiological properties in isolated hearts devoid of autonomic inputs. Aim 4 will determine the extent to which the inflammatory response and autonomic dysfunction contributes to the SHS-induced concentration- and time-dependent adverse effects. Three water soluble and orally available drugs will be tested: 1) epoxide hydrolase inhibitor, t- TUCB (trans-4-21-benzoic acid) that has been shown to attenuate SHS exposure-induced lung inflammation; 2) a commonly used 1 blocker to block cardiac sympathetic activity; and 3) cardiac selective muscarinic (M2) blocker to block cardiac vagal activity. Establishing the concentration- and time-dependent effects of SHS may help to set regulatory policies on smoking exposure and focus public attention on risk assessment. Revealing the underlying mechanism(s) mediating SHS exposure-induced cardiovascular consequences will advance our scientific understanding of the causes of the adverse SHS-induced cardiovascular effects and may introduce new possibilities for novel therapeutic strategies.

描述（由申请人证明）：二手烟（SHS）具有明显的有害心血症心律失常，而不是其他任何疾病风险，挑战是解决该项目的目标。 SHS暴露的心脏自主神经心脏重塑的贡献将确定浓度和时间依赖的SHS暴露诱导的热率（HRV），并使用远程缺失负担增加了远程缺失在其中降低了神经元内固有兴奋性在解剖学中，核中识别出的心走动神经元模棱两可在脑干狭缝中使用全细胞斑块钳技术有助于SHS-诱导n HRV。孤立的心脏中没有自主性输入的生理学特性。 21-苯甲酸）是衰减SHS诱发的肺部炎症； SHS的依赖性影响可能有助于制定监管政策对吸烟的公众评估。