Cardiovascular–Metabolic Integration
Oxygen delivery to tissues depends on cardiac output, blood oxygen content, and microvascular perfusion. The cardiovascular–metabolic coupling links the autonomic model (heart rate, blood pressure) to the energy metabolism model (oxygen-dependent ATP production):
\[ \text{DO}_2 = \text{CO} \cdot \text{CaO}_2 = (\text{HR} \times \text{SV}) \cdot (1.34 \cdot [\text{Hb}] \cdot \text{SaO}_2 + 0.003 \cdot \text{PaO}_2) \tag{1}\]
where DO₂ is oxygen delivery, CO is cardiac output (heart rate \(\\times\) stroke volume), and CaO₂ is arterial oxygen content. Tissue oxygen extraction determines the available oxygen for mitochondrial respiration:
\[ \text{VO}_2 = \text{DO}_2 \cdot \text{O}_2 \text{ER} = \text{DO}_2 \cdot \frac{\text{CaO}_2 - \text{CvO}_2}{\text{CaO}_2} \tag{2}\]
In ME/CFS, reduced cardiac output (due to autonomic dysfunction and hypovolemia), impaired oxygen extraction (due to microvascular dysfunction or mitochondrial uncoupling), or both can reduce tissue VO₂. The oxygen consumption \(\text{VO}_2\) constrains the maximal ETC flux in the energy model: \(J_{\text{CIV,max}} \propto \text{VO}_2\). Reduced cerebral blood flow has been documented in ME/CFS patients (Novak et al. 2022), suggesting that the brain may be particularly vulnerable to this cardiovascular–metabolic mismatch.