Introduction

Vascular calcification is the active deposition process of bone-specific hydroxyapatite crystallization in the blood vessel wall caused by multiple pathogenic factors [1]. Vascular calcification is prevalent and is related to many diseases such as aging, diabetes, atherosclerosis and chronic kidney disease. Long-term vascular calcification can cause vessel stiffness and reduced compliance, leading to adverse cardiovascular events [2]. Raggi et al. documented that the progression of coronary calcification was more common in patients who had clinical coronary events compared with event-free subjects [3]. This view has also been confirmed by a multi-ethnic study of atherosclerosis conducted by Budoff et al., suggesting that vascular calcification is significantly associated with all-cause mortality and atherosclerotic plaque rupture [4]. The assessment of CAC progression makes it possible to monitor the progression of coronary plaque burden and evaluate the modification of risk factors and the success of medical treatments [5, 6]. Computed tomography angiography (CTA) provides a unique diagnostic value in the estimation of CAC progression, and it can be detected, located and quantified, which is of great significance to the risk assessment of coronary artery disease [7].

Furthermore, CAT is a common phenomenon found in coronary angiography [8]. The etiology and clinical significance of CAT remain unclear [9]. Preliminary evidence suggests that it is associated with various diseases, including aging, hypertension, reversible myocardial reperfusion injury, spontaneous coronary artery dissection, fibromuscular dysplasia and connective tissue diseases [10]. Nevertheless, the correlation between CAT and atherosclerosis has been controversial, and few types of research have revealed its correlation with calcification score. It seems to be more beneficial to study the correlation between CAC score and vascular tortuosity in order to identify specific prevention and intervention populations.

Patients and methods

Clinical study design

This is a cross-sectional retrospective study registered in the China Clinical Trial Registration Center (ChiCTR1800020259). The study included patients with suspected coronary artery disease and stable hemodynamics who underwent coronary CTA examinations using 320-row-detector dynamic volume CT from January 1, 2020 to March 9, 2021.The patients with a past history of coronary stent implantation, coronary artery bypass graft, prosthetic valve or pacemaker implantation, pregnancy, chronic renal insufficiency, and those presenting any contraindication for iodinated compounds were excluded.

CT angiography

Coronary CTA images were reviewed by two experienced radiologists who were blind to all clinical profiles of the participants. CAC score was calculated by dedicated software and quantified as the Agatston score [11]. According to the ACCF/AHA 2007 clinical expert consensus, the Agatston score was divided into 4 levels (0, 1–100, 101–400, > 400) [12]. In addition, the severity of coronary stenosis was classified as up to 0, 1–24%, 25–49%, 50–69%, 70–100%.

Biochemical indexes

Venous blood samples were collected from all participants after a 12-h overnight fast. Biochemical parameters were determined in the Department of Clinical Laboratory, Zhong Da hospital affiliated Southeast University.

Risk factors

Hypertension was defined as systolic blood pressure ≥ 140 mmHg or/and diastolic blood pressure ≥ 90 mmHg, or taking antihypertensive drugs. Diabetes was diagnosed according to the WHO criteria. Smokers were defined as those smoking in the past 1 month.

Statistical analysis

IBM SPSS software (version 24.0, SPSS, Inc.) was used for statistical analysis. All data were accomplished a normal distribution test before analysis. Continuous variables were expressed as the mean ± standard deviation (SD) if normally distributed, otherwise as median (interquartile range); in addition, comparisons between groups performed by the t test if normally distributed or the Mann–Whitney test if not normally distributed. Categorical variables were described as percentages and compared by χ2 testing. Multivariable logistic regression was used to assess the association of CAT with calcification score. The final model was adjusted for sex, age, BMI, hypertension, diameter stenosis, uric acid, TG, and HDL. Univariable and multivariable analysis were performed to identify clinical parameters directly affecting coronary tortuosity. All tests were 2-sided and P values < 0.05 were considered statistically significant.

