Challenging dynamic cerebral autoregulation across the physiological CO2 spectrum: Influence of biological sex and cardiac cycle

Abstract

This study applied alterations in partial pressure of end-tidal carbon dioxide ( $P_{\mathrm{ETC}{O}_2}$ ) to challenge dynamic cerebral autoregulation (dCA) responses across the cardiac cycle in both biological sexes. A total of 20 participants (10 females and 10 males; aged 19-34 years) performed 4-min bouts of repeated squat-stand manoeuvres (SSMs) at 0.05 and 0.10 Hz (randomized orders) with $P_{\mathrm{ETC}{O}_2}$ clamped at ∼40 mmHg. The protocol was repeated for hypercapnic (∼55 mmHg) and hypocapnic (∼20 mmHg) conditions. Middle cerebral artery (MCA) and posterior cerebral artery (PCA) were insonated via transcranial Doppler ultrasound. Dynamic end-tidal forcing clamped $P_{\mathrm{ETC}{O}_2}$ , and finger photoplethysmography quantified beat-to-beat changes in blood pressure. Linear regressions were performed for transfer function analysis metrics including power spectrum densities, coherence, phase, gain and normalized gain (nGain) with adjustment for sex. During hypercapnic conditions, phase metrics were reduced from eucapnic levels (all P < 0.009), while phase increased during the hypocapnic stage during both 0.05 and 0.10 Hz SSMs (all P < 0.037). Sex differences were present with females displaying greater gain and nGain systole metrics during 0.10 Hz SSMs (all P < 0.041). Across $P_{\mathrm{ETC}{O}_2}$ stages, females displayed reduced buffering against systolic aspects of the cardiac cycle and augmented gain. Sex-related variances in dCA could explain sex differences in the occurrence of clinical conditions such as orthostatic intolerance and stroke, though the effect of fluctuating sex hormones and contraceptive use on dCA metrics is not yet understood.

Keywords: dynamic end‐tidal forcing; eucapnia; hypercapnia; hypocapnia; sex differences; squat–stand manoeuvres.

FIGURE 1

Representative blood pressure (BP), middle cerebral artery velocity (MCAv), and posterior cerebral artery velocity (PCAv) data from one female and one male participant during 0.05 Hz squat‐stand manoeuvres.

FIGURE 2

Representative blood pressure (BP), middle cerebral artery velocity (MCAv), and posterior cerebral artery velocity (PCAv) data from one female and one male participant during 0.10 Hz squat–stand manoeuvres.

FIGURE 3

Coherence for middle cerebral artery (MCA) and posterior cerebral artery (PCA) obtained across the cardiac cycle during repeated squat–stand manoeuvres performed at frequencies of 0.05 and 0.10 Hz, across three stages: hypocapnia, eucapnia and hypercapnia. The data are categorized by sex, with females represented in red (n = 10) and males in black (n = 10). † indicates a stage that was significantly different from the eucapnia stage, as determined by linear regressions with stages (eucapnia as reference) and sex (female as reference) as predictor variables.

FIGURE 4

Phase for middle cerebral artery (MCA) and posterior cerebral artery (PCA) obtained across the cardiac cycle during repeated squat–stand manoeuvres performed at frequencies of 0.05 and 0.10 Hz, across three stages: hypocapnia, eucapnia and hypercapnia. The data are categorized by sex, with females represented in red (n = 10) and males in black (n = 10). † indicates a stage that was significantly different from the eucapnia stage, as determined by linear regressions with stages (eucapnia as reference) and sex (female as reference) as predictor variables.

FIGURE 5

Gain for middle cerebral artery (MCA) and posterior cerebral artery (PCA) obtained across the cardiac cycle during repeated squat–stand manoeuvres performed at frequencies of 0.05 and 0.10 Hz, across three stages: hypocapnia, eucapnia and hypercapnia. The data are categorized by sex, with females represented in red (n = 10) and males in black (n = 10). † indicates a stage that was significantly different from the eucapnia stage, as determined by linear regressions with stages (eucapnia as reference) and sex (female as reference) as predictor variables. ‡ highlights sex differences observed across the three stages (hypocapnia, eucapnia, hypercapnia).

FIGURE 6

Normalized gain (nGain) for middle cerebral artery (MCA) and posterior cerebral artery (PCA) obtained across the cardiac cycle during repeated squat–stand manoeuvres performed at frequencies of 0.05 and 0.10 Hz, across three stages: hypocapnia, eucapnia and hypercapnia. The data are categorized by sex, with females represented in red (n = 10) and males in black (n = 10). † indicates a stage that was significantly different from the eucapnia stage, as determined by linear regressions with stages (eucapnia as reference) and sex (female as reference) as predictor variables. ‡ highlights sex differences observed across the three stages (hypocapnia, eucapnia, hypercapnia).