Association between atherogenic index of plasma and carotid artery plaque in patients with coronary heart disease in different glucose metabolism states: a RCSCD-TCM study in China

doi:10.21203/rs.3.rs-1520462/v1

Background

The atherogenic index of plasma (AIP) index can be used as a powerful biomarker of dyslipidemia and atherosclerosis (AS). However, there is limited evidence on the relationship between AIP index and carotid artery plaque (CAP) in patients with coronary heart disease (CHD).

Methods

This is a retrospective study of 9281 CHD patients who underwent carotid ultrasound. Participants were divided according to AIP index tertiles (T1: AIP index < 1.02, T2: 1.02≤ AIP index < 1.25, T3: AIP index ≥ 1.25). The presence or absence of CAP was determined by carotid ultrasonography. Logistic regression was used to analyze the relationship between AIP index and CAP in CHD patients . The relationship between AIP index and CAP was also assessed according to sex, age, and glucose metabolic status.

Results

The baseline analysis showed that there were significant differences in related parameters among CHD patients who were divided into three groups according to the tertiles of AIP index. Compared with T1 of AIP index, the odds ratio (OR) of the T3 of AIP index in CHD patients was 2.19 (95% confidence interval [CI]: 1.91-2.52). The association between the AIP index and the CAP was higher in female (OR: 2.42; 95%CI: 2.02-2.90) than in male (OR: 1.89; 95%CI: 1.52-2.35). OR value of patients less than 60 years old (OR: 2.11; 95% CI: 1.70-2.63) is lower than that of patients over 60 years old (OR: 2.18; 95%CI: 1.83-2.61). AIP index was significantly associated with CAP risk in different glucose metabolic states, with diabetes having the highest OR values (OR: 4.18; 95%CI: 2.97-5.88).

Conclusion

AIP index and CAP were significantly associated in CHD patients.In CHD patients, the association between AIP index and CAP was higher in female than in male, and lower in patients aged less than or equal to 60 than in patients aged more than 60. Under different glucose metabolism conditions, the association between AIP index and CAP in CHD patients was the highest in diabetes.

Coronary heart disease

AIP index

Fasting plasma glucose

Carotid plaque

With the quickening pace of modern life and the development of social economy, people limit their physical activities and consume more fat than before, which leads to coronary atherosclerotic disease (CAD) becoming the leading cause of death in the world[1-3].Coronary atherosclerosis (AS), as the basis of CHD, usually occurs simultaneously with carotid AS[4].Coronary AS is the basis of coronary artery stenosis, in which risk factors such as abnormal lipid metabolism, coagulation system and inflammatory factor stimulation damage endothelial cells, promote inflammatory reaction and lipid deposition, and accelerate plaque formation [5]. For a long time, the size of atherosclerotic plaque and the accompanying narrowing of lumen have been the research center of the role of AS in ischemic cardiovascular diseases[6]. The instability of atherosclerotic plaque can lead to the rupture of plaque, resulting in thrombosis, plaque material and thrombus embolism into the intracranial artery located at the distal end [7]. Diabetic Mellitus (DM) is a kind of metabolic disorder characterized by hyperglycemia [8]. DM is caused by insulin secretion defect or insulin resistance (IR) caused by genetic or environmental factors [9-11]. Many studies have shown that patients with coronary heart disease (CHD) have a high risk of poor prognosis during pre-diabetes (pre-DM) and glucose metabolism disorder [12-14].

The atherogenic index of plasma (AIP) index, as a powerful biomarker of dyslipidemia and atherosclerosis (AS), is considered as the main risk factor of cardiac metabolism [15], and has been used to quantify the comprehensive blood lipid level [16]. It is also considered as a biomarker of coronary syndrome and metabolic syndrome [17,18]. Previous studies had shown that it was positively associated with cardiovascular disease risk [19]. However, there is no related research to explore the association between AIP index and carotid artery plaque (CAP) in CHD patients according to different glucose metabolism states.

Therefore, this study aims to clarify the association between AIP index and CAP in CHD patients according to different glucose metabolism states, and further explore the association between AIP index and CAP in sex and age. It is hoped that in the clinical treatment of CHD, the risk of AS such as CAP can be prevented by identifying simple biochemical indicators.

Study design

This large-scale, multi-center retrospective cohort study included 107,301 CHD inpatients who were admitted to six hospitals in Tianjin from January 1, 2014 to September 30, 2020. The root investigation study design excluded age less than 35years or older than 75 years, patients with tumor, infectious, or severe liver or kidney disease, and patients lacking data on lipid, FPG and carotid ultrasound measurements. A total of 9,281 participants were eventually included in the study. A flowchart of the patients’ recruitment was shown in Figure 1. This study was approved by the ethics committee of the Tianjin University of Traditional Chinese Medicine (TJUTCM-EC20190008) and registered with the Chinese Clinical Trial Registry (ChiCTR-1900024535) and in ClinicalTrials.gov (NCT04026724).

