The Association of Arterial Stiffness With Significant Carotid Atherosclerosis and Carotid Plaque Vulnerability

Abstract

Arterial stiffness and its valid index, the cardio-ankle vascular index (CAVI), have emerged as predictors of adverse cardiovascular outcomes. We investigated the relationship of the CAVI with significant carotid stenosis (> 50%) and the related cerebrovascular symptoms or carotid plaque echogenicity, assessed by ultrasound gray-scale median (GSM) score, at baseline and after carotid artery stenting (CAS). We prospectively enrolled 113 patients with carotid stenosis (70-99% for asymptomatic and > 50% for symptomatic participants) eligible for CAS. Age- and sex-matched individuals (n = 38) served as controls (CON). Clinical data, CAVI, and biochemical profile were obtained at baseline. Clinical assessment and CAVI measurement were performed 6 months after CAS. Compared with the CON group, the CAS group had a higher incidence of co-morbidities (diabetes, hypertension, and hyperlipidemia), higher CAVI values (9.94 ± 2.14 vs 7.85 ± .97 m/sec, P < .001), but a better lipid profile due to increased prescription of statins. The symptomatic CAS subgroup showed higher CAVI (P < .001), high-sensitivity C-reactive protein (P = .048), and osteoprotegerin (P = .002) levels than the asymptomatic one. In multivariate analysis, CAVI at baseline was independently associated with the presence of significant carotid atherosclerosis (β = .695, P < .001), cerebrovascular events (β = .474, P < .001), and GSM score (β = −.275, P = .042). Raised CAVI values were independently associated with significant carotid stenosis and plaque vulnerability.

Keywords

arterial stiffness cardio-ankle vascular index carotid atherosclerosis carotid plaque vulnerability carotid artery stenting

Introduction

Arterial stiffness and its widely used index—pulse wave velocity (PWV), are markers of vascular function and good predictors of adverse cardiovascular outcomes.^1,2 PWV may detect subclinical coronary atherosclerosis in patients at high cardiovascular risk,³ or reflect the atherosclerosis burden in patients with established coronary artery disease (CAD).⁴ Regarding carotid atherosclerosis, Joo et al⁵ recently reported the relationship of PWV with the presence of a composite of coronary and carotid atherosclerosis. As a screening test, PWV has also been proposed as a prognostic factor of silent cerebral ischemic lesions in asymptomatic individuals with carotid plaques.⁶ A pilot study implied that local pulse wave imaging of carotid plaques may differentiate their composition, which is of clinical relevance.⁷ In patients undergoing surgical or endovascular carotid revascularization, it remains controversial whether PWV may predict the incidence of cerebral ischemic events.^8,9 Overall, a high PWV has the potential to detect patients with carotid atherosclerosis and estimate the risk of symptom development, but more robust evidence is required.

One of the drawbacks of PWV is its dependence on arterial blood pressure (BP). Therefore, any changes in BP, at the time of measuring, may confound the changes in arterial stiffness.¹⁰ To overcome this disadvantage, an index, the cardio-ankle vascular index (CAVI), independent of BP has been developed.¹¹ This reflects the arterial stiffness from the origin of the aorta to the ankle arteries.¹² CAVI results have been associated with the development of mild, preclinical, carotid atherosclerosis, especially in high-risk patients, such as those with diabetes.^13,14 Nevertheless, there are no data regarding the prognostic value of CAVI in patients with established, carotid atherosclerosis.

Our initial hypothesis was that CAVI is associated with the presence of at least significant carotid atherosclerotic stenosis (≥ 50%) requiring revascularization. We also hypothesized that CAVI can be a predictor of carotid plaque vulnerability indicated by cerebrovascular events (neurological symptoms or ipsilateral ischemic lesions on brain imaging) or reduced carotid plaque echogenicity. Finally, we explored the impact of carotid artery stenting (CAS) on CAVI values.

