Coronary Artery Calcium and Incident Cerebrovascular Events in an Asymptomatic Multi Ethnic Cohort. MESA

Abstract

Objective

We assessed the predictive value of coronary artery calcium (CAC) score for CVA events in an asymptomatic multi-ethnic cohort.

Background

The coronary artery calcium (CAC) score, a measure of atherosclerotic burden, has been shown to improve prediction of coronary heart disease events. However, the predictive value of CAC for cerebrovascular (CVA) events is unclear.

Methods

CAC was measured at baseline exam of participants (N=6779) of the Multi Ethnic Study of atherosclerosis (MESA) and then followed for an average of 9.5(2.4) years for the diagnosis of incident CVA defined as all strokes or TIAs.

Results

During the follow up 234(3.5%) adjudicated CVA events occurred. In Kaplan Meier analysis the presence of CAC was associated with a lower CVA event - free survival versus CAC absent (Log rank χ² = 59.8, p<0.0001). Log transformed CAC was associated with increased risk for CVA after adjusting for age, gender, race/ethnicity, BMI, systolic and diastolic blood pressure, total cholesterol, HDL-C, cigarette smoking status, blood pressure medication use, statin use and interim atrial fibrillation[hazard ratio(95% CI): 1.13(1.07 – 1.20),p<0.0001]. The ACC/AHA recommended CAC cut off was also an independent predictor of CVA and strokes [HR (95%CI): 1.70(1.24–2.35),p=0.001 and 1.59(1.11–2.27), p=0.01 respectively]. CAC was an independent predictor of CVA when analysis was stratified by gender or race/ethnicity, and improved discrimination for CVA when added to the full model (c statistic: 0.744 vs. 0.755). CAC also improved the discriminative ability of the Framingham stroke risk score for CVA.

Conclusion

CAC is an independent predictor of CVA events, and improves the discrimination afforded by current stroke risk factors or the Framingham stroke risk score for incident CVA in an initially asymptomatic multi-ethnic adult cohort.

Introduction

Coronary artery calcium (CAC) is an independent predictor of cardiovascular disease (CVD) events (1–3), a composite which often include strokes, and has also been shown to improve discrimination for CVD events in the general population beyond current risk prediction tools such as the Framingham risk score and Reynolds score (4–6). However, in almost all these studies (1–3), the association between CAC and stroke failed to achieve statistical significance due to relatively small sample sizes. Some authors have questioned the use of CAC to improve stroke risk prediction in the general population based on these data (7).

The recent AHA/ACC guidelines for risk prediction adopted a new composite: atherosclerotic cardiovascular disease (ASCVD), which includes coronary death, nonfatal myocardial infarction, and fatal and nonfatal stroke (8). The new AHA/ACC ASCVD risk score does not consider current subclinical atherosclerosis measures. Given persuasive data on the improvement of discrimination for CVD by subclinical atherosclerotic measures (4, 5) and the similarity of the constituents of the pooled ASCVD risk prediction tool with the Framingham risk score (8, 9), there are ongoing efforts to improve the risk prediction afforded by the new pooled ASCVD risk tool with these subclinical atherosclerotic measures in the general population. However, adding subclinical atherosclerotic measures to the new pooled ASCVD risk tool would only make sense if these measures were associated with strokes. A recent publication from the Heinz Nixdorf Recall (HNR) study with a larger number of strokes than that of prior published data (1–3) showed an independent association between CAC and strokes in low to intermediate risk Caucasians (10). However, the racial homogeneity of the HNR cohort limits its external validity. Thus, the association between CAC and strokes in the general population remains unclear. In this report, we examined the relationship of CAC measured during the baseline examination to adjudicated cerebrovascular events in participants of the Multi Ethnic Study of Atherosclerosis (MESA) over a ten year follow up.

Methods

Study Population and Data Collection

A detailed description of the study design for MESA has been published (11). In brief, MESA is a cohort study that begun in July 2000 to investigate the prevalence, correlates, and progression of subclinical cardiovascular disease (CVD). At baseline, the cohort included 6814 women and men aged 45–84 years old recruited from 6 US communities (Baltimore, MD; Chicago, IL; Forsyth County, NC; Los Angeles County, CA; northern Manhattan, NY; and St. Paul, MN). MESA participants were 38% white, 28% black, 22% Hispanic and 12% Chinese. Individuals with a history of physician-diagnosed myocardial infarction, angina, heart failure, stroke or transient ischemic attack, or who had undergone an invasive procedure for CVD (coronary artery bypass graft, angioplasty, valve replacement, pacemaker placement or other vascular surgeries) were excluded.

