High Spatial Inhomogeneity in the Intima-Media Thickness of the Common Carotid Artery is Associated with a Larger Degree of Stenosis in the Internal Carotid Artery: The PARISK Study

Abstract

Purpose Inhomogeneity of arterial wall thickness may be indicative of distal plaques. This study investigates the intra-subject association between relative spatial intima-media thickness (IMT) inhomogeneity of the common carotid artery (CCA) and the degree of stenosis of plaques in the internal carotid artery (ICA).

Materials and Methods We included 240 patients with a recent ischemic stroke or transient ischemic attack and mild-to-moderate stenosis in the ipsilateral ICA. IMT inhomogeneity was extracted from B-mode ultrasound recordings. The degree of ICA stenosis was assessed on CT angiography according to the European Carotid Surgery Trial method. Patients were divided into groups with a low (≤ 2 %) and a high (> 2 %) IMT inhomogeneity scaled with respect to the local end-diastolic diameter.

Results 182 patients had suitable CT and ultrasound measurements. Relative CCA-IMT inhomogeneity was similar for the symptomatic and asymptomatic side (difference: 0.02 %, p = 0.85). High relative IMT inhomogeneity was associated with a larger IMT (difference: 235 µm, p < 0.001) and larger degree of ICA stenosis (difference: 5 %, p = 0.023) which remained significant (p = 0.016) after adjustment for common risk factors.

Conclusion Regardless of common risk factors, high relative CCA-IMT inhomogeneity is associated with a greater degree of ICA stenosis and is therefore indicative of atherosclerotic disease. The predictive value of CCA-IMT inhomogeneity for plaque progression and recurrence of cerebrovascular symptoms will be determined in the follow-up phase of PARISK.

Zusammenfassung

Ziel Die Inhomogenität der arteriellen Wanddicke ist ein potentieller Indikator für distale Plaques. Diese Studie untersucht beim individuellen Patienten die Assoziation zwischen der relativen räumlichen Inhomogenität der Intima-Media-Dicke (IMT) der A.carotis communis (ACC) und dem Stenosegrad in der A.carotis interna (ACI) auf Grund von Plaquebildung.

Material und Methoden Es wurden 240 Patienten mit akutem Schlaganfall oder einer TIA und einer gering- bis mittelgradigen Stenose der ipsilateralen ACI eingeschlossen. Die IMT-Inhomogenität wurde aus B-Mode Ultraschallmessungen extrahiert. Der Stenosegrad in der ACI wurde mit Hilfe einer CT-Angiografie entsprechend der „European Carotid Surgery Trial“ Methode bestimmt. Die Patienten wurden in zwei Gruppen eingeteilt mit entweder niedriger (≤ 2 %) oder hoher (> 2 %) relativer IMT-Inhomogenität.

Ergebnisse Bei 182 Patienten lagen CT- und Ultraschall-Messungen in ausreichender Qualität vor. Die relative ACC-IMT-Inhomogenität war für die symptomatische und asymptomatische Seite vergleichbar groß (Differenz: 0,02 %, p = 0,85). Eine hohe relative Inhomogenität war mit einer dickeren IMT (Differenz: 235 µm, p < 0,001) und einem höheren Stenosegrad in der ACI assoziiert (Differenz: 5 %, p = 0,023), auch nach Ausschluss klassischer Risikofaktoren (p = 0,016).

Schlussfolgerung Eine hohe ACC-IMT-Inhomogenität ist unabhängig von klassischen vaskulären Risikofaktoren mit einem höheren ACI Stenosegrad assoziiert und daher ein Indikator für Atherosklerose. Der prädiktive Wert der ACC-IMT-Inhomogenität für Plaqueprogression und erneute zerebrovaskuläre Symptome wird in der Follow-up-Phase von PARISK bestimmt werden.

