1. INTRODUCTION

Atherosclerosis is the progression of gradual constriction of the arteries through plaque formation within the artery walls.1 Unstable arterial plaques that lead to thrombus formation and potentially embolism are precursors of more serious cardiovascular diseases (CVDs) such as myocardial infarction and stroke.2–5 Atherosclerotic diseases have a great impact on global health. The deaths from CVD worldwide were estimated to be 12.3 million in 1990 and 17.3 million in 2013.6 The global disability-adjusted life years (DALYs) increased from 314.4 million DALYs in 2007 to 366.0 million DALYs in 2017.7 A more recent report showed that CVD cases worldwide nearly doubled from 271 million in 1990 to 523 million in 2019.8 Significant proportions of the increases in CVD mortality and morbidity were attributable to the aging of the population.6–8 Unfortunately, the rate of aging of the global population is accelerating more rapidly than before; the global aged population was 727.6 million in 2020 and will be 1300.5 million in 2040.9 The impacts of atherosclerotic diseases are doubtlessly enormous and comprehensive; therefore, formulating effective prevention measures are critically relevant and prompt.

Plaque in the extracranial carotid arteries, which can be detected non-invasively and reliably by ultrasound, is a valid indicator of atherosclerosis and is predictive of CVD risk.10,11 Etiological studies on carotid atherosclerosis may provide critical evidence to identify target populations to prevent atherosclerotic diseases. Several studies consistently demonstrated higher risks of carotid atherosclerosis in the male sex, older age, cigarette smoking, high blood pressure, and diabetes mellitus (DM).12–19 High blood lipids have been found to increase the risk of atherosclerosis in several studies,12–14 but not in others.15–17 The inconsistent findings may be due to risk determinants and correlates that varied significantly and the heterogeneities of subjects in previous studies. To the best of our knowledge, only a handful of the population- or community-based studies have contemporarily explored the effects of common CVD comorbidities, including hypertension, hyperlipidemia, and DM, on atherosclerosis. Additionally, the combined effects and relative contributions of these common CVD comorbidities to advanced atherosclerosis have not been well explored.

The prevalence of atherosclerosis increases exponentially with age, and elderly people have a higher risk of CVD. Consequently, the elderly are a reasonable target population for the prevention of atherosclerotic diseases. However, previous studies enrolled subjects with a wide range of age intervals; usually, age was treated as a correlate and only some of the study subjects were elderly.13,14,17–19 It is unknown whether the findings of heterogeneous populations can be applied to older adults. Therefore, we conducted this population-based study in community-dwelling older adults to explore the relative and combined effects of common CVD comorbidities on the presence and severity of carotid atherosclerosis.

2. METHODS 2.1. Study subjects

In September 2010, we conducted a community-based study to explore the relationship between common health problems and modifiable risk factors in adults.20–22 This study recruited 4102 residents aged 40 to 74 years from communities in the northern coastal area of Taiwan. The inclusion criteria were as follows: (1) aged 65 to 74 years; (2) had undergone physical examination and determination of blood pressure, lipids, and glucose; and (3) had received ultrasound scans of their extracranial carotid arteries and had good quality carotid images. A total of 817 participants met the inclusion criteria in the present study. The study was conducted following the 1975 Helsinki Declaration on Medical Research Ethics, and informed consent was obtained from all participants. The Institutional Review Board of the MacKay Medicine College (No. P990001) and MacKay Memorial Hospital (No. 14MMHIS075) reviewed and approved this study.

2.2. Measurements of common CVD comorbidities

Measurements of blood pressure, lipids, and glucose have previously been reported.20,21 Briefly, blood pressure was measured three times, with an interval of 3 minutes, after 10 minutes of rest. For the analyses, the averages of repeated measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were used. A fasting blood sample was obtained from each participant to determine blood sugar and lipid levels. Total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, and glucose levels were determined using an autoanalyzer (Toshiba TBA c16000; Toshiba Medical System, Holliston, MA, USA) and commercial kits (Denka Seiken, Tokyo, Japan).

In this study, hypertension was defined as SBP ≥140 mmHg, DBP ≥90 mmHg, positive history of physician-diagnosed hypertension, or use of antihypertensive medications. DM was defined as a fasting glucose level ≥126 mg/dL, positive history of physician-diagnosed DM, or use of insulin or other hypoglycemic agents. Hyperlipidemia was defined as a total cholesterol level ≥240 mg/dL, LDL-C level ≥160 mg/dL, TG level ≥150 mg/dL, positive history of physician-diagnosed hyperlipidemia, or use of lipid-lowering medications.

