Analysis of Hypoxic and Hypercapnic Ventilatory Response in Healthy Volunteers

Abstract

Introduction: A previous study has suggested that the Human Leukocyte Antigen (HLA) allele DQB1*06:02 affects hypoxic ventilatory response (HVR) but not hypercapnic ventilatory response (HCVR) in an Asian population. The current study evaluated the relationship in Caucasians and Asians. In addition we assessed whether gender or polymorphisms in genes participating in the control of breathing affect HVR and HCVR.

Methods: A re-breathing system was used to measure HVR and HCVR in 551 young adults (56.8% Caucasians, 30% Asians). HLA-DQB1*06:02 and tagged polymorphisms and coding variants in genes participating in breathing (PHOX2B, GPR4 and TASK2/KCNK5) were analyzed. The associations between HVR/HCVR and HLA-DQB1*06:02, genetic polymorphisms, and gender were evaluated using ANOVA or frequentist association testing with SNPTEST.

Results: HVR and gender are strongly correlated. HCVR and gender are not. Mean HVR in women was 0.276±0.168 (liter/minute/%SpO2) compared to 0.429±0.266 (liter/minute/%SpO2) in men, p<0.001 (55.4% higher HVR in men). Women had lower baseline minute ventilation (8.08±2.36 l/m vs. 10.00±3.43l/m, p<0.001), higher SpO2 (98.0±1.3% vs. 96.6±1.7%, p<0.001), and lower EtCO2 (4.65±0.68% vs. 4.82±1.02%, p = 0.025). One hundred and two (18.5%) of the participants had HLA-DQB1*06:02. No association was seen between HLA-DQB1*06:02 and HVR or HCVR. Genetic analysis revealed point wise, uncorrected significant associations between two TASK2/KCNK5 variants (rs2815118 and rs150380866) and HCVR.

Conclusions: This is the largest study to date reporting the relationship between gender and HVR/ HCVR and the first study assessing the association between genetic polymorphisms in humans and HVR/HCVR. The data suggest that gender has a large effect on hypoxic breathing response.

Fig 1. Measurement of ventilatory response to hypoxemia.

Illustration of 4 metrics to calculate ventilatory response to hypoxemia (HVR): Hypoxia-all, Hypoxia-90, Regression _(Hypoxia-all) and Regression _(Hypoxia-90). The first two variables were calculated by taking the increase in minute ventilation (ΔV_e) between baseline and maximal hypoxemia (mh) and dividing it by the corresponding change in SpO₂ (ΔSpO₂). Baseline minute ventilation differed for Hypoxia-all and Hypoxia-90. In Hypoxia-all baseline minute ventilation was the minute ventilation at the beginning of the study (bl). In Hypoxia-90 baseline minute ventilation was the minute ventilation measured at 90% saturation (90%SpO₂). Hypoxia-all was calculated using the equation $\mathrm{H}\mathrm{y}\mathrm{p}\mathrm{o}\mathrm{x}\mathrm{i}\mathrm{a}-\mathrm{a}\mathrm{l}\mathrm{l}\mathrm{H}\mathrm{V}\mathrm{R}=\frac{\mathrm{\Delta }\mathrm{V}\mathrm{e}\left(\mathrm{b}\mathrm{l}-\mathrm{m}\mathrm{h}\right)}{\mathrm{\Delta }\mathrm{S}\mathrm{p}\mathrm{O}2\left(\mathrm{b}\mathrm{l}-\mathrm{m}\mathrm{h}\right)}$ Whereas, Hypoxia-90 was calculated using the equation $\mathrm{H}\mathrm{y}\mathrm{p}\mathrm{o}\mathrm{x}\mathrm{i}\mathrm{a}-90\mathrm{H}\mathrm{V}\mathrm{R}=\frac{\mathrm{\Delta }Ve\left(90\%-mh\right)}{\mathrm{\Delta }SpO2\left(90-mh\right)}$ Linear regression was applied to the measurements. Regression _(Hypoxia-all) used the regression line of all measurements. Regression _(Hypoxia-90) used only measurements done when SpO₂ was 90% or lower.

Fig 2. Measurement of ventilatory response to hypercapnia.

Illustration of 2 different methods to calculate the ventilatory response to hypercapnia (HCVR) using the following 2 variables: Hypercapnia-all and Regression _{(Hypercapnia-all)}. Hypercapnia-all is the change in V_e (ΔV_e) between baseline and the end of the study, divided by the reciprocal change in EtCO₂ (ΔEtCO₂) in the following form: HCVR = ΔV_e/ΔCO₂. Regression _{(Hypercapnia-all)} is the slope of regression line of all measurements.

Fig 3. Correlation between test and re-test of hypoxic (N = 28 participants) and hypercapnic (N = 16 participants) responses.

Fig 4. Association between Hypoxic and Hypercapnic Ventilatory Responses.

R = 0.392, p<0.001.