Predictors of subclinical atherosclerosis in asymptomatic healthy non-diabetic postmenopausal women
Abstract
Background and Aim
Cardiovascular disease progresses after menopause. Conventional risk factors, particularly diabetes, for atherosclerosis are well-established predictors of phenotypic arterial disease. The aim of this study is to assess the predictors of subclinical atherosclerosis in asymptomatic non-diabetic postmenopausal women.
Methods
This prospective study included 117 consecutive postmenopausal women (mean age 59 ± 7 years) referred from the outpatient Rheumatology Clinic of the University Clinical Centre of Kosovo, recruited between September 2021 and December 2022. Clinical, biochemical, carotid ultrasound and coronary CT angiography data were analysed. Subclinical atherosclerosis was diagnosed when plaque and/or carotid intima-media thickness >1.00 mm were present.
Results
Women who had subclinical atherosclerosis had higher erythrocyte sedimentation (p = 0.022), higher total cholesterol (p = 0.013), higher CAC score (p = 0.017), and higher prevalence of CAC > 100 HU and CAC > 400 HU (p = 0.017 and p = 0.034, respectively) compared to those without subclinical atherosclerosis. Women who had mild coronary calcification (CAC score ≥10 HU) were older (p = 0.005), in longer menopause (p = 0.005), had thicker CIMT (p = 0.008) with higher prevalence (p = 0.03) compared to those with CAC score <10 HU. Women with moderate coronary calcification (CAC score ≥100 HU) had higher triglycerides, worse CIMT (p = 0.005) with higher prevalence (p = 0.039) compared to those with CAC score <100 HU. In multivariate analysis [odds ratio 95% confidence interval], age [1.101 (1.032–1.174), p = 0.037] and cholesterol [2.020 (1.225–3.331), p = 0.006] independently predicted the presence of subclinical atherosclerosis.
Conclusions
In addition to the impact of age, hypercholesterolaemia is an important predictor of subclinical atherosclerosis in non-diabetic postmenopausal women.
1 INTRODUCTION
Cardiovascular disease (CVD) is the main cause of death in women in developed countries (Benjamin et al., 2017). The disease progression increases dramatically after menopause despite lagging behind its respective effect in men by 10 years (Khan et al., 2018). Although it is evident that the risk of CVD rises sharply in women after the perimenopausal period, the exact underlying mechanism of CVD during this transitional period of life remains uncertain (Atsma et al., 2006). Age is a well-established factor that promotes atherosclerosis with its impact on the CV system, irrespective of gender. Oestrogen deficiency during menopause is another risk factor for atherosclerosis and osteoporosis (Bhatnagar and Kekatpure, 2022), despite having an unclear relationship with coronary and carotid artery disease (Savonitto et al., 2018). These established facts explain the well-documented findings of increased carotid intima-media thickness (CIMT) (Ieamtairat et al., 2019) and plaque formation (Li et al., 2021; Zhou et al., 2015) seen in postmenopausal women. Such carotid pathology is not in isolation since they have been shown to be related to coronary artery events, particularly the presence of carotid plaques (Shimoda et al., 2020). In addition, several sex differences in coronary atherosclerosis have been shown: women have smaller extent of coronary plaque burden, have more diffuse and less obstructive plaque, are less likely to have calcified and fibrous plaques, have more fibro-fatty and mixed plaques, more often microvascular dysfunction, more common spontaneous coronary artery dissection, and more likely to experience plaque erosion without concurrent coronary artery calcification (CAC), compared to men (Bugiardini and Bairey Merz, 2005; Kim, 2020; Sato et al., 2022; Shaw et al., 2009). Conventional risk factors for atherosclerosis are also well-established predictors of phenotypic arterial disease (de Barros et al., 2018), with diabetes being the most powerful predictor of subclinical atherosclerosis in postmenopausal women (Hong et al., 2015). Moreover, it was shown that diabetes and smoking have a more harmful impact on women than on men. In addition, women-specific risk factors, including autoimmune and rheumatic diseases and factors associated with menopause, have a substantial effect on women's CVD and prognosis (Kim, 2024; Vakhtangadze et al., 2021). This study aimed to assess the predictors of subclinical atherosclerosis in asymptomatic, non-diabetic postmenopausal women.