Results

Baseline characteristics

Baseline characteristics of participants in the study were presented (Table 1). A total of 1280 subjects were included in the analysis, of whom 445 (35%) were CAT group (Fig. 1), and 835 (65%) were N-CAT group. The mean ± SD age of the participants was 62.3 ± 12.7 years. All variables, except gender (P < 0.001), age (P < 0.001), BMI (P < 0.001), hypertension (P = 0.014), uric acid (P = 0.018), triglycerides (TG) (P = 0.047), and high-density lipoprotein (HDL) (P < 0.001) were similar in both groups.

Table 1 General characteristics of patients included in the study
Full size table
Fig. 1
figure 1

CTA shows tortuous coronary

Full size image

No correlation between CAT and CAC score

The correlation between CAT and CAC score was analyzed (Table 2). Individuals with an Agatston score from 101 to 400 were more likely to coexist with CAT than those with an Agatston score 0 (OR 1.49, 95% CI 1.05–2.10, P = 0.025) in unadjusted analysis (Table 3 and Additional file 1: Table S1). However, on multivariable analysis, CAT was not significantly associated with Agatston score after adjusting for covariates (sex, age, BMI, hypertension, diameter stenosis, uric acid, TG, and HDL) (Table 2).

Table 2 Associations between CAT and CAC score
Full size table
Table 3 Univariable and multivariable analysis of which factors are related to CAT
Full size table

Factors affecting the incidence of CAT

On univariable analysis, female was more likely to have CAT than male (OR 1.92, 95% CI 1.52–2.42, P < 0.001) (Table 3 and Additional file 1: Table S1). The increase of age was also significantly related to CAT (OR 1.03, 95% CI 1.02–1.04, P < 0.001). Participants with hypertension were more possible than those without to be CAT (OR 1.34, 95% CI 1.06–1.70, P = 0.015). Compared with patients without lumen stenosis, patients with moderate lumen stenosis were associated with CAT (OR 1.47, 95% CI 1.04–2.09, P = 0.029). In addition, overweight (BMI 24–27.9) (OR 0.71, 95% CI 0.55–0.92, P = 0.009) and obese patients (BMI > 28) (OR 0.41, 95% CI 0.29–0.59, P < 0.001) were less likely to coexist with CAT than normal weight patients (BMI 18.5–23.9) on univariable analysis.

On multivariable analysis, after adjusting for the parameters that affect CAT, female (OR 1.68, 95% CI 1.30–2.17, P < 0.001), age (OR 1.02, 95% CI 1.01–1.03, P = 0.001), and hypertension (OR 1.35, 95% CI 1.04–1.75, P = 0.024) remained significantly associated with CAT (Table 3). Furthermore, those who were overweight (OR 0.76, 95% CI 0.58–1.00, P = 0.044) and obese (OR 0.46, 95% CI 0.31–0.68, P < 0.001) were less likely to have CAT than those with normal weight.

Moderate calcification score is related to CAT in female patients

In order to explore the correlation between coronary tortuosity and CAC score in special populations, gender was stratified and further analyzed. Univariate analysis revealed that in female patients, compared with patients with an Agatston score of 0, patients with a high Agatston score were significantly associated with CAT (1–100, OR 1.49, 95% CI 1.01–2.18, P = 0.042; 101–400, OR 2.36, 95% CI 1.36–4.07, P = 0.002; > 400, OR 1.82, 95% CI 1.07–3.11, P = 0.028), while this correlation was not found in male patients (Table 4 and Additional file 1: Table S2). However, on multivariate analysis, CAT in female patients was only significantly associated with moderate Agatston score after adjusting for age and BMI (OR 1.94, 95% CI 1.09–3.45, P = 0.024), and after full adjustment (age, BMI, hypertension, and HDL) (OR 1.80, 95% CI 1.00–3.22, P = 0.048). Moreover, CAT in female patients was positively correlated with hypertension (OR 1.54, 95% CI 1.07–2.22, P = 0.021) and HDL (OR 1.86, 95% CI 1.07–3.24, P = 0.028), and negatively correlated with obesity (OR 0.51, 95% CI 0.31–0.84, P = 0.008), while it in male patients was positively associated with age (OR 1.03, 95% CI 1.02–1.04, P < 0.0001) and negatively associated with overweight (OR 0.72, 95% CI 0.56–0.94, P = 0.014) and obesity (OR 0.46, 95% CI 0.32–0.66, P < 0.0001) (Tables 5 and 6).

