Carotid artery calcification as a predictor of systemic vascular events

Abstract

Background:

Coronary calcification is a well-known predictor of coronary events, yet the impact of carotid artery calcification on systemic vascular events (e.g., cerebral ischemic, coronary, and peripheral artery events) remains unclear. The aim of this study was to determine whether carotid calcification can be used to predict systemic vascular events.

Methods:

This single-center, retrospective cohort study included 194 patients who had a history of vascular disease, including carotid stenosis or occlusion, coronary artery disease, valvular heart disease, ischemic stroke, or transient ischemic attack. We collected data pertaining to risk factors and laboratory parameters. Calcification of the carotid arteries was assessed via whole-body computed tomography, and the modified carotid Agatston calcium score (CCS) was determined. Participants were divided into two CCS groups according to the cut-off value determined via receiver operating characteristic curve analysis; high CCS ≥ 126 and low CCS < 126. Coronary, ischemic cerebrovascular, and peripheral vascular events were recorded over a 5-year follow-up period, and their incidence was compared between the groups using Cox proportional hazards regression analysis.

Results:

Older age, hypertension, and chronic kidney disease had a significant positive impact on the CCS. Systemic vascular events (hazard ratio [HR]: 2.70, CI: 1.07–6.79, p = 0.022), coronary events (HR: 4.29, CI: 0.87–21.1, p = 0.045), and peripheral vascular events (p = 0.032) were significantly more frequent in the high versus low CCS group.

Conclusion:

The CCS may be a useful tool for predicting future systemic vascular events, including those related to coronary and peripheral artery diseases.

Keywords

atherosclerosis calcification carotid artery disease computed tomography (CT)coronary artery disease (CAD)peripheral artery disease (PAD)

Background

Systemic atherosclerotic plaques continuously progress and calcify over time to form advanced lesions if left untreated.¹ Calcification of the coronary arteries and distal aorta starts at an early age, and calcification of the carotid arteries and other vascular beds occurs subsequently.² Coronary artery calcification correlates with plaque volume. The Agatston calcium score (ACS) of the coronary arteries has been used to predict coronary artery disease in White populations,^3,4 and the Multi-Ethnic Study of Atherosclerosis (MESA) study group has applied this score to multiethnic populations.⁵

Whether calcification of other major vessels, such as the aorta and carotid artery, predicts vascular events has been investigated. For example, calcification of the abdominal aorta has been shown to be a risk factor for symptomatic aneurysms and subsequent rupture.^6,7 Some studies suggest that calcium deposits in the cervical carotid artery can predict symptomatic and asymptomatic strokes,^8,9 whereas others contend that they are not good predictors because they are associated with plaque stability.¹⁰ Owing to these contradictory claims, the relationship between carotid artery calcification and stroke remains controversial.

The effect of carotid artery calcification on systemic vascular events, especially in the population who have already undergone treatment for systemic artery disease, has not been investigated to date. Therefore, the present study aimed to elucidate the relationship between the carotid Agatston calcium score (CCS) and future vascular events in patients with advanced vascular diseases.

Methods

Study participants

After the protocol was approved by our local institutional review board, we provided explanations regarding this study to patients hospitalized at the National Cerebral and Cardiovascular Center between June 2011 and March 2013. The patients included those admitted to the department of neurosurgery for elective surgeries for carotid artery stenosis or occlusion, those admitted to the division of cerebrovascular medicine for ischemic cerebrovascular disease or transient ischemic attack (TIA), and those admitted to the department of cardiovascular surgery for elective surgeries for atherosclerotic valvular disease or coronary artery disease. A total of 199 patients who fully understood the significance of this study, which included whole-body computed tomography (CT) scans, blood tests, and urine analyses conducted purely for research purposes, and who provided voluntary written informed consent for participation in the study and publication of their data, were enrolled (Figure 1). The initial prospective study did not include plans for long-term follow up. However, 5 years after the conclusion of the enrollment period, a retrospective study was conducted to investigate the incidence of vascular events over a 5-year period, following a new internet-based opt-out process and approval from the local institutional review board.