Methods

Eligible Patients and Study Groups

In the present prospective, observational study, we initially recruited 124 consecutive patients with established carotid atherosclerosis causing significant stenosis (≥ 50%) of the unilateral or bilateral internal carotid arteries, with indications for CAS.¹⁵ The study lasted from February 2012 to March 2015. All patients were evaluated by experienced neurologists and underwent at baseline anthropometrical/clinical assessment, carotid ultrasound, blood analyses, brain computed tomography (CT) scan, and/or brain magnetic resonance imaging (MRI), when CT findings were questionable. General exclusion criteria were cerebral hemorrhage; significant peripheral arterial disease (ankle-brachial index—ABI < .9); atrial fibrillation; severe liver (AST ≥ 3 times the upper normal limit) or renal impairment (creatinine ≥ 2 mg/dl); heart failure (New York Heart Association (NYHA) classification stage II-IV); concurrent conditions/diseases interfering with the expression of inflammatory mediators, like major trauma, surgery, and cardiovascular ischemic events within the previous month; malignancies; chronic inflammatory or autoimmune diseases, as well as acute infection at study entrance. Finally, 121 patients undergoing CAS were considered eligible for the study. At baseline, those patients were divided into the following subgroups for a dedicated post-intervention follow-up for 6 months:

A1) Symptomatic significant carotid artery stenosis ≥ 50% (n = 38). Those patients appeared within the last 6 months with neurological symptoms and/or brain scan findings, indicating ipsilateral to the carotid stenosis transient ischemic attack (TIA) (n = 14), stroke (n = 22), or amaurosis fugax (n = 2).

A2) Asymptomatic severe carotid artery stenosis 70-99% (n = 83). Those patients were free from any neurological symptoms and the brain scan did not detect any ischemic lesions.

Thirty-eight age- and sex-matched individuals served as controls (CON group) and were only assessed at baseline. Those subjects had visited our hospital for a regular health check-up. They had no evidence of overt cardiovascular disease; their carotid and lower limbs arteries were free from atherosclerotic plaques based on vascular ultrasound; and they had, within the last year, a functional test negative for myocardial ischemia.

Written informed consent from each participant was obtained before enrollment, and all procedures were performed according to the principles of Helsinki Declaration and were approved by the hospital human ethics committee.

Clinical Data Collection

To obtain a clinical profile, all medications were recorded and co-morbidities were defined as follows: hypertension, BP ≥ 140/90 mmHg measured on repeated occasions or receipt of anti-hypertensive drugs; hyperlipidemia, fasting serum low-density lipoprotein cholesterol (LDL-C) ≥ 160 mg/dl or statin therapy; active smokers, current or within the previous 6 months; diabetes mellitus, fasting plasma glucose (FPG) ≥ 126 mg/dl, or HbA1c ≥ 6%, or antidiabetic drugs; coronary artery disease (CAD), history of stable or unstable angina, myocardial infarction, percutaneous or surgical myocardial revascularization. The following clinical data were obtained at the entrance and at the end of the study and included CAVI (Vasera VS-1500, Fukuda Denshi, Tokyo, Japan), body mass index (BMI), BP, and ABI.

Carotid Ultrasound Examination

Two experienced operators performed all carotid ultrasound examinations at baseline (whole study cohort) and at the end of follow-up (CAS group). Following a previously validated protocol, we measured the peak systolic velocity (PSV) and internal carotid artery (ICA)/common carotid artery (CCA), PSV ratio in all patients, and thereafter, we graded the percentage of arterial stenosis.^16,17 The process of morphological and textural feature evaluation of the plaques has already been described by our group.¹⁸ The gray-scale median (GSM) score is a quantified index of carotid plaque echogenicity, which has been inversely associated with carotid plaque vulnerability.¹⁹ In the present study, we averaged GSM scores from all carotid plaques in asymptomatic patients, while in symptomatic patients, the GSM score of the culprit lesion, ipsilateral to brain infarct, was reported.²⁰ GSM calculation has been extensively used in our laboratory and has been validated.

Blood Assays

For all patients, blood samples were obtained at baseline after an overnight fast, between 8.00 and 10.00 am. FPG and lipid parameters were all measured in an automatic enzymatic analyzer (Olympus AU560, Hamburg, Germany). Using a commercially available enzyme immunoassay kit, we assayed serum concentrations of osteoprotegerin (OPG) (Metra, San Diego, USA). The intra- and inter-assay coefficients of variance were 7% and 6.8%, respectively. High-sensitivity C-reactive protein (hsCRP) was assayed using an immunoturbidimetric assay (Hitachi 917 analyzer, Boehringer Mannheim, Germany). All samples were stored at −80⁰C until analysis, blinded to any clinical information.

