Role of Genetic Variation in Collateral Circulation in the Evolution of Acute Stroke

Collateral vessels are anastomoses that connect adjacent arterial trees and reroute perfusion around obstructed arteries or veins. Variation among individuals in the extent of native collaterals (ie, number or diameter) may serve as a prognostic determinant of stroke severity and improve clinical risk benefit decisions for treatment options. Angiographic studies grading collateral circulation in patients with acute stroke have found that final infarct size and functional outcome deficit vary inversely with collateral flow. Patients with robust collateral circulation also have improved outcomes after tissue-type plasminogen activator (tPA) administration (including reduced risk of hemorrhaging) or intra-arterial revascularization, suggesting that collateral extent significantly impacts the success of therapeutic interventions for acute ischemic stroke. Imaging of perfusion in acute stroke patients using computed tomography or magnetic resonance imaging (MRI) is routine for accurate diagnosis and volumetric assessments of ischemic tissue. Contrast-enhanced computed tomography, MRI, and arterial spin–labeled perfusion MRI are also used clinically to differentiate hemorrhagic stroke and assess collateral status. Ischemic stroke registries that centrally store these data have been used retrospectively to examine how collateral circulation alters lesion evolution. Such Background and Purpose—No studies have determined the effect of differences in pial collateral extent (number and diameter), independent of differences in environmental factors and unknown genetic factors, on severity of stroke. We examined ischemic tissue evolution during acute stroke, as measured by magnetic resonance imaging and histology, by comparing 2 congenic mouse strains with otherwise identical genetic backgrounds but with different alleles of the Determinant of collateral extent-1 (Dce1) genetic locus. We also optimized magnetic resonance perfusion and diffusion– deficit thresholds by using histological measures of ischemic tissue. Methods—Perfusion, diffusion, and T 2 -weighted magnetic resonance imaging were performed on collateral-poor (congenicBc) and collateral-rich (congenic-B6) mice at 1, 5, and 24 hours after permanent middle cerebral artery occlusion. Magnetic resonance imaging–derived penumbra and ischemic core volumes were confirmed by histology in a subset of mice at 5 and 24 hours after permanent middle cerebral artery occlusion. Results—Although perfusion-deficit volumes were similar between strains 1 hour after permanent middle cerebral artery occlusion, diffusion-deficit volumes were 32% smaller in collateral-rich mice. At 5 hours, collateral-rich mice had markedly restored perfusion patterns showing reduced perfusion-deficit volumes, smaller infarct volumes, and smaller perfusion–diffusion mismatch volumes compared with the collateral-poor mice (P<0.05). At 24 hours, collateral-rich mice had 45% smaller T 2 -weighted lesion volumes (P<0.005) than collateral-poor mice, with no difference in perfusion– diffusion mismatch volumes because of penumbral death occurring 5 to 24 hours after permanent middle cerebral artery occlusion in collateral-poor mice. Conclusions—Variation in collateral extent significantly alters infarct volume expansion, transiently affects perfusion and diffusion magnetic resonance imaging signatures, and impacts salvage of ischemic penumbra after stroke onset. (Stroke. 2017;48:754-761. DOI: 10.1161/STROKEAHA.116.015878.)