Patient demographic and clinical data (including risk factors for atherosclerosis) were collected at the time of enrollment. The diagnostic criteria were as follows: blood pressure ≥ 130/85 mmHg or current use of antihypertensive drugs for hypertension;¹¹ fasting plasma glucose ≥ 7.0 mmol/L, hemoglobin A1c ≥ 48 mmol/mol, or previous diagnosis with or without treatment for diabetes mellitus;¹² and serum cholesterol ≥ 5.17 mmol/L or current use of cholesterol-regulating agents for hyperlipidemia.¹³ An estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m² was indicative of chronic kidney disease. Smoking was defined as the current use of tobacco or a past smoking habit that had persisted for more than 10 years. Laboratory data and calcium scores (obtained via whole-body CT) were collected within 1 week after the enrollment.

Protocol for calcium score acquisition

All assessments were conducted using a SOMATOM Definition Flash computed CT scanner (Siemens, Munich, Germany). Whole-body CT for each patient was performed from the orbitomeatal line to the ischial tuberosity in a single session, and arterial visualization was achieved without contrast. The slice thickness was 3 mm, and the X-ray voltage was 120 kV with a 500-ms exposure time. The area of interest was the bilateral carotid arteries (common, internal, and external carotid arteries; the region 30 mm below and above the carotid bifurcation).

All images were analyzed using AW Volume Share 2 and Smart Score 3.5 (GE Medical Systems, Chicago, IL, USA) by an observer blinded to the patient’s clinical history. The ACS was determined for each vessel according to the original ACS method.³ The calcification volume was defined in Hounsfield units (HUs) weighted by maximal signal intensity scalers within the area (scalar 1, 130–199 HU; scalar 2, 200–299 HU; scalar 3, 300–399 HU; scalar 4, ≥ 400 HU). For example, if a calcified area in a CT slice has a maximum attenuation value of 350 HU (scaler 3) and occupies a 9-mm² area, its calcium score is 27 (3 × 9). The scores for all slices were added together to obtain the CCS. The total scores for the carotid arteries were summed. If carotid endarterectomy or carotid stenting was performed before enrollment, the score was excluded from the analysis.

Follow up

We conducted a 5-year investigation using medical records to track the occurrence of vascular events, vascular surgeries, interventions in the area of interest, and cause of death in all patients. Patients who discontinued follow up at our hospital during the 5-year study period owing to relocation or transfer to another facility were surveyed via telephone.

The primary outcome was a symptomatic vascular event (e.g., an ischemic cerebrovascular, coronary, aortic, or peripheral artery event). Ischemic cerebrovascular events were defined as focal neurological deficits that resulted in disability for more than 24 h and were confirmed by magnetic resonance imaging (MRI). Coronary events were diagnosed when two or more of the following four conditions were satisfied: (1) typical chest pain; (2) serum creatinine kinase-MB accounting for more than 5% of total creatinine kinase, with its level more than twice the upper limit of the normal range; (3) typical electrocardiogram changes, including new ST or Q-wave changes; and (4) a new cardiac motion dyssynchrony on echocardiography continuing for more than 24 h. Symptomatic aortic events included ruptures and new symptomatic dissecting aneurysms of the aorta or its major branches. Symptomatic peripheral artery diseases included acute and chronic limb ischemia presenting typical symptoms including pain, intermittent claudication, and pallor or chronic limb-threatening ischemia due to stenosis or occlusion of the iliac artery or its major branches that were not noted at the time of enrollment, intervention, or surgery. Lesions were confirmed by angiography or CT angiography.