Demographics, medical history, anthropometric and laboratory data for these analyses were obtained at the first MESA examination (July 2000 to August 2002). Current smoking was defined as having smoked a cigarette in the last 30 days. Diabetes mellitus was defined as fasting glucose ≥126 mg/100 dL or use of hypoglycemic medications. Use of antihypertensive and other medications was based on the review of prescribed medication containers. Resting blood pressure was measured three times in seated position, and the average of the second and third readings was used. Hypertension was defined as a systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg or use of medication prescribed for hypertension. Body mass index was calculated as weight (kg)/height² (m²). Total and high-density lipoprotein cholesterol were measured from blood samples obtained after a 12-h fast. Low-density lipoprotein cholesterol was estimated by the Friedewald equation (12). The MESA study was approved by the institutional review boards of each study site, and written informed consent was obtained from all participants.

Measurement of Coronary Artery Calcium (CAC) Score

Details of the MESA CT scanning and interpretation methods have been reported by Carr et al (13). Scanning centers assessed CAC by non-contrast cardiac computed tomography (CT) with either an electron-beam CT scanner (Chicago, Illinois; Los Angeles, California; and New York, New York field centers) or a multi-detector CT system (Baltimore, Maryland; Forsyth County, North Carolina; and St Paul, Minnesota field centers). Certified technologists scanned all participants twice over phantoms of known physical calcium concentration. A radiologist or cardiologist read all CT scans at a central reading center (Los Angeles Biomedical Research Institute at Harbor–UCLA, Torrance, California). We used the mean Agatston score for the 2 scans in all analyses (15) Intra- and inter-observer agreements were excellent (κ = 0.93 and κ = 0.90, respectively).

Ascertainment of Cerebrovascular Events

Strokes and TIAs and other cardiovascular events were adjudicated by a MESA committee that included cardiologists, physician epidemiologists, and neurologists. A detailed description of the adjudication process has been published (11). For the purposes of this study, we defined cerebrovascular events as fatal or non fatal strokes due to hemorrhage or infarcts or transient ischemic attack (TIA). TIAs and strokes were also used individually as secondary outcomes for this analysis. Interim incident atrial fibrillation which occurred during the follow up period was adjusted for in the full model as a time-varying covariate. Interim atrial fibrillation in MESA is a combination of adjudicated, ICD-9 code and self reported cases.

Statistical Analysis

Demographic and other characteristics were compared according to cerebrovascular event. CAC was introduced into models as a binary variable (CAC present/absent), as a continuous variable (In [CAC +1]), or as 4 categories (CAC: <0, 0–100, 100–400 and >400 Agatston units). Kaplan Meier and Cox Proportional Hazards analysis were used to evaluate the association between CAC and incident cerebrovascular events. Among participants with more than one type of event adjudicated during the follow-up period, the first event was used in this analysis. Covariates entered in models were chosen based on their association with incident cerebrovascular events in the present analyses and in published data. The covariates include age, gender, race/ethnicity, BMI, systolic and diastolic blood pressure, total cholesterol, HDL, cigarette smoking status, blood pressure medication use, statin use and interim atrial fibrillation that occurred during the follow up period. The full multivariable model was then stratified by gender and race/ethnicity. The above analysis was repeated with all strokes and TIAs as the outcome.

The improvement of discrimination for incident CVA afforded by the addition of CAC to our full model was evaluated using the receiver operating curve analysis. The Framingham stroke risk score (FSRS) (14) was calculated for each MESA participant (using baseline data only) using the following variables; age, SBP, diabetes mellitus, cigarette smoking, prior CVD, atrial fibrillation, left ventricular hypertrophy (ECG criteria) and BP medications. No MESA participant had prior CVD or atrial fibrillation during the baseline exam and so was introduced as such in the FSRS calculation. The improvement in discrimination afforded by the addition of CAC to the FSRS (and also using the constituents in the model) was also assessed using receiver operating curve analysis. A 2-tailed value of P<0.05 was considered significant. All statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC).

