Stroke volume reduction impairs cerebrovascular regulation through ETCO in postural orthostatic tachycardia syndrome

Patients with postural orthostatic tachycardia syndrome (POTS) experience disabling symptoms such as brain fog related to reduced cerebral perfusion. The objective of this study is to determine the mediating role of carbon dioxide in the relationship between stroke volume and cerebral blood flow. A total of 15 female patients with POTS underwent head-up tilt testing under two conditions: with lower-body compression (higher stroke volume) and without (lower stroke volume). We analyzed cerebral blood flow velocity, respiratory, and cardiovascular responses using linear mixed-effects and mediation models to examine stroke volume-cerebral blood flow interactions. Granger causality and wavelet coherence assessed cerebral autoregulation. Lower-body compression attenuated the reduction in stroke volume (-34 ml versus -23 ml; p < 0.01), end-tidal CO (-6.4 mmHg versus -3.2 mmHg; p < 0.01), and mean middle cerebral artery blood flow velocity (-11.2 cm/s versus -4.2 cm/s; p < 0.01) during tilt. Mediation analysis revealed that carbon dioxide completely mediated the relationship between stroke volume and middle cerebral artery blood flow velocity, with a significant indirect effect (0.18 cm/s/ml, 95% confidence interval (CI) 0.058-0.33) and a nonsignificant direct effect (0.04 cm/s/ml, p = 0.5). Compression attenuated the association between stroke volume and carbon dioxide (-0.07 mmHg/ml; 95% CI -0.12 to -0.010; p = 0.02), as shown by the linear mixed-effect model, and reduced the directional influence of blood pressure on cerebral blood flow (ΔGranger causality: 0.12 (0.05-0.18) versus 0.05 (0.02-0.08); p < 0.01). Reduction in stroke volume leads to reduced cerebral perfusion in POTS, an effect likely mediated by decreased carbon dioxide.