2.3. Measurements of anthropometric attributes and health behaviors

Body weight, height, and circumference of the subject’s waist and hip were measured as described previously.20,21 In brief, we used a digital system (BW-2200; NAGATA Scale Co. Ltd., Tainan, Taiwan) to measure the body weight and height of the subjects. Waist circumference was measured mid-distance between the bottom of the rib cage and the top of the iliac crest. Hip circumference was the distance around the largest part of the subjects’ hips.

In this study, we also used a structured questionnaire to collect data on the health behaviors of the participants. Cigarette smoking was defined as smoking cigarettes ≥3 days per week during the month before enrollment. Similarly, alcohol drinking was defined as consuming alcohol-containing beverages ≥3 days per week during the month before enrollment.

2.4. Determination of carotid plaque

This study determined the presence of carotid plaque, as previously described.22 In short, high-resolution B-mode ultrasonography systems (GE Healthcare Logie E, Vivid 7, and Vivid E9; General Electric Company, Milwaukee, USA) were equipped with a multifrequency linear array transducer. Following the protocol recommended by the American Society of Echocardiography,23 two experienced technicians operated the ultrasonographic system to obtain transverse and cross-sectional ultrasound images of the bilateral extracranial carotid arteries. A well-trained technician retrieved ultrasonographic images and measured the thickness between the lumen-intima and media-adventitia interfaces using automatic contouring software (GE Healthcare EchoPAC version 112.0.2; General Electric Vingmed, Horten, Norway). The three technicians were blinded to the clinical profiles of the subjects. In the study, the plaque was defined as a focal protrusion 50% greater than the surrounding vessel wall, an intima-media thickness ≥1.5 mm, or local thickening ≥0.5 mm.24 In the presence of observable carotid plaque, its site, segment, size, and degree of carotid stenosis were recorded.

In this study, we used the total number of carotid plaques and maximum degree of carotid stenosis as indicators of the severity of carotid atherosclerosis. We followed the criteria proposed by the European Carotid Surgery Trial (ECST)25 and calculated the percentage of diameter reduction in the carotid plaque segment (Fig. 1). In this study, severe carotid atherosclerosis was defined as a maximum diameter stenosis of ≥50% or multiple medium plaques (diameter stenosis 30% to 49%), and moderate carotid atherosclerosis was defined as multiple plaques with at least one medium plaque. A representative photo of carotid plaque is shown in Fig. 2.

Fig. 1:

The measurement of carotid stenosis by the ECST criteria. The degree of stenosis at CCA and ECA can be calculated by (A–B) × 100%/A and (C–D) × 100%/C, respectively. BIF = bifurcation; CCA = common carotid artery; ECA = external carotid artery; ICA = internal carotid artery; ECST = European Carotid Surgery Trial.

Fig. 2:

Two plaques were detected at the left CCA of a middle-aged male. The lengths of the whole and remaining lumen were 0.76 and 0.52 cm (stenosis = 31.6%), respectively, for the distal plaque and were 0.75 and 0.54 cm (stenosis = 28.0%), respectively, for the proximal plaque.

2.5. Statistical analyses

In this study, we used Student’s t test to compare whether there were differences in the means of continuous variables between subjects with and without observable carotid plaque or between subjects with mild and advanced carotid atherosclerosis. Differences in the proportions of categorical variables between groups were tested using Pearson’s test. Factors that showed promising associations with a p-value <0.10, with the probability of having carotid plaque or advanced carotid atherosclerosis in univariate analyses were included in multivariate analyses with a stepwise selection method. The criteria for entry and stay in the regression model were both 0.10. Odds ratios (OR) and 95% CIs were calculated using an unconditional logistic regression model. All statistical analyses were performed with SAS 9.4 (SAS Institute Inc., Cary, NC, USA).

3. RESULTS 3.1. Baseline anthropometric and clinical characteristics of the subjects

Table 1 shows the baseline anthropometric and clinical characteristics of the participants. The mean (SD) age at enrollment was 68.6 (2.6) years, and approximately 44% of the participants were males. The prevalence rates for cigarette smoking and alcohol drinking were 6.2% and 8.0%, respectively. The percentages of hyperlipidemia, hypertension, and DM were 37.1%, 45.4%, and 16.8%, respectively. Approximately 44% of the subjects had any of these common CVD comorbidities, and ≥30% of the subjects had two or more common CVD comorbidities.