Results

After a mean (SD) of 9.5(2.4) years, 234(3.5%) adjudicated cerebrovascular events (180 strokes and 67 TIAs) were identified. Ischemic cerebrovascular events (cerebral infarcts and TIAs)) were observed in 206(3.4%) participants, of whom 152(2.2%) had cerebral infarcts. Participants who developed a cerebrovascular event were older, had a worse cardiovascular risk profile and developed atrial fibrillation more often (17.1% vs. 5.6%) during the follow up period than those who did not have a cerebrovascular event (Table 1). As shown in Table 2, similar proportions of the participants within each CAC category had hemorrhagic strokes during the follow up period. However increased proportion of participants had cerebral infarcts, TIAs and atrial fibrillation with higher CAC category.

Table 1.

Demographic characteristics of MESA participants with and without cerebrovascular events during the follow up period (mean ±SD = 9.5± 2.4 years.)

Variable	No Cerebrovascular Event(N=6545) Mean ± SD	Cerebrovascular Event (N= 234) Mean ± SD
Age (years)	61.9 ± 10.2	67.9 ± 9.6
Male Gender (%)	3089(47.1)	111(47.6)
Race/Ethnicity (%)
Caucasian	2526(38.5)	93(39.7)
Chinese	791(12.0)	12(5.2)
African American	1823(27.7)	69(29.5)
Hispanic	1435(21.8)	60(21.8)
Body Mass Index(Kg/m2)	28.3 ± 5.5	28.7 ± 5.1
Cholesterol (mg/dl)
Total	194.1± 35.8	194.1 ±33.8
LDL	117.2± 31.5	118.4 ±30.4
HDL	51.1 ± 14.9	48.0 ±12.5
Triglycerides	131.2 ±89. 1	140.8 ±75.5
Cigarette Smoking (%)
Never	3302(50.4)	114(48.9)
Former	2406(36.7)	78(33.5)
Current	846(12.9)	41(17.6)
Diabetes Mellitus (%)	804(12.3)	52(22.2)
Blood Pressure(mmHg)
Systolic	126.1± 21.2	140.0±22.2
Diastolic	71.8 ±10.2	74.9 ±11.5
Anti-hypertensive use (%)	2144(32.6)	121(51.7)
Statins use (%)	957(14.8)	31(13.3)
Coronary artery Calcium score[IQR](Agatston)	80.8[0 – 140.7]	289.8[0 – 313.7]
Developed Atrial Fibrillation (%)	368(5.6)	40(17.1)

IQR indicates interquartile range.

Table 2.

Occurrence of cerebrovascular events, hemorrhagic strokes, cerebral infarcts and TIAs that occurred within each CAC category after a mean (SD) of 9.5(2.4) years of follow up in the MESA cohort.

CAC Category (Agatston)	Cerebrovascular Events (%)	Hemorrhagic Strokes (%)	Cerebral Infarcts (%)	TIAs (%)
0 (N= 3399)	69(2.0)	13(0.4)	40(1.2)	19(0.6)
0 –100 (N=1786)	67(3.8)	9 (0.5)	41(2.3)	20 (1.1)
100 – 400 (N=923)	52(5.6)	4 (0.4)	36 (3.9)	15 (1.6)
>400 (N=671)	46(6.9)	2 (0.3)	35 (5.2)	13 (1.9)
	234	28	152	67

TIA indicates transient ischemic attacks. CAC indicates coronary artery calcium score.

CAC and Cerebrovascular Event Prediction

In Kaplan Meier analyses, participants with CAC present during the baseline exam had a lower cerebrovascular event-free survival compared with participants with CAC absent at baseline [Log rank Chi square = 59.84, P<0.0001] (Figure 1). When participants were divided into 4 groups based on baseline CAC (CAC=0, 0–100,100–400 and >400Agatston), a significant graded cerebrovascular event-free survival rate was observed [log rank Chi square for trend = 95.78, p<0.0001] (Figure 2).

Figure 1. Incident CVA in subjects with and without CAC.

Kaplan Meier analysis showing the event- free survival of participants with and without coronary artery calcium and incident cerebrovascular events in the MESA cohort

Figure 2. Incident CVA by CAC Categories.