The secondary outcome was the elective procedure for asymptomatic lesions; these procedures included carotid stenting, carotid endarterectomy, coronary artery stenting, endovascular aortic repair, and lower-extremity revascularization. Patients with symptomatic vascular lesions and related vascular events that occurred prior to study enrollment were excluded from the analysis of future vascular events. Deaths related to complications of elective surgery, which was scheduled at the time of enrollment, were not included in the symptomatic vascular events. However, all symptomatic vascular events that occurred after enrollment were analyzed, regardless of whether they were recurrences of the preenrollment vascular lesion or distinct from the initial disease.

Statistical analysis

JMP 17.0 software was used for statistical analysis of the data. The optimal cut-off value for the CCS was based on receiver operating characteristic curves for the occurrence of all CCS-related vascular events over the 5-year period (Figure 2). Patients were accordingly divided into a high CCS group (a score of 126 or more) and a low CCS group (a score of less than 126). Potential associations between the two groups and traditional vascular risk factors were evaluated using the chi-squared test. The relationship of the CCS as a continuous variable with age, and blood and urine test data, was assessed using Spearman’s rank correlation coefficient and by determining p-values.

Differences in the frequency of the outcomes between the two CCS groups were analyzed using Fisher’s exact test. To compare the frequencies of the primary outcomes, Kaplan–Meier cumulative event curves were generated, and Cox proportional hazards regression analysis was performed. The regression analysis was adjusted for background variables (e.g., hypertension, age > 70 years-old, and chronic kidney disease) with p < 0.1 in a univariate analysis. In the regression analysis, only the first event in each vascular territory was considered. For all vascular events, only the earliest occurring event across the territories was considered.

All patients were included in the Kaplan–Meier and Cox proportional hazards regression analysis until their last visit or death, as long as either occurred within 5 years after their enrollment in the study. The elective procedure for asymptomatic lesions may introduce arbitrariness into the choice of timing and was therefore excluded from this analysis.

Results

Demographic data

Over a 24-month period, 199 patients were admitted with a history of, or the need for treatment of, the following: carotid artery stenosis or occlusion (n = 96), atherosclerotic valvular disease or coronary disease (n = 38), or ischemic cerebral stroke or TIA (n = 65). Five patients were excluded from the analysis because they had a prior history of carotid artery intervention or surgery. Of the 194 enrolled patients, 110 and 84 were assigned to the high (CCS ≥ 126) and low CCS groups (CCS < 126), respectively (Figure 1). Table 1 presents the baseline characteristics of the study cohort.

Table 1.

Relationships between clinical characteristics and carotid Agatston calcium score.

Clinical characteristics, mean ± SD	All participants (N = 194)	R ^a	p-value
Age	70.1 ± 8.5	0.314	< 0.001
C-reactive protein (mg/dL)	0.37 ± 0.72	0.151	0.046
HbA1c (NGSP, %)	6.12 ± 0.84	0.128	0.143
Serum LDL (mmol/L)	2.56 ± 0.88	–0.083	0.285
Serum HDL (mmol/L)	1.25 ± 0.88	–0.022	0.778
Serum triglycerides (mmol/L)	1.47 ± 0.79	–0.143	0.064
Serum calcium (mmol/L)	2.34 ± 0.11	0.129	0.096
Serum phosphate (mmol/L)	1.10 ± 0.21	0.158	0.042
Intact PTH (pmol/L)	5.73 ± 3.37	0.150	0.059
Serum creatinine (mmol/L)	0.10 ± 0.11	0.353	< 0.001
Urine creatinine (mmol/L)	8.50 ± 5.25	–0.262	0.001
eGFR (mL/min)	62.4 ± 21.1	–0.320	< 0.001
Carotid calcium score (CCS), median (IQR)	CCS Present	CCS Absent	p-value^b
Age > 70 years old	265 (31–792)	118 (1–330)	0.001
Male sex	176 (15–637)	130 (8–561)	0.328
Hypertension	226 (29–727)	29 (0–166)	0.002
Diabetes mellitus	206 (26–673)	161 (5–589)	0.386
Hyperlipidemia	223 (25–628)	124 (5–658)	0.216
Smoking	172 (8–555)	162 (28–708)	0.846
Chronic kidney disease	313 (69–789)	79 (1–332)	< 0.001

Spearman’s rank order correlation coefficient.

