A total of 542 subjects originally participated in this study. After receiving ultrasonic examination for the carotid and right subclavian arteries, 37 subjects (25 men and 12 women) were excluded due to the diagnosis of carotid and/or subclavian stenosis. Up to the date when the analysis was performed, two patients refused to be continuously followed up and seven lost contacts with the investigation team. Therefore, 473 participants were finally involved in the study, including 284 (60.0%) men and 189 (40.0%) women. The average age of all the 473 participants at admission was 63.57 ± 10.82 (range from 23 to 81) years, where women were a few years older than men (66.93 ± 9.37 vs. 61.34 ± 11.15, p < 0.001). The average follow-up period were 25.3 ± 9.6 months with a range from 10.6 to 35.8 months. The prevalence of RSP and CP at baseline examination was 244/473 (51.6%, 95% confidence interval (C.I.) [47.0%, 56.2%]) and 289/473 (61.1%, 95%C.I. [56.5%, 65.5%]) respectively. Up to the day when the paper preparation work began, 39/473 (8.2%, 95%C.I. [5.9-11.1%] participants suffered from endpoint events, including 19(4.0%) cases of MI (15 undergoing PCI and 5 death), 4(0.8%) heart failure (all also involved in the myocardial infarction group), 3(0.6%) ischemic stroke (1 death), and 17(3.6%) UA (7 undergoing PCI). No death due to other reasons was recorded.
According to the incidence of endpoints events, the participants were then divided into two groups (events n = 39 and no events n = 434). The demographic data, physical findings, ultrasonic results and blood test results were listed and compared in Table 1 and Table 2 for continuous variables and categorized variables respectively. The continuous variables included age (years), history of hypertension (years), systolic blood pressure (mmHg), diastolic blood pressure (mmHg), heart rate (beats per minute), body mass index (BMI) (m/kg2), levels of aspartate amino transferase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), glomerular filtration rate (GFR), a lkaline phosphatase, cholinesterase, albumin, globulin, fibrinogen, alpha hydroxybutyrate dehydrogenase (α-HBDH), total protein, total bilirubin, direct bilirubin, gamma-glutamyl transpeptidase (GGT), blood urea nitrogen (BUN), uric acid, glucose, glycosylated hemoglobin (HbA1c) (%), total Cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (APOA1), apolipoprotein B (APOB), electrolytes, hemoglobin (Hb), total triiodothyronine (TT3), total tetraiodothyronine (TT4), thyroid stimulating hormone (TSH), left ventricular ejection fraction (LVEF), and left ventricular end-diastolic dimension (LVEDD). The categorized variables included sex(male), histories of diabetes (yes/no), dyslipidemia (yes/no), atrial fibrillation (AF)(yes/no), smoking(current smoker, ex-smoker, and never), ultrasonic findings of CP (yes/no), RSP(yes/no) and multisite plaques (MPs) including plaques detected in both carotid and right subclavian arteries (yes/no), and baseline medications of angiotensin converting enzyme inhibitors (ACEIs)(yes/no), β-blockers (yes/no), calcium channel blockers (CCBs)(yes/no), diuretics (yes/no), aspirin (yes/no).
Table 1
Baseline characteristics (continuous variables) of the participants grouped by endpoint events (n = 473)
Variables* | Endpoint events | P |
Yes (n=39) | No (n=434) |
Age (years) | 65.59±11.03 | 63.39±10.79 | 0.224 |
History of hypertension (years) | 12.61±12.36 | 13.34±11.16 | 0.741 |
Systolic blood pressure (mmHg) | 129.12±13.91 | 130.45±18.97 | 0.690 |
Diastolic blood pressure (mmHg) | 77.62±8.07 | 77.14±12.31 | 0.823 |
Heart rate (beats per minute) | 73.67±10.91 | 73.18±11.47 | 0.799 |
Levels of | | | |
BMI (m/kg2) | 25.41±3.42 | 26.78±3.62 | 0.027 |
AST (U/L) | 23.16±20.18 | 21.12±11.93 | 0.352 |
ALT (U/L) | 21.09±11.18 | 24.86±19.04 | 0.231 |
Lactate dehydrogenase (LDH) (U/L) | 200.19±60.16 | 182.36±55.12 | 0.059 |
Creatine kinase (CK) (U/L) | 118.43±100.05 | 91.58±77.62 | 0.050 |
GFR (ml/min) | 91.24±28.43 | 100.33±19.06 | 0.064 |
