Exercising in Hypoxia and Other Stimuli: Heart Rate Variability and Ventilatory Oscillations

Abstract

Periodic breathing is a respiratory phenomenon frequently observed in patients with heart failure and in normal subjects sleeping at high altitude. However, until recently, periodic breathing has not been studied in wakefulness and during exercise. This review relates the latest findings describing this ventilatory disorder when a healthy subject is submitted to simultaneous physiological (exercise) and environmental (hypoxia, hyperoxia, hypercapnia) or pharmacological (acetazolamide) stimuli. Preliminary studies have unveiled fundamental physiological mechanisms related to the genesis of periodic breathing characterized by a shorter period than those observed in patients (11~12 vs. 30~60 s). A mathematical model of the respiratory system functioning under the aforementioned stressors corroborated these data and pointed out other parameters, such as dead space, later confirmed in further research protocols. Finally, a cardiorespiratory interdependence between ventilatory oscillations and heart rate variability in the low frequency band may partly explain the origin of the augmented sympathetic activation at exercise in hypoxia. These nonlinear instabilities highlight the intrinsic "homeodynamic" system that allows any living organism to adapt, to a certain extent, to permanent environmental and internal perturbations.

Keywords: acetazolamide; exercise; heart rate variability; hypercapnia; hyperoxia; hypoxia; mathematical modeling; periodic breathing.

Figure 1

Example of an IBI spectral density (logarithmic scale), including the different bands: Ultra-low, very low, low, and high frequencies (ULF, VLF, LF, and HF, respectively). Extracted from [7].

Figure 2

Breath-by-breath output of minute ventilation ($\dot{\mathrm{V}}$E), pulse O₂ saturation (SpO₂), and end tidal PCO₂ (PETCO₂) during a hypoxia exercise test. Lower panel: Subject with a high HVRe (0.93 L.min⁻¹.kg⁻¹). Upper panel: Subject with a low HVRe (0.60 L.min⁻¹.kg⁻¹). From [17].

Figure 3

Example of spectral analysis of minute ventilation by Fast Fourier Transform in the 4 phases of a hypoxia exercise test. RN: Rest in normoxia, RH: Rest in hypoxia, EH: Exercise in hypoxia, EN: Exercise in normoxia. PSD: Power Spectral Density. Note that the frequency of the main peak in hypoxic exercise conditions (EH) is around 0.08 Hz, which corresponds to a period of 12.5 s. From [17].

Figure 4

$\dot{\mathrm{V}}$E power of the main peak obtained from the spectral analysis of minute ventilation during the various phases of a hypoxia exercise test. RN: Rest in normoxia, RH: Rest in hypoxia, EH: Exercise in hypoxia, EN: Exercise in normoxia. Mean ± SD. Condition vs RN: ++, p < 0.01, +++, p < 0.001. High HVRe vs. low HVRe: *, p < 0.05; **, p < 0.01. From [17].

Figure 5

Power spectral density of the ventilation signal at exercise: Normoxia and hypercapnic hyperoxia. From [20].

Figure 6

Power spectral density of the ventilation signal at exercise: Normoxia and hyperoxia. From [24].

Figure 7

Example of breath-by-breath ventilation recordings under placebo (upper panel) and acetazolamide (lower panel) treatment. Inlets: Ventilatory response to CO₂ (upper right: Placebo, lower right: Acetazolamide). From [24].

Figure 8

Left panel: Example of breath-by-breath ventilation recordings in hypoxia without and with added dead space (respectively upper and lower panels). Right panel: Power spectral densities of ventilation signal at exercise in 2 conditions: Hypoxia without added dead space (aDS) and hypoxia with aDS. From [48]. Copyright permission has been obtained from Elsevier.

Figure 9

Schematic diagram of potential mechanisms involved in the genesis of ventilatory oscillations in normal subjects at exercise. Breathing instability is directly related to the intensity of $\dot{\mathrm{V}}$E and $\dot{\mathrm{Q}}$c. Exercise, hypoxia, and hypercapnia increase $\dot{\mathrm{V}}$E and $\dot{\mathrm{Q}}$c, and therefore increase ventilatory oscillations. ACZ inhibits the effect of hypoxia and enhances the effect of hypercapnia on ventilation and blunts the relation between $\dot{\mathrm{V}}$E or $\dot{\mathrm{Q}}$c and ventilatory oscillations. From [24].

Figure 10

Diagrams of a central/peripheral interactive model of ventilation control system. The central respiratory command receives direct or indirect afferences from peripheral (through nucleus tractus solitaries, NTS) and central chemoreceptors (PCR and CCR, respectively), modulated by PaO₂ and PaCO₂. Hence, the level of hypoxia and hypercapnia acts on respiratory outputs via O₂ gain (peripheral GO₂, as a ventilatory response to a change of FIO₂) and CO₂ gain (peripheral GCO_2P and central GCO_2C, to a change of FICO2). From [56]. Copyright permission has been obtained from Elsevier.

Figure 11

Variation of $\dot{\mathrm{V}}$E for 2 levels of FIO₂ in the additive model: Normoxia (FIO₂ = 0.21) and hypoxia (FIO₂ = 0.14). From [56]. Copyright permission has been obtained from Elsevier.

Figure 12

Period of ventilatory oscillations according to several cardiorespiratory variables from their nominal values: Peripheral O₂ gain (GO₂), central CO₂ gain (GCO_2C), inhaled fraction of O₂ (FIO₂), delay of blood convection from lung to carotid bodies (DeltaTp), arterial O₂ partial pressure at SaO₂ = 50% (P50), total lung capacity (TLC), and alveolar/total ventilation ratio (rVAVE). From [56]. Copyright permission has been obtained from Elsevier.

Figure 13

Magnitude of ventilatory oscillations according to several cardiorespiratory variables from their nominal values: Peripheral O₂ gain (GO₂), central CO₂ gain (GCO_2C), inhaled fraction of O₂ (FIO₂), delay of blood convection from lung to carotid bodies (DeltaTp), arterial O₂ partial pressure at SaO₂ = 50% (P50), total lung capacity (TLC), and alveolar/total ventilation ratio (rVAVE). Magnitude mainly increases with GCO_2C, GO₂ (in a nearly linear manner), and DeltaTp and decreases with P50, rVAVE, TLC, and FIO₂. From [56]. Copyright permission has been obtained from Elsevier.

Figure 14

Spectrum analysis of a breath-by-breath ventilation recording and RR signal in hypoxia during exercise. From [7]. Copyright permission has been obtained from SPRINGER.