Table 1 - Basic clinical characteristics of 817 elders Mean SD Age at enrollment (years) 68.6 2.6 Body height (cm) 159.1 8.0 Body weight (kg) 63.1 10.7 Body mass index (BMI; kg/m2) 24.9 3.4 Waist circumference (cm) 89.1 9.4 Hip circumference (cm) 96.8 6.9 Waist-to-hip ratio (%) 91.9 6.5 SBP (mmHg) 131.4 17.7 DBP (mmHg) 76.6 12.0 Total cholesterol (mg/dL) 199.1 37.7 HDL-C (mg/dL) 54.8 14.3 LDL-C (mg/dL) 116.7 30.6 Fasting triglycerides (mg/dL) 117.2 78.4 Fasting glucose (mg/dL) 101.1 26.7 n % Male sex 355 43.5 Cigarette smoking 51 6.2 Alcohol drinking 65 8.0 Schooling years ≤12 years 575 70.4 Hyperlipidemia 303 37.1 Hypertension 371 45.4 Diabetes mellitus 137 16.8 Number of common CVD comorbiditiesa  0 208 25.5  1 359 43.9  2 188 23.0  3 62 7.6

CVD = cardiovascular disease; DBP = diastolic blood pressure; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; SBP = systolic blood pressure.

aIncluding hypertension, hyperlipidemia, and diabetes mellitus.

3.2. Prevalence rate for carotid atherosclerosis

The prevalence rate for carotid atherosclerosis is shown in Table 2. Approximately 63% of elderly patients had positive images of plaques in their carotid arteries. A total of 258 (31.6%) elders had multiple plaques, and 45 (5.5%) had maximum diameter stenosis of ≥50%. The prevalence rate for unilateral and bilateral carotid atherosclerosis was 27.7% and 35.3%, respectively. The prevalence rate for moderate or severe carotid atherosclerosis was 35.5%.

Table 2 - Prevalence rates of carotid atherosclerosis in 817 elders  n % Right carotid arteries 399 48.8 Left carotid arteries 403 49.3 Any segment of extracranial carotid arteries 514 62.9 Number of carotid plaques  −2 256 31.3  ≥3 258 31.6 Maximum carotid stenosis (%)  1-29 297 36.4  30-49 172 21.1  ≥50 45 5.5 Site  Unilateral 226 27.7  Bilateral 288 35.3 Severity of carotid atherosclerosis  Mild 224 27.4  Moderate or severe 290 35.5
3.3. Comparisons between subjects with and without carotid plaques

Comparisons of baseline anthropometric and clinical characteristics between subjects with and without carotid plaques are shown in Supplementary Table 1, https://links.lww.com/JCMA/A166. The results showed that subjects with carotid plaque had a significantly higher mean age at enrollment and body height and a nonsignificant higher mean body weight and SBP, but significantly lower mean total cholesterol levels. The presence of carotid plaque was positively correlated with male sex, cigarette smoking, hyperlipidemia, hypertension, and DM. There was a significant difference in the distribution of the number of common CVD comorbidities between subjects with and without carotid plaques (p < 0.0001).

3.4. Univariate and multivariable analyses for the presence of carotid plaques

The results of univariate analyses for the presence of carotid plaques showed that older age, male sex, higher body height, cigarette smoking, hyperlipidemia, hypertension, and DM were correlated with significantly higher ORs of carotid plaque (Table 3). Subjects with higher body weight and SBP had non-significantly elevated ORs for carotid plaques. Higher total cholesterol levels were inversely correlated with the presence of carotid plaques. There was a linear trend for the number of common CVD comorbidities with the likelihood of having carotid plaques (OR, 1.55; 95% CI, 1.30-1.80).

Table 3 - Multivariable logistic regression analyses for carotid plaques Univariable Multivariable Model 1 Model 2 OR (95% CI) OR (95% CI) OR (95% CI) Age at enrollment (per 1 year) 1.10** (1.04-1.17) 1.09** (1.03-1.16) 1.09* (1.02-1.15) Sex (male vs female) 1.58** (1.18-2.11) 1.34+ (0.99-1.83) 1.28+ (0.94-1.74) Body height (per 10 cm) 1.20* (1.00-1.44) - - Body weight (per 10 kg) 1.12+ (0.98-1.29) - - SBP (per 10 mmHg) 1.09+ (1.00-1.18) - - Total cholesterol (per 10 mg/dL) 0.96* (0.92-0.99) - - Cigarette smoking 4.75** (2.00-11.27) 3.92** (1.60-9.61) 3.94** (1.61-9.66) Hyperlipidemia 1.37* (1.01-1.84) - - Hypertension 1.99** (1.49-2.66) - 1.85** (1.38-2.48) Diabetes mellitus 1.76** (1.19-2.60) - 1.63* (1.09-2.43) Number of common CVD comorbidities 1.55** (1.30-1.80) 1.52** (1.28-1.81) -

-, not included; +, 0.05<p<0.10; *, 0.005 < p < 0.05; **, p < 0.005.