Kaplan Meier analysis showing the CVA event-free survival of participants with < 0, 0–100, 100–400 and >400 coronary artery calcium(Agatston) and incident cerebrovascular events in the MESA cohort

In (CAC+1) was a predictor for cerebrovascular events, strokes and TIAs in both univariate and multivariable models across sex and race/ethnic strata, except Chinese (Table3). Table 4 shows univariate and multivariable hazard ratios for cerebrovascular event, strokes, TIAs according to presence of CAC, stratified by gender and race/ethnicity. The hazard ratio for females and all race/ethnicities did not reach conventional statistical significance, although point estimates and directions were similar to those in Table 2.

Table 3.

Predictive value of coronary artery calcium score [In (CAC +1)] for incident cerebrovascular events after mean follow up of 9.5(2.4) years in the MESA cohort

Outcome	# of Events	Univariate Model Hazard Ratio( 95%CI)	P value	*Multivariable Model Hazard Ratio(95%CI)	P value
Cerebrovascular	234	1.28(1.22 – 1.34)	<0.0001	1.13(1.07 – 1.20)	<0.0001
All Stroke	180	1.23(1.17 – 1.31)	<0.0001	1.10(1.03 – 1.18)	0.003
TIA	67	1.25(1.14 – 1.37)	<0.0001	1.16(1.04 – 1.31)	0.007
Gender Stratified
Male	111	1.26(1.17 – 1.37)	<0.0001	1.15(1.05 – 1.24)	0.001
Female	123	1.32(1.23 – 1.42)	<0.0001	1.11(1.03 – 1.21)	0.010
Race/Ethnicity
Stratified	93	1.32(1.21 – 1.43)	<0.0001	1.14(1.03 – 1.25)	0.008
Caucasian	12	1.32(1.04 – 1.67)	0.02	1.18(0.89 – 1.56)	0.25
Chinese	69	1.24(1.15 – 1.36)	<0.0001	1.14(1.02 – 1.26)	0.016
African	60	1.33(1.21 – 1.47)	<0.0001	1.14(1.01 – 1.28)	0.036
American Hispanic

Footnote: TIA indicates transient ischemic attack.

^*Multivariable model was adjusted for age, gender, race/ethnicity, BMI, diabetes mellitus, systolic and diastolic blood pressure, total cholesterol, HDL, cigarette smoking status, blood pressure medication use, statin use and interim atrial fibrillation that occurred during the follow up period.

Table 4.

Predictive value of coronary artery calcium (present vs. absent) for incident cerebrovascular events after mean follow up of 9.5(2.4) years in the MESA cohort.

Outcome	# of Events	Univariate Model Hazard Ratio( 95%CI)	P value	Multivariable Model* Hazard Ratio(95%CI)	P value
Cerebrovascular	234	2.88(2.18 – 3.82)	<0.0001	1.13(1.07 –1.20)	<0.0001
Stroke	180	2.57(1.86 – 3.55)	<0.0001	1.45(1.01 –2.07)	0.043
TIA	67	2.71(1.59 – 4.61)	0.0002	1.81(1.00 – 3.27)	0.049
Gender Stratified
Male	111	3.02(1.88 – 4.81)	<0.0001	1.84(1.11 –3.05)	0.018
Female	123	2.95(2.05 –4.25)	<0.0001	1.33(0.88 – 2.00)	0.174
Race/Ethnicity
Stratified	93	3.41(2.08 – 5.60)	<0.0001	1.65(0.95 – 2.89)	0.075
Caucasian	12	2.74(0.82 – 9.17)	0.10	1.57(0.40 – 6.12)	0.513
Chinese	69	2.35(1.45 – 3.83)	0.0005	1.53(0.89 – 2.63)	0.123
African American	60	3.71(2.14 –6.47)	<0.0001	1.79(0.96 – 3.34)	0.061
Hispanic

Footnote: TIA indicates transient ischemic attack.

^*Multivariable model was adjusted for age, gender, race/ethnicity, BMI, diabetes mellitus, systolic and diastolic blood pressure, total cholesterol, HDL, cigarette smoking status, blood pressure medication use, statin use and interim atrial fibrillation that occurred during the follow up period.

