The Effects of Capillary Transit Time Heterogeneity (CTH) on Brain Oxygenation

Abstract

We recently extended the classic flow-diffusion equation, which relates blood flow to tissue oxygenation, to take capillary transit time heterogeneity (CTH) into account. Realizing that cerebral oxygen availability depends on both cerebral blood flow (CBF) and capillary flow patterns, we have speculated that CTH may be actively regulated and that changes in the capillary morphology and function, as well as in blood rheology, may be involved in the pathogenesis of conditions such as dementia and ischemia-reperfusion injury. The first extended flow-diffusion equation involved simplifying assumptions which may not hold in tissue. Here, we explicitly incorporate the effects of oxygen metabolism on tissue oxygen tension and extraction efficacy, and assess the extent to which the type of capillary transit time distribution affects the overall effects of CTH on flow-metabolism coupling reported earlier. After incorporating tissue oxygen metabolism, our model predicts changes in oxygen consumption and tissue oxygen tension during functional activation in accordance with literature reports. We find that, for large CTH values, a blood flow increase fails to cause significant improvements in oxygen delivery, and can even decrease it; a condition of malignant CTH. These results are found to be largely insensitive to the choice of the transit time distribution.

Influence of feeding hematocrit and perfusion pressure on hematocrit reduction (Fåhræus effect) in an artificial microvascular network

“…The velocity of RBC flow in brain capillaries of rats and mice ranges 0.15‐8.6 mm/s (with a mean of 2.0 ± 1.4 mm/s) . However, such a dramatic heterogeneity of capillary blood flow has only a minor influence on brain oxygenation, likely because oxygen offloading from hemoglobin can still occur at RBC velocities up to 5 mm/s, and thus, cerebral tissue oxygenation in mice may take place in arterioles and first‐order capillary branches, where V RBC can be that high …”

Red blood cell phase separation in symmetric and asymmetric microchannel networks: effect of capillary dilation and inflow velocity

“…The brain requires a constant availability of oxygen and glucose1; given its limited energy reserves, normal functioning mainly relies on oxygenated blood provided continuously through the vascular network2. Microcirculatory networks in brain as well as in other tissues feature a complex topology with irregularly bifurcating blood vessels34.…”

Reliable estimation of microvascular flow patterns in patients with disrupted blood–brain barrier using dynamic susceptibility contrast MRI

“…While CBF determines oxygen supply , oxygen can escape extraction if deficient capillary flow control introduces fast “functional shunts” for blood through the capillary bed, a mechanism proposed to explain the paradox hypoxia in seemingly well‐perfused tumors . We recently modified the classical flow‐perfusion equation to take this effect into account, using realistic distributions to model the heterogeneity of capillary flow patterns, and the standard deviation of these as a single index of capillary transit time heterogeneity (CTH) . The severity of “functional shunting” can then be quantified in terms of the oxygen extraction fraction (OEF) that can be achieved for a given combination of MTT, CTH, and tissue oxygen tension (P t O 2 ) in steady state .…”

“…The severity of “functional shunting” can then be quantified in terms of the oxygen extraction fraction (OEF) that can be achieved for a given combination of MTT, CTH, and tissue oxygen tension (P t O 2 ) in steady state . Multiplying this OEF by CBF yields a “maximum” CMRO 2 that can serve as a more accurate relation between cerebral hemodynamics and oxygen availability . Our preliminary analysis suggests that deficient capillary flow control may contribute to poorly understood phenomena such as reperfusion injury in stroke, neurodegenerative changes in patients with cardiovascular risk factors, and both hypoxia and aerobic glycolysis in tumors …”

“…4 We recently modified the classical flow-perfusion equation to take this effect into account, using realistic distributions to model the heterogeneity of capillary flow patterns, and the standard deviation of these as a single index of capillary transit time heterogeneity (CTH). 3,5 The severity of "functional shunting" can then be quantified in terms of the oxygen extraction fraction (OEF) that can be achieved for a given combination of MTT, CTH, and tissue oxygen tension (P t O 2 ) in steady state. 3 Multiplying this OEF by CBF yields a "maximum" CMRO 2 that can serve as a more accurate relation between cerebral hemodynamics and oxygen availability.…”