A Lkaline Phosphatase (U/L) | 62.12±14.50 | 65.30±20.32 | 0.353 |
Cholinesterase(U/L) | 8010.05±2046.74 | 8374.75±1833.52 | 0.252 |
Albumin (g/L) | 39.72±3.77 | 40.70±2.91 | 0.046 |
Globulin (g/L) | 25.42±4.25 | 24.09±3.87 | 0.056 |
Fibrinogen (g/L) | 3.08±0.79 | 2.85±0.61 | 0.035 |
α-HBDH (U/L) | 163.20±55.66 | 143.50±51.23 | 0.027 |
Total protein | 65.14±6.51 | 64.73±4.49 | 0.714 |
Total Bilirubin (µmol/L) | 12.59±6.24 | 12.88±5.85 | 0.778 |
Direct Bilirubin (µmmol/L) | 3.88±1.91 | 4.14±2.13 | 0.487 |
GGT (U/L) | 30.75±27.42 | 35.22±38.39 | 0.490 |
BUN (mmol/L) | 7.18±5.20 | 6.10±3.43 | 0.223 |
Uric Acid (µmmol/L) | 376.75±108.31 | 358.07±87.82 | 0.225 |
Glucose (mmol/L) | 6.96±2.94 | 6.27±2.57 | 0.116 |
HbA1c (%) | 6.59±1.11 | 6.51±1.22 | 0.690 |
Total Cholesterol (mmol/L) | 3.98±0.96 | 3.86±0.92 | 0.426 |
Triglyceride (mmol/L) | 1.57±1.40 | 1.67±1.08 | 0.587 |
HDL-C (mmol/L) | 1.15±0.38 | 1.07±0.27 | 0.094 |
LDL-C (mmol/L) | 2.35±0.83 | 2.27±0.80 | 0.584 |
APOA1 (g/L) | 1.29±0.30 | 1.28±0.24 | 0.641 |
APOB (g/L) | 0.90±0.21 | 0.89±0.23 | 0.850 |
Ca (mmol/L) | 2.30±0.10 | 2.31±0.09 | 0.665 |
Na (mmol/L) | 139.82±3.38 | 140.62±3.15 | 0.132 |
K (mmol/L) | 4.06±0.46 | 3.98±0.37 | 0.193 |
P (mmol/L) | 1.12±0.21 | 1.17±0.17 | 0.145 |
Cl (mmol/L) | 104.09±3.03 | 104.55±3.27 | 0.399 |
Hemoglobin (Hb) (g/L) | 133.74±19.07 | 136.52±16.16 | 0.317 |
TT3 (pmol/L) | 1.23±0.25 | 1.36±0.22 | 0.001 |
TT4 (pmol/L) | 94.22±20.29 | 90.50±18.19 | 0.240 |
TSH (pmol/L) | 2.13±0.96 | 2.32±1.48 | 0.777 |
LVEF (%) | 63.37±8.52 | 64.46±6.59 | 0.343 |
LVEDD (mm) | 45.42±6.94 | 45.32±4.27 | 0.900 |
* Values are presented as mean ± standard deviation |
BMI = body mass index; AST = aspartate amino transferase; ALT = alanine transaminase; GFR = glomerular filtration rate; α-HBDH = Alpha hydroxybutyrate dehydrogenase; GGT = gamma-glutamyl transpeptidase; BUN = Blood Urea Nitrogen; HbA1c = glycosylated hemoglobin; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; APOA1 = apolipoprotein A1; APOB = apolipoprotein B; TT3 = total triiodothyronine; TT4 = total Tetraiodothyronine; TSH = Thyroid Stimulating Hormone; LVEF = left ventricular ejection fraction; LVEDD = left ventricular end-diastolic dimension. |
Table 2
Baseline characteristics (proportion of categorized variables) of the participants grouped by endpoint events (n = 473)
| Events (n = 39) | % | 95% C.I. | No events (n = 434) | % | 95% C.I. | P |
Sex (male) | 23 | 59.0 | 42.1-74.4 | 261 | 60.1 | 55.4-64.8 | 0.887 |
Histories of | |
Diabetes (yes) | 17 | 43.6 | 27.8-60.1 | 176 | 40.6 | 35.9-45.3 | 0.712 |
Dyslipidemia (yes) | 20 | 51.3 | 34.8-67.6 | 219 | 50.5 | 45.7-55.3 | 0.461 |
Atrial fibrillation (yes) | 3 | 7.7 | 1.6-20.9 | 38 | 8.8 | 6.3-11.8 | 1.000* |
Smoking | | | | | | | |
Current smoker | 8 | 20.5 | 9.3-36.5 | 73 | 16.8 | 13.4-20.7 | 0.814* |
Ex-smoker | 0 | 0.0 | 0.0-9.0 | 7 | 1.6 | 0.7-3.3 |
Never | 31 | 79.5 | 63.5-90.7 | 354 | 81.6 | 77.6-85.1 |
Ultrasonic findings | |
CP | 32 | 82.1 | 66.5-92.5 | 257 | 59.2 | 54.4-63.9 | 0.005 |
RSP | 29 | 74.4 | 57.9-87.0 | 215 | 49.5 | 44.7-54.3 | 0.003 |
MPs | 30 | 76.9 | 60.7-88.9 | 192 | 44.2 | 39.5-49.1 | <0.001 |
Medications | |
ACEIs | 25 | 69.4 | 66.5-92.5 | 287 | 69.3 | 61.5-70.6 | 0.988 |
β-blockers | 27 | 75.0 | 52.4-83.0 | 275 | 67.4 | 58.6-67.9 | 0.349 |
CCBs | 26 | 72.2 | 49.8-80.9 | 244 | 59.7 | 51.4-60.9 | 0.139 |
Diuretics | 12 | 33.3 | 17.0-47.6 | 80 | 19.6 | 14.9-22.4 | 0.051 |
Aspirin | 0 | 0.0 | 0.0-9.0 | 12 | 2.9 | 1.4-4.8 | 0.611* |
* Based on Fisher’s exact test |
CP = carotid artery plaques; RSP = right subclavian artery plaques; MPs = multisite plaques including plaques detected in both carotid and right subclavian arteries; ACEI = angiotensin converting enzyme inhibitors; CCB = calcium channel clockers; 95% C.I. = 95% Confidence intervals |
