Relationship between Vascular Risk Factors and Location of Intracranial Atherosclerosis in the SAMMPRIS Trial

Abstract

Background:

Previous studies have reported that different locations of intracranial atherosclerosis (ICAS) are associated with different demographic features and vascular risk factors. We aimed to examine this observation in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial population.

Methods:

SAMMPRIS was a randomized controlled trial that enrolled 451 patients with recent transient ischemic attack or stroke-related due to severe (70-99%) stenosis of a major intracranial artery. We compared the baseline demographic features and vascular risk factors between the symptomatic artery locations. Wilcoxon test was used to compare continuous variables, and chi-square test was used for categorical variables.

Results:

Of 449 patients included in the analysis; 289 (64.4%) had ICAS in the anterior circulation and 160 (35.6%) in the posterior circulation. Features that were significantly different between patients with anterior versus posterior ICAS were: median age (58.3 years vs. 64.0 years, P<0.001), males / females (52.9% / 47.1% vs. 74.4% / 25.6% P<0.001), white / black (66.8% / 26.6% vs. 79.4% / 16.9%, P=0.02), and history of hyperlipidemia (85.5% vs. 92.5%, P=0.03).

Conclusion:

The observed differences in the distribution of demographic characteristics and vascular risk factors depending on the location of symptomatic ICAS suggest the possibility of different underlying pathological processes involved in the formation of atherosclerotic plaques in different locations.

Introduction:

Intracranial atherosclerosis stenosis (ICAS) is among the leading causes of stroke worldwide and carries a high risk of stroke recurrence.^{1, 2} Yet the pathological drivers of atherosclerosis in the intracranial location are not well understood. Post-hoc analyses from the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial showed that older white men with hyperlipidemia accounted for the majority of patients with posterior circulation ICAS whereas females and blacks, especially those with diabetes, were much more likely to develop ICAS in the anterior circulation than in the posterior circulation.³ These findings suggest some risk factors may predispose to the development or worsening of ICAS in certain vascular locations. We sought to validate these findings in a large multicenter randomized trial cohort of patients with symptomatic severe ICAS from the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) trial.

Methods:

The design, patient characteristics and primary outcome results of SAMMPRIS have been reported previously.^{4, 5} In brief, the SAMMPRIS trial enrolled patients with a stroke or a transient ischemic attack attributed (TIA) to angiographically determined severe (70-99%) ICAS in the intracranial internal carotid artery (ICA), middle cerebral artery (MCA), intracranial vertebral artery (VA), or basilar artery (BA). Patients were randomized within 30 days of the index event to treatment with percutaneous transluminal angioplasty and stenting (PTAS) in addition to aggressive medical management (AMM) or AMM alone. The baseline variables recorded at enrollment included baseline demographic features (e.g. age, sex, and race), as well as vascular risk factors (e.g. comorbidities such as hypertension, diabetes, smoking, hyperlipidemia and baseline laboratory tests).

Baseline features were compared between subjects with severe symptomatic ICAS in the anterior circulation to those with ICAS in the posterior circulation. Then, we compared the demographic features and vascular risk factors depending on the symptomatic ICAS artery (e.g. basilar, vertebral, etc.).

Descriptive statistics were used to report patient demographic and clinical characteristics in the included patients. The normality of distributions was assessed graphically and using the Shapiro-Wilk test. Wilcoxon test was used to compare continuous variables (because of the non-normal distribution), and chi-square test was used for categorical variables. In order to assess the association between race, gender and ICAS location (ICA, MCA, vertebral, or basilar), we used the Cochran Mantel Haenszel test. P-values less than 0.05 were considered statistically significant, and we did not make adjustments for multiple comparsions given that these analyses were exploratory. The analyses were conducted using Statistical Analysis Software (SAS) version 9.4 (SAS Institute, North Carolina, USA) and SPSS version 25 (IBM Corporation, New York, USA).

