Prevalence of Intracranial Atherosclerotic Stenosis Using High Resolution Magnetic Resonance Angiography in the General Population – The ARIC Study

Abstract

Background and Purpose

Intracranial atherosclerotic stenosis (ICAS) is a common cause of stroke, but little is known about its epidemiology. We studied the prevalence of ICAS and its association with vascular risk factors using high resolution magnetic resonance angiography (MRA) in a U.S. cardiovascular cohort.

Methods

The Atherosclerosis Risk in Communities (ARIC) study recruited participants from four U.S. communities from 1987-1989. Using stratified sampling, we selected 1980 participants from visit-5 (2011-2013) for high resolution 3T-MRA. All images were analyzed in a centralized lab and ICAS was graded as — no stenosis, <50% stenosis, 50-69% stenosis, 70-99% stenosis and complete occlusion. We calculated per-vessel and per-person prevalence of ICAS (weighted for n=6,538 visit-5 participants), and also estimated the U.S. prevalence. We used multivariable logistic regression to identify variables independently associated with ICAS.

Results

Subjects who had an adequate MRA (n=1765) were aged 67-90 years, 41% were men, 70% were white and 29% were African-American. ICAS was prevalent in 31% of participants and 9% had ICAS ≥50%. Estimated U.S. prevalence of ICAS≥50% for 65-90 years old was 8% for Whites and 12% for African-Americans. Older age, African-American race, higher systolic blood pressure, and higher low density lipoprotein cholesterol levels were associated with increased odds of ICAS, while higher levels of high density lipoprotein cholesterol and use of cholesterol lowering medications were associated with decreased odds of ICAS. Body mass index and smoking were not associated with ICAS.

Conclusion

The prevalence of ICAS in older adults is high, and could be a target for primary prevention of stroke and dementia in this population.

Introduction

Intracranial atherosclerotic stenosis (ICAS) is responsible for approximately 8% of ischemic strokes and 34% of dementia diagnoses in the U.S.^1,2 Despite targeted reduction of LDL cholesterol using statins, treatment of hypertension, and use of antiplatelet agents, the risk of recurrent ischemic stroke is approximately 14% over one year for patients with severe ICAS.³ Intracranial atherosclerosis may also be a major contributor to variations in stroke incidence and mortality,⁴ and to disparities in stroke burden among minority populations in the U.S. Among patients with brain ischemic events, Asians^5-7 and African-Americans^8-10 had disproportionately more intracranial atherosclerosis than Whites. ICAS is also believed to be associated with cognitive deficits of varying severity, including impaired executive function, slowing of activity and thinking, and even anterograde amnesia.⁴

Despite its clinical importance, there is minimal data, especially in the U.S., about the prevalence of ICAS. Estimates of the prevalence of ICAS are based either on autopsy series or on the detection of arterial calcification, MRA of selected asymptomatic subjects or transcranial Doppler studies in population-based surveys.¹¹ Two Chinese studies have reported population-based prevalence of ICAS based on transcranial Doppler examination of a single community door-to-door survey^12,13. Other Asian and European studies have used MRA, which has better accuracy for identification of ICAS than transcranial Doppler¹⁴, but in a selected group of asymptomatic subjects.^15,16 The prevalence of ICAS in the U.S. may be very different from other regions and within various racial and ethnic groups.¹⁷ A small pilot study of 99 U.S. elderly subjects estimated the prevalence of ICAS to be 16%.¹⁸

Given the paucity of data, and the prominent role of ICAS in ischemic stroke and dementia, we performed a cross sectional evaluation using MR angiography (MRA) in a well-defined community-based cohort. The large sample size and standardized ascertainment of demographic and clinical characteristics of the cohort also allowed an assessment of risk factors for ICAS.

Methods

Study Population

The ARIC cohort initially comprised 15,792 participants aged 45-64 years recruited in 1987-1989 randomly selected from four communities: Forsyth County, NC, Jackson, MS, suburban Minneapolis, MN, and Washington County, MD. From 2011 to 2013, the ARIC study conducted the fifth follow-up examination. Among 10,036 participants who were still alive at the time of study, 6,538 (65%) took part in visit 5. From those with no known contraindications to MRA, we offered scans to: 1) those who had received an ARIC brain MR scan in 2004-6; 2) those with low current cognitive test scores or large declines on the longitudinally-administered tests; and 3) an age-stratified random sample of the remaining individuals. The goal was to achieve MRA scans in approximately 2000 participants. We added high-resolution MRI sequences to identify plaque and measure the intracranial vessel wall, lumen area and plaque when present. The study was approved by the institutional review board at each field site, and all participants provided written informed consent.