Diagnostic criteria

Hypertension is defined as systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥80mmHg [20]. Hyperlipidemia was defined as TC ≥ 6.2mmol/L (240mg/dL), TG ≥ 2.3mmol/L (200mg/dL), LDL-C ≥ 4.1mmol/L (160mg/dL), or HDL-C ≤ 1.0mmol/L (40mg/dL) [21,22]. Normal glucose tolerance (NGT) was defined as FPG <5.6 mmol/L or HbA1c <5.7%, pre-DM was defined as FPG 5.6-6.9 mmol/L or HbA1c of 5.7-6.4%, DM was defined as FPG ≥ 7.0 mmol/L or HbA1c ≥ 6.5% [23].

Data collection

After fasting for 12 hours, venous blood was collected from each participant. In this study, the standard structured questionnaire [24,25] was used to record the patients' age, sex, smoking, drinking and medication history. SBP and DBP are measured by experienced technicians at the heart level using automatic blood pressure monitors. Automatic biochemical analyzer was used to analyze biochemical parameters, including fasting plasma glucose (FPG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and glycosylated hemoglobin (HbA1c), and the quality inspection was carried out strictly according to laboratory standard procedures. To avoid negative AIP value, multiply TG/HDL-C by 10, and then obtain the logarithmic value as the adjusted AIP (aAIP) [lg(TG/HDL-C*10)][26].

Carotid artery ultrasonography is performed by certified professional technicians using diagnostic ultrasound system. In B-mode imaging, the common carotid artery, internal carotid artery and carotid bifurcation are scanned and imaged. Professional doctors analyze the color of carotid artery according to the results of Doppler ultrasound, and record the number of CAP, which can be divided into single (n=1) and multiple (n≥2). In this study, strict quality control procedures were adopted to keep the consistency of detection, image acquisition and analysis. The quality of laboratories was evaluated by licensed experimenters.

Statistical analyses

All statistical analysis was conducted with SPSS24.0 (IBM, New York, USA). Missing values are calculated by multiple interpolation method. Variables with non-normal distribution were expressed as median and interquartile distance (IQR) and compared by Kruskal Wallis test. Classification variables were evaluated by χ² test and compared by Pearson. Logistic regression analysis was used to explore the relationship between AIP index and CAP risk. Age, sex, SBP, DBP, TC, LDL-C, smoking, drinking, hypertension, hyperlipidemia, using antihypertensive drugs and hypolipidemic drugs are considered as potential confounding factors of this association. A two-sided P-value < 0.05 was considered statistically significant.

Baseline characteristics

The basic characteristics of the study population of 9,281 patients were shown in Table 1. The median age of the study subjects was 64 years, with a slightly higher proportion of female (51.2%) than that of male (48.8%). Among them, 6868 patients (74.0%) had carotid plaque, and the proportion of diabetic patients was 36.7%. The subjects were divided into three groups according to the tertile level of AIP index. Generally speaking, SBP, DBP, FPG, LDL-C, TG, TC, HbA1c, smoking, drinking, hyperlipidemia, hypertension, use of hypolipidemic drugs, use of antihypertensive drugs, the incidence of plaque was positively associated with the level of tertiles of AIP index, while HDL-C was negatively associated with the level of tertiles of AIP index.

