Mechanisms underlying secondhand smoke-induced cardiovascular dysfunction

 描述（由申请人提供）：二手烟 (SHS) 对心血管有显着的有害影响，包括心源性猝死和心律失常，其死亡人数比任何其他疾病都多。事实证明，通过公共场所禁烟来减少二手烟暴露可以改善非吸烟者的心血管健康。然而，接触二手烟仍然是一个主要的公共卫生问题。虽然毫无疑问，二手烟暴露会带来重大的心血管健康风险，但挑战在于解决其原因和机制。该项目的目标是系统地研究 1) 心脏迷走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，这些变化是二手烟暴露引起的心血管功能障碍的基础； 2）炎症、心脏自主神经系统和心脏重塑在二手烟暴露引起的心血管功能障碍中的作用。目标 1 将使用意识小鼠的遥测心电图记录和专门的数据分析软件来确定浓度和时间依赖性的 SHS 暴露引起的心率变异性 (HRV) 降低和心律失常负担增加。目标 2 将确定神经元内在兴奋性降低的程度 在脑干切片中使用全细胞膜片钳技术，在解剖学上确定的核模糊的心脏迷走神经元中，有助于 SHS 诱导的 HRV 浓度和时间依赖性变化。目标 3 将使用缺乏自主输入的离体心脏的电生理特性的光学成像来确定心脏电特性的直接重塑在多大程度上有助于 SHS 诱导的浓度和时间依赖性心律失常易感性增加。目标 4 将确定炎症反应和自主神经功能障碍对 SHS 诱导的浓度和时间依赖性不良反应的影响程度。将测试三种水溶性和口服药物：1）环氧化物水解酶抑制剂，t-TUCB（反式4-21-苯甲酸）已被证明可以减轻二手烟暴露引起的肺部炎症； 2) 常用的1阻滞剂来阻断心脏交感神经活动； 3) 心脏选择性毒蕈碱 (M2) 阻滞剂，以阻断心脏迷走神经活动。确定二手烟的浓度和时间依赖性影响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到风险评估上。揭示二手烟暴露引起的心血管后果的潜在机制将促进我们对二手烟引起的不良心血管影响的原因的科学理解，并可能为新的治疗策略带来新的可能性。

 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.