Elsevier

Atherosclerosis

Volume 230, Issue 2, October 2013, Pages 399-405
Atherosclerosis

The utility of ultrasonic tissue characterization of carotid plaque in the prediction of cardiovascular events in diabetic patients

https://doi.org/10.1016/j.atherosclerosis.2013.08.015Get rights and content

Highlights

  • Cardiovascular disease (CVD) is the main cause of death in diabetic patients.

  • We examine the association between the carotid plaque echogenicity and the CVD risk.

  • The risk of CVD is higher in diabetic subjects with echolucent carotid plaques.

  • The presence of echolucent carotid plaques is an independent risk factor for CVD.

  • The evaluation of carotid plaque echogenicity improves the risk prediction of CVD.

Abstract

Objective

The aim of this study was to evaluate whether non-invasive ultrasonic tissue characterization of carotid plaque using gray-scale median (GSM) can be a predictor of future cardiovascular disease (CVD) events in type 2 diabetic patients.

Methods

A total of 287 type 2 diabetic patients with carotid plaque but without CVD were enrolled (male 72%, mean age 65 ± 7 years). We prospectively evaluated the association between GSM, a quantitative parameter of the plaque echogenicity, and CVD.

Results

The median follow-up period was 55 months, and there were 34 new CVD events. The risk of CVD event was significantly higher in the patients with echolucent (GSM ≤ 37) plaque (n = 67) as compared to those without (n = 220) (HR = 6.99, 95% CI 3.46–14.14, p < 0.001). Cox proportional hazards regression analysis showed that the presence of echolucent plaque (HR = 4.55, 95% CI 2.10–19.84, p < 0.001) as well as plaque thickness (HR = 1.44, 95% CI 1.01–2.06, p = 0.005) were independent predictors of CVD, even after adjustment for other risk factors. Time-dependent receiver-operating-characteristic curve analysis revealed that the addition of plaque thickness to Framingham risk score (FRS) resulted in significant increase in area under the curve (AUC) [from 0.60 (95% CI; 0.49–0.70) to 0.73 (95% CI; 0.63–0.82), p < 0.05]. Notably, the addition of plaque echogenicity (presence/absence of echolucent plaque) to the FRS and plaque thickness resulted in further and significant increase in AUC [from 0.73 (95% CI; 0.63–0.82) to 0.82 (95% CI; 0.75–0.88), p < 0.05].

Conclusion

Ultrasonic tissue characterization of carotid plaque using the GSM can improve the risk prediction of cardiovascular event in asymptomatic type 2 diabetic patients with carotid plaque.

Introduction

Since cardiovascular disease (CVD) remains the main cause of death and impairment of quality of life in diabetic patients, early identification of individuals at high risk for CVD events and subsequent rapid interventions are important. Recently, ultrasound examination of the carotid artery has been in use to non-invasively identify individuals at high risk for CVD. Some studies have shown that the presence/absence of carotid plaque assessed by ultrasound could improve the prediction ability for CVD over and above conventional coronary risk factors [1], [2], [3], [4], [5].

It is well known that disruption of an atherosclerotic plaque plays a crucial role in the pathogenesis of CVD event and that plaque disruption is dependent on the content of lipid, neovascular vessel, and inflammatory cells in the atheroma, and the thickness of the fibrous cap [6], [7], [8], [9]. Therefore, tissue characterization of a plaque lesion is considered to be useful for identifying patients at high risk for CVD and death. Presently, various modalities such as Computed Tomography (CT), Magnetic Resonance Imaging (MRI), or Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) are being used to detect vulnerable plaque in coronary and carotid arteries [10], [11], [12]. However, it is unrealistic to screen all the asymptomatic patients for individuals at high risk for CVD with these tools, since these tests are limited by the potential of significant adverse effects, technical difficulty, availability, and cost.