MRA protocol and image analysis

A total of 1,959 participants completed the MRA as per protocol. Details of MRI protocol, image analysis, quality control and reliability have been reported.¹⁹ Percent agreement was 94.4% (inter-reader), 93.8% (intra-reader) and 93.2% (inter-scan) for ordinal stenosis (manuscript submitted and under review). All MRI scans were performed on 3.0T Siemens scanners. High-resolution vascular sequences were acquired at the end of a standardized brain MRI protocol and included a 3D time-of-flight (TOF) MRA. The 3D TOF MRA was acquired in a transverse plane through the circle of Willis, centered to include the distal vertebral artery segments inferiorly and the middle cerebral artery branches superiorly. Acquired resolution was 0.50×0.50 mm² and slice thickness was 0.55mm. MRI images were analyzed by seven certified readers at the MRI reading center without knowledge of the participant characteristics. We excluded studies with poor image quality or poor protocol adherence (n=194). MRA images for the remaining participants had adequate or excellent quality for ICAS identification in the vessels of interest, and were included in the current analysis.

Vessel segments analyzed included the supraclinoid and cavernous segments of the internal carotid artery (ICA), middle cerebral artery (MCA, M1 to M4 segments), anterior cerebral artery (ACA, A1-A3 segment), intracranial segments of the vertebral artery (VA), basilar artery (BA), and posterior cerebral artery (PCA, P1 to P3 segments). For each territory, the ordinal degree of narrowing (i.e., no detectable stenosis, <50%, 51%-70%, 71-99%, and occlusion) was recorded for the most stenotic plaque, measured on TOF MRA images using criteria established in the Warfarin-Aspirin Symptomatic Intracranial Disease trial²⁰. Since the objective of the study was to report intracranial stenosis prevalence, lesions noted to have plaque but without any measurable stenosis, were not included. We identified the most stenotic segment of each vessel analyzed, and used the severity of most stenotic lesion in each participant to determine the per-person prevalence of intracranial stenosis.

Demographic and clinical risk factors

Clinical risk factors were assessed at the time of visit 5 examination and included history of smoking (current, past or never), use of antihypertensive or cholesterol lowering medications, body mass index BMI (kg/m²), prevalent myocardial infarction, prevalent stroke, systolic blood pressure, plasma low density lipoprotein cholesterol (LDL), plasma high density lipoprotein cholesterol (HDL), and plasma triglycerides. We defined hypertension as blood pressure ≥140/90 mmHg or use of antihypertensive medications; and diabetes as fasting glucose ≥126 mg/dl, non-fasting glucose ≥200 mg/dl, use of antidiabetic medications, or a self-reported physician diagnosis of diabetes.

Analysis

Weights based on the probability of being sampled for the MRI exam were applied to adjust for the stratified sampling design and thus estimate the prevalence of ICAS in all ARIC participants alive at visit 5. To estimate age- and gender-adjusted prevalence of ICAS in the U.S. white and African-American populations (based on U.S. census 2010), we extrapolated using the following age groups — 65-69, 70-74, 75-79, 80-84 and 85-90 years.

To determine the independent associations of demographic and clinical variables with any-ICAS or ICAS >50% (compared to no ICAS), we computed odds ratios (ORs) using logistic regression. We examined the following variables in the regression analysis — age, gender, race (White, African-American), BMI, hypertension, diabetes, LDL cholesterol, smoking status, SBP, use of antihypertensive medication, triglycerides, HDL cholesterol, and use of cholesterol lowering medications. As the definition of hypertension was based on SBP and use of antihypertensive medications, to avoid collinearity in analysis we excluded ‘hypertension’ from the primary model. All analyses were done using SAS version 9.3 (SAS Institute, Cary NC) and R version 3.0.2²¹. R package ‘survey’²² and SAS PROC SURVEYLOGISTIC were used to adjust for stratification weights for all regression analysis.