2 METHODS
2.1 Patients
In this study, we included 117 consecutive postmenopausal women (mean age 59 ± 7 years) who were referred from the outpatient Rheumatology Clinic of the University Clinical Centre of Kosovo and were recruited between September 2021 and December 2022. All subjects gave informed consent to participate in the study, which was approved by the Ethics Committee of Medical Faculty, University of Prishtina. Patients with heart failure, active malignancy, hepatic or pulmonary disease, known CAD, diabetes, and those with established arterial hypertension were excluded.
2.2 Clinical data
Demographic details, physical examination, and anthropometric measurements were taken of all participants. Body mass index (BMI) was measured and was calculated by dividing dry weight by body height (kg/m2). Blood pressure was recorded with a brachial sphygmomanometer after the subject had rested in the supine position for at least 10 min. The use of contraceptives and milk products was also registered.
2.3 Blood investigations
Haematology, fasting plasma glucose, blood urea nitrogen, creatinine, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, erythrocyte sedimentation rate, C-Reactive protein, total calcium, ionised calcium, anti-CCP, and vitamin D3 levels were measured using standard methods at the main hospital laboratory is accredited according to ISO 15189. All samples for a given assay were tested simultaneously, in duplicate, and in appropriate dilutions, according to conventional protocols.
2.4 Echocardiographic examination
2.4.1 Cardiac structure and function
A single operator performed all echocardiographic examinations using a Philips Intelligent E-33 system with a multi-frequency transducer and harmonic imaging as appropriate. Images were obtained with the patient in the left lateral decubitus position during quiet expiration. Measurements of LV dimensions were made at end-diastole and end-systole, according to the American Society of Echocardiography and the European Association of Cardiovascular Imaging (Galderisi et al., 2017; Lang et al., 2015). LV volumes and EF were calculated from the apical 2 and 4 chamber views using the modified Simpson method. The ventricular long-axis function was studied using the M-mode technique and placing the cursor at the lateral and septal angles of the mitral annulus and the lateral angle of the tricuspid annulus. The total amplitude of ventricular long-axis motion was measured as previously described (Höglund et al., 1988) from peak inward to peak outward points. The indices were registered as lateral and septal mitral annular plane systolic excursion and tricuspid annular plane systolic excursion. LV and right ventricular (RV) long-axis myocardial velocities were also recorded using the Doppler myocardial imaging technique. From the apical 4-chamber view, longitudinal velocities were obtained with the sample volume placed at the basal part of LV lateral and septal segments as well as the RV free wall. Systolic (s'), as well as early and late (e' and a') diastolic myocardial velocities, were measured with the gain optimally adjusted, and the mean values of lateral and septal LV velocities were calculated (Nagueh et al., 2016). Mitral regurgitation severity was assessed by colour and continuous wave Doppler and was graded as mild, moderate, or severe according to the relative jet area to that of LA as well as the flow velocity profile, according to the American Society of Echocardiography and the European Association of Cardiovascular Imaging (Galderisi et al., 2011; Zoghbi et al., 2017). In the same way, tricuspid regurgitation severity was assessed by colour Doppler and continuous-wave Doppler. Retrograde trans-tricuspid pressure drop > 35 mmHg was taken as evidence of pulmonary hypertension (Gardin et al., 2002). All M-mode and Doppler recordings were made at a fast speed of 100 mm/s with a superimposed ECG (lead II).
2.4.2 Carotid ultrasound measurements
A 12–3 MHz Esaote Biomedica MyLab40 Ultrasound System was used to study the carotid arteries. All image acquisitions were performed by a single expert. The distal common carotid segment was assessed for CIMT, and the presence of plaques was defined according to the Mannheim CIMT and Plaque Consensus: focal structures encroaching into the arterial lumen of at least 0.5 mm, or demonstrates a thickness >1.5 mm as measured from the intima–lumen interface to the media–adventitia interface (Nyman et al., 2020; Touboul et al., 2012). The measurements of CIMT were obtained at the distal segment of the left and right common carotid arteries. Carotid atherosclerosis (CA) was identified by CIMT > 1 mm and/or the presence of plaques. The data were recorded and subsequently analysed using a semi-automated software (Radiofrequency-based software-guided technique quality intima-media thickness - RF-QIMT, Esaote, Genoa, Italy), which was used to determine CIMT normative values. The CIMT measurement was defined as a composite measure that combined the maximum left and right common carotid IMT and the arithmetic average of these measurements.