Carotid arteries as well as the aorta develop foam cell lesions and lipid core plaque at an early age [13]. Interestingly, a recent study reported that the prevalence of lipid-rich plaques in carotid arteries was higher in coronary death than in non-coronary death [14]. Another study using carotid endarterectomy specimens also reported that a soft carotid plaque with a large necrotic core and a marked inflammatory component may be predictive of an increased risk of cerebrovascular events [15]. These findings indicate that the individuals who have vulnerable plaques in their carotid arteries are prone to also have vulnerable plaques in their coronary and/or cerebral arteries, which will lead to CVD events, and thus, the assessment of tissue characteristics of carotid plaques will help to identify the patients with a high risk for CVD event. Indeed, based on a prospective study in 85 asymptomatic type 2 diabetic patients, we have already shown that a quantitative ultrasonic tissue characterization of carotid plaque using integrated backscatter (IBS) analysis can be a predictor of future CVD event [16]. However, the measurement of IBS values requires a specific software package, “Acoustic Densitometry,” installed in a SONOS echocardiograph system (Philips Medical Systems), which would limit the widespread use of this approach. In a qualitative evaluation using conventional B-mode ultrasound imaging performed by experienced sonographers, vulnerable plaques, which consist mainly of neovascular vessel, high lipid content, and inflammatory infiltration [8], [9], are believed to appear “hypoechoic.” On the other hand, stable plaques, which consist mainly of fibrous tissue and calcific components, appear “hyperechoic” [17]. Recently, echogenicity of carotid plaques has become semi-quantitatively evaluable with high-resolution B-mode ultrasound and computer-assisted image processing: the gray-scale median (GSM) of the frequency distribution of gray values of the pixels within the plaque serves as a measure of echogenicity. Since the evaluation of GSM values in carotid plaques requires neither specific software nor a specific ultrasonograph, it can be a more universal and practical approach as compared with IBS analysis.

Based on the background described above, the current study prospectively evaluated whether non-invasive and inexpensive ultrasonic tissue characterization of carotid plaque using GSM can improve the risk prediction of CVD event in asymptomatic type 2 diabetic patients with carotid plaque.

Section snippets

Subjects

Middle-aged and older Japanese type 2 diabetic patients with carotid plaque but without apparent CVD participated in this study. Patients who fulfilled the following criteria were considered eligible: (1) age ≥ 40 years at the time of enrollment, and (2) diagnosed with type 2 diabetes based on the criteria of the Japan Diabetes Society. Exclusion criteria were (1) history of ischemic stroke, coronary heart disease, or peripheral artery disease; (2) elevated liver enzymes (GOT or GPT ≥ 2.5 times

Patient characteristics

The baseline characteristics of the study population are shown in Table 1. Among a total of 287 patients (males, 72%; age, 65 ± 7 years (mean ± SD); diabetes duration, 13 ± 9 years; HbA1c, 7.5 ± 1.1%.), 236 (82%) patients had hypertension and 215 (75%) had dyslipidemia.

During a median follow-up of 55 months, 34 of the 287 patients (12%) had new CVD events: 11 had ischemic stroke, 21 had coronary heart disease, and 2 had peripheral artery disease (Supplementary Table 1). During the observation

Discussion

Atherosclerotic changes such as intima-media thickness (IMT) and plaque formation in carotid artery, markers of early atherosclerosis and vascular remodeling that can be assessed quickly, non-invasively, and economically with high-resolution ultrasound, are correlated with conventional coronary risk factors and regarded as surrogates of CVD. Indeed, previous studies showed that carotid IMT was an independent predictor of CVD in asymptomatic patients [1], [24], [25], [26]. However, previous

Author contributions

Y.I., N.K., M.T. and H.K. researched data and wrote the manuscript. M.N., R.K., K.S., Y.Um., and S.S. researched the data. Y.Ue., K.K, and I.S. contributed to the interpretation of the results and the discussion. All authors reviewed and approved the report. N.K. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.

Funding sources

The Diabetes Masters Conference supported by the Japan Diabetes Foundation and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports, Culture and Technology [KAKENHI 25461349].

Conflict of interest disclosures

None.

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