Statistical Analysis

Results of normally distributed continuous variables were expressed as the mean ± SD. Normality of distribution was assessed with the Kolmogorov-Smirnov test. Comparisons of continuous and categorical variables were analyzed with the student’s t-test and chi-square test, respectively. To test the univariate and multivariate associations of CAVI with any of the study population characteristics, we performed a Pearson correlation and multiple linear regression analysis for normally distributed variables and adjusted for age and sex. A two-tailed P < .05 was considered to be significant. The computer software package SPSS (version 25.0; SPSS Inc, Chicago, IL, USA) was used for statistical analysis.

Results

Among the 121 patients with significant carotid atherosclerosis, 113 completed the study. During follow-up, 2 patients died for reasons unrelated to carotid stenosis (chest infection and myocardial infarction), and 6 patients were lost in follow-up. Clinical and biochemical characteristics of both groups at baseline are shown in Table 1. Importantly, the presence of co-morbidities (diabetes, hyperlipidemia, and hypertension) and the usage of statins and anti-hypertensive medications were higher in the CAS vs CON group (P < .05). As expected, patients with significant carotid atherosclerosis showed significantly higher hsCRP and white blood cell count than the control subjects (P < .05). The better lipid profile in the CAS group was attributed to the significantly higher prescription rate of statins. Most importantly, the CAS group exhibited higher CAVI values compared with controls (P < .001), while the difference in osteoprotegerin serum levels was marginally non-significant between groups (P = .055).

Table 1.

Baseline clinical, biochemical and hemodynamic characteristics of the carotid artery stenting (CAS) and control (CON) groups.

	CAS Group (n = 113)	CON Group (n = 38)	p
Age, years	70 ± 9	66 ± 10	.243
Males/females	76/37	26/12	.894
CAD	44 (39%)	0 (0%)	—
Diabetes	38 (33.6%)	4 (10.5%)	.041
Smoking	25 (22.1%)	10 (26.3%)	.108
Statins	109 (96.5%)	10 (26.3%)	<.001
Anti-hypertensive medications	104 (91.2%)	14 (36.8%)	<.001
BMI, kg/m²	29.3 ± 5.8	27.9 ± 3.8	.123
SBP, mmHg	133 ± 17	129 ± 22	.723
DBP, mmHg	81 ± 10	81 ± 9	.965
FPG, mg/dl	107 ± 49	91 ± 22	<.001
hsCRP (mg/L)	3.9 ± 1.5	2.1 ± 0.8	<.001
WBC, cells/μL	9222 ± 2331	7850 ± 2001	.044
TC, mg/dl	169 ± 39	189 ± 46	.155
HDL-C, mg/dl	44 ± 9	49 ± 11	.031
LDL-C, mg/dl	93 ± 31	120 ± 22	.045
TG, mg/dl	121 ± 54	101 ± 31	.067
CAVI, m/s	9.94 ± 2.14	7.85 ± .97	<.001
Osteoprotegerin, pmol/L	8.88 ± 2.74	6.72 ± 2.88	.055
GSM	85 ± 27	—	—

Data are expressed as mean ± SD or number of participants and (%).

CAD, coronary artery disease; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; BP, blood pressure; hsCRP, high-sensitivity C-reactive protein; WBC, white blood cells count; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; CAVI, cardio-ankle vascular index; GSM, gray-scale median.

Within the CAS group, we further compared the symptomatic (n = 35) and asymptomatic subgroups (n = 78) (Table 2). As expected, carotid plaque echogenicity, described by the GSM score, was found lower in the former subgroup (P < .001). Moreover, hsCRP, osteoprotegerin, and CAVI levels were higher in the symptomatic subgroup than the asymptomatic one (P < .01). No significant differences were found in the remaining variables between those subgroups (P > .05).

Table 2.

Comparison between symptomatic and asymptomatic patients with significant carotid stenosis undergoing carotid artery stenting (CAS).

	Symptomatic patients (n = 35)	Asymptomatic patients (n = 78)	p
Age, years	69 ± 11	71 ± 8	.406
Gender, males/females	23/12	51/29	.778
CAD	17 (48.6%)	27 (34.6%)	.235
Diabetes	14 (40%)	24 (30.8%)	.590
Smoking	6 (17.1%)	19 (24.4%)	.312
Statins	34 (97.1%)	75 (96.2%)	.954
Anti-hypertensive medications	33 (94.3%)	71 (91%)	.901
BMI, kg/m²	30.12 ± 5.79	29.01 ± 3.8	.389
SBP, mmHg	137 ± 15	131 ± 20	.598
DBP, mmHg	81 ± 11	81 ± 8	.978
FPG, mg/dl	98 ± 44	112 ± 52	.511
hsCRP (mg/L)	4.67 ± 1.90	3.64 ± 1.34	.048
WBC, cells/μL	9551 ± 1995	9074 ± 2613	.289
TC, mg/dl	167 ± 44	163 ± 38	.840
HDL-C, mg/dl	47 ± 10	49 ± 9	.622
LDL-C, mg/dl	90 ± 33	88 ± 32	.942
TG, mg/dl	128 ± 49	117 ± 57	.653
CAVI, m/s	11.40 ± 2.05	9.39 ± 1.99	<.001
Osteoprotegerin, pmol/L	10.88 ± 3.31	7.98 ± 2.22	.002
GSM	55 ± 18	98 ± 31	<.001