Table 1

General characteristics of the study participants according to AIP index

Characteristic		AIP index			P-value
	Total (N=9281)	T1	T2	T3
	Total (N=9281)	(n=3025)	(n=3060)	(n=3196)
Sex, n (%)					＜0.001
male	4529(48.8)	1314 (43.4)	1472 (48.1)	1743 (54.5)
Female	4752(51.2)	1711 (56.6)	1588 (51.9)	1453 (45.5)
Age, years, median (IQR)					＜0.001
Total	64 (59-69)	65 (60-71)	65 (60-70)	63 (57-68)
≤60	56 (52-58)	56 (53-59)	56 (53-59)	55 (51-58)
＞60	67 (64-71)	68 (64-72)	68 (64-71)	67 (64-70)
SBP, mmHg, median (IQR)	140 (128-156)	140 (126-155)	140 (128-157)	140 (130-157)	0.002
DBP, mmHg, median (IQR)	82 (77-90)	80 (75-90)	82 (77-90)	85 (79-90)	＜0.001
FPG, mmol/L, median (IQR)	6.17 (5.25-8.13)	5.81 (5.10-7.25)	6.08 (5.22-7.94)	6.76 (5.50-9.30)	＜0.001
LDL-C, mmol/L, median (IQR)	2.74 (2.13-3.41)	2.61 (2.02-3.21)	2.86 (2.22-3.53)	2.78 (2.17-3.44)	＜0.001
HDL-C, mmol/L, median (IQR)	1.06 (0.90-1.26)	1.30 (1.13-1.49)	1.06 (0.93-1.20)	0.90 (0.79-1.02)	＜0.001
TG, mmol/L, median (IQR)	1.44 (1.05-2.05)	0.92 (0.75-1.11)	1.43 (1.23-1.67)	2.36 (1.95-3.12)	＜0.001
TC, mmol/L, median (IQR)	4.56 (3.81-5.35)	4.36 (3.68-5.12)	4.55 (3.78-5.32)	4.79 (4.01-5.57)	＜0.001
HbA1c, mmol/L, median (IQR)	6.10 (5.60-7.00)	5.90 (5.50-6.50)	6.10 (5.60-7.00)	6.30 (5.70-7.50)	＜0.001
AIP index	1.14 (0.96-1.33)	0.87 (0.76-0.95)	1.13 (1.07-1.19)	1.40 (1.32-1.55)	＜0.001
smoking, n (%)	4047 (43.6)	1143 (37.7)	1326 (43.3)	1575 (49.2)	＜0.001
Drinking, n (%)	2983 (32.1)	849 (28.0)	970 (31.6)	1164 (36.4)	＜0.001
Hyperlipidemia, n (%)	13 (0.1)	3 (0.1)	4 (0.1)	6 (0.1)	＜0.001
Hypertension, n (%)	2879 (31.0)	853 (28.1)	972 (31.7)	1054 (32.9)	0.002
Use of antilipidemic, n (%)	6150 (66.3)	1979 (65.4)	2021 (66.0)	2150 (67.3)	0.290
Use of antihypertensives, n (%)	6778 (73.0)	2155 (71.2)	2277 (74.4)	2346 (73.4)	0.017
Carotid artery plaque, n (%)	6868 (74.0)	2140 (70.7)	2294 (75.0)	2434 (76.2)	＜0.001
Glucose regulation state, n (%)					＜0.001
Normal glucose regulation	3318 (35.8)	1315 (43.5)	1129 (36.9)	874 (27.4)
Prediabetes	2553 (27.5)	865 (28.6)	853 (27.9)	835 (26.1)
Diabetes	3410 (36.7)	845 (27.9)	1078 (35.2)	1487 (46.5)
No. of carotid artery plaque, n (%)					＜0.001
0	2413 (26.0)	885 (29.3)	766 (25.0)	762 (23.8)
1	357 (3.8)	97 (3.2)	130 (4.3)	130 (4.1)
≥ 2	6511 (70.2)	2043 (67.5)	2164 (70.7)	2304 (72.1)

Data are expressed as median (interquartile distance) or numbers (proportion,%).

T1: AIP index < 1.02, T2: 1.02≤ AIP index < 1.25, T3: AIP index ≥ 1.25.

AIP (aAIP): [lg(TG/HDL-C*10)], SBP: systolic blood pressure, DBP: diastolic blood pressure, FPG: fasting plasma glucose, TC: total cholesterol, TG: triglyceride, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol, HbA1c: glycosylated hemoglobin, IQR: interquartile distance.

Association between the AIP index and carotid artery plaques

When AIP index was taken as a continuous variable in multivariate logistic regression analysis, it was significantly related to the risk of CAP (OR: 3.39; 95%CI: 2.78-4.14; P＜0.001). In addition, AIP index was used as a classification variable to further explore the relationship between AIP index and CAP. Multivariate logistic regression analysis showed that the AIP index levels of T2 and T3 were associated with the OR increase of CAP when T1 was used as reference, and T3 had the highest association (OR: 2.19; 95%CI: 1.91-2.52). (Table 2)

Table 2 Association between the AIP index and the risk of carotid artery plaques
Variables	Carotid artery plaques
Variables	OR (95% CI)^a	P-value	OR (95% CI)^b	P-value	OR (95% CI)^c	P-value	OR (95% CI)^d	P-value
AIP index	1.47 (1.25-1.73)	＜0.001	1.81 (1.52-2.15)	＜0.001	1.73 (1.45-2.07)	＜0.001	3.39 (2.78-4.14)	＜0.001
T1	Reference		Reference		Reference		Reference
T2	1.24 (1.11-1.39)	＜0.001	1.27 (1.12-1.43)	＜0.001	1.26 (1.12-1.43)	＜0.001	1.45 (1.28-1.66)	＜0.001
T3	1.32 (1.18-1.48)	＜0.001	1.53 (1.35-1.73)	＜0.001	1.50 (1.33-1.70)	＜0.001	2.19 (1.91-2.52)	＜0.001

^aModel 1: unadjusted;

^bModel 2: adjusted for age, sex;

^cModel 3: adjusted for age, sex,SBP, DBP;

^dModel 4: adjusted for age, sex, SBP, DBP, TC, LDL-C, smoking, drinking, hypertension, hyperlipidemia, use of antihypertensives, use of antilipidemic.

