Relevance of the cerebral collateral circulation in ischaemic stroke: time is brain, but collaterals set the pace

Abstract

Blood supply to the brain is secured by an extensive collateral circulation system, which can be divided into primary routes, i.e., the Circle of Willis, and secondary routes, e.g., collaterals from the external to the internal carotid artery and leptomeningeal collaterals. Collateral flow is the basis for acute stroke treatment, since neurones will only survive long enough to be rescued with reperfusion therapies if there is sufficient collateral flow. Poor collateral flow is associated with worse outcome and faster growth of larger infarcts in acute stroke treatment. Therapeutic promotion of collateral flow theoretically offers the chance for outcome improvement, but randomised trials are lacking. The extent of collateral flow is highly variable between individuals. As a consequence, the speeds of infarct growth are highly variable, resulting in varying individual treatment time windows until the whole salvageable tissue has become infarcted. An ideal patient selection for reperfusion therapies should be based on imaging of the salvageable tissue, the so called penumbra. The penumbra can be approximately visualised by computed tomography (CT) and magnetic resonance imaging (MRI), but both methods are significantly inaccurate in about 25% of the patients. There is a need for improved penumbra imaging by CT and MRI, and first studies applying machine learning techniques have shown promising results.

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

“…Nevertheless, it is necessary to mention that in the ischemic core, also surviving and even newly formed viable neurons have been detected (Zhang et al, 2017). On the contrary, there is a residual blood flow in the penumbra due to the presence of collateral arteries (Harukuni and Bhardwaj, 2006;Jung et al, 2017), with only lowered concentrations of ATP, to some extent maintained ionic concentrations, recurrent episodes of cortical spreading depression (or peri-infarct depolarization; Hinzman et al, 2015;Oliveira-Ferreira et al, 2019), and apoptosis as typical cellular death (Rossi et al, 2007;Doyle et al, 2008; Figure 1). Moreover, glial elements, astrocytes and NG2 glia, in this area form the so-called glial scar that prevents detrimental compounds from entering the spared nervous tissue (Adams and Gallo, 2018), while NG2 cells also display a multipotent differentiation potential .…”

Improved collateral flow and reduced damage after remote ischemic perconditioning during distal middle cerebral artery occlusion in aged rats

“…Cerebral collaterals are subsidiary vascular channels in the cerebral circulation which can sustain blood flow to ischemic tissue when principal vascular routes fail 1 – 6 . Blood flow through the collateral circulation is a primary determinant of the degree of ischemia in the penumbra, and thus a major predictor of infarct size and growth 8 , 3 , 7 , 9 – 12 . Cerebral collaterals can be classified as primary or secondary collaterals.…”

“…Ischemia leads to insufficient nutrient and oxygen supply to meet metabolic demand of the brain, thus inducing the damage or death of brain cells. Cerebral collaterals are subsidiary vascular channels in the cerebral circulation which can sustain blood flow to ischemic tissue when principal vascular routes fail [1][2][3][4][5][6] . Blood flow through the collateral circulation is a primary determinant of the degree of ischemia in the penumbra, and thus a major predictor of infarct size and growth 8,3,7,[9][10][11][12] .…”

“…Rates of hemorrhagic transformation after recanalization are also reduced in patients with good collateral blood flow 4,43,44 . Strategies that can augment collateral blood flow to reduce expansion of the infarct core before recanalization treatment may therefore extend the time window for reperfusion interventions and allow more patients to benefit 3 .…”

“…However, aging is one of the primary risk factors for ischemic stroke and it is known that the brain of the elderly has reduced ischemic tolerance 50,9,51,52 . Preclinical studies have reported that increasing age is associated with rarefaction of cerebral collaterals, leading to insufficient ability to maintain blood flow during ischemia 9,50,3,16,53 . Notably, the hemodynamic evolution of the pial collateral circulation is also influenced by aging.…”