Data are expressed as mean ± SD or number of participants and (%).

CAD, coronary artery disease; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; hsCRP, high-sensitivity C-reactive protein; WBC, white blood cell count; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; CAVI, cardio-ankle vascular index; GSM, gray-scale median.

All patients with significant carotid stenosis underwent CAS. During or post-procedure, 4 patients experienced cerebrovascular events: 3 patients had TIAs, and 1 patient had an ischemic stroke. No other adverse events were reported. At the end of follow-up period, we repeated clinical evaluation in the remaining patients. No significant changes in CAVI values (from 9.94 ± 2.14 to 9.65 ± 2.55, P = .704), pharmaceutical regimens, and in the rest of clinical parameters (BMI, BP, and ABI) was observed compared with baseline measurements (data not shown).

At baseline, we first examined in the whole study cohort the unadjusted correlations of CAVI with all parameters. CAVI was positively correlated with age (r = .181, P = .026), osteoprotegerin (r = .365, P < .001), presence of significant carotid atherosclerosis (asymptomatic 70-99%, symptomatic > 50%, r = .774, P < .001), and cerebrovascular events (neurological symptoms or ischemic lesions ipsilateral to carotid stenosis in brain scans) (r = .377, P < .001) and negatively correlated with statins use (r = −.255, P < .001) and GSM score (r = −.291, P = .009). Multivariate analysis after adjustment for age and gender showed that CAVI was independently associated with the presence of significant carotid atherosclerosis (β = .695, P < .001), cerebrovascular events (β = .474, P < .001), and GSM score (β = −.275, P = .042).

Discussion

In the present study, we demonstrated elevated values of CAVI, a valid index of arterial stiffness, in patients with significant carotid atherosclerosis requiring revascularization compared with atherosclerosis-free control subjects. Furthermore, CAVI showed a positive, independent association with both the presence of significant carotid atherosclerosis and carotid plaque vulnerability (based on symptom, brain scan, and/or ultrasound evidence) in the whole cohort. Undergoing CAS did not significantly alter CAVI after 6 months.

It has been previously mentioned that arterial stiffness markers, such as brachial-ankle PWV (baPWV) or CAVI, are associated with preclinical carotid atherosclerosis, reflected by carotid intima-media thickness (cIMT).^21-23 Τwo small studies have demonstrated significantly higher PWV (baPWV or carotid-femoral PWV—cfPWV) in patients with established carotid atherosclerosis.^24,25 Compared with previous data, our study tested for first time the usage of CAVI, as an index of PWV, in a population with significant carotid atherosclerotic stenosis requiring revascularization. The significantly higher CAVI values in those patients than controls are of clinical importance, indicating a high cardiovascular risk. CAVI has the advantage of being independent of BP changes compared with other indices of PWV, using sensors at brachial, carotid, and femoral arteries.²⁶ The independent association of CAVI with the presence of significant carotid stenosis provides another potential screening tool to detect among the general population of patients with advanced cardiovascular disease, who require further thorough investigation. This concept should be further evaluated.

