The Role of the Cerebral Capillaries in Acute Ischemic Stroke: The Extended Penumbra Model

Abstract

The pathophysiology of cerebral ischemia is traditionally understood in relation to reductions in cerebral blood flow (CBF). However, a recent reanalysis of the flow-diffusion equation shows that increased capillary transit time heterogeneity (CTTH) can reduce the oxygen extraction efficacy in brain tissue for a given CBF. Changes in capillary morphology are typical of conditions predisposing to stroke and of experimental ischemia. Changes in capillary flow patterns have been observed by direct microscopy in animal models of ischemia and by indirect methods in humans stroke, but their metabolic significance remain unclear. We modeled the effects of progressive increases in CTTH on the way in which brain tissue can secure sufficient oxygen to meet its metabolic needs. Our analysis predicts that as CTTH increases, CBF responses to functional activation and to vasodilators must be suppressed to maintain sufficient tissue oxygenation. Reductions in CBF, increases in CTTH, and combinations thereof can seemingly trigger a critical lack of oxygen in brain tissue, and the restoration of capillary perfusion patterns therefore appears to be crucial for the restoration of the tissue oxygenation after ischemic episodes. In this review, we discuss the possible implications of these findings for the prevention, diagnosis, and treatment of acute stroke.

The Oxygen Paradox of Neurovascular Coupling

“…Evidence accumulates that dysfunction of the neurovascular unit has a role in Alzheimer's disease and stroke/small vessel disease and impairment of neurovascular coupling may be part of this dysfunction. 80,81,87,88 It can be speculated that impaired neurovascular coupling could lead to repeated drops in tissue pO 2 upon neuronal activation with initial short-term preservation of normal neuronal function but induction of inflammatory pathways that ultimately lead to long-term tissue damage. 80 However, no disease affects neurovascular coupling specifically while leaving baseline CBF, capillary morphology, endothelial function, etc.…”

Reliable Estimation of Capillary Transit Time Distributions Using DSC-MRI

“…Under such conditions, additional increases in CTH (caused for example by altered blood viscosity after infections or dehydration) or minor CBF changes (hypotensive episodes or a minor thromboembolic event) may elicit critical reductions in tissue oxygenation and trigger neurologic symptoms. 5 While such patients may present with symptoms of an acute stroke and display lesions on both diffusion and perfusion-weighted MRI, this hypothesis predicts that tissue oxygenation can be improved by reducing CTH, for example, by managing blood rheology via rehydration or reduction of leukocytosis by appropriate management of infections. In this way, some neuroprotection may be instigated before thrombolytic therapy, and in patients who are ineligible for recanalization therapy.…”

“…3 By extending the classic flow-diffusion equation, we showed that the capillary blood mean transit time (MTT) and capillary transit time heterogeneity (CTH) combined determines the maximum oxygen extraction fraction (OEF max ) that can be achieved for a given tissue oxygen tension. In a series of recent papers, we review the putative effects of elevated CTH as a result of changes in capillary morphology in Alzheimer's disease, 4 acute ischemic stroke, 5 tumors, 6 and subarachnoid hemorrhage. 7 These reviews suggest that elevated CTH may reduce tissue oxygen availability, and thereby add to the propagation of tissue damage in these diseases.…”

Microcirculatory dysfunction and tissue oxygenation in critical illness

“…3 for the renal cortex and medulla, the heart, and the brain 26. The green surface in each plot surrounds combinations of MTT, CTH, and P t O 2 that, biophysically, can support the metabolic needs of these organs in the resting, awake state.…”