Mann–Whitney U-test.

eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NGSP, National Glycohemoglobin Standardization Program; PTH, parathyroid hormone.

Age greater than 70 years (p = 0.001), hypertension (p < 0.002), and chronic kidney disease (p < 0.001) were associated with high CCS. Based on examination of atherosclerosis-related test data using Spearman’s rank correlation coefficient, the CCS as a continuous variable positively correlated with age (R = 0.314, p < 0.001), serum phosphate level (R = 0.158, p = 0.042), and serum creatinine level (R = 0.353, p < 0.001) and negatively correlated with urine creatinine level (R = −0.262, p = 0.001) and eGFR (R = −0.320, p < 0.001). Among patients with a history of vascular disease, peripheral artery disease was slightly (although not significantly) associated with a high CCS (p = 0.12) (Table 2).

Table 2.

Baseline comorbidities.

	High CCS (n = 110)	Low CCS (n = 84)	p-value^a
Medical history, n (%)
Ischemic cerebrovascular disease	48 (43.6)	38 (45.2)	0.88
Coronary artery disease	40 (36.4)	25 (30.0)	0.36
Peripheral artery disease	13 (11.8)	4 (4.8)	0.12
Any of the above	78 (70.9)	56 (66.7)	0.53

High carotid calcium score (CCS) was defined as ≥ 126, and low CCS was defined as < 126.

Fisher’s exact test.

Long-term outcomes

Table 3 shows the outcomes for the 167 (86.1%) patients who completed the 5-year follow up. Fifteen (7.7%) patients died, 11 (10.0%) and four (4.8%) in the high and low CCS groups, respectively; there was no significant difference in the mortality rate between the groups (p = 0.27). Three patients died of perioperative complications from the elective cardiovascular surgery soon after enrollment, which was not included in the cardiovascular event. Three patients in the high CCS group died of acute coronary syndrome compared with none in the low CCS group; this difference was not significant. One patient in the low CCS group died of ischemic stroke. Eight patients died of causes unrelated to vascular disease: malignancy (n = 3), pneumonia (n = 3), and unknown (n = 2). Twelve patients (6.2%) dropped out during the follow-up period.

Table 3.

Long-term outcomes.

	High CCS (n = 110)	Low CCS (n = 84)	p-value^a
Death, n (%)	11 (10.0)	4 (4.8)	0.27
Operative complication-related	3 (2.7)	0	0.26
Ischemic stroke-related	0	1 (1.2)	0.43
Acute coronary syndrome-related	3 (2.7)	0	0.26
Aorta and its major branch-related	0	0	1.0
Others^b	5 (4.5)	3 (3.6)	1.0
All (symptomatic) vascular events, n (%)	23 (20.9)	6 (7.1)	0.008
Ischemic cerebrovascular events, n (%)	10 (9.1)	5 (6.0)	0.59
Coronary events, n (%)	9 (8.2)	2 (2.4)	0.12
Aortic events, n (%)	0	0	1.0
Peripheral artery events, n (%)	5 (4.6)	0	0.071
Elective procedure for asymptomatic lesion, n (%)
Carotid stenting or carotid endarterectomy	0	0	1.0
Coronary artery stenting	2 (1.8)	2 (2.4)	1.0
Endovascular aortic repair	2 (1.8)	1 (1.2)	1.0
Lower-extremity revascularization	0	0	1.0

High carotid calcium score (CCS) was defined as ≥ 126, and low CCS was defined as < 126.

Fisher’s exact test

Death unrelated to vascular disease such as infectious disease, trauma, or malignancy.