Among these variables, the baseline prevalence of CP, RSP, MPs were significantly different between those with and without cardiovascular events (p = 0.005, 0.003 and < 0.001 respectively) (Table 2). To put it another way, the incidence of endpoint events was significantly higher in participants with plaques than in those without (see Table 3 for detail). Also, Table 2 shows that BMI, levels of albumin, fibrinogen, α-HBDH, TT3 were significantly different between the two groups (p = 0.027, 0.046, 0.035, 0.027 respectively). Then these variables and others with p < 0.100 based on univariate analyses, including levels of LDH, CK, GFR, globulin, and usage of diuretics, were entered into multivariate logistic regression models, except for CP, RSP, and MPs were entered as an independent variable separately. A backward stepwise method was used to perform the multiple logistic regression with entry standard as p < 0.050 and removal standard as p > 0.100. Base on clinical practice and previous studies, [22] BMI was transformed to a trinomial categorized variable as 0 for normal weight (BMI < 24kg/m2), 1 for overweight (24 kg/m2 ≤ BMI < 28 kg/m2), and 2 for obese (BMI > 28 kg/m2), where group 0 were considered as reference using indicator method in SPSS logistic regression module; while the level of TT3 was categorized as a quadrinomial variable using its quartiles as cut-off points, where the first quartile was considered as reference category. The detailed results are listed in Table 4.
Table 3
Incidence of endpoint events groups by CP, RSP, and MPs.
| | Endpoint events | P |
| | n | % |
CP | Yes (n=289) | 32 | 11 | 0.005 |
No (n=184) | 7 | 3.8 |
RSP | Yes (n=244) | 29 | 11.9 | 0.003 |
No (n=229) | 10 | 4.4 |
MPs | Yes (n=222) | 30 | 13.5 | < 0.001 |
No (n=251) | 9 | 3.6 |
CP = carotid artery plaque, RSP = right subclavian artery plaque, MPs = multisite plaques detected in both CP and RSP |
Table 4
Associations between CP/RSP and the incidence of future cardiovascular events based on multiple logistic regression (n = 473)
Variable** | Model A* | | Model B* | | Model C* |
OR | 95% C.I. | P | | OR | 95% C.I. | P | | OR | 95% C.I. | P |
CP | 2.229 | 0.924, 5.375 | 0.074 | RSP | 2.428 | 1.098, 5.370 | 0.028 | MPs | 3.539 | 1.547, 8.096 | 0.003 |
Glb | 1.128 | 1.022, 1.245 | 0.016 | | 1.140 | 1.032, 1.259 | 0.010 | | 1.150 | 1.038, 1.273 | 0.007 |
Alb | 0.871 | 0.771, 0.984 | 0.027 | | 0.867 | 0.768, 0.979 | 0.021 | | 0.881 | 0.777, 0.997 | 0.046 |
HDL-C | 2.984 | 0.955, 9.325 | 0.060 | | 3.172 | 1.024, 9.828 | 0.045 | | 2.742 | 0.875, 8.588 | 0.083 |
* CP, RSP, and MPs were entered into the multiple logistic regression model A, B, and C respectively. |
** Variables entered in the first step of the logistic regression model included levels of lactate dehydrogenase (LDH), creatine kinase (CK), Glb, Alb, fibrinogen, Alpha hydroxybutyrate dehydrogenase, HDL-C, usage of diuretics, total triiodothyronine categorized by quartile, Body Mass Index categorized by obesity standards. |
CP = carotid artery plaque, RSP = right subclavian artery plaque, MPs = multisite plaques detected in both CP and RSP, Glb = level of globulin, Alb = level of albumin, HDL-C = level of high-density lipoprotein cholesterol, 95% C.I. = 95% Confidence intervals. |
As Table 4 presents, after adjusted for other potentially significant risk factors, the association between prevalence of CP at baseline and incidence of future endpoint events became weaker and even insignificant (p = 0.074), as seen in Model A, while that between RSP and events remained significant (OR = 2.428, 95%C.I. [1.098, 5.370], p=0.028), as seen in Model B, despite the fact that p value was lower indicating that the association also became weaker than in univariate analysis. However, the prevalence of positive detection of atherosclerosis plaque in both carotid artery and subclavian artery, when incorporated as one potential predictor, was still highly significantly correlated to the incidence of future cardiovascular events (OR = 3.539, 95%C.I. [1.547, 8.096], p = 0.003), as seen in Model C of Table 4.
Interestingly, the three models in Table 4 constantly indicates that levels of albumin and globulin at admission also tended to significantly be associated with the incidence of future events.