Regardless of sex, the relationship remained statistically significant after adjusting for the variables. As shown in Table 3, we found that after multivariate adjustment, the association between female AIP index and CAP was (OR: 3.79; 95% CI: 2.93-4.91), higher than that of male (OR: 2.83; 95%CI: 2.06-3.90). As shown in Table 4, after multivariable adjustment, the AIP index of CHD patients in different ages was significantly associated with CAP. Patients aged over 60 years had a higher OR (OR: 3.36; 95%CI: 2.60-4.36) than patients aged younger than or equal to 60 years (OR: 3.04; 95%CI: 2.24-4.13). When T1 was as a reference, T2 and T3 were significantly related to the increase of CAP risk in different sex and ages. Even after multivariable adjustment, this relationship was still significant.

Table 3 Association between the AIP index and the risk of carotid artery plaques in different sex
Sex	Variables	Carotid artery plaques
Sex	Variables	OR (95% CI)^a	P-value	OR (95% CI)^b	P-value	OR (95% CI)^c	P-value	OR (95% CI)^d	P-value
Male	AIP index	0.86 (0.66-1.11)	0.246	1.50 (1.14-1.98)	0.004	1.43 (1.08-1.89)	0.012	2.83 (2.06-3.90)	＜0.001
	T1	Reference		Reference		Reference		Reference
	T2	1.11 (0.91-1.35)	0.303	1.23 (1.01-1.51)	0.044	0.74 (0.61-0.90)	0.003	1.40 (1.13-1.73)	0.002
	T3	0.96 (0.80-1.16)	0.697	1.37 (1.12-1.66)	0.002	0.92 (0.76-1.11)	0.371	1.89 (1.52-2.35)	＜0.001
Female	AIP index	1.70 (1.37-2.10)	＜0.001	2.01 (1.60-2.52)	＜0.001	1.93 (1.54-2.43)	＜0.001	3.79 (2.93-4.91)	＜0.001
	T1	Reference		Reference		Reference		Reference
	T2	1.25 (1.08-1.44)	0.003	1.28 (1.10-1.49)	0.002	0.63 (0.53-0.74)	＜0.001	1.49 (1.26-1.75)	＜0.001
	T3	1.42 (1.22-1.65)	＜0.001	1.63 (1.39-1.91)	＜0.001	0.79 (0.67-0.94)	0.006	2.42 (2.02-2.90)	＜0.001

^aModel 1: unadjusted;

^bModel 2: adjusted for age;

^cModel 3: adjusted for age, SBP, DBP;

^dModel 4: adjusted for age, SBP, DBP, TC,LDL-C, smoking, drinking, hypertension, hyperlipidemia, use of antihypertensives, use of antilipidemic.

Table 4 Association between the AIP index and the risk of carotid artery plaques in different age
Age	Variables	Carotid artery plaques
Age	Variables	OR (95% CI)^a	P-value	OR (95% CI)^b	P-value	OR (95% CI)^c	P-value	OR (95% CI)^d	P-value
≤60	AIP index	1.88 (1.48-2.40)	＜0.001	1.46 (1.13-1.88)	0.003	1.41 (1.09-1.83)	0.009	3.04 (2.24-4.13)	＜0.001
	T1	Reference		Reference		Reference		Reference
	T2	1.48 (1.22-1.79)	＜0.001	1.39 (1.13-1.70)	0.002	1.36 (1.11-1.68)	0.003	1.63 (1.31-2.03)	＜0.001
	T3	1.62 (1.36-1.95)	＜0.001	1.37 (1.13-1.65)	0.001	1.37 (1.13-1.66)	0.002	2.11 (1.70-2.63)	＜0.001
＞60	AIP index	1.84 (1.46-2.31)	＜0.001	1.74 (1.38-2.19)	＜0.001	1.71 (1.36-2.17)	＜0.001	3.36 (2.60-4.36)	＜0.001
	T1	Reference		Reference		Reference		Reference
	T2	1.19 (1.03-1.38)	0.017	1.17 (1.01-1.35)	0.042	1.18 (1.02-1.37)	0.031	1.36 (1.16-1.60)	＜0.001
	T3	1.53 (1.31-1.79)	＜0.001	1.47 (1.25-1.72)	＜0.001	1.46 (1.25-1.72)	＜0.001	2.18 (1.83-2.61)	＜0.001

^aModel 1: unadjusted;

^bModel 2: adjusted for sex;

^cModel 3: adjusted for sex, SBP, DBP;

^dModel 4: adjusted for sex, SBP, DBP, TC,LDL-C, smoking, drinking, hypertension, hyperlipidemia, use of antihypertensives, use of antilipidemic.

Association between the AIP index and carotid artery plaques in different glucose regulation state

As can be seen in Table 5, there was a significant association between AIP index and CAP risk in CHD patients with different glucose metabolism status after multivariable adjustment, in which the OR value of diabetes was the highest (OR: 4.18; 95%CI: 2.97-5.88). With T1 as reference, T2 and T3 were significantly associated with the increase of CAP risk in different glucose metabolism states, but T3 was more significantly associated.