Results

The mean age (±SD) of the 1,765 participants with adequate quality MRA was 76±5 years, 732 (41%) were men, 1242 (70%) were white, 520 (29%) were African-American and 3 were categorized as other races. Sixty (3%) participants had history of stroke and 164 (9%) had history of myocardial infarction. Compared to participants who had adequate quality MRA, participants with inadequate quality MRA (n=194) were more likely to be women and white, to have a higher BMI, and to have diabetes mellitus or hypertension (Supplemental Table I). There was no statistically significant difference between the two groups in regards to smoking status, LDL levels, history of myocardial infarction, or history of stroke.

Per-person prevalence (as shown in Table 1) of ICAS ≥50% was 9% (95% CI 8%-10%) and ICAS ≥70% was 5% (95% CI 4%-5%). After excluding subjects with previous history of stroke (n=60), prevalences of ICAS ≥50% and ≥70% were 9% and 4%, respectively. Among all vessels included in the analysis, ICAS was most prevalent in ICA (16%). However, ICAS of ≥50% was most commonly identified in PCA (4%). About 52% of the participants with any-ICAS had more than one lesion (Figure 1). After age and gender adjustment to the 2010 US population²³ by direct standardization²⁴, the estimated prevalence of ICAS≥50% for the U.S. population aged 65-90 years was 8% for Whites and 12% for African-Americans.

Table 1.

Counts and weighted prevalence (to the entire ARIC visit 5 cohort, 2011-2013) per-vessel type of ICAS, according to severity of stenosis identified, in n=1,765 participants

	≥50% stenosis	51-69% stenosis	71-99% stenosis	total occlusion
MCA	38 (1.7%)	28 (1.1%)	8 (0.6%)	2 (0.1%)
ICA	31 (1.5%)	25 (1.2%)	2 (0.1%)	4 (0.3%)
BA	15 (0.7%)	12 (0.6%)	2 (0.1%)	1 (0.03%)
VA	49 (2.4%)	11 (0.5%)	16 (0.6%)	22 (1.2%)
ACA	19 (0.9%)	10 (0.4%)	9 (0.5%)	0 (0%)
PCA	86 (4.0%)	45 (2.1%)	37 (1.8%)	4 (0.2%)
Total	188 (9.0%)	94 (4.2%)	64 (3.1%)	30 (1.7%)

ICA — intracranial segment of internal carotid artery (intracranial segments), MCA — middle cerebral artery (M1 to M3 segments), ACA — anterior cerebral artery (A1 segment), VA — vertebral artery (intracranial segment), BA — basilar artery, PCA — posterior cerebral artery (P1-P3 segments).

Figure 1.

Per-person number of ICAS lesions (all vessels) in participants with at least one lesion (n=641), ARIC, 2011-2013

Table 2 shows the prevalence of ICAS according to demographic characteristics and vascular risk factors. Patients with ICAS were more likely to be older, men and African-American; and more likely to have diabetes, hypertension and treatment for hypertension. BMI, systolic blood pressure, triglycerides and LDL cholesterol were higher; and HDL and cholesterol medication use were lower in those with ICAS. There was no statistically significant difference in the cigarette smoking status between those with and without ICAS. The odds of ICAS were 1.9 times higher in those with a history of myocardial infarction and 4.3 times higher in those with a history of stroke, compared to their counterparts without these disease histories.

Table 2.

