Association between multi-site atherosclerotic plaques and systemic arteriosclerosis: results from the BEST study (Beijing Vascular Disease Patients Evaluation Study)

The rationale and design of the BEST study (Beijing Vascular Disease Patients Evaluation Study, Clinical Trials.gov Identifier: NCT02569268) have been described before [7]. Briefly, The BEST was a prospective cohort study of measuring all vascular parameters in patients with various related cardiovascular disease (CVD), including coronary artery disease (CAD), stroke, peripheral artery disease (PAD), hypertension, diabetes mellitus, dyslipidemia, as well as apparently healthy participants, and were consecutively recruited since 2010 from the vascular medicine center of Peking University Shougang Hospital in Beijing, China.

The present study was part of the BEST study and was aimed at systematic vascular evaluation, e.g. vascular ultrasound, arterial stiffness and blood examination. Subjects were enrolled if they were: (i) ≥18 years old; (ii) male or female; (iii) had a written informed consent. Exclusion criteria included: (i) deep venous thrombosis of lower extremities; (ii) known alcohol abuse; (iii) severe active liver and kidney disease; (iv) severe heart failure; (v) acute pulmonary embolism; (vi) abdominal aortic aneurysm.

The BEST study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ethics committee of Peking University Shougang Hospital (the updated Ethics number IRBK-2017-017-01). Before enrollment, all study participants provided written informed consent.

The history of cardiovascular disease (CAD, Stroke, PAD, hypertension, diabetes, dyslipidemia), drugs (CVD drugs, hypoglycemic drugs, lipid-lowering drugs) and lifestyle (smoke and alcohol) were obtained by medical records. CVD drugs included angiotensin converting enzyme inhibitors (ACEI), Angiotensin Receptor Blocker (ARB), β-receptor blocker, calcium channel blockers and diuretics.

Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were obtained by CF-PWV equipment. Body mass index was calculated as weight (kg) / height (m)². Blood biochemical examination, including fasting blood glucose (FPG), total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), homocysteine (HCY), uric acid (UA), blood urea nitrogen (BUN) and creatinine (CR) was carried out by the clinical lab.

The 2-dimensional vascular ultrasound (EUB 7500, Hitachi, Japan) were conducted by a linear array probe. The presence of atherosclerotic plaques was assessed through cross-sectional and longitudinal sweep of the right and left carotids and subclavian artery, the abdominal aorta, and the right and left lower extremities arteries. Plaque was defined as a focal protrusion into the arterial lumen of thickness ≥ 0.5 mm or ≥ 50% of the surrounding intima-media thickness or a diffuse thickness ≥ 1.5 mm measured between the media-adventitia and intima-lumen interfaces recommended by Manheim consensus [8]. The multi-site atherosclerotic plaques was defined according to the number of vascular sites affected (right or left carotid or subclavian artery = 1, abdominal aorta = 1, left or right lower extremities arteries = 1) (see Fig. 3a to d). Participants were grouped as 0 or 1 site affected (control group) and multi-site affected (multi-site atherosclerotic plaques group, 2 or 3 sites affected). Figure 1a-d showed the presence of plaque in carotid artery, subclavian artery, femoral artery and abdominal aorta.

CF-PWV was measured by an automated vascular equipment (Complior SP, Artech Medical, Pantin, France). The measurement was undertaken with the participant resting for 5 to 10 min in a supine position. CF-PWV was obtained from the right common carotid artery and the right femoral artery by inputting the pulse transit time and the distance between the carotid and femoral arteries. The foot-to-foot method was used for estimating the transit time, and the time delay (△t) was measured between the feet of the two waveforms. The foot of the wave was defined at the end of diastole, when the steep rise of the wavefront began. The transit time was the time of the foot wave traveling over a known distance. The distance (D) covered by the waves was assimilated to the surface distance between the two recording sites. CF-PWV was calculated as CF-PWV = D (meters)/ △t (seconds) [9]. CF-PWV was grouped as CF-PWV < 10 m/s, CF-PWV 10–12 m/s, CF-PWV > 12 m/s.