2.4.3 Coronary CT angiography
Coronary multidetector computed tomography was performed using a 64-slice scanner (Siemens Somatom Volume Zoom) with a gantry rotation time of 330 ms (collimation 64 × 0.6 mm, reconstruction increment 0.3 mm, tube voltage 100 kV). Image acquisition was performed during 10 s inspiratory breath-hold. Patients whose heart rate was >65 beats/min were given metoprolol 100 mg orally, 1 h before the CT examination. A non-enhanced scan was performed for CAC detection, using prospective ECG triggering, usually at 70% of the RR interval. The collimation was set to 30 × 0.6 mm, and the reconstructed slice thickness was 3 mm (adapted field of view depending on heart size, matrix 512 × 512, pixel size usually 0.5 × 0.5 mm). CAC score was calculated using the Agatston method, which is determined by the calcified area and calcium score density, using a commercially available software package (‘SyngoCaScore’, SiemensHealthcare) (Agatston et al., 1990). Calcium was defined as the presence of >2 contiguous pixels with >130 Hounsfield units, and these lesions were automatically identified and marked in colour by the workstation. The final value for the CAC score was calculated as the sum of calcium scores in each coronary branch. An observer blinded to the angiogram results and clinical data measured the CAC score.
2.5 Statistical analysis
Values are expressed as means ± standard deviation (SD). Differences between the postmenopausal women with and without subclinical atherosclerosis were analysed using the unpaired Student t-test following the analysis of variance. The Chi-square test was used to compare the categorical variables. We used the Mann–Whitney U nonparametric test to compare the CAC score between patients with carotid plaques and those without carotid plaques. p values < 0.05 were considered statistically significant. Pearson correlations were performed to identify simple correlations between variables. We also reported kappa coefficients (Agatston et al., 1990) for intra- and inter-observer agreement in the presence of plaque at each of the carotid arteries or their branches. Predictors of mortality were identified with univariate analysis, and multivariate logistic regression was performed using the stepwise method. A significant difference was defined as p < 0.05 (two-tailed). All analyses were performed using SPSS 22 for Windows.
3 RESULTS
3.1 Clinical and biochemical data in women with and without subclinical atherosclerosis (Table 1)
Of the 117 included postmenopausal women, 44 (37.6%) had subclinical atherosclerosis based on CIMT >1 mm. Twenty-six (22%) of study subjects had a carotid plaque, based on Mannheim concensus criteria. The presence of plaque had an excellent intra- and inter-observer agreement, with a Kappa coefficient of 0.96 and 0.99, respectively. Postmenopausal women with subclinical atherosclerosis had higher erythrocyte sedimentation (p = 0.022), higher level of total cholesterol (p = 0.013), and higher CAC score (p = 0.017) compared to those without subclinical atherosclerosis (Table 1). In addition, they had significantly higher prevalence of CAC > 100 HU and CAC > 400 HU (p = 0.017 and p = 0.034, respectively) compared to those without atherosclerosis.