The total number of symptomatic vascular events was significantly higher in the high CCS group (23 [20.9%]) than in the low CCS group (6 [7.1%], p = 0.008). Ischemic cerebrovascular events occurred in 10 (9.1%) patients in the high CCS group and five (6.0%) in the low CCS group. Coronary events occurred in nine (8.2%) and two (2.4%) patients in the high and low CCS groups, respectively. No symptomatic aortic events occurred in either group. Five (4.6%) patients in the high CCS group (but none in the low CCS group) experienced symptomatic peripheral artery disease. The elective procedures for asymptomatic lesions were as follows: coronary artery stenting (two in each group) and endovascular aortic repair (two in the high CCS group and one in the low CCS group).

In the Kaplan–Meier analysis, all vascular events were more frequent in the high CCS group than in the low CCS group (hazard ratio [HR]: 2.70, CI: 1.07–6.79, p = 0.022; Cox proportional hazards regression analysis) (Figure 3A). The percentage of ischemic cerebrovascular events was greater, although not significantly so, in the high CCS group (Figure 3B). In the Cox proportional hazards analysis, the cumulative incidence of symptomatic coronary events (HR: 4.29, CI: 0.87–21.1, p = 0.045) (Figure 3C) and peripheral vascular events (p = 0.032) (Figure 3D) was greater in the high CCS group than in the low CCS group. The HR and CI for the peripheral artery events could not be calculated because there were no peripheral artery events in the low CCS group.

Discussion

In the present study, the percentage of cumulative symptomatic vascular events was significantly greater in the high versus low CCS group during the 5-year follow-up. The cumulative incidence of symptomatic coronary events and peripheral artery events was also higher in the high CCS group. Previous studies have often used carotid echocardiography^14
–16 and carotid MRI^17
–19 to describe the relationship between carotid artery atherosclerosis and systemic vascular events and between carotid artery stenosis¹⁴ or carotid plaque vulnerability^17
–19 and stroke or another cardiovascular event. Other studies examined the association between carotid artery calcification and future cardiovascular events using carotid ultrasonography;^15,16 however, this procedure is subject to inter-evaluator variability and potential interpretative bias when classifying calcification as present or absent. The novelty of the current study is our use of objective carotid artery calcification scores (determined via noncontrast-enhanced carotid CT) to predict systemic vascular events. We believe that this method can be easily incorporated into routine preoperative examinations, even in local facilities without magnetic resonance imagers. Because the ACS is calculated using automatic measuring software, interrater variation is unlikely to occur.

The percentage of symptomatic peripheral vascular events (common iliac, external iliac, or femoral artery stenosis) in a major aortic branch was significantly greater in the high versus low CCS group (p = 0.032). The percentage of cumulative coronary events tended to be higher in the high CCS group (p = 0.045), perhaps owing to the close association of the CCS with the coronary calcification and aortic calcification. These results are supported by prior studies^2,20,21 showing that several common risk factors affect carotid and aortic calcification in healthy adults, particularly men.^21,22 Carotid calcification has been associated with a higher incidence of residual stenosis after stenting,²³ as well as a lower rate of restenosis after carotid endarterectomy.²⁴

Importantly, the results of the present study suggest that the CCS can be used to predict the occurrence of future vascular events. Notably, although the relationship between the CCS and stroke was not proportional, a high CCS may be a risk factor for coronary or peripheral artery disease. Previous studies investigating the association between carotid artery calcification and ischemic cerebrovascular disease have yielded mixed results, with some demonstrating a positive correlation^8,9 and others a negative correlation.¹⁰ This discrepancy may reflect the opposing effects of carotid artery calcification, namely induction of stenosis and plaque stabilization, and is not resolved by the findings of the current study. However, carotid artery calcification clearly correlates with calcification in the systemic arteries, including the coronary and peripheral arteries, and is considered a determinant of future vascular events. Coronary artery calcification has also been associated with subsequent coronary artery events,^3,5 as well as carotid stenosis and ischemic cerebrovascular events.^5,25
–27