The BEST cohort comprised 14,337 participants and 1178 in-hospital participants with complete data of systematic vascular ultrasound were enrolled into the study. General demographic characteristics and cardiovascular factors were summarized in Table 1. The average age of the participants was 67.4 years and 52% were male. The prevalence of CF-PWV > 12 m/s and multi-site atherosclerotic plaques were 40.2% and 74.4%. The most common cardiovascular factor was hypertension (74.1%), followed by dyslipidemia (73.9%), CAD (61.0%), stroke (39.8%), smoking (38.6%), diabetes (38.4%), PAD (30.8%) and alcohol (24.9%). Additionally, the proportion of participants with treatments were CVD drug (83.8%), antidiabetic drug (29.5%) and lipid-lowering drug (69.4%), respectively. Participants with multi-site atherosclerotic plaques (compared with site <=1) had higher level of age, SBP, CF-PWV, FPG, CRP, HCY, UA, BUN, CR, and had higher proportion of CF-PWV > 12 m/s, male, CAD, stroke, PAD, hypertension, diabetes, dyslipidemia, smoking, alcohol, drugs of CVD, antidiabetic drug and lipid-lowering drug, and had lower BMI, DBP, TC, HDL-C and LDL-C.

The results of multivariable logistic regressions were showed in Table 2, with age, male, BMI, HR, SBP, DBP, CF-PWV, FPG, TC, TG, HDL-C, LDL-C, CRP, HCY, UA, BUN, CR, diseases history (CAD, Stroke, PAD, hypertension, diabetes, dyslipidemia), drugs (CVD drugs, hypoglycemic drugs, lipid-lowering drugs) and life style (smoke, alcohol) as independent variables. Eventually, CF-PWV > 12 m/s (odds ratio, OR 2.249, 95% Confidence Interval, 95% CI 1.379 to 3.668, p = 0.001), age (OR 1.085, 95% CI 1.065 to 1.105, p < 0.001), male sex (OR 1.842, 95% CI 1.169 to 2.901, p = 0.008), stroke (OR 1.638, 95% CI 1.097 to 2.445, p = 0.016), PAD (OR 3.882, 95% CI 2.158 to 6.982, p < 0.001), dyslipidemia (OR 1.894, 95% CI 1.274 to 2.815, p = 0.002), hypoglycemic drugs (OR 1.555, 95% CI 1.034 to 2.339, p = 0.034), and smoking (OR 2.485, 95% CI 1.522 to 4.057, p < 0.001) were included into the model. In participants with CF-PWV > 12 m/s, the odds ratio (OR) for multi-site atherosclerotic plaques was 2.249 comparing with CF-PWV < 10 m/s, independently of age, sex, and other CVD factors. In addition, patients with PAD showed the highest association (OR 3.882, 95% CI 2.158 to 6.982, p < 0.001) with multi-site atherosclerotic plaques, followed by smoking (OR 2.485, 95% CI 1.522 to 4.057, p < 0.001), CF-PWV > 12 m/s (OR 2.249, 95% CI 1.379 to 3.668, p = 0.001), dyslipidemia (OR 1.894, 95% CI 1.274 to 2.815, p = 0.002), male sex (OR 1.842, 95% CI 1.169 to 2.901, p = 0.008), stroke (OR 1.638, 95% CI 1.097 to 2.445, p = 0.016), hypoglycemic drugs (OR 1.555, 95% CI 1.034 to 2.339, p = 0.034) and age (OR 1.085, 95% CI 1.065 to 1.105, p < 0.001).

The proportion of plaque formation in 0, 1, 2 and 3 sites were 6.6%, 18.9%, 31.2% and 43.2% respectively. Most participants (74%) had multi-site atherosclerotic plaques. Plaques formation were detected in 93.4% of participants (6.5% without any plaque, 90.1% in the carotids, 70.5% in the lower extremities arteries, and 50.5% in the abdominal aorta). In addition, 31.2% and 43.2% of the participants were with 2 and 3 sites affected. In male, atherosclerotic plaque formation in 3 sites was more prevalent (48.9% versus 36.9% in female, p < 0.001), and also more prevalent across all single vascular site in carotid (92.7% versus 87.2% in female, p < 0.05) or lower extremities artery (77.2% versus 63.1% in female, p < 0.001) or abdominal aorta (55.1% versus 45.5% in female, p < 0.05).

Participants with CF-PWV < 10 m/s, CF-PWV 10–12 cm/s and CF-PWV > 12 m/s corresponded to an age and sex-adjusted mean 64%, 73% and 82% probability of multi-site atherosclerotic plaques, respectively.