Table 5 Association between the AIP index and the risk of carotid artery plaques in different glucose regulation state
Glucose regulation state	Variables	Carotid artery plaques
Glucose regulation state	Variables	OR (95% CI)^a	P-value	OR (95% CI)^b	P-value	OR (95% CI)^c	P-value	OR (95% CI)^d	P-value
Normal glucose regulation	AIP index	1.38 (1.04-1.83)	0.024	1.60 (1.17-2.19)	0.003	1.55 (1.13-2.12)	0.006	3.09 (2.18-4.40)	＜0.001
	T1	Reference		Reference		Reference		Reference
	T2	1.09 (0.92-1.30)	0.325	1.07 (0.88-1.29)	0.514	1.07 (0.88-1.30)	0.498	1.25 (1.02-1.54)	0.031
	T3	1.22 (1.01-1.48)	0.042	1.43 (1.15-1.77)	0.001	1.40 (1.13-1.74)	0.002	2.13 (1.68-2.70)	＜0.001
Prediabetes	AIP index	1.02 (0.75-1.37)	0.916	1.20 (0.87-1.66)	0.278	1.18 (0.85-1.64)	0.314	2.31 (1.60-3.35)	＜0.001
	T1	Reference		Reference		Reference		Reference
	T2	1.23 (1.00-1.52)	0.054	1.22 (0.97-1.53)	0.083	1.22 (0.97-1.53)	0.087	1.40 (1.10-1.78)	0.006
	T3	1.04 (0.84-1.28)	0.740	1.12 (0.89-1.41)	0.325	1.12 (0.89-1.41)	0.336	1.67 (1.29-2.16)	＜0.001
Diabetes	AIP index	1.64 (1.25-2.16)	＜0.001	2.16 (1.61-2.89)	＜0.001	2.09 (1.56-2.81)	＜0.001	4.18 (2.97-5.88)	＜0.001
	T1	Reference		Reference		Reference		Reference
	T2	1.40 (1.14-1.73)	0.002	1.53 (1.23-1.91)	＜0.001	1.53 (1.23-1.92)	＜0.001	1.73 (1.37-2.19)	＜0.001
	T3	1.54 (1.26-1.87)	＜0.001	1.85 (1.50-2.29)	＜0.001	1.84 (1.49-2.28)	＜0.001	2.55 (2.01-3.23)	＜0.001

^aModel 1: unadjusted;

^bModel 2: adjusted for age, sex;

^cModel 3: adjusted for age, sex, SBP, DBP;

^dModel 4: adjusted for age, sex, SBP, DBP, TC, LDL-C, smoking, drinking, hypertension, hyperlipidemia, use of antihypertensives, use of antilipidemic.

Regardless of male or female, Table 6 showed that there was a significant association between AIP index and CAP risk in different glucose metabolism states. Association between AIP index and CAP risk in male patients with NGT (OR: 4.01; 95% CI: 2.29-7.05) was higher than that of female (OR: 2.68; 95%CI: 1.69-4.24). However, the association between female AIP index and CAP risk was in pre-DM (OR: 2.33; 95% CI: 1.45-3.77) and diabetes (OR: 5.92; 95% CI: 3.75-9.34) all higher than that of male (OR: 2.19; 95%CI: 1.20-4.01), (OR: 2.57; 95%CI: 1.50-4.40).