Key words

carotid arteries - ultrasound 2 D - arteriosclerosis - IMT inhomogeneity - stroke/TIA

Introduction

Atherosclerosis involves changes in structural and mechanical properties of an artery, specifically of the intima. An increase in the mean and maximal intima-media thickness (IMT) of the common carotid artery (CCA) is associated with the presence of an atherosclerotic plaque in the internal carotid artery (ICA) [1] [2] [3]. In addition, after adjustment for cardiovascular risk factors, such as age, smoking and diabetes mellitus, an enlarged maximal CCA-IMT is associated with an increased risk of myocardial infarction and stroke in a large population without stroke at enrollment [4] [5]. In a stroke population, an enlarged mean and maximal IMT is a predictor of recurrent stroke [6] [7]. In addition, the mean CCA-IMT may also be used to discriminate brain or lacunar infarction from intracerebral hemorrhage in stroke patients [8] [9]. Although the mean IMT is a significant predictor of prevalent cardiovascular disease on a population basis [10], including the mean IMT does not improve the traditional cardiovascular risk prediction models on an individual basis [11] [12] [13] [14]. Although IMT progression is more pronounced in patients with cardiovascular events [15], drug therapies inducing regression or slower progression of IMT do not improve clinical outcome, i. e., reduction in cardiovascular events [16].

As an alternative, one may consider the CCA-IMT irregularity. It increases with age and is significantly greater in patients with coronary artery disease (CAD) compared to patients without CAD [17]. Similarly, dialysis patients with cardiovascular disease (CVD) exhibit greater IMT irregularity than dialysis patients without CVD [18]. Furthermore, abnormal IMT irregularity is more often observed in subjects who recently had a stroke or transient ischemic attack (TIA) than in asymptomatic subjects [19].

The association between IMT and cardiovascular disease is only present in studies involving large patient groups. Moreover, IMT exhibits a wide distribution across gender, age and within the same age category [20]. IMT therefore cannot be used to predict the risk of (future) cardiovascular events for an individual patient. As an alternative, the intra-subject spatial IMT inhomogeneity, defined as the wall thickness irregularity along the vessel within a B-mode ultrasound image, might be a promising tool. In a mixed population of patients with cerebro- and cardiovascular disease, wall irregularity as deduced from duplicate B-mode recordings is associated with nearby atherosclerosis [21]. Alternatively, one may consider the spatial IMT inhomogeneity within a single ultrasound measurement [22], either in absolute terms or relative to the artery diameter. An irregular vessel wall, i. e., high inhomogeneity, may affect the wall stress distribution and local hemodynamics. Therefore, IMT inhomogeneity might provide information in addition to the IMT as extracted from the same recording.

The aim of the present study is to investigate whether spatial CCA-IMT inhomogeneity is related to plaque burden of the carotid bifurcation or ICA in patients with recent ischemic stroke or TIA. More specifically, we will 1) compare the relative CCA-IMT inhomogeneity between ipsilateral and contralateral arteries and 2) investigate the association between relative CCA-IMT inhomogeneity and degree of ICA stenosis. This study pertains to the baseline measurements of a 2-year follow-up study which will relate wall inhomogeneity and future/recurrent cerebrovascular events.

Methods

Study subjects

A total of 240 patients with a recent ischemic stroke, TIA or amaurosis fugax were recruited for the Plaque At RISK (PARISK) study (clinical trials.gov NCT01 208 025) [23]. This is an ongoing, prospective multicenter (MUMC, EMC, UMCU, AMC) observational cohort study which investigates (a combination of) noninvasive imaging techniques to improve the identification of patients at increased risk of recurrent stroke during a 2-year follow-up. Patients who had an ipsilateral mild-to-moderate carotid artery stenosis were included within three months after the clinical event. Details of the study protocol, including considered cardiovascular risk factors, have been previously described [23]. The study was approved by the medical ethics committees of all four participating centers. All patients gave written informed consent.

Data acquisition

Ultrasound examinations of the CCA were performed bilaterally on 233 patients with a Philips iU22 scanner (Philips Medical Systems, Bothell, USA) operating in B-mode at a frame rate of approximately 40 Hz using a 17 – 5 MHz, 12 – 5 MHz or 9 – 3 MHz probe, depending on the depth of the CCA. Two-dimensional recordings were acquired in duplicate from anterolateral and posterolateral angles (i. e., four CCA recordings per patient) for about five seconds, covering on average 5 heartbeats. In addition, blood pressure was measured from the brachial artery using a semi-automatic oscillometric device (Omron 705IT, OMRON Healthcare Europe B.V., Hoofddorp, Netherlands). Due to CT contraindications, only 201 patients had a multidetector CT angiogram (MDCTA) for further analysis of the degree of stenosis in the carotid bifurcation or ICA. The maximum degree of stenosis perpendicular to the central lumen line was manually scored according to the European Carotid Surgery Trial (ECST) criteria [24] by a trained observer using a Siemens workstation with dedicated 3 D analysis software.