A study used whole-body magnetic resonance angiography to assessed the prevalence and distribution of atherosclerosis in 1528 participants with 10-year risk of cardiovascular disease less than 20%, the results showed 49.4% participants had at least one stenotic vessel, and 27.0% participants had multiple stenotic vessels, and pointed out although disease prevalence was low on a per-vessel level, vascular disease was common on a per-participant level, even in a low- to intermediate- risk cohort [11]. The progression of early subclinical atherosclerosis (PESA) study including 4184 asymptomatic participants 40 to 54 years of age was designed to evaluate the systemic extent of atherosclerosis in the carotid, abdominal aortic, and iliofemoral territories by ultrasound. They found subclinical atherosclerosis was present in 63% of participants, and 83% of participants at high risk had atherosclerosis, with 66% classified as intermediate or generalized [12]. Inspired by the previous study and as data supplement for current research from China, the present study including in-hospital participants (mean age 67.40 years, 61.0% CAD, 39.8% stroke, 30.8% PAD, 74.1% hypertension, 38.4% diabetes, 73.9% dyslipidemia, 3.4% without any above diseases), only about 7% were free of atherosclerosis in any of the three vascular sites, and the prevalence of multi-site atherosclerotic plaques was 74.4% which was similar to other studies. To further evaluate the prevalence in different vessel bed, we found in the studied population from China, with carotid plaque was the most common, which was different from the PESA in which presence of ilio-femoral artery was the most common [12, 13]. The main reasons are that the study population (asymptomatic vs high-risk participants) and different high incidence diseases (coronary heart disease vs stoke) vary from other country to China. More research tips showed, among 1812 subjects (49% female, 21% black, 14% Chinese, and 25% Hispanic), the presence of multi-site atherosclerosis (≥ 3 of the abdominal aorta calcium, coronary artery calcium, ankle brachial index, carotid intimal medial thickness) ranged from 20% in women and 30% in men, and was highest in Caucasians (28%) and lowest in Chinese (16%) [14]. As for the presence of plaque in any vessel, previous studies have also assessed. For carotid artery, the prevalence rate varied from 78 to 87% [15, 16]. In addition, in the present study, male showed a higher prevalence of multi-site atherosclerosis than female which was consistent with the previous data [6, 12, 13].

Studies showed that traditional risk factors including aging, hypertension, current smoking, diabetes and the level of HDL-C were associated with subclinical carotid atherosclerosis and plaque burden [6, 15, 17]. In our study from in-hospital population, we also found CF-PWV, age, sex, stroke, PAD, dyslipidemia, hypoglycemic agents and smoke were independently associated with multi-site atherosclerosis. As an important finding, CF-PWV > 12 m/s was an independent factor related to multi-site atherosclerotic plaques compared with CF-PWV < 10 m/s, which indicated the potential impact of vascular function on vascular structure. As for the important influence of combine vascular lesions on cardiovascular events had been explored by various studies [4, 5, 18, 19]. A study assessed the relation of Framingham risk score (FRS) to subclinical atherosclerosis evaluated across three arterial sites, by measuring subclinical atherosclerosis in the coronary arteries and aorta with the presence of calcium and in the common carotid artery by intima-media thickness in 498 healthy subjects. The results showed the FRS were significantly independently associated with these subclinical atherosclerosis measures of the three arterial sites and increased with the number of arterial sites with atherosclerosis [19]. The BioImage Study directly quantifying atherosclerosis in different vascular beds performed in a single cohort indicated major adverse cardiac events rates increased simultaneously with higher levels of both carotid plaque burden and coronary artery calcification [4]. A study in Male Marathon Runners found the prevalence of carotid and peripheral atherosclerosis in 100 marathon runners was high and was related to cardiovascular risk factors and the coronary atherosclerotic burden [18]. Furthermore, CF-PWV as the gold standard for arterial stiffness, has been confirmed the predicting value for future cardiovascular disease and recommended by various guidelines [1‐3]. Therefore, the present cross-sectional study showed some indication for the relationship between arteriosclerosis and multi-site atherosclerosis, which maybe as an earlier marker for the evaluation of multi-site atherosclerosis. Our follow-up data will further confirm the value of arteriosclerosis as an earlier marker.