CVD = cardiovascular disease; SBP = systolic blood pressure.

Multivariable analyses showed that the most predictive models included age, sex, cigarette smoking, and number of common CVD comorbidities (model 1). The multivariable-adjusted OR for per 1.0 comorbidity was 1.52 (95% CI, 1.28-1.81). The second predictive model included age, sex, cigarette smoking, hypertension, and DM (model 2). The multivariable-adjusted ORs were 1.85 (95% CI, 1.38-2.48) and 1.63 (95% CI, 1.09-2.43) for hypertension and DM, respectively.

3.5. Comparisons between subjects with mild and moderate-to-severe carotid atherosclerosis

Comparisons of baseline anthropometric and clinical characteristics between subjects with mild and moderate-to-severe carotid atherosclerosis are shown in Supplementary Table 2, https://links.lww.com/JCMA/A166. Compared with subjects with mild carotid atherosclerosis, subjects with advanced carotid atherosclerosis had significantly higher mean age and fasting glucose levels and higher prevalence rates of cigarette smoking, hyperlipidemia, hypertension, and DM. The distribution of the number of common CVD comorbidities between subjects with mild and moderate-to-severe carotid atherosclerosis was significantly different (p < 0.0001). In contrast, participants with mild carotid atherosclerosis had higher mean total cholesterol and HDL-C levels.

3.6. Univariate and multivariable analyses for advanced carotid atherosclerosis

Univariate analyses showed that older age, male sex, higher blood glucose level, cigarette smoking, hyperlipidemia, hypertension, DM, and number of common CVD comorbidities were positively correlated with higher ORs of advanced carotid atherosclerosis (Table 4). The relationships were inversely related to total cholesterol and HDL-C levels. Multivariate analyses showed that the most predictive models included age, sex, cigarette smoking, and the number of common CVD comorbidities (Model 1). The second predictive model included age, sex, cigarette smoking, hypertension, and DM (Model 2). The multivariable-adjusted ORs for per 1.0 comorbidity were 1.57 (95% CI, 1.28-1.93) and were 1.63 (95% CI, 1.12-2.37), and 2.02 (95% CI, 1.27-3.21) for hypertension and DM, respectively.

Table 4 - Multivariable logistic regression analyses for advanced carotid plaques Univariable Multivariable Model 1 Model 2 OR (95% CI) OR (95% CI) OR (95% CI) Age at enrollment (per 1 year) 1.11** (1.03-1.19) 1.11* (1.03-1.19) 1.11* (1.03-1.19) Sex (male vs. female) 1.69** (1.19-2.40) 1.51* (1.03-2.21) 1.40+ (0.96-2.05) Total cholesterol (per 10 mg/dL) 0.96+ (0.91-1.01) - - HDL-C (per 5 mg/dL) 0.94* (0.88-1.00) - - Fasting glucose (per 10 mg/dL) 1.08* (1.01-1.16) - - Cigarette smoking 2.59* (1.28-5.24) 2.23* (1.05-4.75) 2.16* (1.02-4.59) Hyperlipidemia 1.49* (1.04-2.13) - - Hypertension 1.77* (1.23-2.55) - 1.63* (1.12-2.37) Diabetes mellitus 2.15** (1.37-3.38) - 2.02** (1.27-3.21) Number of common CVD comorbidities 1.56** (1.27-1.91) 1.57** (1.28-1.93) -

-, not included; +, 0.05 < p < 0.10; *, 0.005 < p < 0.05; **, p < 0.005.

CVD = cardiovascular disease; HDL-C = high-density lipoprotein cholesterol.