Edge tracking

To extract wall thickness and diameter statistics, edge detection and tracking of B-mode images of the CCA (image width 4 cm) was performed by a trained observer blinded to the MDCTA results using dedicated software developed by Maastricht University Medical Centre (MUMC, Maastricht, The Netherlands) [25]. A clear section of the artery of the B-mode image was selected and divided into approximately 15 half-overlapping segments (width: 3.7 mm, 7 – 23 segments depending on section length). Media-adventitia edge detection was performed within a short window at a depth of 1.6 mm following the same procedure as previously described [25]. The edge threshold was set to 65 % of the maximal grey value of the local adventitia in the anterior and posterior position. To prevent erratic switching towards the lumen-intima transition in case of an echogenic intima boundary, wall detection was repeated with a threshold of 83 %. If a large difference (> 0.23 mm) between the threshold positions of 65 % and 83 % was observed, the edge position for the highest threshold (adventitia transition) was used. The local difference between the anterior and posterior media-adventitia transition provides an estimate for the instantaneous adventitia- adventitia local diameter. The above procedure was repeated for all subsequent frames. The resulting distribution of diameter waveforms was smoothed over time with a 2nd order Savitsky-Golay filter (filter span 0.2 s). The end-diastolic frames were identified from the mean diameter waveform after spatial averaging of the waveform distribution.

In those end-diastolic phases, the lumen-intima transition across the artery section was identified. Starting from the observed media-adventitia position ([Fig. 1]), the first local minimum of the first derivative was found for each segment within a 0.68 mm depth window. Starting from this minimum position, the local maxima of the first derivative were found using a sliding window with a width of 0.45 mm, which is approximately 2 times the depth resolution. A local maximum is identified if the same peak is observed twice within consecutive window positions (spaced at one depth resolution). The last maximum found is considered the lumen-intima transition, provided its value is not lower than 60 % of the first maximum after the minimum. The distribution of the lumen-intima transitions along the artery section was corrected interactively if necessary ([Fig. 1]).

Fig. 1 Example of edge detection of the lumen-intima transition for one segment (left) and of a CCA with irregular IMT (right). In the left image, the blue line indicates the echo signal for the posterior wall and the green line indicates its first derivative, scaled by a factor 5 for visibility. Starting from the media-adventitia edge position (black dot), the first minimum of the derivative is found which is followed by an iterative search for a local maximum. In the right image, the yellow line indicates the media-adventitia transition and the green line indicates the lumen-intima transition, which can be manually modified if necessary.

Statistical processing

The IMT was defined as the end-diastolic difference between the lumen-intima and media-adventitia transitions at the posterior wall. The median of the end-diastolic diameter, the distension (i. e., diameter change over the cardiac cycle), and the IMT over all segments were calculated. To correct for diameter-related variations [26] [27], the IMT was scaled relative to the local end-diastolic adventitia-adventitia diameter. The spatial standard deviation of the distension and relative IMT over all segments is considered as a measure for distension inhomogeneity and relative IMT inhomogeneity (intra-recording variation), e. g., a zero IMT inhomogeneity implies that the IMT has the same value everywhere. Intra-subject precision of all parameters was calculated by the standard deviation of differences, i. e., between duplicate recordings and their average, over all recordings and patients. All other parameters were averaged over all available beats and recordings. The degree of stenosis was averaged over the left and right ICA for each patient to obtain a global measure of atherosclerosis.