In our study, older age, hypertension, and chronic kidney disease positively correlated with carotid artery calcification. In patients with hypertension or chronic kidney disease, bone matrix proteins are upregulated and α-smooth muscle actin is downregulated in the media via the renin-angiotensin and aldosterone pathways.^28,29Additionally, hypercalcemia and hyperphosphatemia have been reported to promote the progression of calcification in patients with chronic kidney disease.^30,31 In the present study, and in agreement with a previous report,³⁰ calcification correlated with higher intact parathyroid hormone levels, though not reaching statistical significance. Serum and urine creatinine levels, as well as the estimated glomerular filtration rate, directly reflect the stage of chronic kidney disease and have a strong association with carotid calcification.

Diabetes mellitus is a well-known risk factor for coronary artery calcification. The expression of bone matrix proteins in the medial layer of the arteries is increased in patients with diabetes mellitus,³² and hyperglycemia directly induces the transformation of vascular smooth muscle cells to an osteoblast-like phenotype.³³ However, in the present study, diabetes was not associated with carotid calcification (Table 1). The Rotterdam study suggested that the effect of diabetes on vascular calcification varies depending on the specific vascular bed. Although coronary calcification tends to be higher in all patients with diabetes, carotid artery calcification is apparently higher in women versus men.²¹ This difference may account for the lack of correlation between diabetes and carotid calcification in the present study, as the majority of patients were men.

The presence of calcified atherosclerosis in a given vascular bed moderately correlates with the presence of calcified atherosclerosis in other vascular beds, even in the early stages of vascular disease.² The present study shows that the severity of calcification among the systemic large arteries is very similar in patients with advanced vascular disease.

In a previous study, calcified atherosclerosis in the carotid artery and aorta was related to mortality, especially when due to noncoronary causes, whereas coronary calcification was mainly associated with deaths due to coronary causes.²⁰ In agreement, we found that the mortality rate tended to be higher in the high ACS group than in the low CCS group. Further studies are required to determine whether a high CCS is a risk factor for mortality in the advanced stages of atherosclerosis.

This study identifies the CCS as an indicator of systemic vascular calcification and a potential predictor of future systemic vascular events, even in patients with advanced atherosclerosis. To lower the risk of perioperative myocardial infarction, preoperative screening for coronary syndrome is important when planning carotid revascularization procedures.³⁴ Indeed, multidetector CT screening of the carotid artery (with or without contrast enhancement) is routinely performed before carotid revascularization to evaluate the operative risks, as well as the risks associated with the other vascular beds, including the coronary and peripheral arteries. The possibility of vascular disease in patients with high CCS should be investigated to prevent future events. Furthermore, carotid stenosis should be considered as a local manifestation of systemic atherosclerosis.

Limitations

The main limitation of this study was the small sample size. Most of the participants had multiple vascular risk factors and either underwent elective surgery or an intervention for carotid, coronary, or valvular heart disease. And only a subset of inpatients during the study period provided voluntary consent to participate in this research, and the possibility of some selection bias cannot be ruled out. Therefore, our results may not apply to populations (e.g., young populations) with a low risk of vascular events. Furthermore, the decreased risk of ischemic cerebrovascular and coronary events after surgical intervention may have mitigated the difference between the high and low CCS groups.

Conclusion

We identified the carotid calcium score (CCS) as a useful tool for predicting future systemic vascular events, including those related to coronary and peripheral artery disease.

Footnotes

Acknowledgements

Editing assistance was provided by Editage (editage.com).

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Koji Iihara reports lecture fees from Daiichi Sankyo Co. Ltd, and is a stockholder in Megwel.co.jp. The remaining authors have no conflicting interests.

Funding

This study was supported by the Intramural Research Fund (22-1-7) for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center.

ORCID iD

Noritaka Sano

Data availability statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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