Frontiers review
Mechanism of augmented exercise hyperpnea in chronic heart failure and dead space loading

https://doi.org/10.1016/j.resp.2012.12.004Get rights and content

Abstract

Patients with chronic heart failure (CHF) suffer increased alveolar VD/VT (dead-space-to-tidal-volume ratio), yet they demonstrate augmented pulmonary ventilation such that arterial PCO2 (PaCO2) remains remarkably normal from rest to moderate exercise. This paradoxical effect suggests that the control law governing exercise hyperpnea is not merely determined by metabolic CO2 production (V˙CO2) per se but is responsive to an apparent (real-feel) metabolic CO2 load (V˙CO2o) that also incorporates the adverse effect of physiological VD/VT on pulmonary CO2 elimination. By contrast, healthy individuals subjected to dead space loading also experience augmented ventilation at rest and during exercise as with increased alveolar VD/VT in CHF, but the resultant response is hypercapnic instead of eucapnic, as with CO2 breathing. The ventilatory effects of dead space loading are therefore similar to those of increased alveolar VD/VT and CO2 breathing combined. These observations are consistent with the hypothesis that the increased series VD/VT in dead space loading adds to V˙CO2o as with increased alveolar VD/VT in CHF, but this is through rebreathing of CO2 in dead space gas thus creating a virtual (illusory) airway CO2 load within each inspiration, as opposed to a true airway CO2 load during CO2 breathing that clogs the mechanism for CO2 elimination through pulmonary ventilation. Thus, the chemosensing mechanism at the respiratory controller may be responsive to putative drive signals mediated by within-breath PaCO2 oscillations independent of breath-to-breath fluctuations of the mean PaCO2 level. Skeletal muscle afferents feedback, while important for early-phase exercise cardioventilatory dynamics, appears inconsequential for late-phase exercise hyperpnea.

Section snippets

Whipp's law on ventilatory compensation for changes in physiological VD/VT

Despite more than a century of extensive and intensive research and continuing passionate debates, the mechanisms underlying the control of exercise hyperpnea in health and in disease remain far from clear. It is well established that in healthy subjects undergoing incremental exercise, the ventilatory response (in terms of total pulmonary ventilation, V˙E) increases with metabolic CO2 production (metabolic CO2 flow to the lungs, V˙CO2) according to a linear V˙EV˙CO2 relationship over a wide

Exercise hyperpnea relationship in CHF

According to Whipp's law, the regulation of PaCO2 (Fig. 1a) through the interplay between physiological VD/VT and V˙E/V˙CO2 (Figs. 1b, c) accounts for the small positive Y-intercept in the linear V˙EV˙CO2 relationship in healthy subjects (Fig. 1d). By the same token, one would expect that under conditions where physiological VD/VT is increased (making V˙E less efficient with respect to alveolar ventilation) the controller would also “know” that V˙E “needs” to increase more per unit V˙CO2 to

Exercise hyperpnea relationship in dead space loading

In CHF, apparent metabolic CO2 load is augmented primarily by increases in parallel (alveolar) VD/VT and secondarily by increases in series (anatomical) VD/VT (see footnote 4). In both healthy subjects and CHF patients, series VD/VT can be exaggerated by dead space loading (tube breathing). The resultant augmentation in V˙CO2o relative to V˙CO2 explains the increase in V˙EV˙CO2 slope that is typical during dead space loading (Poon, 1992b, Poon, 2008, Ward and Whipp, 1980, Wood et al., 2011) (

Influence of within-breath PaCO2 oscillations on respiratory chemosensing

A fundamental premise of Eq. (9) is that the controller's perception of V˙CO2i or V˙ˆCO2i (real or virtual) and V˙CO2o under varying disturbances of the chemical plant (CO2 breathing or changes in series or parallel VD at rest and during exercise) is influenced by putative dynamic chemoreceptor signaling mediated by within-breath PaCO2 oscillations instead of (or in addition to) breath-to-breath fluctuations of the mean PaCO2 level. To test this hypothesis, we next apply Eq. (9) to three

Concluding remarks

The general framework of respiratory chemosensing presented above rectifies several deep-rooted misconceptions and ill-conceived dogmas and taboos in the field that have long impeded understanding of ventilatory control mechanisms in health and in disease. First, we have shown that the control of V˙E at rest and during exercise is determined not only by the total V˙CO2 to be eliminated but also by the total VD/VT that impairs pulmonary CO2 elimination. The resultant V˙E is coupled to the

Acknowledgments

We thank Drs. S.A. Ward, K. Wasserman and the late Dr. N.S. Cherniack for generous advice and encouragement and Drs. P.G. Agostoni, M. Amann, T.G. Babb, A.J. Coats, J.A. Dempsey, J. Duffin, B.D. Johnson, M.J.Joyner, H.R. Middlekauff, C.F. Notarius, D.J. Paterson, R. Pellegrino, M.F. Piepoli, H.T. Robertson, N.H. Secher, G.D. Swanson, J.W. Severinghaus, G. Song, D.S. Ward, J.B. West, and C.B. Wolff for valuable comments on the final manuscript. C. Tin was supported by an American Heart

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    Current address: Department of Mechanical and Biomedical Engineering, City University of Hong Kong, Hong Kong, China.

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