A paired t-test was used to compare the relative IMT inhomogeneity between the ipsilateral and contralateral arteries, before data was averaged over both common carotid arteries (CCAs) for each patient. The intra-subject precision and inter-subject values of wall characteristics of the four centers were compared with an F-test and ANOVA. Small random variations in IMT are expected due to the limitations imposed by the depth resolution of the ultrasound system used (300 µm), which converts to a maximum variation in IMT of 150 µm, i. e., a relative IMT inhomogeneity of 2 % for an 8 mm end-diastolic diameter. A Student t-test was used to assess the difference in CCA wall characteristics and the degree of ICA stenosis between patients with low and high relative IMT inhomogeneity, using the noise cut-off level of 2 %. Additionally, Pearson correlation and stepwise linear regression were used to further investigate the association between relative IMT inhomogeneity and the degree of ICA stenosis. To adjust for the effect of traditional risk factors, i. e., age, BMI, smoking, diabetes mellitus and hypertension on the association, those risk factors were included as confounders in the linear regression model. Values are quantified as mean ± standard variation (SD). The significance level was set at p < 0.05.

Results

In total, 194 patients underwent both MDCTA and US examination of both carotid arteries. 7 US examinations and 2 MDCTA registrations were unsuitable for further analysis due to technical recording failure (N = 5) or quality (N = 4). In addition, the degree of ICA stenosis could not be determined in 3 patients due to an occluded ICA or stent on the contralateral side. Therefore, 182 patients (mean age: 68 ± 9 years) were available for a complete data analysis. Baseline patient characteristics are shown in [Table 1]. Because the relative IMT inhomogeneity of the ipsilateral CCA was similar to that of the contralateral CCA (difference 0.02 %, paired t-test: p-value = 0.85), data were averaged over both CCAs of each patient.

Table 1 Patient characteristics.

n	182	–
age	68 ± 9	years
male	73	%
BMI	27 ± 4	kg/m2
diastolic blood pressure (during US)	79 ± 10	mmHg
systolic blood pressure (during US)	140 ± 19	mmHg
pulse pressure (during US)	61 ± 16	mmHg
classification event
stroke	46	%
TIA	43
amaurosis fugax	11
current smoking	23	%
diabetes mellitus[1]	20	%
hypercholesterolemia¹	56	%
hypertension¹	57	%

Data are presented as mean ± standard deviation.

¹ Definitions of diabetes mellitus, hypercholesterolemia or hypertension as previously described [21].

Wall characteristics across participating centers

The intra-subject precision of all wall characteristics ([Table 2]), except IMT, was larger for one center (EMC, F-test, p-value< = 0.03 compared to MUMC). The inter-subject values ([Table 2]) were not significantly different across the four centers (ANOVA: p-value = > 0.1, respectively), thus allowing pooling of data.

Table 2 Wall characteristics for the four centers.

		all	MUMC	EMC	UMCU	AMC	unit	p-value
n = 182	n	182	98	45	28	11	–	–
end-diastolic diameter	intra-subject precision	194	176	260	154	115	μm	–
	diameter	8012 ± 960	8063 ± 927	7860 ± 876	8145 ± 1038	7834 ± 1362	μm	0.51
distension	intra-subject precision	59	47	86	39	52	μm	–
	distension	440 ± 153	431 ± 154	481 ± 181	433 ± 97	369 ± 92	μm	0.11
distension inhomogeneity	intra-subject precision	27	25	32	23	26	μm	–
	inhomogeneity	98 ± 36	94 ± 37	104 ± 34	106 ± 36	83 ± 23	μm	0.12
IMT	intra-subject precision	99	97	99	106	91	μm	–
	IMT	1007 ± 202	1002 ± 228	1003 ± 164	1007 ± 168	1070 ± 171	μm	0.77
IMT inhomogeneity	intra-subject precision	54	47	70	45	57	μm	–
	inhomogeneity	136 ± 68	137 ± 74	136 ± 59	137 ± 75	126 ± 34	μm	0.96

Values are presented as mean ± standard deviation. Intra-subject precision is defined as the standard deviation of differences between all recordings and arteries. IMT: intima-media thickness; MUMC: Maastricht University Medical Center; EMC: Erasmus Medical Center; UMCU: University Medical Center Utrecht; AMC: Academic Medical Center.

