Transit time homogenization in ischemic stroke – A novel biomarker of penumbral microvascular failure?

Abstract

Cerebral ischemia causes widespread capillary no-flow in animal studies. The extent of microvascular impairment in human stroke, however, is unclear. We examined how acute intra-voxel transit time characteristics and subsequent recanalization affect tissue outcome on follow-up MRI in a historic cohort of 126 acute ischemic stroke patients. Based on perfusion-weighted MRI data, we characterized voxel-wise transit times in terms of their mean transit time (MTT), standard deviation (capillary transit time heterogeneity - CTH), and the CTH:MTT ratio (relative transit time heterogeneity), which is expected to remain constant during changes in perfusion pressure in a microvasculature consisting of passive, compliant vessels. To aid data interpretation, we also developed a computational model that relates graded microvascular failure to changes in these parameters. In perfusion-diffusion mismatch tissue, prolonged mean transit time (>5 seconds) and very low cerebral blood flow (≤6 mL/100 mL/min) was associated with high risk of infarction, largely independent of recanalization status. In the remaining mismatch region, low relative transit time heterogeneity predicted subsequent infarction if recanalization was not achieved. Our model suggested that transit time homogenization represents capillary no-flow. Consistent with this notion, low relative transit time heterogeneity values were associated with lower cerebral blood volume. We speculate that low RTH may represent a novel biomarker of penumbral microvascular failure.

Oxygenation differs among white matter hyperintensities, intersected fiber tracts and unaffected white matter†

“…RTH) are therefore thought to reflect abnormal capillary flow patterns, indicative of severe disturbances of capillary morphology and function across tissue microcirculation. Consistent with this notion, we and others have found RTH changes to correlate with disease severity in human conditions known to be associated with microvascular changes, including Alzheimer’s disease ( Eskildsen et al , 2017 ; Nielsen et al , 2017 ), ischemia ( Ostergaard et al , 2015 ; Engedal et al , 2018 ) and X-linked adrenoleukodystrophy ( Lauer et al , 2017 ). When utilizing perfusion MRI sensitized to capillary-sized vessels, we found RTH to be significantly elevated in both WMHs and in the tracts they intersect when compared with NAWM, although the comparison of tracts to NAWM remained a tendency after adjustment for multiple comparisons.…”

“…Cardiovascular risk factors, such as hypertension, diabetes and low-grade inflammation, can therefore critically reduce the oxygen availability by disturbing capillary flow patterns in terms of increasing the ‘shunting’ of oxygenated blood though microcirculation. This phenomenon, ‘capillary dysfunction’ ( Ostergaard et al , 2013 a ), has now been implicated in the pathophysiology of dementia ( Eskildsen et al , 2017 ; Nielsen et al , 2017 ), ischemia ( Ostergaard et al , 2015 ; Engedal et al , 2018 ) and inherited white matter disease ( Lauer et al , 2017 ) by specialized perfusion MRI tecniques ( Mouridsen et al , 2014 ). Given the evidence of capillary changes in SVD ( Ostergaard et al , 2016 ), we speculate, that capillary dysfunction reduces oxygen availability within WMHs, over and beyond the effects of altered perfusion and capillary density.…”

Capillary flow disturbances after experimental subarachnoid hemorrhage: A contributor to delayed cerebral ischemia?

“…Taken together, studies of capillary flow pattern disturbances in animal models (the present study) and humans may provide new insight into the better understanding of pathophysiological mechanisms involved in DCI development and pave the way to find better treatment strategies.…”

Neutrophil-mediated dynamic capillary stalls in ischemic penumbra: persistent traffic jams after reperfusion contribute to injury

“…By expanding our previous observations under physiological conditions (17), we see that the capillary RBC flow is extremely irregular and intermittent in the ischemic penumbra, with cells repeatedly getting stuck and released in the microcirculation. We already know that within brain tissue, capillary flow velocities are very different from each other, plasma and red blood cells are differentially partitioned at bifurcations (58), causing a spatial heterogeneity which can lower oxygen extraction efficiency (16,(59)(60)(61)(62). Simulations have revealed that the flow kinetics and partitioning in the tight lumen of capillaries are dominated by complex physical cell-cell interactions and rheological parameters which are influenced by temporal events affecting the incidental cell distributions (58).…”