Lynn, Michael

Background: Pressure gradients across an intracranial stenosis, or fractional flow (FF), may identify the hemodynamic significance of symptomatic lesions. Computational fluid dynamic (CFD) simulations on 3D morphology of such lesions can calculate these pressure gradients and model effects of systemic physiology interacting with these lesions, such as hypotension and induced hypertension. We studied SAMMPRIS angiography to calculate FF across symptomatic intracranial stenoses and modeled the downstream effect of systemic blood pressure (BP) fluctuations. Methods: Conventional angiography of symptomatic intracranial stenoses in the SAMMPRIS trial was converted from biplanar images to a 3D geometric mesh. CFD simulations were conducted with Ansys CFX on a Cray supercomputer to calculate FF derived from distal/proximal pressure gradients for each of 3 inflow conditions: normal BP (120/80 mm Hg), hypotension (90/60 mm Hg) and hypertension (180/120 mm Hg). Abnormal FF was defined as ≤ 0.8 during diastole to define hemodynamic significance of a stenosis. Results: 407 patients with 70-99% symptomatic stenosis had conventional angiography with biplanar views available for 3D reconstruction in 249, and CFD simulations in 188 (25 VA, 45 BA, 32 ICA, 86 MCA). Under simulated normal inflow conditions (120/80 mm Hg), only 76/188 (40%) cases had low FF. During simulated hypertension, FF improved to normal in 10/188 (5%) cases. Simulated hypotension caused FF to worsen from normal in 12/188 (6%) cases. Other hemodynamic parameters including shear stress could also be calculated and visually depicted in all cases. Conclusions: CFD and hemodynamic modeling of FF can be retrospectively performed after 3D conversion of biplanar angiogram views. FF estimates predict that only 40% of severe (70-99%) symptomatic intracranial stenoses are hemodynamically significant. Systemic BP fluctuations can be modeled during phases of the cardiac cycle to show downstream flow changes.

Background: Severe intracranial atherosclerosis, in excess of 70% luminal stenosis, is an established cause of recurrent stroke. Collateral circulation and the hemodynamic effects of such stenoses, however, may further delineate such risk. We conducted angiographic analyses in the SAMMPRIS trial to correlate the degree of collaterals and hemodynamic effects of such stenoses with baseline clinical and imaging characteristics of enrolled subjects. Methods: Baseline angiography of SAMMPRIS subjects was submitted for blinded review to grade collaterals with the ASITN/SIR scale and antegrade flow across the lesion with TICI. Hemodynamic effect was defined as any flow reduction (a partial TICI score). The association of these angiographic scores (dichotomized as none/partial versus complete collaterals and partial versus complete TICI) and baseline demographic, clinical and imaging variables were evaluated using chi-square tests for percentages and independent group t-tests for means. Results: 424/451 subjects enrolled in SAMMPRIS had baseline angiography available for review, with adequate information to score collaterals in 376 cases. Complete collaterals were noted in 117 (31%). Hemodynamic effects (partial TICI scores) were noted in only 188 (50%) of these lesions, which were all in excess of 70% luminal stenosis. Mean lesion length (n=184, from stenting arm) did not differ between the two categories of either collaterals or hemodynamic impairment. Mean percent stenosis was higher for patients with complete collaterals (none/partial, mean 73.7%; complete, 77.4%; p<0.001) and hemodynamic impairment was more common (p<0.001). More robust collaterals (complete versus none/partial) were associated with patients who at baseline were younger (mean age 58.0 versus 61.5 years; p=0.009), had higher serum HDL (40.0 versus 37.7 mg /dL, p=0.035), participated in moderate exercise (43.1 versus 27.9%, p=0.004) and did not smoke (79.5 versus 69.4%, p=0.042). Previously reported associations with collateral circulation (diabetes, statins, presence of infarction on CT or MRI) were inapparent. These relationships of collaterals with hemodynamic impairment and other baseline variables were established across all anatomical distributions of intracranial stenosis. Conclusions: Severe intracranial atherosclerotic lesions are not always associated with hemodynamic effects. Collateral circulation may also frequently compensate for severe stenosis, with more robust collaterals in younger and healthier individuals.

