Chimowitz, Marc I.

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.

Purpose: The safety of revascularization for asymptomatic carotid stenosis, and the efficacy of medical therapy for stroke prevention have improved. Therefore, results of prior randomized trials may not apply to current treatment decisions. The NINDS-funded CREST-2 will compare carotid endarterectomy and intensive medical therapy (IMT) versus IMT alone (n=1240), and carotid stenting and IMT versus IMT alone (n=1240) in asymptomatic patients with≥70% stenosis. Materials & Methods: CREST-2 consists of two parallel randomized clinical trials to be conducted at a target of ≈120 centers, including within NINDS StrokeNet. The composite primary outcome is stroke or death during the peri-procedural period or ipsilateral ischemic stroke thereafter up to 4 years. Blinded assessment of cognition will be done periodically. Centrally directed IMT includes tight control of blood pressure (systolic target <140 mm Hg) and cholesterol (LDL target <70 mg/dl) as well as lifestyle coaching. Results: As of June 12, 2015, 94 centers have been approved by the Site Selection Committee. Credentialing is ongoing, with 198 approved surgeons and 64 approved interventionists; 124 additional conditionally approved interventionists will be able to submit additional cases for review under the CREST-2 Registry. The Centers for Medicare and Medicaid will offer CAS reimbursement for Registry enrollees. As of June 12, 2015, there are 39 actively enrolling centers, and 37 patients have been randomized. Conclusion: CREST-2 is designed to identify the best approach for asymptomatic carotid stenosis. The first patient was randomized in December, 2014. An update will be provided regarding the numbers of patients randomized, centers certified, as well as surgeons and interventionists fully approved. Registration: ClinicalTrials.gov Identifier: NCT02089217

Background: Presence of atherosclerotic disease in more than one vascular bed (polyvascular disease) is associated with an increased risk of long-term vascular events. In the setting of asymptomatic carotid stenosis, the predictors of disease in other vascular beds is not well delineated. Objective: To identify the frequency and predictors of disease in other vascular beds the CREST 2 randomized trial population with hemodynamically significant stenosis. Methods: Recorded baseline characteristics among CREST 2 participants included: demographics, past medical history, lifestyle factors, and laboratory studies. Each variable was tested against three potential definitions of disease in other beds (cardiac, peripheral arterial disease (PAD) or disease in cardiac + PAD). Statistical analysis was done with Chi square and t tests as appropriate. Results: Data from 1447 patients were available for analysis. In these subjects with carotid disease, 51% also had cardiac disease, 24% also had PAD, and 16% had disease in in both cardiac and PAD. There was no relationship between age or race and presence of disease in other beds. Those with cardiac disease were more likely to be male. Diabetes, hypertension, hypercholesterolemia, and former history of smoking were all more common in those with either cardiac and PAD (TABLE). Elevated triglyceride and low HDL levels were also associated with all three definitions of disease in other beds. Those with either PAD or cardiac + PAD were more likely to be current smokers. Conclusions: Among CREST 2 participants, several medical conditions and lifestyle factors were associated with an increased frequency of disease in other vascular beds. Smoking, in particular, appears to be more common in those with PAD. Future analyses will address whether those with disease in other beds have higher rates of stroke or death.

Baseline Differences in Risk Factor Control and Medication Use Between 2 Trials Employing Intensive Medical Management (SAMMPRIS & CREST2) Background: The CREST2 trial Intensive Medical Management (IMM) protocol was adapted from the SAMMPRIS trial. However, since the 2011 publication of initial results of SAMMPRIS, there has been a greater appreciation for the importance of risk factor control in patients at risk of stroke associated with atherosclerosis. Therefore, we sought to determine differences in baseline risk factor control and medication use between SAMMPRIS and CREST2. Methods: Baseline risk factor and medication use data from 451 patients enrolled in SAMMPRIS (2008-2011) with severe symptomatic intracranial atherosclerosis and 1473 patients enrolled in CREST2 (2014-2019) with severe asymptomatic carotid stenosis were compared using the Chi-square test and t-test. Results: The Table shows baseline risk factor values and medications. SAMMPRIS patients were younger but had significantly worse risk factor control than CREST2 patients for all measures. There was no significant difference in statin use at baseline, but the mean SAMMPRIS subjects’ LDL was 16.1 mg/dL higher than in CREST2. CREST2 patients had higher rates of use of angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and thiazides, but lower rates of use of angiotensin converting enzyme (ACE) inhibitors. Conclusions: Despite being older, CREST2 patients have significantly better baseline risk factor profiles than SAMMPRIS patients. This could be due to greater appreciation of the importance of risk factor control and healthy lifestyle habits for stroke prevention or more aggressive treatment targets in guideline recommendations. Although risk factor control appears to be improving since SAMMPRIS, many CREST2 patients are still not meeting recommended risk factor goals at baseline and may benefit from IMM protocols.