Table 4 Associations between CAT and CAC score in female
Full size table
Table 5 Univariable and multivariable analysis of parameters directly affecting for CAT in female
Full size table
Table 6 Univariable and multivariable analysis of factors directly affecting for CAT in male
Full size table

Discussion

In this study of 1280 participants, it is documented that age and hypertension may be the main factors for the occurrence of CAT, which is consistent with the results of other researchers [8, 13]. It should be understood that arteries are usually straight tubes that can effectively transport blood to remote organs. However, due to developmental abnormalities or vascular disease, arteries may be tortuous. The maintenance of arterial stability in vivo mainly depends on a certain degree of axial tension, pressure and traction, and the retraction force produced by elastin which can resist pressure and traction [14,15,16,17]. These forces are essential in preventing tortuosity. The age-related coronary tortuosity is related to the degradation and decrease of elastin [18,19,20]. In addition, the axial tension may decrease with aging [17, 21]. Hypertension or increased blood flow also contributes to artery tortuosity associated with elastin degradation and fragmentation, which has been considered the cause of vessel lengthening [22, 23].

The results of the study on the correlation between gender differences and CAT are also consistent with the findings of other current works [13, 24]. It also explains why women often show symptoms of chest pain, but have better angiographic results being normal coronary arteries or less severe disease than men [24]. In addition, the uniqueness of this work is that it shows the correlation between BMI and CAT. Compared with people with normal weight, overweight or obesity is negatively correlated with CAT. Previous studies have reported that the incidence of tortuosity increased as the heart size and mass decreased [25]. Based on this theory, we speculate that long-term overweight and obesity are accompanied by an increase in the thickness of epicardial adipose tissue, which may have a certain impact on the shape and length of blood vessels.

We did not find a negative correlation between CAT and atherosclerosis described by Li et al. [8], which may be due to different methods used to calculate the coronary tortuosity. Beyond that, our study displays no correlation between Agatston score and CAT except in the female population. Result contrasts with research by Tahlawi et al., who revealed that CAT is associated with Agatston score even in the absence of significant obstructive lesion [9]. This may be due to the large population cohort and detailed stratification of calcification score included in our study. Even so, the CAC score is highly specific in atherosclerosis [26]. However, the result that compared with patients without vascular calcification, those with moderate calcification score are associated with CAT in females is discovered. It is known that severe intravascular calcification can lead to the stiffness and rigidity of the vascular wall, which may be the reason for the insignificant difference in severe CAC score (Agatston score > 400) between the two groups. Another interesting finding is that there is a significant correlation between HDL and CAT when female patients are analyzed independently. In this way, previous hypothesis that there was no significant difference between both groups regarding HDL level was overturned by us. HDL is known to exert an anti-atherosclerotic effect by interacting with macrophages and other inflammatory immune cells [27]. As other studies have shown that CAT is inversely associated with atherosclerosis [8]. Perhaps a high level of HDL may be a potential protection mechanism.

Limitations

This study is a single-center cross-sectional study, which limits the comparability of our findings to the general population. In addition, there is a lack of classification in CAT severity, which is uniformly defined as at least three consecutive curvatures greater than 45 degrees in a major epicardial coronary artery. Moreover, there may be some differences between the two methods of coronary angiography and CTA in the assessment of coronary artery stenosis.

Conclusions

Tortuous arteries are common in humans. Although slight tortuosity is asymptomatic, severe tortuosity may cause an ischemic attack in remote organs. Our results show that tortuous arteries are related to aging, hypertension, BMI, and gender. However, little is known about the mechanism of its formation and development. In the future, more research is needed to explore the mechanism and provide new technologies to prevent and treat vascular curvature.