3.7. Combined effects of hyperlipidemia, hypertension, and DM on carotid atherosclerosis

Table 5 shows the prevalent rates and adjusted ORs for the presence of carotid plaque among different combinatory groups of hyperlipidemia, hypertension, and DM. The adjusted OR was the highest for subjects who had all three common CVD comorbidities (OR, 3.78; 95% CI, 1.85-7.74), followed by subjects who had DM and HBP (OR, 3.56; 95% CI, 1.40-9.09). Hyperlipidemia and DM alone did not increase the likelihood of having carotid plaque. Table 5 also shows that subjects with two or more common CVD comorbidities had significantly higher ORs (range, 2.71 to 5.29) of having advanced carotid plaque. Adjusted OR for subjects with hyperlipidemia alone was not elevated compared to subjects with none of these common CVD comorbidities.

Table 5 - Prevalence rates and adjusted ORs of carotid atherosclerosis among different combinatory groups of common CVD comorbidities None HBL alone DM alone HBP alone HBL + HBP DM + HBL DM + HBP All three p for trend Total no. 208 86 43 230 140 15 33 62 Presence of carotid arteries  n 112 43 25 146 101 9 27 51  Prevalence rate, % 53.8 50.0 58.1 63.5 72.1 60.0 81.8 82.3 <0.0001  ORa 1.00 0.96 0.99 1.43+ 2.08** 1.50 3.56** 3.78** <0.0001  (95% CI) (0.57-1.60) (0.49-1.97) (0.97-2.11) (1.30-3.32) (0.51-4.41) (1.40-9.09) (1.85-7.74) Moderate or severe atherosclerosis  n 49 18 15 78 66 8 21 35  Prevalence rate, % 23.6 20.9 34.9 33.9 47.1 53.3 63.6 56.5 <0.0001  ORa 1.00 0.99 1.35 1.56* 2.71** 4.79** 5.29** 4.07** <0.0001  (95% CI) (0.53-1.86) (0.64-2.85) (1.01-2.41) (1.68-4.36) (1.63-14.09) (2.39-11.75) (2.20-7.51)

CVD = cardiovascular disease; DM = diabetes mellitus; HBL = hyperlipidemia; HBP = hypertension; OR = odds ratio.

aORs were adjusted for age, sex, and cigarette smoking.

4. DISCUSSION

In this study, we enrolled 817 elderly individuals from communities and scanned their carotid arteries using high-resolution ultrasound systems. We found that carotid atherosclerosis was highly prevalent and concurred with the significant relationships of common CVD comorbidities (ie, hypertension, hyperlipidemia, and DM) with carotid plaque. These comorbidities were positively correlated with advanced carotid atherosclerosis. To our knowledge, only a limited number of community-based or population-based studies have assessed the effects of these common CVD comorbidities on the presence of carotid plaque, and none have assessed their combined effects and relative contribution to carotid atherosclerosis in elderly individuals.

Numerous studies have shown that older age is positively correlated with the presence of carotid atherosclerosis.12–19 However, most previous studies have treated age as a correlate; consequently, only a few studies have reported the age-specific morbidity rate of carotid atherosclerosis. In this study, we found that carotid plaques were highly prevalent in community-dwelling elderly individuals. The prevalence rates were 65.8% and 70.0% in males aged 65 to 69 and 70 to 74 years, respectively, and 54.2% and 70.4% in females, respectively. A recent meta-analysis study in China showed that the prevalence rate of carotid plaque in males of the same age group was 53.2% and 63.8%, respectively, and 42.7% and 53.5% in females, respectively.26 The global prevalence rate of carotid plaque in males of the same age groups was estimated to be 51.7% and 60.8%, respectively, and 36.5% and 45.0% in females, respectively.27 The observed prevalence rates for carotid plaque in this study were significantly higher than those in the global estimates and those in China. Moreover, we found that the prevalence rate of severe carotid atherosclerosis, which was defined as a maximum carotid diameter stenosis of ≥50%, in males aged 65 to 69 and 70 to 74 years were 5.1% and 8.3%, respectively, and 4.3% and 7.8% in females, respectively. These values are higher than the upper confidence limits of global estimates in the study by Song.27 The high prevalence rates of carotid stenosis ≥50% in this study may accountable for two possible explanations. First, there are two criteria for carotid stenosis, that is, the North American Symptomatic Endarterectomy Trial and the ECST and the degree of stenosis tends to be more severe by the ECST criteria.28,29 The present study used the ECST criteria to define carotid stenosis but it was not described in the study by Song.27 The second, hypertension, hyperlipidemia, and DM are the well-known determinant of atherosclerosis.30 A previous northern Taiwan study, which enrolled subjects from the Chi