IMT inhomogeneity

[Fig. 2] shows the relative CCA-IMT inhomogeneity as a function of the degree of ICA stenosis. Patients with high relative IMT inhomogeneity (> 2 %) are more often seen with a greater degree of stenosis, whereas patients with low relative inhomogeneity have a wide range of plaque sizes.

Fig. 2 Relative CCA-IMT inhomogeneity as a function of the degree of ICA stenosis. Patients with high relative inhomogeneity (> 2 %) have a larger degree of stenosis, whereas patients with low relative inhomogeneity have a wide range of plaque sizes.

[Table 3] shows the wall characteristics for low and high relative IMT inhomogeneity with a 2 % cut-off. The mean end-diastolic diameter and distension were similar for both groups (difference 54 µm and 12 µm, respectively, Student t-test: p-value > 0.6). The 40 patients (28 %) with a high relative IMT inhomogeneity exhibited a higher mean IMT (difference 235 µm, Student t-test: p-value < 0.001) and distension inhomogeneity (difference 16 µm, Student t-test: p-value = 0.01) compared to patients with a low relative IMT inhomogeneity. Moreover, a high relative IMT inhomogeneity in the CCA was associated with a larger degree of ICA stenosis (difference 5 %, Student t-test: p-value = 0.023). Furthermore, relative IMT inhomogeneity was significantly correlated with the degree of ICA stenosis (Pearson correlation: ρ = 0.21, p = 0.004). After adjustment for risk factors, i. e., age, BMI, smoking, diabetes mellitus and hypertension, only hypertension and relative IMT inhomogeneity remained independently associated with the degree of ICA stenosis (standardized β = 0.27, p < 0.001 and standardized β = 0.18, p = 0.016, respectively).

Table 3 Wall characteristics of the CCA and degree of ICA stenosis determined for patients with low and high relative IMT inhomogeneity (cut-off 2 %).

	IMT inhomogeneity/diastolic diameter		p-value
	≤ 2 %	> 2 %
n	142	40	–
age	67 ± 9	69 ± 8	0.18
diastolic diameter (µm)	8000 ± 1004	8054 ± 797	0.75
IMT (µm)	956 ± 132	1190 ± 285	< 0.001
IMT/diastolic diameter (%)	12 ± 2	15 ± 3	< 0.001
max. IMT (µm)	1335 ± 329	2028 ± 456	< 0.001
distension (µm)	437 ± 146	449 ± 176	0.66
distension/diastolic diameter (%)	5.5 ± 1.8	5.6 ± 2.0	0.79
distension inhomogeneity (µm)	94 ± 34	111 ± 38	0.01
distension inhomogeneity/diastolic diameter (%)	1.2 ± 0.4	1.4 ± 0.5	0.008
degree of distal stenosis (%)	47 ± 13	52 ± 11	0.023

Discussion

We evaluated the characteristics of the CCA wall in patients who recently experienced an ischemic stroke or TIA and had a mild-to-moderate plaque in the carotid artery bifurcation or ICA. Ipsilateral and contralateral arteries had a similar relative IMT inhomogeneity. A high (> 0.2 %) relative CCA-IMT inhomogeneity is associated with a larger mean IMT, higher distension inhomogeneity and a greater degree of ICA stenosis. The association between relative CCA-IMT inhomogeneity and degree of ICA stenosis remained significant after adjustment for common risk factors, i. e., age, BMI, smoking, diabetes mellitus and hypertension.

The intra-subject precision of all wall characteristics, except IMT, was greater for one participating center, i. e., the wall characteristics were less precisely determined. Due to a diverging CCA near the bifurcation and slightly different locations of the CCA scanning plane for duplicate recordings, spatial changes in wall characteristics can be expected. Despite differences in precision, inter-subject values were not significantly different across centers, so that data can be pooled. Multiple centers are necessary to provide a large sample size to ensure sufficient power for the follow-up phase. Similar values across centers imply that this method can be easily implemented in clinical practice.

