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

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.