Table 6 Association between the AIP index and the risk of carotid artery plaques in different glucose regulation state and sex
Sex	Glucose regulation state	Variables	Carotid artery plaques
Sex	Glucose regulation state	Variables	OR (95% CI)^a	P-value	OR (95% CI)^b	P-value	OR (95% CI)^c	P-value	OR (95% CI)^d	P-value
Male	Normal glucose regulation	AIP index	0.92 (0.59-1.45)	0.731	1.93 (1.18-3.15)	0.009	1.89 (1.15-3.11)	0.012	4.01 (2.29-7.05)	＜0.001
		T1	Reference		Reference		Reference		Reference
		T2	1.00 (0.74-1.35)	0.995	1.14 (0.83-1.56)	0.437	1.14 (0.83-1.57)	0.428	1.26 (0.90-1.76)	0.181
		T3	0.86 (0.63-1.16)	0.320	1.39 (1.00-1.93)	0.054	1.38 (0.99-1.92)	0.061	1.97 (1.36-2.84)	＜0.001
	Prediabetes	AIP index	0.67 (0.41-1.10)	0.113	1.19 (0.71-1.99)	0.520	1.21 (0.72-2.04)	0.480	2.19 (1.20-4.01)	0.011
		T1	Reference		Reference		Reference		Reference
		T2	1.13 (0.78-1.63)	0.524	1.25 (0.85-1.84)	0.251	1.30 (0.88-1.91)	0.190	1.67 (1.11-2.53)	0.014
		T3	0.84 (0.60-1.19)	0.329	1.17 (0.81-1.69)	0.409	1.21 (0.83-1.75)	0.324	1.74 (1.15-2.62)	0.008
	Diabetes	AIP index	0.85 (0.55-1.32)	0.469	1.31 (0.83-2.06)	0.254	1.20 (0.75-1.90)	0.448	2.57 (1.50-4.40)	0.001
		T1	Reference		Reference		Reference		Reference
		T2	1.24 (0.86-1.77)	0.245	1.35 (0.93-1.94)	0.115	1.32 (0.91-1.91)	0.148	1.40 (0.95-2.05)	0.089
		T3	1.15 (0.83-1.60)	0.403	1.49 (1.06-2.09)	0.023	1.44 (1.02-2.03)	0.041	1.98 (1.35-2.90)	＜0.001
Female	Normal glucose regulation	AIP index	1.28 (0.88-1.86)	0.202	1.39 (0.92-2.08)	0.117	1.34 (0.89-2.02)	0.168	2.68 (1.69-4.24)	＜0.001
		T1	Reference		Reference		Reference		Reference
		T2	1.07 (0.86-1.34)	0.551	1.02 (0.80-1.31)	0.853	1.02 (0.80-1.31)	0.862	1.27 (0.97-1.65)	0.082
		T3	1.29 (1.00-1.68)	0.055	1.46 (1.10-1.94)	0.009	1.43 (1.07-1.90)	0.014	2.26 (1.64-3.11)	＜0.001
	Prediabetes	AIP index	1.02 (0.69-1.52)	0.907	1.17 (0.77-1.79)	0.457	1.14 (0.75-1.74)	0.543	2.33 (1.45-3.77)	0.001
		T1	Reference		Reference		Reference		Reference
		T2	1.21 (0.93-1.58)	0.161	1.20 (0.91-1.59)	0.199	1.19 (0.89-1.58)	0.236	1.28 (0.95-1.72)	0.112
		T3	1.00 (0.76-1.31)	0.979	1.08 (0.80-1.44)	0.624	1.05 (0.79-1.42)	0.724	1.69 (1.21-2.36)	0.002
	Diabetes	AIP index	2.26 (1.57-3.24)	＜0.001	2.98 (2.03-4.39)	＜0.001	2.97 (2.01-4.38)	＜0.001	5.92 (3.75-9.34)	＜0.001
		T1	Reference		Reference		Reference		Reference
		T2	1.44 (1.11-1.88)	0.007	1.65 (1.25-2.19)	＜0.001	1.67 (1.26-2.21)	＜0.001	1.95 (1.44-2.64)	＜0.001
		T3	1.69 (1.31-2.19)	＜0.001	2.13 (1.62-2.80)	＜0.001	2.15 (1.63-2.83)	＜0.001	3.02 (2.21-4.13)	＜0.001

^aModel 1: unadjusted;

^bModel 2: adjusted for age;

^cModel 3: adjusted for age,SBP, DBP;

^dModel 4: adjusted for age, SBP, DBP, TC, LDL-C, smoking, drinking, hypertension, hyperlipidemia, use of antihypertensives, use of antilipidemic.

As shown in Table 7, there was a significant association between AIP index and CAP risk at different ages in different glucose metabolism states. There was a significant association between AIP index and CAP risk at different ages and different glucose metabolism states. Whether the subjects were younger than or older than 60 years old, the OR values of AIP and carotid plaque were the highest in diabetic state. In diabetes, the OR value over 60 years old was higher than that under 60 years old.