The degree of stenosis was defined according to ECST criterion, i. e., lumen diameter divided by vessel diameter at the same location. In clinical practice, the degree of stenosis according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criterion [28] is commonly used for selecting patients with severe plaques for carotid endarterectomy. In the latter case, the lumen diameter at the site of the plaque is divided by the vessel diameter of the ICA just distally. Since the degree of stenosis according the NASCET criterion underestimates the actual burden of atherosclerosis [29], we decided to use the ECST criterion.

The mean IMT of our population (1007 ± 202 µm) is substantially greater compared to the IMT reference value (677 µm) of a 68-year-old healthy male [20]. Additionally, it was also greater than values reported for patients with cardiovascular disease (779 ± 196 µm) [30] and with plaques in the bifurcation (760 ± 180 µm) [21]. Moreover, the spatial IMT inhomogeneity (136 ± 68 µm) is also substantially higher than values reported for an elderly healthy population (50 µm male; 40 µm female) [31] and values reported for an elderly patient population (59 ± 49 µm) obtained with duplicate recordings [21]. All our patients had suffered from a recent cerebrovascular event associated with atherosclerosis, which explains the higher IMT and its inhomogeneity.

Since wall thickness is related to end-diastolic diameter [26] [27], we looked at relative IMT inhomogeneity. Patients with a mean end-diastolic diameter in the first quartile (25 %, < 7287 µm, N = 47) indeed had a significantly lower IMT and IMT inhomogeneity (mean difference IMT 193 µm and IMT inhomogeneity 47 µm, Student t-test, p-value ≤ = 0.005) than patients with a mean end-diastolic diameter in the fourth quartile (75 %, > 8646 µm, N = 38). Nonetheless, absolute IMT inhomogeneity showed a similar trend to that of relative IMT inhomogeneity, i. e., a higher IMT inhomogeneity is associated with a greater degree of distal stenosis.

In this study, a cut-off of 2 % is chosen for relative IMT inhomogeneity to account for the baseline random fluctuations due to US resolution. A low relative IMT inhomogeneity is therefore considered a normal stochastic variation. Further studies are needed to determine whether the selected cut-off is the optimal value.

Patients with a low relative IMT inhomogeneity exhibit a wide range of plaque sizes, as shown in [Fig. 2], without a direct relationship between relative IMT inhomogeneity and degree of ICA stenosis. On the other hand, a high relative inhomogeneity is associated with a larger degree of ICA stenosis and, hence, is indicative for atherosclerotic burden. However, most plaques with a high degree of ICA stenosis do not necessarily have a greater IMT inhomogeneity, which might be possibly explained by a different plaque composition.

Relative IMT inhomogeneity reflects an irregular vessel wall and will increase for a higher maximal IMT. Therefore, it remains unclear whether irregularity itself is a valuable parameter in addition to maximal CCA-IMT values, as already noted by Bots [32]. Nonetheless, the observed association between IMT inhomogeneity and degree of stenosis, which remained significant after adjustment for common risk factors, may indicate the clinical value of IMT inhomogeneity. Whether this is mainly driven by maximal IMT or irregularity itself is not important as long as its effect is stronger than the individual values. The follow-up phase of the PARISK study will consider the value of IMT inhomogeneity independent of maximal IMT values in relation to recurrent cerebrovascular events.

One of the limitations of the current study is that patients were included after a recent ischemic stroke or TIA, which may be years after the initial development of atherosclerotic plaques. The current cross-sectional study can only demonstrate an association between high relative IMT inhomogeneity and larger plaque size when plaques have already developed. Whether IMT inhomogeneity is also present prior to plaque development and whether IMT inhomogeneity can predict new plaque development is a topic for future longitudinal studies.

In conclusion, a high relative CCA-IMT inhomogeneity is associated with a greater degree of ICA stenosis, independent of common risk factors, and hence is indicative for atherosclerotic burden. In the follow-up of the PARISK study, we will analyze whether IMT inhomogeneity can predict plaque progression and/or the occurrence of a recurrence of cerebrovascular symptoms.

No conflict of interest has been declared by the author(s).

Acknowledgements

This research was performed within the framework of the Center for Translational Molecular Medicine (www.ctmm.nl), project PARISK (Plaque At RISK; grant 01C-202) and supported by the Dutch Heart Foundation.

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