A Rational Engineering Design Approach to Minimizing the Off-Target Effects of Baroreceptor Activation Therapy

摘要 尽管医疗管理有所改善，高血压仍然影响着25%的成年人，20%到30%的人 他们对药物治疗有抵抗力。同样，射血分数降低的心力衰竭患者 继续表现出预期寿命显著减少，频繁住院，以及总体质量较差 生活。颈动脉窦压力感受性反射的慢性电刺激--称为压力感受性反射激活疗法 (BAT)-FDA批准用于缓解与高血压和高血压相关的显著交感神经激活 心力衰竭。BAT在多个对照临床试验中得到证实，可产生持续显著的 对传统药物治疗无效的患者的高血压和心力衰竭结局的改善 管理；然而，治疗受到副作用的限制。我们提出了一种综合的方法来缓解 副作用，从而提高BAT的治疗效果。 我们试图确定导致BAT副作用的功能神经解剖学，并使用这些 为设计和测试更有效的BAT神经接口的方法提供数据。这些经过优化的设计将 扩大压力感受器激活和限制靶外效应之间的治疗窗口。结果是 将产生一个优化的BAT界面设计，可以快速转换为解决 明确的临床需求。此外，我们还将为合并局部神经和组织提供所需的框架 控制治疗的解剖学-限制副作用-进入神经接口设计过程，可以 易于应用于无数神经调节疗法的靶点。

Abstract Despite improvements in medical management, hypertension still affects >25% of adults, and 20 to 30% of them are resistant to pharmacological treatment. Similarly, heart failure patients with reduced ejection fraction continue to exhibit dramatically reduced life expectancy, frequent hospitalization, and overall poor quality of life. Chronic electrical stimulation of the baroreflex at the carotid sinus—known as baroreflex activation therapy (BAT)—is FDA-approved to mitigate the marked sympathetic activation associated with both hypertension and heart failure. BAT was demonstrated in multiple controlled clinical trials to produce sustained significant improvements in both hypertension and heart failure outcomes in patients non-responsive to traditional medical management; however, the therapy is limited by side effects. We propose an integrated approach to mitigate side effects and thereby improve the therapeutic efficacy of BAT. We seek to determine the functional neuroanatomy responsible for the side effects of BAT and to use these data to design and test approaches for more effective BAT neural interfaces. These optimized designs will expand the therapeutic window between baroreceptor activation and limiting off-target effects. The outcomes of this project will produce an optimized BAT interface design that could be quickly translated to address a clear clinical need. In addition, we will provide a needed framework for incorporation of local neural and tissue anatomy—which govern therapy-limiting side effects—into the neural interface design process that can be readily applied to myriad neuromodulation therapy targets.