| Variable | All included patients | Maximal CIMT ≤ 1 mm | Maximal CIMT > 1 mm | p-Value |
|---|---|---|---|---|
| (n = 117) | (n = 73) | (n = 44) | ||
| Age (years) | 59 ± 7 | 57.6 ± 6 | 61.5 ± 7 | 0.003 |
| Years of menopause | 9.5 ± 8 | 8.2 ± 7 | 11.7 ± 8 | 0.020 |
| Smoking (%) | 10 | 10 | 11 | 0.762 |
| Body-mass index (kg/m2) | 28.9 ± 5 | 29 ± 5 | 28.6 ± 4 | 0.668 |
| Erythrocyte sedimentation rate (mm/h) | 22.6 ± 14 | 20 ± 13 | 28 ± 16 | 0.022 |
| C-Reactive protein (%) | 7.1 ± 7.6 | 6.0 ± 5.6 | 9.7 ± 11 | 0.075 |
| Total calcium (mmol/L) | 2.3 ± 0.2 | 2.3 ± 0.3 | 2.4 ± 0.2 | 0.131 |
| Ionised calcium (mmol/L) | 1.5 ± 0.4 | 1.5 ± 0.4 | 1.6 ± 0.4 | 0.147 |
| Vitamin D3 (IU) | 23.8 ± 13 | 23.9 ± 13 | 23.5 ± 11 | 0.868 |
| Anti-CCP (μ/mL) | 7.2 ± 3.9 | 7.3 ± 4 | 7.0 ± 4 | 0.671 |
| Glucose (mmol/L) | 5.3 ± 0.9 | 5.4 ± 0.8 | 5.2 ± 0.9 | 0.303 |
| Total cholesterol (mmol/L) | 5.4 ± 0.9 | 5.3 ± 0.9 | 5.7 ± 0.9 | 0.013 |
| Triglycerides (mmol/L) | 1.7 ± 0.6 | 1.7 ± 0.6 | 1.9 ± 0.5 | 0.067 |
| Creatinine (μmol/L) | 78 ± 18 | 78 ± 17 | 78 ± 24 | 0.678 |
| Urea (mmol/L) | 6.0 ± 2 | 5.8 ± 1.9 | 6.5 ± 2.4 | 0.689 |
| Haemoglobin (g/dL) | 124 ± 14 | 124 ± 12 | 126 ± 16 | 0.586 |
| Heart rate at admission (beats/min) | 67 ± 10 | 68 ± 11 | 67 ± 9 | 0.686 |
| Use of contraceptives (%) | 12 | 16 | 5 | 0.077 |
| Using milk products (%) | 92 | 90 | 95 | 0.481 |
| CAC score (HU) | 67 ± 10 | 28 ± 90 | 100 ± 224 | 0.017 |
| Patients with CAC (%) | 79 | 78 | 80 | 0.852 |
| Patients with CAC > 10 HU (%) | 36 | 27 | 50 | 0.017 |
| Patients with CAC > 100 HU (%) | 15.4 | 9.6 | 25 | 0.034 |
3.2 Cardiac structure and function (Table 2)
Cardiac structure and function measurements by Doppler echocardiography were not different between the two groups of women, with and without subclinical atherosclerosis (Table 2).
| Variable | Maximal CIMT ≤ 1 mm (n = 73) | Maximal CIMT > 1 mm (n = 44) | p-Value |
|---|---|---|---|
| LV end-diastolic volume (mL) | 108 ± 10 | 114 ± 9 | 0.492 |
| LV end-systolic volume (mL) | 38 ± 8 | 42 ± 9 | 0.248 |
| LV systolic function | |||
| LV ejection fraction (%) | 63 ± 9 | 62 ± 6 | 0.173 |
| LV shortening fraction (%) | 35 ± 6 | 34 ± 5 | 0.625 |
| Lateral s' (cm) | 8.9 ± 1.7 | 8.5 ± 1.8 | 0.461 |
| Septal s' (cm/s) | 8.5 ± 1.7 | 8.2 ± 1.1 | 0.396 |
| Septal MAPSE (cm) | 1.4 ± 0.2 | 1.4 ± 0.2 | 0.090 |
| Lateral MAPSE (cm) | 1.6 ± 0.2 | 1.5 ± 0.2 | 0.310 |
| Lateral e' (cm/s) | 8.9 ± 3.0 | 9.4 ± 3.0 | 0.604 |
| Lateral a' (cm/s) | 12.3 ± 2.4 | 11.4 ± 3.4 | 0.345 |
| Septal e' (cm/s) | 9.1 ± 2.0 | 8.4 ± 2.0 | 0.276 |
| Septal a' (cm/s) | 12.4 ± 2.9 | 10.9 ± 2.5 | 0.065 |
| LA transversal diameter (ml) | 58 ± 6 | 60 ± 7 | 0.572 |
- Abbreviations: a′, late annular diastolic velocity; a′, late diastolic myocardial velocity; e′, early annular diastolic velocity; e', early diastolic myocardial velocity; CIMT, carotid intima-media thickness; LA, left atrium; LV, left ventricular; MAPSE, mitral annular plane systolic excursion; s', systolic annular velocity; s', systolic myocardial velocity.