Background: Data from the CDC show that approximately one-quarter of adults have elevated triglyceride (TG) levels. Recent trials have demonstrated that pharmacologic treatment of high TG levels, in patients already on statin therapy, reduces the rate of major vascular events such as myocardial infarction and stroke (REDUCE-IT trial). We sought to assess how often patients with asymptomatic carotid stenosis (CS) have elevated TG levels and factors associated with high TG values. Methods: Patients enrolled in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST 2) were analyzed. Baseline lipid profiles were evaluated to determine high TG treatment eligibility as per the REDUCE-IT trial. We also evaluated baseline use of pharmacologic treatment for high TG levels. Demographic factors and baseline medical conditions were studied in relation to high (>150 mg/dl) TG values. Chi square and t tests were used to assess baseline factors and abnormal TG values. Results: As of August 10, 2020, 1655 of 1689 randomized patients (mean age 69.7 years, 61% men) had baseline lipid profiles suitable for analysis. Treatment eligibility according to REDUCE-IT (LDL 41-100 mg/dl, TG>150 mg/dl) was present in 21% (345) of subjects. In these patients, the median TG value was 205 (IQR 93) mg/dl. Fibrate medications were used at baseline in 4.5% of patients. Analysis of demographic and medical history factors and TG values greater than 150 mg/dl is found in the Table. There was significant positive correlation between baseline hemoglobin A1C and triglyceride values (p<0.0001) Conclusions: One in five patients in CREST 2 has TG values that potentially justify pharmacologic treatment. Elevated TG levels are most correlated with diabetes, hypertension, obesity, decreased physical activity, and heart disease. Clinicians should investigate treatment of elevated TG levels as a component of intensive medical therapy for stroke prevention.

Background and Purpose: The CREST2 trial (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis) is comparing intensive medical management (IMM) alone to IMM plus revascularization with carotid endarterectomy or transfemoral carotid artery stenting for preventing stroke or death within 44 days after randomization or ipsilateral ischemic stroke thereafter. There are extensive clinical trial data on outcomes after revascularization of asymptomatic carotid stenosis, but not for IMM. As such, the experimental treatment in CREST2 is IMM, which is described in this article. Methods: IMM consists of aspirin 325 mg/day and intensive risk factor management, primarily targeting systolic blood pressure <130 mm Hg (initially systolic blood pressure <140 mm Hg) and LDL (low-density lipoprotein) cholesterol <70 mg/dL. Secondary risk factor targets focus on tobacco smoking, non-HDL (high-density lipoprotein), HbA1c (hemoglobin A1c), physical activity, and weight. Risk factor management is performed by site personnel and a lifestyle coaching program delivered by telephone. We report interim risk factor data on 1618 patients at baseline and last follow-up through 24 months. Results: The mean baseline LDL of 80.5 mg/dL improved to 66.7 mg/dL. The mean baseline systolic blood pressure of 139.7 mm Hg improved to 130.3 mm Hg. The proportion of patients in-target improved from 43% to 61% for systolic blood pressure <130 mm Hg and from 45% to 67% for LDL<70 mg/dL (both changes P <0.001). Conclusions: The rigorous multimodal approach to intensive stroke risk factor management in CREST2 has resulted in significant improvements in risk factor control that will enable a comparison of cutting-edge medical care to revascularization in patients with asymptomatic carotid stenosis. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02089217.

Background: Low wall shear stress (LSS) is an established cause of pro-atherogenic endothelial pathophysiology, yet it has never been demonstrated in the cerebral circulation affected by intracranial atherosclerotic disease (ICAD). Noninvasive CT angiography (CTA) computational fluid dynamics (CFD) enables high-resolution investigation of detailed post-stenotic phenomena. We used all available CTA data in the SAMMPRIS trial of ICAD to detect and quantify post-stenotic LSS. Methods: CTA source images from SAMMPRIS were reconstructed in 3D followed by geometry refinements to generate a mesh of the diseased arterial lesion and adjacent segments. CFD was performed with Ansys (ICEM, Fluent), applying reference boundary conditions with k-omega turbulence and non-Newtonian modeling of the traversing blood viscosity. 3D CFD parameter maps illustrated velocity, velocity swirling and corresponding wall shear stress. Results: 144 subjects enrolled in SAMMPRIS had CTA at baseline, including 140 with CTA source images enabling CFD. Post-stenotic velocity profiles revealed vortices in all cases, quantified by swirling and turbulent kinetic energy. These luminal flow changes were adjacent to focal regions of LSS in the post-stenotic region (Figure). Conclusions: Low wall shear stress is associated with vortices of fluid flow in CTA CFD modeling of ICAD from SAMMPRIS. CTA source images may be used to noninvasively quantify LSS and model this pro-atherogenic factor in ICAD across a wide variety of lesions. Future studies should examine the related endothelial biology and potential link with plaque evolution.