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：
9210098
负责人：
CHAO-YIN CHEN
金额：
$ 42.93万
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/9210098
关键词：
Action Potentials Acute Adverse effects Age Air Pollution Anatomy 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 Electrophysiology (science)Environmental Tobacco Smoke Epoxide hydrolase Exposure to Functional disorder Goals Heart Heart Block Heart Diseases Impairment Inflammation Inflammatory Inflammatory Response Iron Lung Lung Inflammation Mediating Morbidity - disease rate Mus Muscarinic M2 Receptor Muscarinics Myocardial Neuronal Plasticity Neurons Oral 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（由适用提供）：二手烟（SHS）具有明显的有害心血管影响，包括心脏猝死和心律不齐，杀死的心律失常比任何其他疾病都要多。在公共场所，通过吸烟禁令减少SHS暴露，可改善非吸烟者的心血管健康。但是，对SHS的接触仍然是一个主要的公共卫生问题。毫无疑问，SHS暴露具有重大的心血管健康风险，但挑战是解决原因和机制。该项目的目的是系统地研究1）心迷走神经元的神经质量的浓度和时间依赖性变化以及SHS暴露引起的心脏功能障碍的基础的心脏电气特性； 2）在SHS暴露引起的心血管功能障碍中，炎症，心脏自主神经系统和心脏重塑的贡献。 AIM 1将使用有意识的小鼠和专业数据分析软件中的遥测ECG记录来确定浓度和时间依赖的SH暴露诱导的降低心率变异性（HRV）和心律不齐的伯良。 AIM 2将确定降低神经元内在的刺激程度的程度在核模棱两可的解剖学上鉴定出的心脏迷走神经元中，使用脑干切片中的全细胞斑块钳技术在HRV中促进了SHS诱导的浓度和时间依赖性变化。 AIM 3将确定心脏电性能的直接重塑在多大程度上有助于通过使用无自主输入的分离心脏中电生理特性的光学成像对心律失常敏感性的浓度和时间依赖性增加。 AIM 4将确定炎症反应和自主功能障碍有助于SHS诱导的浓度和时间依赖性的不良反应的程度。将测试三种水固体和口服药物：1）环氧水解酶抑制剂T-TUCB（Trans-4-21-苯甲酸），已显示可减弱SHS暴露诱导的肺部感染； 2）常用的1阻滞剂以阻止心脏交感神经活动； 3）心脏选择性毒蕈碱（M2）阻滞剂以阻断心脏迷走神经活动。建立SHS的浓度和时间依赖性影响可能有助于制定有关吸烟暴露的监管政策，并将公众注意力集中在风险评估上。揭示了介导SHS暴露引起的心脏血管后果的基本机制将提高我们对不良SHS引起的心脏血管作用的原因的科学理解，并可能引入新的治疗策略的新可能性。