Table 7 Association between the AIP index and the risk of carotid artery plaques in different glucose regulation state and age
Age	Glucose regulation state	Variables	carotid artery plaques
Age	Glucose regulation state	Variables	OR (95% CI)^a	P-value	OR (95% CI)^b	P-value	OR (95% CI)^c	P-value	OR (95% CI)^d	P-value
≤60	Normal glucose regulation	AIP index	2.18 (1.43-3.32)	＜0.001	1.40 (0.89-2.19)	0.142	1.36 (0.86-2.14)	0.186	2.69 (1.59-4.56)	＜0.001
		T1	Reference		Reference		Reference		Reference
		T2	1.20 (0.89-1.61)	0.228	1.05 (0.77-1.44)	0.748	1.01 (0.73-1.39)	0.954	1.15 (0.82-1.61)	0.427
		T3	1.70 (1.27-2.28)	＜0.001	1.29 (0.94-1.77)	0.110	1.26 (0.92-1.73)	0.158	1.92 (1.34-2.74)	＜0.001
	Prediabetes	AIP index	1.24 (0.79-1.96)	0.347	0.91 (0.57-1.47)	0.712	0.95 (0.58-1.55)	0.839	2.04 (1.14-3.67)	0.017
		T1	Reference		Reference		Reference		Reference
		T2	1.57 (1.08-2.29)	0.017	1.44 (0.97-2.12)	0.070	1.44 (0.97-2.14)	0.074	1.78 (1.17-2.73)	0.007
		T3	1.23 (0.87-1.73)	0.238	0.98 (0.68-1.41)	0.903	1.04 (0.72-1.51)	0.827	1.64 (1.08-2.50)	0.021
	Diabetes	AIP index	1.54 (1.01-2.34)	0.045	1.34 (0.88-2.06)	0.175	1.33 (0.86-2.05)	0.205	3.23 (1.88-5.55)	＜0.001
		T1	Reference		Reference		Reference		Reference
		T2	1.61 (1.11-2.35)	0.012	1.63 (1.11-2.39)	0.012	1.69 (1.14-2.49)	0.008	2.19 (1.44-3.32)	＜0.001
		T3	1.53 (1.10-2.14)	0.013	1.42 (1.01-2.00)	0.046	1.47 (1.04-2.09)	0.030	2.38 (1.61-3.54)	＜0.001
＞60	Normal glucose regulation	AIP index	1.58 (1.05-2.37)	0.028	1.43 (0.94-2.17)	0.094	1.43 (0.94-2.18)	0.100	2.86 (1.80-4.55)	＜0.001
		T1	Reference		Reference		Reference		Reference
		T2	1.11 (0.88-1.40)	0.388	1.09 (0.86-1.38)	0.476	1.12 (0.88-1.42)	0.369	1.33 (1.03-1.72)	0.028
		T3	1.38 (1.04-1.82)	0.025	1.32 (0.99-1.76)	0.055	1.34 (1.00-1.79)	0.047	2.05 (1.49-2.80)	＜0.001
	Prediabetes	AIP index	1.32 (0.86-2.01)	0.204	1.20 (0.78-1.85)	0.402	1.21 (0.78-1.87)	0.389	2.48 (1.52-4.03)	＜0.001
		T1	Reference		Reference		Reference		Reference
		T2	1.11 (0.85-1.45)	0.461	1.07 (0.81-1.40)	0.633	1.08 (0.82-1.43)	0.565	1.26 (0.94-1.68)	0.129
		T3	1.18 (0.89-1.57)	0.253	1.11 (0.83-1.48)	0.484	1.11 (0.83-1.48)	0.498	1.76 (1.26-2.45)	0.001
	Diabetes	AIP index	2.49 (1.70-3.65)	＜0.001	2.41 (1.64-3.53)	＜0.001	2.40 (1.63-3.54)	＜0.001	4.60 (2.97-7.12)	＜0.001
		T1	Reference		Reference		Reference		Reference
		T2	1.40 (1.08-1.81)	0.012	1.36 (1.04-1.77)	0.023	1.36 (1.04-1.77)	0.023	1.49 (1.13-1.97)	0.005
		T3	1.98 (1.52-2.58)	＜0.001	1.91 (1.46-2.49)	＜0.001	1.90 (1.46-2.49)	＜0.001	2.65 (1.96-3.57)	＜0.001

^aModel 1: unadjusted;

^bModel 2: adjusted for sex;

^cModel 3: adjusted for sex, SBP, DBP;

^dModel 4: adjusted for sex, SBP, DBP, TC,LDL-C, smoking, drinking, hypertension, hyperlipidemia, use of antihypertensives, use of antilipidemic.

The results of this study showed that there was a significant association between AIP index and CAP in CHD patients. This study proved the relationship between AIP index and CAP in CHD patients, and evaluated this relationship according to sex, age and different glucose metabolism status. In addition, this study showed that the relationship between AIP index and CAP was influenced by sex, age and sugar metabolism status, and this relationship still existed even after establishing models to exclude various confounding factors.

Coronary atherosclerosis is the pathological basis of CAD, and lipid deposition is the main cause of coronary atherosclerosis [26]. Most acute cardiovascular events are attributed to fragile carotid atherosclerotic plaque rupture and secondary thrombosis [27, 28]. TG and HDL-C are two lipid parameters routinely measured in clinical practice; AIP index, as a new lipid index, is considered as an excellent index of atherosclerosis, and can provide benefits for identifying the risk of cardiovascular diseases [29]. Meta-analysis of an observational study found that higher AIP index was independently associated with higher CAD after adjusting for conventional cardiovascular risk factors [30]. This is consistent with the results of this study. Our research results showed that AIP index was associated with CAP, and the association was stronger with the increase of AIP index. Atherosclerotic plaques are rich in lipids, and lipid components are considered to affect the stability of atherosclerotic plaques [4]. In addition, lipid content strongly determines the impenetrability and stenosis rate of plaque [31]. This study showed that there was a significant association between AIP index and CAP, even after we excluded confounding factors. Our research was consistent with the above results.