Background: The degree of collateral circulation is a powerful risk factor for recurrent stroke in the setting of medical therapy for symptomatic intracranial atherosclerosis. The impact of collaterals on the short-term risk for stroke in patients treated by stenting or intensive medical therapies is not known. We systematically evaluated baseline angiographic features of collateral circulation and antegrade flow across intracranial stenoses in randomized subjects of the multicenter SAMMPRIS trial and correlated these to their 30-day risk of ischemic stroke. Methods: Digital review of baseline angiograms in SAMMPRIS was conducted to score ASITN/SIR collateral grade and TICI antegrade flow, blind to other data. Dichotomized collateral and TICI scores (none/partial versus complete) were analyzed independently and in combinations with trial endpoints of territorial ischemic stroke or stroke in territory (SIT) and intracranial hemorrhage (ICH) within 30 days in the intensive medical and stenting arms of the study. Log-rank tests with follow-up time censored at 30 days were used in the analysis. Results: Collaterals could be assessed on 376/424 baseline angiography studies available for digital imaging review for the 451 randomized subjects in SAMMPRIS (186 medical, 190 stenting). Early territorial stroke (SIT) occurred in 6/186 (3.2%) subjects in the medical arm and 20/190 (10.5%) after stenting. SIT was not associated with TICI in either arm, whereas collaterals exerted a potent protective influence in medical (p=0.067) and stented (p=0.004) cases, with 0/66 (0%) SIT in the medical arm and 0/51 (0%) SIT in the stented arm when collaterals were complete. SIT in medical cases was associated with partial TICI/partial collaterals (5/25 (20.0%)) versus complete TICI/partial collaterals (1/95 (1.1%)) and partial TICI/complete collaterals (0/66 (0%)), p<0.001. SIT in stented cases was associated with partial TICI/partial collaterals (11/46 (23.9%)) versus complete TICI/partial collaterals (9/93 (9.7%)) and partial TICI/complete collaterals (0/51 (0%)), p<0.001. ICH within 30 days occurred in 0/186 (0%) subjects randomized to medical therapy. In the stenting arm, early ICH occurred in 8/190 (4.2%) and was associated with TICI (p=0.036) and collaterals (p=0.077). Overall, early ICH after stenting was associated with partial TICI/partial collaterals (7/46 (15.2%)) versus complete TICI/partial collaterals (1/93 (1.1%)) and partial TICI/complete collaterals (0/51 (0%)), p<0.001. Conclusions: Patients with impaired collateral flow associated with severe intracranial stenosis had the highest risk for stroke within 30 days, both with intensive medical therapy and as a complication of angioplasty and stenting.

Background: Noninvasive fractional flow measures with CT angiography (CTA) have revolutionized cardiology, yet the complex anatomy of the cerebral circulation and boundary conditions challenge the study of intracranial atherosclerosis. We developed a framework for systematic computational fluid dynamics (CFD) of middle cerebral artery (MCA) stenosis with CTA in SAMMPRIS. Methods: A 3D geometric mesh was generated from CTA source images, followed by CFD processing in Ansys (ICEM, CFX) on a Cray supercomputer. Reference boundary conditions were applied with an ICA inlet and outlets at the ACA and distal MCA to yield quantitative maps of intraluminal pressure drops (ΔP or fractional flow), blood flow velocity (V) and turbulent kinetic energy (TKE) with wall shear stress (WSS) mapped along the arteries. CFD parameters were then compared with SAMMPRIS angiography variables. Results: Of 451 SAMMPRIS (70-99% symptomatic stenosis) subjects, CTA was acquired at enrollment in 41 MCA cases. CFD results were successfully attained in 30, limited by anatomy (e.g. across branch points) in 7/11 and poor CTA resolution in 4/11. Fractional flow (ΔP) across stenosis was mean 0.64 ± SD 0.33, with maximal stenosis velocity of mean 192 ± SD 101 cm/s and maximal WSS 0.36 ± SD 0.25 mm Hg. SAMMPRIS angiography percent stenosis was unrelated to ΔP -0.163 (p=0.399), velocity 0.126 (p=0.514) or WSS 0.078 (p=0.689). Worse collateral blood flow grades were associated with larger ΔP (p=0.137), higher velocity (p=0.059), higher WSS (p=0.112). Asymmetric WSS with high and low regions on opposing arterial walls was measured in the post-stenotic segment in 25/30 (83%). TKE maps revealed focal increases in the post-stenotic region, yet not above abnormal thresholds based on arterial diameter. Conclusions: CTA CFD of intracranial atherosclerosis provides detailed noninvasive measures of hemodynamics.

