Discordant ventilatory and efferent sympathetic responsiveness to peripheral and central chemoreflex stimulation in heart failure with reduced ejection fraction

Peripheral or central chemoreceptor sensitization is a well-documented cause of reflex sympathetic excitation in patients with heart failure and reduced ejection fraction (HFrEF).1 In one series, augmented ventilatory responsiveness to hypercapnia and hypoxia, present in ∼half the patient cohort, predicted a 4-year survival of 49%.2 The carotid body has been identified as a target for surgical or percutaneous intervention with the aim of benefiting such individuals by restoring autonomic equilibrium.3,4 Importantly, this strategy is predicated on the assumption that transient intermittent hypoxic tests can accurately characterize a sensitized peripheral chemoreflex, with the conjecture that the slope or sensitivity of the efferent sympathetic response then parallels that of ventilation. However, chemoreceptor-mediated regulation of breathing and autonomic outflow engage different brainstem circuits.5 To date, selection of patients for peripheral chemoreflex intervention has involved quantification of ventilatory responses to intermittent hypoxia3: 100% nitrogen is inhaled over a short duration (∼2–8 breaths) to achieve a range of oxygen saturations (70%–100% SaO2). The peak of ventilation (V̇E) elicited by each exposure is inversely related to the prior nadir in SaO2, generating a V̇E–SaO2 slope for peripheral chemoreflex sensitivity with units of L·min−1·%SaO2−1. This measure is often called the ‘hypoxic ventilatory response’ (HVR).6 In patients with HFrEF, a value ≥0.75 L·min−1·%SaO2−1 is considered an ‘exaggerated’ HVR and used as an indication for carotid body intervention.7