Association of demographic and clinical variables with ICAS, ARIC, 2011-2013

	No ICASa,b	Any ICASa,b	Any vs no ICAS p-value	ICAS ≥50%a,b	≥50% vs no ICAS p-value
Age (mean ± SD)	75±5	76±5	<0.0001	78±5	<0.0001
Gender
Men	67%	33%	Reference	10%	Reference
Women	71%	29%	<0.0001	8%	0.005
Race
White	71%	29%	Reference	8%	Reference
African-American	63%	37%	<0.0001	12%	<0.0001
Other	67%	33%	0.4	0%	0.3
Body mass index (mean ± SD, kg/m2)	28±5	28±6	0.05	29±6	0.01
Diabetes mellitus
No	71%	29%	Reference	8%	Reference
Yes	64%	36%	<0.0001	11%	0.0013
Hypertension
No	77%	23%	Reference	6%	Reference
Yes	67%	33%	<0.0001	10%	<0.0001
SBP (mean ± SD, mmHg)	129±17	133±20	<0.0001	135±19	<0.0001
Use of antihypertensive medication
No	73%	27%	Reference	7%	Reference
Yes	68%	33%	<0.0001	10%	0.0004
Triglycerides (mean ± SD,mg/dl)	124±53	133±71	<0.0001	142±89	<0.0001
LDL cholesterol (mean ± SD, mg/dl)	106±35	108±36	0.11	108±37	0.39
HDL cholesterol (mean ± SD,mg/dl)	54±15	50±12	<0.0001	51±15	<0.0001
Use of cholesterol lowering medication in past 4 weeks
No	68%	32%	Reference	9%	Reference
Yes	71%	30%	0.01	9%	0.6
Cigarette smoking status
Never	70%	30%	Reference	9%	Reference
Past	70%	30%	0.8	9%	0.6
Current	71%	29%	0.8	9%	0.9
Prevalent myocardial infarction
No	71%	30%	Reference	9%	Reference
Yes	56%	44%	<0.0001	13%	0.01
Prevalent stroke
No	70%	30%	Reference	9%	Reference
Yes	33%	67%	<0.0001	26%	<0.0001
Field center
Forsyth Co., NC	71%	30%	-	7%	-
Jackson, MS (African-Americans)	63%	37%	-	13%	-
Minneapolis suburbs	70%	30%	-	8%	-
Washington Co., MD	73%	27%	-	9%	-

^aFor categorical variables — prevalence of ICAS per-person (based on most stenotic lesion) weighted for all ARIC visit 5 participants

^bFor continuous variables — weighted mean ± standard deviation

Risk factors association with any-ICAS and ICAS ≥50% after multiple logistic regression analysis are shown in table 3. Odds of any-ICAS were higher for greater age, African-American race (compared to whites), greater SBP, greater LDL, lesser HDL . Inclusion of ‘field center’ (after excluding ‘race’) in regression model did not affect the association of other variables. In separate analysis (not shown), after excluding ‘use of antihypertensive medication’ and including ‘hypertension’, odds of any-ICAS were 30% greater in those with hypertension. After excluding LDL and HDL, use of cholesterol lowering medication was significantly associated with lower odds of any-ICAS (OR 0.69, 95% CI 0.52– 0.92). There was no change in association of LDL and HDL after excluding cholesterol-lowering medications.

Table 3.

Odds Ratios (OR) and 95% confidence intervals of any-ICAS and ICAS≥50% for selected risk factors in logistic regression analysis (weighted for entire ARIC visit-5 cohort, 2011-2013). Models included all the variables in the table simultaneously.

	Odds Ratio (95% confidence interval)
	Any-ICAS	ICAS ≥50%
Age (every one year greater)	1.06 (1.03-1.09)	1.11 (1.08-1.15)
Gender (vs men)	0.83 (0.61-1.12)	0.69 (0.44-1.07)
African-American and others (vs Whites)	1.46 (1.07-1.98)	1.70 (1.09-2.64)
BMI (every 5kg/m2 greater)	1.02 (0.89-1.18)	1.19 (0.98-1.44)
Diabetes mellitus (vs no)	1.21 (0.88-1.66)	1.12 (0.71-1.78)
SBP (every 10 mmHg greater)	1.11 (1.02-1.20)	1.10 (0.99-1.23)
Use of antihypertensive medication	1.17 (0.85-1.60)	1.17 (0.74-1.86)
Triglycerides (every 10 mg/dl greater)	1.01 (0.99-1.04)	1.05 (1.00-1.09)
LDL cholesterol (every 10 mg/dl greater)	1.05 (1.00-1.09)	1.02 (0.95-1.09)
HDL cholesterol (every 10 mg/dl greater)	0.87 (0.77-0.97)	0.98 (0.81-1.19)
Use of cholesterol lowering medication (vs no)	0.79 (0.59-1.07)	0.96 (0.61-1.50)
Cigarette smoking status
Current vs Never	0.91 (0.50-1.65)	1.25 (0.50-3.16)
Past vs Never	0.96 (0.72-1.27)	0.92 (0.62-1.38)
Prevalent myocardial infarction (vs no)	1.47 (0.93-2.31)	1.10 (0.60-2.02)
Prevalent stroke (vs no)	4.64 (2.25-9.55)	3.04 (1.43-6.44)

Age and race were more strongly associated with ICAS≥50% than to any-ICAS. Association of other variables with ICAS≥50% was similar to any-ICAS. We also repeated the regression model after excluding participants with previous history of myocardial infarction or stroke, and noted no change in associations.