Diabetic patients are more likely to develop coronary atherosclerosis than non-diabetic patients, which may be significantly associated with so-called diabetic dyslipidaemia, which is composed of elevated plasma concentrations of TG-rich lipoproteins and small dense LDL-C particles and low levels of HDL-C[32]. It is confirmed that AIP index can be used as an independent predictor of long-term follow-up prognosis of type 2 diabetes (T2DM) patients, suggesting that it can more accurately reflect the comprehensive situation of blood lipid and glucose metabolism in diabetic patients [33]. In addition, other studies have also shown that AIP index is also a simple and useful tool for identifying insulin resistance patients with high risk of cardiac metabolism [34], and it is more effective than the visceral obesity index traditionally used [35]. In DM patients with CAD, the pathological features of coronary artery lesions are more complex, characterized by calcification, diffuse, multi-vessel lesions and greater atherosclerotic plaque burden [36, 37]. When CHD patients were divided into different groups of glucose metabolism, our study found that AIP index and CAP were more significant in patients with CHD and DM, which was consistent with existing studies. In addition, AIP index of CHD patients in pre-DM period and DM period were associated with CAP after excluding various confounding factors.

Studies show that the number of CVD incidents and deaths in female is higher than that in male [38]. Similarly, the results of a large-scale study in China show that the relative risk of vascular mortality associated with DM in female is higher than that in male [39]. The adverse differences of risk factors of cardiac metabolism between pre-DM and NGM individuals are more obvious in female than in male [40]. In this study, the subjects were also analyzed by age and sex subgroups to compare the relationship between AIP index and CAP among different subgroups. The results showed that both female and male showed the association between AIP index and CAP, and the association was more significant in female than in male. In the further grouping of different glucose metabolism, we found that the AIP index was associated with CAP after excluding various confounding factors, and the OR value of female was higher than that of male in pre-DM and diabetes. The research results were consistent with the existing research. The AIP index was associated with CAP for participants who were younger than or equal to 60 years old or older. But this association was more significant among participants over 60 years old. In addition, when divided the age into different groups of sugar metabolism, this study found that this relationship still existed after excluding many confounding factors.

To sum up, optimizing medical management according to AIP may reduce the risk of subsequent cardiovascular events.

Strengths and limitations

This large-scale multicenter cohort study has several limitations. First of all, this study is a multi-center study, so there may be deviations in the measurement methods of different research centers. Secondly, the value of AIP index can be calculated directly without extra cost. At the same time, because this is a retrospective cohort study, not all potential confounding factors are under control. Therefore, the exact mechanism of the relationship between AIP index and CAP needs further prospective large-scale research.

This study showed that there was a significant association between AIP index and CAP in CHD patients. In addition, this assocation was higher in female than in male, and higher in patients over 60 years old than those under 60 years old. Among DM patients, the assocation between AIP index and CAP in CHD patients was higher. AIP index is easy to calculate and can reflect the risk of CAP in CHD patients. In clinical practice, we should pay attention to the blood lipid level and blood glucose level of CHD patients in time to reduce the incidence of CAP.

AIP: The atherogenic index of plasma

AS: Atherosclerosis

CAP: carotid artery plaque

CHD: Coronary heart disease

OR: Odds ratio

CAD: Coronary atherosclerotic disease

DM: Diabetic Mellitus

IR: Insulin resistance

pre-DM: pre-diabetes

SBP: Systolic blood pressure

DBP: Diastolic blood pressure

NGT: Normal glucose tolerance

FPG: Fasting plasma glucose

TC: Total cholesterol

HDL-C: High-density lipoprotein cholesterol

TG:Triglyceride

LDL-C: Low-density lipoprotein cholesterol

HbA1c: Glycosylated hemoglobin

IQR: Interquartile distance

T2DM: Type 2 diabetes

Ethics approval and consent to participate

This study was approved by the ethics committee of Tianjin University of Traditional Chinese Medicine (TJUTCM-EC20190008) and registered in the Chinese Clinical Trial Registry (ChiCTR-1900024535) and in Clinical Trials.gov ( NCT04026724).

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed in the study are available from the corresponding author upon reasonable requests.

Competing interests

The authors declare no competing interests.

Funding

This study were supported by the National Basic Research Program of China (973 project, grant number: 2014CB542902) and the National Natural Science Fund project (approval number: 82074140).

Authors' contributions

CQY, SG, XLW and YYH participated in the study design and statistical analysis; YYH and ZL analyzed the data together and drafted the manuscript; LY, YJL, LL, and RRY participated in data collection. All authors have read and approved the final manuscript.

Acknowledgments

We thank all the participants in the study and the members of the survey teams, and the groups providing financial support.

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No competing interests reported.

Graphicalabstract.docx

Association between atherogenic index of plasma and carotid artery plaque in patients with coronary heart disease in different glucose metabolism states: a RCSCD-TCM study in China

Status:

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Abstract

Figures

Background

Methods

Study design

Diagnostic criteria

Data collection

Statistical analyses

Results

Baseline characteristics

Association between the AIP index and carotid artery plaques

Association between the AIP index and carotid artery plaques in different glucose regulation state

Discussion

Strengths and limitations

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1