Results:

Of the 451 patients enrolled in SAMMPRIS, data on the location of stenosis was missing in two subjects leaving 449 patients for this analysis - 289 (64.4%) with anterior circulation ICAS and 160 (35.6%) with posterior circulation ICAS. As shown in the comparison of patients with anterior versus posterior circulation ICAS in Table 1, posterior circulation ICAS patients were significantly older (64 years (IQR 55.8-72.0) vs. 58.3 years (IQR 50.1-67.3), P=<0.001), had a much higher percentage of men (119 (74.4%) vs. 153 (52.9%),P=<0.001), a higher percentage of white patients (127 (79.4%) vs. 193 (66.8%), P=0.02) and a higher percentage of patients with hyperlipidemia (148 (92.5%) vs. 247 (85.5%) vs, P=0.03). While the ratio of anterior to posterior circulation ICAS was 1.8 in all patients (289:160), it was much higher in females (3.3; 136:41) compared with males (1.3; 153:119) and in blacks (2.9; 77:17) compared with whites (1.5; 193:127). There was no significant difference between the anterior or posterior circulation groups in baseline body mass index (BMI), history of hypertension, history of diabetes, diabetes control (as measured by A1C levels), history of smoking or history of prior stroke. .

Table 1:

Baseline characteristics of patients in the Stenting versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial population

	Total (n=449)	Anterior circulation (n=289)	Posterior circulation (n=160)	P-value*
Age, median (IQR)	60.0 (52.369.3)	58.3 (50.1-67.3)	64.0 (55.8-72.0)	<0.001
Females, n (%)	177 (39.4)	136 (47.1)	41 (25.6)	<0.001
Race, n (%)				0.02
*White	320 (71.3)	193 (66.8)	127 (79.4)
*Black	104 (23.2)	77 (26.6)	27 (16.9)
*Other	25 (5.5)	19 (6.6)	6 (3.7)
BMI, median (IQR)	29.3 (26.5-33.8)	29.4 (26.1-35.2)	29.0 (26.6-32.9)	0.44
History of smoking, n (%)	166 (37)	111 (38.4)	55 (34.4)	0.42
History of HTN, n (%)	401 (89.3)	254 (87.9)	147 (91.9)	0.19
History of DM, n (%)	192 (42.8)	130 (45.0)	62 (38.8)	0.20
HbA1C, median (IQR)	6.4 (5.8-7.4)	6.5 (5.8-7.8)	6.3 (5.7-7.3)	0.29
History of hyperlipidemia, n (%)	395 (88.0)	247 (85.5)	148 (92.5)	0.03
HDL, median (IQR)	37 (31-45)	37 (32-45)	37 (30-43)	0.17
LDL, median (IQR)	100 (76-130)	98 (75-128)	107 (82-133)	0.07
vLDL, median (IQR)	26 (19-40)	25 (19-40)	26 (20-41.5)	0.47
Triglyceride, median (IQR)	133 (97-196)	132 (94-197)	139 (101-196)	0.57
History of CAD, n (%)	105 (23.4)	59 (20.4)	46 (28.7)	0.05
History of stroke, n (%)	118 (26.3)	76 (26.3)	42 (26.3)	0.99

Abbreviation:

BMI: body mass index, CAD: coronary artery disease, DM: diabetes mellitus, HbA1C: hemoglobin A1C, HDL: high-density lipoprotein, HTN: hypertension, IQR: interquartile range, LDL: low-density lipoprotein, n: number, vLDL: very low-density lipoprotein.

^*Calculated using chi-suare test for categorical variables and Wilcoxon test for the continuous variables (because of the non-normal distribution).

The distribution of the location of stenosis in all patients was as follows: 196 middle cerebral artery (MCA) (43.7%), 93 internal carotid artery (ICA) (20.7%), 100 basilar artery (BA) (22.3%) and 60 vertebral artery (VA) (13.3%). Table 2 shows the location of stenosis amongst black males, black females, white males and white females. Although both race and gender were independently associated with anterior vs. posterior circulation stenosis (see Table 1), when considering race and gender jointly with location, there was not an independent association (p=0.178). However, this may have been due to low power given the small size of some of the cells in Table 2.

Table 2.