Coronary heart disease (CHD) is a known predictor of CVA’s so as a sensitivity analysis, we excluded participants with incident CHD during the follow up exam (N=449). In (CAC +1) was a predictor of CVA (n=205 events) in univariate and full model [hazard ratio (95%CI): 1.29(1.22 – 1.36), p<0.0001 and 1.13(1.06 – 1.20),p<0.001 respectively]; for all strokes(n=153)[hazard ratio(95%CI): 1.24(1.16 – 1.31),P<0.001 and 1.10(1.03 – 1.18), P=0.007 respectively] and TIAs(n=63)[hazard ratio(95%CI): 1.26(1.15–1.39),p<0.001 and 1.17(1.05 – 1.31),p=0.006 respectively] in this subcohort. CAC (present/absent) also showed similar associations with incident CVA, all strokes and TIAs in this subcohort (Data not shown). The new ACC/AHA⁸ recommended cut off for improving risk assessment using CAC [≥300 Agatston units or ≥75 percentile for age, sex, and ethnicity] was also an independent predictor of cerebrovascular events and strokes in this cohort [for strokes: HR(95%CI): 3.02(2.18–4.20),p<0.0001 and 1.59(1.11–2.27),p=0.01 respectively).

There was significant reduction in power when the analysis was stratified by CAC categories: 0, 0–100, 100–400 and >400 Agatston. With CAC = 0 as the reference, the univariate and multivariable hazard ratios in the Cox model were for CAC= 0–100[HR (95%CI): 1.38(1.08–1.78), p=0.01 and 1.19(0.92 – 1.55), p=0.18 respectively]; CAC= 101–400 [HR (95%CI): 2.27(1.16 – 4.47), p=0.08 and 2.26(1.11–4.57), p=0.02 respectively] and CAC>400 [HR(95%CI): 1.56(0.97–2.52),p=0.06 and 1.38(0.81–2.36), p=0.23 respectively].

In age stratified analysis (by median age of 62 years), CAC was a predictor of CVA and strokes in those ≥ the median age in both the univariate and multivariable Cox model. For those below the median age (<62 years) CAC was a predictor of CVA and strokes in only univariate Cox models but not in the multivariable Cox models (Data not shown).

Figure 3 shows the effect of CAC predicting cerebrovascular events across baseline Framingham stroke risk (stratified by the median = 5.7%) in this MESA cohort.

Figure 3. CAC predicting CVA by global Risk.

Plot of incident cerebrovascular (CVA) event rates within CAC categories [CAC=0 (1ST), CAC=0–100(2nd), CAC=101–400(3rd) and CAC>400 Agatston] across the median Framingham stroke risk score(FSRS) in MESA participants after 9.5 years of follow up.

CAC and Cerebrovascular Event Discrimination

For cerebrovascular events (# of events = 234), c-statistic for CAC (continuous) alone was 0.642 and it was 0.744 in the full multivariable model without CAC. The addition of CAC improved discrimination of our full multivariable model (Table 3) by 0.011(c-statistic: 0.744 vs. 0.755). The c-statistic for the Framingham stroke risk score (FSRS) was 0.664. The addition of CAC improved its discrimination, as reflected by a c-statistic of 0.706(p<0.01) (Figure 4). The cstatistics when constituents of the FSRS (risk factors) were in the model was 0.721 and when CAC was added to the model was 0.735(data not shown).

Figure 4. Predictive Accuracy of CAC, FSRS and CAC + FSRS.

Receiver Operating curves showing the discriminative ability of the full model, full model + coronary artery calcium (CAC), the Framingham stroke risk score(FSRS) and the FSRS + CAC for incident cerebrovascular events in the MESA cohort.

For ischemic CVA events (cerebral infarcts + TIAs, n = 206), the c-statistic values related to CAC alone, our full model (minus CAC) and the addition of CAC to the full model were 0.657, 0.751 and 0.763 (p<0.01), respectively. For cerebral infarcts (non TIA, non hemorrhagic strokes) (# of events =152), these values were 0.664, 0.767 and 0.777 (p<0.01).

Discussion

The goal of this study is to determine the predictive value of CAC for incident cerebrovascular events and to assess the improvement in discrimination afforded by the addition of CAC to known risk factors for cerebrovascular events in a multi-ethnic cohort. Our study, which is the largest and has the longest follow-up so far, shows that CAC is an independent predictor and improves the discrimination for cerebrovascular events.