Discussion

In this general population study of four US communities, the prevalence of ICAS in at least one artery was 31%, and 9% of participants had ICAS with 50% or more stenosis. Age, African-American race, diabetes mellitus, hypertension, greater LDL cholesterol levels, greater triglyceride levels and lesser HDL levels were associated with presence of ICAS. Smoking status was not associated with prevalent ICAS.

Prevalence of ICAS

The 31% prevalence of ICAS—a common cause for ischemic stroke^1,25—is much higher than reported in other studies, which all used transcranial doppler.^12,13,15,18 Wong et al found the prevalence of ICAS in a door-to-door survey of inhabitants 40 years or older in a Chinese village to be 6.9%.¹² Huang et al, in a larger (n=1068) and similar study, reported a prevalence of ICAS in the MCA of 5.9%.¹³ We performed a small (n=99) population-based study in the Twin Cities (mean age of 72 years) and noted the prevalence of ICAS to be 16%, and ICAS ≥50% was 6%.¹⁸ Recently, Lopez-Cancio studied the prevalence of ICAS in a Spanish cardiovascular cohort participants (n=933, mean age 66 years) with vascular risk factors.¹⁵ ICAS was identified in 8.6%, and 3.3% had moderate-severe stenosis. Although participants in this study were selected using a stratified random sampling from a cardiovascular cohort, they were not selected based on their vascular risk factors or history of cardiovascular disease. Our sample was older than previous studies, and expected to have higher prevalence of ICAS. The accuracy of 1.5T-MRA is better than TCD for detecting ICAS.¹⁴ The reported accuracy of 3T-MRA for ICAS, using digital subtraction angiography as gold-standard, is even higher than 1.5T-MRA.^14,26 To further improve the accuracy of our image analysis, we excluded all MRAs for which quality was considered inadequate. In addition, we were able to include vessel segments which are small and distal and cannot be investigated with transcranial Doppler techniques. Thus, the prevalence of ICAS noted in our study was not only expected to be higher but also more accurate than previously reported.

We estimated the prevalence of ICAS to be 29% and 37% for U.S. elderly Whites and African-Americans, respectively. This is the first large study to estimate the prevalence of ICAS among different races in the U.S. Baker et al studied intracranial atherosclerosis in 3,942 autopsies in Minneapolis, Minnesota. More than 90% of specimens, for subjects aged 70-90 years, were noted to have some degree of intracranial atherosclerosis.¹⁷ McGarry et al inspected 1093 randomly selected specimens in New Orleans, Louisiana. For those aged 65-69 years, on average, Whites had 8%, African-American men had 32% and African-American women had 20% of intracranial vasculature covered with plaque.⁸ Intracranial atherosclerosis detected in these studies includes both stenotic and non-stenotic plaques, whereas we measured only stenotic intracranial atherosclerosis with MRA. Therefore, these studies cannot be used to estimate the prevalence of stenotic intracranial atherosclerosis, and cannot be directly compared to our study. In addition, due to increased mortality in subjects with ICAD⁴, the autopsy studies are biased toward artifactually higher prevalence of intracranial atherosclerosis. Other U.S. based studies investigating the prevalence of ICAS were limited because of selection bias or small samples.^18,27,28

Per-vessel prevalence of ICAS

There are limited data about the per-vessel prevalence of intracranial atherosclerosis. In an autopsy study, Baker et al noted that the most common locations for intracranial atherosclerosis were the BA and ICA, followed by the PCA.²⁹ Homburg et al studied ICAS in patients with brain ischemic events and noted that the PCA was one of the most common location for ICAS.²⁷ Our observation was similar to these studies. ICAS was more common in vessels with known larger diameters³⁰ — the ICA followed by MCA, VA and BA. However, the high prevalence of ICAS noted in PCA, in our and in previous studies, is an exception to this observation. It appears that the PCA has a higher predilection for ICAS compared to other intracranial vessels.

Association of ICAS with demographic and vascular risk factors

Vascular risk factors were associated with ICAS in the expected directions. African-Americans had higher odds of ICAS compared to Whites. Sacco et al noted that etiology for stroke is more likely to be ICAS in African-Americans compared to Whites.¹ Salina et al compared the incidence of stroke between White and African-American patients enrolled in the WASID trial.³¹ African-Americans were 50% more likely to have an ischemic stroke during follow-up than Whites. Our study suggests that an important reason why African-Americans have higher odds of stroke compared to Whites is their higher prevalence of ICAS.

