• Scott A Sands, Yoseph Mebrate, Bradley A Edwards, Shamim Nemati, Charlotte H Manisty, Akshay S Desai, Andrew Wellman, Keith Willson, Darrel P Francis, James P Butler, and Atul Malhotra.
• 1 Division of Sleep and Circadian Disorders and.
• Am. J. Respir. Crit. Care Med. 2017 Jan 15; 195 (2): 237-246.

RationaleIn patients with chronic heart failure, daytime oscillatory breathing at rest is associated with a high risk of mortality. Experimental evidence, including exaggerated ventilatory responses to CO2 and prolonged circulation time, implicates the ventilatory control system and suggests feedback instability (loop gain > 1) is responsible. However, daytime oscillatory patterns often appear remarkably irregular versus classic instability (Cheyne-Stokes respiration), suggesting our mechanistic understanding is limited.ObjectivesWe propose that daytime ventilatory oscillations generally result from a chemoreflex resonance, in which spontaneous biological variations in ventilatory drive repeatedly induce temporary and irregular ringing effects. Importantly, the ease with which spontaneous biological variations induce irregular oscillations (resonance "strength") rises profoundly as loop gain rises toward 1. We tested this hypothesis through a comparison of mathematical predictions against actual measurements in patients with heart failure and healthy control subjects.MethodsIn 25 patients with chronic heart failure and 25 control subjects, we examined spontaneous oscillations in ventilation and separately quantified loop gain using dynamic inspired CO2 stimulation.Measurements And Main ResultsResonance was detected in 24 of 25 patients with heart failure and 18 of 25 control subjects. With increased loop gain-consequent to increased chemosensitivity and delay-the strength of spontaneous oscillations increased precipitously as predicted (r = 0.88), yielding larger (r = 0.78) and more regular (interpeak interval SD, r = -0.68) oscillations (P < 0.001 for all, both groups combined).ConclusionsOur study elucidates the mechanism underlying daytime ventilatory oscillations in heart failure and provides a means to measure and interpret these oscillations to reveal the underlying chemoreflex hypersensitivity and reduced stability that foretells mortality in this population.

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