Arterial stiffness has emerged, in conjunction with other atherosclerotic risk factors, as an important cardiovascular prognostic factor in healthy individuals or patients with metabolic syndrome.^27,28 Accumulated data have documented the predictive role of PWV for cerebral ischemic events, silent or not, related to carotid atherosclerosis.⁶ Novel evidence supports the prognostic power of arterial stiffness in the post-stroke period as well.^29,30 In this context, our symptomatic patients undergoing CAS appeared with higher CAVI than their asymptomatic counterparts. Moreover, this is the first study, to our knowledge, demonstrating a positive, independent association of arterial stiffness with carotid plaque vulnerability as indicated by clinical or brain imaging evidence of past cerebrovascular event or low GSM levels, in patients with significant carotid stenosis. We cannot imply a direct pathophysiological mechanism between them. Hence, we hypothesized that high CAVI levels do not indicate the existence of vulnerable plaques, but they reflect a high-risk profile of a “vulnerable patient.” Such a patient, with past cerebrovascular event, or at high risk for it, clusters risk factors which mediate carotid plaque destabilization. Similarly, increased arterial stiffness has been found in patients with previous cardiac events due to coronary plaque destabilization, depicting a group with higher morbidity and mortality rate.^31,32 Presumably, CAVI may aid risk stratification of patients with carotid atherosclerosis, who are likely to benefit from prompt and intensive therapy. Our hypothesis requires further verification.

As expected in our study, the CAS group showed higher concentrations of pro-inflammatory markers at baseline, while osteoprotegerin was marginally elevated compared with controls. Those differences might have been attenuated by the pre-operative control of risk factors (hypertension, hyperlipidemia, and diabetes) in our CAS group. For example, we ascribed the better lipid profile and the non-significant difference in osteoprotegerin levels between groups, to the high prescription rate of statins in our atherosclerotic patients.¹⁹ Osteoprotegerin is a vascular calcification inhibitor,³³ whose concentration is suppressed by statins.^17,18 The extensive use of statins may also explain the lack of relationship between osteoprotegerin and arterial stiffness in our CAS cohort.³⁴ In contrast, we observed a significant elevation of osteoprotegerin in symptomatic than asymptomatic subgroup, where statin prescription was comparable. Although the impact of statins on CAVI values is still questionable,³⁵ we presumed that the observed differences in inflammatory burden and arterial stiffness might have been larger between statin-free patients and controls.

There is a single study investigating the impact of carotid revascularization (carotid endarterectomy) on PWV in a short-term (6 weeks) period.⁸ Although carotid revascularization may reduce peripheral arterial stiffness, it does not directly change systemic aortic stiffness. In agreement with that study, we did not observe any significant change in systemic arterial stiffness at 6 months after CAS. We have previously reported the contribution of large thoracic and abdominal aorta to systemic arterial stiffness in patients undergoing endograft implementation with either thoracic aortic aneurysm³⁶ or abdominal aortic aneurysm.³⁷ In contrast, revascularization of the short-length carotids may reduce the related morbidity and mortality, but this is not explained by arterial stiffness changes. Only sustained modification of atherosclerotic risk factors (e.g., hypertension and hyperlipidemia) is capable of altering PWV.²⁶ Recently, an observational study demonstrated the positive association of baPWV with silent cerebral embolism after CAS.⁹ However, the small sample size and the low accuracy of baPWV might have biased those results.

We tried to establish the peri-interventional prognostic value of PWV. However, our study was underpowered due to the small sample and the low number of peri-CAS cerebrovascular events (< 3%). Hence, the present data do not support PWV changes in patients undergoing carotid revascularization, while CAVI seems not yet powered to predict the intervention-related complications.

The major limitation of the present study was the small sample size. The number of both patients and control participants was relatively small to allow detecting any relationship of CAVI with clinical endpoints. So, larger studies are needed to support CAVI as a screening test to discriminate carotid atherosclerosis severity and vulnerability. One of the CAVI usage limitations is the assumption that vascular diameter, blood pressure, and the elasticity from the aortic valve to the ankle are constant, which is not always the case. Strength of our study was the optimum medical therapy pre-operatively. However, this might have alleviated the long-term adverse impact of atherosclerotic risk factors on arterial stiffness and the stability of carotid atherosclerosis. Finally, we considered only symptoms to assess CAS-related complications. Presumably, a new brain scan after CAS might have detected more cerebral embolisms,³⁸ shedding light on the prognostic value of CAVI.

In conclusion, the present findings indicate that CAVI is independently associated with the presence of significant carotid atherosclerosis and carotid plaque vulnerability. Our study thus provides evidence of the utility of the CAVI as a new screening option in patients at high cardiovascular risk, but this requires further investigation.

Footnotes

Author contributions

All authors contributed to (1) substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Co-funded by the Operational Program “Competitiveness and Entrepreneurship” and Regional Operational Programmes of the National Strategic Reference Framework (NSRF) 2007-2013. “SYNERGASIA”: “Collaborative projects of small and medium scale”.

ORCID iD

Konstantinos G. Moulakakis

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