Previous studies noted higher magnitude of association of ICAS with hypertension (OR 1.8-9.2) than identified in our study.^12,13,15 There was also a strong association of diabetes (2.9-5.9) to ICAS in these studies, whereas we failed to identify an association. This could be because of differences in race, community, and age compared to our study. In addition, many ARIC hypertensives were treated to normal blood pressure and the sample had a high prevalence of lipid lowering medication, all of which could reduce the ORs for hypertension and diabetes. Higher LDL and lower HDL cholesterol were independently associated with the presence of ICAS. These associations were not identified in previous studies. Again, this could be because of difference in population characteristics, but a larger sample size and a higher prevalence of ICAS in our sample, compared to previous studies, also increases the power of our study to identify associations of smaller magnitude.

After excluding LDL and HDL, use of cholesterol lowering medications was independently associated with 31% lower odds of ICAS in our study. Use of statins has been shown to slow the progression, and even cause regression of atherosclerosis in non-cerebral circulations.^32-34 Statins have been shown to reduce stroke incidence in clinical trials³⁵ and may prevent ICAS.

Surprisingly, cigarette smoking status was not associated with ICAS. Since our study population was elderly, the sample size of current smokers was small (only 5%) and selective attrition of smokers before old age may play a role. Also, among former smokers, there is a wide variation in the time since they quit smoking, thus affecting the risk factor exposure. Our study sample had only 5% subjects who are current smokers as compared to the 9.5% of U.S. population aged ≥65 in 2010³⁶. It is possible that we could not find an association with smoking because of selection bias i.e. subjects who are smokers and had ICAS were more sick and were unable to come for the exam. Interestingly, Lopez-Cancio et al¹⁵, Wong et al¹², and Huang et al¹³ also did not find any association of smoking with ICAS.

Despite lower prevalence of ICAS≥50% (9%) compared to any-ICAS (31%), associations of age, and race were stronger with ICAS≥50%. Since ICAS≥50% is a more specific and severe outcome measure, this adds credibility to these associations. Associations of other variables remained similar but lost statistical significance in some, likely because of loss of power and broadening of confidence interval.

Limitations

Although the original ARIC cohort was a population sample of four US communities, most of the African Americans (93%) were from Jackson, MS. The prevalence of diabetes mellitus and hypertension in our sample was similar to what has been reported for the U.S. elderly population.^37,38 However, participants included in the analysis tended to have fewer risk factors for ICAS than those excluded for an inadequate MRA. ARIC cohort was not designed to estimate prevalence of disease in the U.S. population. Since there were no good estimates of ICAS in the U.S. population, we used age and gender adjustment to best estimate the prevalence of ICAS in the U.S. Risk factor associations were based on cross-sectional analyses and may not reflect those that might be obtained prospectively and especially in a sample never treated with antihypertensive or antihyperlipidemic medications. We reported ORs as magnitudes of association. However, as the prevalence of any-ICAS was high (31%), ORs would markedly overestimate the prevalence ratios. Compared to digital subtraction angiography, MRA can overestimate degree of stenosis in the cavernous segment of ICA, distal ICA bifurcation or MCA bifurcation area.²⁶ We did not perform digital subtraction angiography to validate stenosis measurements. Our MRA scans were acquired at 3T using technique (0.5mm × 0.5mm × 0.55mm), minimizing the effects of dephasing artifacts that would exaggerate stenosis. Furthermore, unlike MRA studies, there are no population studies based on DSA measurements that we could use to reference our reported measurements. We did not study concurrent extracranial carotid stenosis, and based on our study, cannot comment if risk factor profile for intra- and extra-cranial stenosis is different.

Conclusion

This is first study to estimate the burden of ICAS (9% prevalence for ICAS≥50%) and study the association of main risk factors associated with ICAS in a large U.S. population-based sample of older adults. The higher prevalence of ICAS in African-Americans helps explain the higher likelihood of ICAS being the cause of stroke compared with whites. Finding use of cholesterol lowering medications to carry 31% lower odds of ICAS, compared with non-use, raises the possibility of a protective role for statins, which needs further study.