Mechanisms underlying secondhand smoke-induced cardiovascular dysfunction

 描述（由申请人提供）：二手烟（SHS）具有显著的有害心血管效应，包括心脏性猝死和心律失常，比任何其他疾病都要致命。通过在公共场所禁烟来减少SHS暴露已被证明可以改善非吸烟者的心血管健康。然而，暴露于SHS仍然是一个主要的公共卫生问题。虽然SHS暴露无疑会造成重大的心血管健康风险，但挑战在于解决原因和机制。本研究的目的是系统地研究1）心脏迷走神经神经元的神经可塑性和心脏电特性的浓度和时间依赖性变化在SHS应激诱导的心血管功能障碍中的作用; 2）炎症、心脏自主神经系统和心脏重构在SHS应激诱导的心血管功能障碍中的作用。目的1将确定浓度和时间依赖性的SHS消融诱导的心率变异性（HRV）降低和心律失常负荷增加，使用遥测心电图记录在清醒的小鼠和专门的数据分析软件。目标2将确定神经元内在兴奋性降低的程度 在脑干切片上，用全细胞膜片钳技术观察到SHS诱导的心率变异性的浓度依赖性和时间依赖性变化中，迷走神经核团中的神经元参与了SHS诱导的心率变异性变化。目的3将确定在何种程度上直接重塑心脏电特性有助于SHS诱导的浓度和时间依赖性增加心律失常的易感性，使用光学成像的电生理特性在孤立的心脏缺乏自主输入。目的4将确定炎症反应和自主神经功能障碍在多大程度上有助于SHS诱导的浓度和时间依赖性不良反应。将测试三种水溶性和口服可用的药物：1）环氧化物水解酶抑制剂，t-TUCB（反式-4-21-苯甲酸），其已显示减弱SHS压迫诱导的肺部炎症; 2）常用的阻断心脏交感神经活性的β 1受体阻滞剂;和3）阻断心脏迷走神经活性的心脏选择性毒蕈碱（M2）阻滞剂。确定SHS的浓度和时间依赖性效应可能有助于制定吸烟暴露的监管政策，并将公众的注意力集中在风险评估上。揭示介导SHS诱发心血管后果的潜在机制将促进我们对SHS诱发心血管不良反应的原因的科学理解，并可能为新的治疗策略引入新的可能性。

 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.