Background: Collateral blood flow, modulated by inflammation and arteriogenesis, alters ischemic injury in intracranial atherosclerosis. We investigated the potential link between several inflammatory and arteriogenic biomarkers with angiographic findings at enrollment in BIOSIS/SAMMPRIS. Methods: Baseline angiography and blood biomarkers of BIOSIS/SAMMPRIS, which included subjects with stroke or TIA due to 70-99% intracranial stenosis were analyzed. Collateral blood flow status at angiography was categorized by the combination of antegrade flow (TICI) and corresponding extent of collaterals (ASITN/SIR). Collateral status was analyzed with respect to blood progenitor cell markers (CD34) at baseline and inflammatory biomarkers (Plasminogen Activator Inhibitor-1 (PAI-1), E-selectin, high sensitivity C-reactive protein (hsCRP) and Lipoprotein-associated phospholipase A2 (Lp-PLA 2 ) activity and concentrations) at baseline, 30 days and 4 months. Results: 376 subjects (mean age 60.44 years SD 11; 149/376 (39.6%) women) enrolled in BIOSIS/SAMMPRIS had angiography of collaterals and biomarker data. Collateral perfusion was impaired in 71 (19%) and intermediate in 188 (50%), with robust collaterals in 117 (30%) subjects. Better collateral status was associated with younger age (p=0.001), male sex (p=0.029) and greater baseline physical activity (p=0.007). Baseline blood progenitor cell (CD34+) counts were unrelated to angiographic features at enrollment, whereas inflammatory Lp-PLA 2 activity was linked (p=0.059) with blood flow categories, and lower hsCRP (p=0.025) with better collaterals. Lp-PLA 2 activity was lowest in those with robust collaterals at 30 days (p=0.070) and 4 months (p=0.120). Those with robust collaterals had the greatest decrease in Lp-PLA 2 activity (p=0.021) and concentration (p=0.027) by 30 days, with a continued decline of Lp-PLA 2 activity (p=0.037) to 4 months. Disparate trends in inflammatory markers were seen in the medical and stenting arms. Conclusions: Inflammatory biomarkers are linked with collateral blood flow status in intracranial atherosclerosis. The impact of physical activity, medications and other therapeutic investigations may disclose important mechanisms to avert ischemia.

Collateral circulation in intracranial atherosclerosis has never been systematically characterized. We investigated collaterals in a multicenter trial of symptomatic intracranial atherosclerotic disease. Baseline angiography was reviewed for information on collaterals in stenoses of the internal carotid, middle cerebral, vertebral, and basilar arteries. A battery of angiographic scales was utilized to evaluate lesion site, arterial patency, antegrade flow, downstream territorial perfusion, and collateral circulation, blinded to all other data. Collateral circulation was adequately available for analysis in 287/569 (50%) subjects with proximal arterial stenoses ranging from 50% to 99%. Extent of collaterals was absent or none in 69%, slow or minimal in 10%, more rapid, yet incomplete perfusion of territory in 7%, complete but delayed perfusion in 11%, and rapid, complete collateral perfusion in 4%. Extent of collateral flow correlated with percentage of stenosis ( P < 0.0001), with more severe stenoses exhibiting greater compensation via collaterals. Overall, collateral grade increased with diminished antegrade flow across the lesion (thrombolysis in myocardial ischemia) and resultant downstream perfusion (thrombolysis in cerebral infarction) (both P<0.001). Our findings provide the initial detailed description of collaterals across a variety of stenoses, suggesting that collateral perfusion is a pivotal component in pathophysiology of intracranial atherosclerosis and implicating the need for further evaluation in ongoing studies.

Background and Purpose— We sought to determine the vascular risk factors and demographic features associated with the severity and location of intracranial stenosis. Methods— Data on patients enrolled in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial were used for the analyses. Demographic features and vascular risk factors were compared in patients with moderate stenosis (n=336) versus severe stenosis (n=225) and according to the location of intracranial stenosis (middle cerebral, internal carotid, basilar, or vertebral artery). Results— History of a lipid disorder (77% in severe vs 67% in moderate, P =0.01), metabolic syndrome (63% in severe vs 53% in moderate, P =0.05), and diabetes (43% in severe vs 35% in moderate, P =0.04) were more common in patients with severe intracranial stenosis by univariate analyses. A history of a lipid disorder was independently associated with severe stenosis (odds ratio=1.62; 95% CI, 1.09 to 2.42; P =0.02). The distribution of stenosis location differed among age groups ( P =0.0015), sexes ( P =0.0001), races ( P =0.0243), qualifying events ( P =0.0156), diabetes ( P =0.0030), coronary artery disease ( P =0.0030), and hyperlipidemia ( P =0.054). Patients with basilar artery stenoses were older and more likely to have hyperlipidemia. Patients with middle cerebral artery stenoses were more likely to be women and black. Patients with internal carotid artery stenoses were more likely to have diabetes. Patients with vertebral artery stenoses were more likely to have coronary artery disease. Conclusions— History of a lipid disorder had the strongest association with severity of intracranial stenosis and should be the target of prevention therapies. Different locations of intracranial stenoses are associated with different vascular risk factors and demographic features, suggesting that there may be a difference in the underlying pathophysiology of stenoses among the intracranial arteries.