The distribution of the location of intracranial stenosis amongst different genders and races

	Total	ICA	MCA	BA	VA
Black males, n (%)	55	16 (29.1)	25 (45.5)	8 (14.5)	6 (10.9)
Black females, n (%)	49	11 (22.4)	25 (51.0)	12 (24.5)	1 (2.0)
White males, n (%)	203	36 (17.7)	67 (33.0)	60 (29.6)	40 (19.7)
White females, n (%)	117	25 (21.4)	65 (55.6)	17 (14.5)	10 (8.5)

Amongst patients with different locations of stenosis, a history of diabetes was present in 78 of 196 (39.8%) patients with MCA stenosis, 52 of 93 (55.9%) with ICA stenosis, 37 of 100 (37%) with BA stenosis, and 25 of 60 (41.7%) with VA stenosis (p=0.03). A history of hyperlipdemia was present in 166 of 196 (84.7%) patients with MCA stenosis, 81 of 93 (87.1%) with ICA stenosis, 96 of 100 (96%) with BA stenosis, and 52 of 60 (86.7%) with VA stenosis (p=0.04). Finally, a history of coronary artery disease (defined as history of angina, myocardial infarction, coronary stent placement, or coronary bypass surgery) was present in 31 of 196 (15.8%) patients with MCA stenosis, 28 of 93 (30.1%) with ICA stenosis, 26 of 100 (26.0%) with BA stenosis, and 20 of 60 (33.3%) with VA stenosis (p=0.006).

Discussion:

These analyses show that among the SAMMPRIS trial cohort, patients with different ICAS locations have different vascular risk factor profiles, including demographic features and co-morbid medical conditions. Patients in SAMMPRIS with posterior circulation ICAS were much more likely to be older white males with hyperlipidemia whereas patients with anterior circulation were much more likely to be evenly distributed amongst males and females (Table 1). While anterior circulation ICAS is more common than posterior circulation ICAS in both males and females and in whites and blacks, the risk of developing anterior rather posterior circulation ICAS is much higher in females and blacks than in males and whites. These findings are consistent with a similar analysis done on the WASID cohort³ despite differences in the severity of stenosis included in the trial populations (i.e. WASID included patients with 50-99% stenosis, SAMMPRIS 70-99%). Similar observation was made by Gorelick et al. in 1984 when they reported that black patients were more likely to have symptomatic occlusive cerebrovascular disease in the anterior circulation ⁷.

While there was only a trend toward a higher percentage of patients with basilar artery ICAS in patients with hyperlipidemia (P=0.054) in the WASID cohort³, the current analysis also shows that patients with severe ICAS in the posterior circulation, particularly the basilar artery (Table 2), are more likely to have hyperlipidemia (P=0.03) compared to those with ICAS in the anterior circulation. The stronger association between posterior circulation (especially basilar) stenosis and hyperlipidemia in the SAMMPRIS cohort compared to the WASID cohort is likely because hyperlipidemia is associated with more severe stenosis³ and SAMMPRIS only included patients with severe stenosis, whereas WASID included patients with moderate stenosis. Yasaka, et al. and Caplan, et al^{6, 7} also reported an association between hyperlipidemia and the basilar artery location. We also found a higher percentage of diabetes among patients with ICA stenosis compared with stenosis in other locations. This finding was also noted in the WASID analysis³.

One possible explanation for our findings relating risk factors to location of stenosis could be the histopathological differences between the anterior and posterior circulation intracranial arteries, which could lead to variability in the underlying pathological processes involved in the development and progression of atherosclerotic plaques. Roth et al. examined the cerebral circulation in 194 autopsied individuals and found that posterior circulation arteries have thinner walls, less elastin, and more concentric intima thickening than anterior circulation arteries ⁸ Additionally, different arterial locations are exposed to variable blood flow dynamics that could impact the susceptibility to risk factors. For example, the anterior cerebral circulation carries 82% of the blood supply to the brain while it composes 67% of the total vascular cross-sectional area⁹. Moreover, the distribution of vasa vasorum differs between different intracranial vasculatures with the lowest rate of vasa vasorum being observed in the posterior circulation^{10, 11}. This is especially important given recent reports suggesting that the adventitia plays a role in the development and progression of ICAS^{12, 13} However, the actual mechanism by which structural differences in arteries could result in a susceptibility to atherogenesis driven by specific risk factors remains unknown.

Our analysis has a few limitations including that it was performed post-hoc and the sample size was relatively small in some groups (e.g. only 60 with VA stenosis). Nevertheless, our findings are likely not due to chance given that they validate previous observations from the WASID trial (one of the largest cohorts of patients with angiographically proven ICAS in a mixed-race North American population) and other smaller studies of patients with ICAS.^7-9 .