Compared with other subclinical and novel markers, CAC has been shown to be superior for predicting, in the general population, coronary heart disease (CHD) and cardiovascular events composites, which include cerebrovascular events(4, 5, 15, 16). The predictive value of CAC with regard to cerebrovascular events –which had been questionable before the present study— was clearly shown in our study. Unlike the HNR study, we did not observe that CAC predicts stroke events in younger but not in older adults. Furthermore, our results strongly suggest that CAC improves the discrimination of incident cerebrovascular events above and beyond that related to known risk factors and by a similar magnitude as the CHD risk prediction in the MESA cohort (6).

CAC is a measure of atherosclerosis burden in the coronary circulation (17). Atherosclerosis is a known systemic disease which is almost always present in other vascular beds once detected in the coronary bed (18, 19). Thus, observation of atherosclerosis in the coronary bed suggests presence of atherosclerosis in the cerebral circulation and elsewhere. However, unlike coronary heart disease, the underlying pathophysiology of which is mainly atherosclerosis, cerebrovascular disease/event has more heterogeneous pathophysiology (20), including hemorrhage, small vessel lacunar strokes and ischemia. The heterogeneous pathophysiology of cerebrovascular disease/event makes predicting events using a single marker such as CAC in one of the pathophysiologic pathways unappealing. However, as evident from the present study (152 out of 180 strokes) and others, most cerebrovascular disease/events (approximately 85%) are due to cerebral infarcts (21). With a few exceptions, such as cerebral infarcts from cardioembolic source, most of these cerebral infarcts may either be due to in-situ atherosclerosis, small vessel disease including micro-atheroma or embolism of plaques from extracranial vessels or the aorta; all of which CAC would be a good surrogate marker. Thus despite the heterogeneous pathophysiology of cerebrovascular disease, CAC a measure of atherosclerotic burden in the coronary bed can still be a good predictor and can be used to identify most subjects at risk for aggressive preventive therapy such as statins.

Epidemiological and observational studies have shown clear association between hypertension and incident CVA suggesting that blood pressure control may be a good target for primary stroke prevention (22, 23). Primary stroke prevention trials with upstream modification of blood pressure have shown a significant reduction in incident CVA (24–26). However current data on the association between dyslipidemia and incident CVA are mixed (27–30). To date no clinical trial data exist on the effects of lipid lowering therapy on CVAs in asymptomatic individuals. However, secondary analysis of primary prevention trials and long term clinical trials which evaluated CVA as a secondary outcome in patients with established coronary heart disease showed a reduction in CVAs with statin therapy (31–35). Thus, CAC a non invasive test, can identify individuals with asymptomatic CHD but at high risk for CVA, for statin therapy. Clinical trials primarily evaluating the effect of statins on CVAs in individuals without clinical cardiovascular disease but positive CAC are needed.

Although our study shows an improvement in discrimination by CAC over current risk factors, we caution the incorporation of CAC into primary stroke prevention strategies until concerns about ionizing radiation exposure (~1 mSv) are weighed and this approach has been deemed cost effective. Our results also need to be replicated in other cohorts.

The strength of our study includes its large sample size, multi ethnic cohort, relatively long follow up and t adjudicated cerebrovascular. The limitations include the relatively small number of cerebrovascular events, which limited our ability to make definitive inferences in subgroups formed by gender and race/ethnicity. MESA is an observational study and thus residual confounding may have influenced our results. MESA does not include other ethnic groups such as American Indians and other Asian groups except Chinese. In addition the proportion of each ethnic group in MESA does not accurately reflect that of the US population. Although our primary outcome, cerebrovascular events and its constituents were adjudicated, atrial fibrillation that occurred during the follow up were a combination of adjudicated events, ICD-9 code derived and self reports. The Framingham stroke risk score includes prior CVD and atrial fibrillation and was derived for stroke prediction in individuals with and without these comorbidities. MESA participants were free of CVD and atrial fibrillation at baseline but should not affect the discriminative ability of the FSRS in this cohort (asymptomatic multi ethnic cohort). Lastly, because the present study involved individuals without clinical cardiovascular disease at baseline, our results may not be applicable to other populations.

Conclusion

CAC was found to be an independent predictor of cerebrovascular events, strokes and TIAs in a large multi ethnic cohort. CAC also seems to have improved prediction over known risk factors for cerebrovascular events, including atrial fibrillation and the Framingham stroke risk score.

Abbreviations

CAC

Coronary artery calcium

CVA

Cerebrovascular events

MESA

Multi Ethnic Study of Atherosclerosis

TIA

Transient Ischemic Attack