Baroreflex Activation Therapy in Left Ventricular Assist Device Patients Study

Left ventricular assist devices (LVADs) provide a meaningful therapeutic option for patients with end-stage systolic heart failure who cannot receive cardiac transplantation. For these patients, LVADs have been shown to improve mortality, functional capacity, and quality of life [1-3]. With ever-improving technological and procedural advances, the number of LVAD implantations for patients with end-stage cardiomyopathy as bridge to transplant, recovery, or even as destination therapy continues to rise [4]. Despite the short term clinical benefits of LVAD support, studies show that deleterious neurohormonal activation does not abate after LVAD implantation and that left ventricular scarring (or fibrosis) does not regress and may worsen. Similarly, the prevalence of myocardial recovery with LVAD support has been dismally low with <1% of patients recovering to the point where their LVAD can be safely explanted. Given that the majority of patients undergoing LVAD are now doing so with a destination therapy designation, and that the median estimated survival time on LVAD support ranges from 4-6 years, the importance of therapies to maximize chances for myocardial recovery while LVAD supported is evident.

The pathophysiologic reasons underlying the lack of abrogation of sympathetic and neurohormonal signaling with LVAD support, even in the face of adequate hemodynamic support, may center around the non-pulsatile nature of the device. Markham and Levine described sympathetic nerve activity in both pulsatile and nonpuslatile LVAD patients in 2013, demonstrating that patients with nonpulsatile devices had markedly elevated muscle sympathetic nerve activity, though pulsatile LVAD patients and normal controls had similar sympathetic activity. In a sequence of experiments, the authors demonstrated that this was at least partly due to baroreceptor unloading in the nonpulsatile patients. Further studies have demonstrated that plasma norepinephrine levels remain elevated after VAD implant, as do neurohormones in the renin-angiotensin-aldosterone axis. Sympathetic neurohormone levels have been shown to correlate with clinical response to LVAD therapy (defined by significant improvement in quality of life determined by the KCCQ), with reduced B-adrenergic receptor kinase-1 and DHPG levels differentiating those with better clinical response. Further, pathologic studies pre- and post-LVAD have demonstrated an acceleration of deleterious myocardial fibrosis during LVAD support, potentially driven by sympathetic and/or RAAS signaling pathways.

As demonstrated in preclinical studies and the clinical BeAT-HF trial, autonomic modulation with baroreflex activation therapy (BAT) with the BAROSTIM NEO system reduced sympathetic signaling, leading to increased NT-proBNP, 6-minute hall walk distance (6MHW), and improved quality of life in patients with chronic systolic heart failure.

However, the role of BAT in the unique physiologic LVAD-supported state has not be characterized. Given the concerns that LVAD support by augment sympathetic and thereby RAAS signaling, and that BAT may abrogate those deleterious pathways, we propose to study the clinical and neurohormonal effects of BAT in LVAD supported patients.