Determinants of transvenous phrenic nerve stimulation-induced improvements in left ventricular function in central sleep apnea and heart failure

STUDY OBJECTIVES: Central sleep apnea (CSA) is common in heart failure (HF) patients, but its treatment's impact on cardiac function is unclear. Transvenous phrenic nerve stimulation (TPNS) is an emerging CSA therapy that may improve long-term left ventricular systolic function (LVEF) in HF. Given that the cardiovascular risk of sleep apnea appears contingent on respiratory event-related heart rate surges ("high ∆HR"), we hypothesized that TPNS treatment may preferentially improve LVEF in CSA patients with high ∆HR. METHODS: In the remedē System pivotal trial, ∆HR was calculated from baseline polysomnography in patients with HF. Primary analysis quantified whether treatment-related change in left ventricular ejection fraction (∆LVEF; echocardiography, biplane method) versus control was greater in "high ∆HR" (>14.6 beats/min, i.e. fourth quartile) versus "low ∆HR (≤4.2 beats/min, i.e. first quartile)" at 6 months (treatment × "high ∆HR" interaction). Longitudinal analysis quantified whether favorable LVEF changes from baseline were maintained longer term (6-12 months). RESULTS: In primary analysis (N = 79, M:F = 74:5, LVEF = 34 ± 12% [mean ± SD]), TPNS versus control was associated with a markedly greater improvement in LVEF in patients with high ∆HR versus low ∆HR (estimate [95% CI]: +7.8% [0.37, 15.2], pinteraction = 0.04). In longitudinal analysis, LVEF increased in patients with high ∆HR at 6, 9, and 12 months (+2.5% [-0.1, 5.1]; +3.9% [1.2, 6.5]; and +3.7% [1.0, 6.4] from baseline, respectively) but not among low ∆HR (-0.1% [-2.8, 2.6]; -0.3% [-3.1, 2.4]; and -0.8% [-3.7, 2.1]). CONCLUSIONS: Compared to low ∆HR, patients with high ∆HR showed greater LVEF improvement with TPNS for CSA. High ∆HR, a potential reflection of CSA-related sympathetic overactivity, may identify those who benefit most from CSA treatment.