3.3 Clinical and biochemical data of women with and without mild coronary calcification (Tables 3 & 4)
From all postmenopausal women included in our study, 21% had CAC score = 0, 43% had CAC score 1–10 HU, 21% had CAC score 11–100 HU, 10% had CAC score 101–400 HU, and 5% had CAC score >400 HU. Study subjects who had carotid plaques had higher CAC score compared to those without carotid plaques (Mean Rank 53 HU vs. Mean Rank 80 HU, p < 0.001). Postmenopausal women who had mild coronary calcification (CAC score ≥ 10 HU) were older (p = 0.005) and were in longer menopause (p = 0.005) compared to those with less than mild calcification (CAC score < 10 HU) (Table 3). They also had thicker CIMT (p = 0.008) and a higher prevalence of thickened CIMT (p = 0.03) compared to those with the CAC score < 10 HU (Table 4). There was no other significant clinical and biochemical difference between the two groups.
| Variable | All included patients (n = 117) | CAC score < 10HU (n = 75) | CAC score ≥ 10HU (n = 42) | p-Value |
|---|---|---|---|---|
| Age (years) | 59 ± 7 | 58 ± 6 | 61 ± 7 | 0.005 |
| Years of menopause | 9.5 ± 8 | 7.9 ± 6 | 12.4 ± 9 | 0.005 |
| Smoking (%) | 10.3 | 6.7 | 16.7 | 0.084 |
| Body-mass index (kg/m2) | 28.9 ± 5 | 28.3 ± 5 | 30 ± 4 | 0.062 |
| Erythrocyte sedimentation rate (mm/h) | 22.6 ± 14 | 21 ± 13 | 25 ± 17 | 0.232 |
| C-Reactive protein (%) | 7.1 ± 7.6 | 6.7 ± 6.9 | 7.9 ± 8.8 | 0.466 |
| Total calcium (mmol/L) | 2.3 ± 0.2 | 2.3 ± 0.3 | 2.3 ± 0.2 | 0.876 |
| Ionised calcium (mmol/L) | 1.5 ± 0.4 | 1.5 ± 0.4 | 1.5 ± 0.4 | 0.464 |
| Vitamin D3 (IU) | 24 ± 13 | 23 ± 7 | 24 ± 8 | 0.864 |
| Anti-CCP (μ/mL) | 7.2 ± 3.9 | 6.6 ± 2.5 | 8.3 ± 5.5 | 0.086 |
| Glucose (mmol/L) | 5.3 ± 0.9 | 5.3 ± 0.8 | 5.4 ± 0.9 | 0.436 |
| Total cholesterol (mmol/L) | 5.4 ± 0.9 | 5.5 ± 0.8 | 5.4 ± 0.9 | 0.661 |
| Triglycerides (mmol/L) | 1.7 ± 0.6 | 1.7 ± 0.7 | 1.8 ± 0.4 | 0.064 |
| Creatinine (μmol/L) | 78 ± 18 | 78 ± 21 | 78 ± 15 | 0.997 |
| Urea (mmol/L) | 6.0 ± 2 | 6.0 ± 2 | 5.9 ± 2 | 0.697 |
| Haemoglobin (g/dL) | 124 ± 14 | 125 ± 13 | 123 ± 13 | 0.411 |
| Heart rate at admission (beats/min) | 67 ± 10 | 66 ± 9 | 69 ± 12 | 0.142 |
| Use of contraceptives (%) | 12 | 12 | 11.9 | 0.618 |
| Using milk products (%) | 92.2 | 91.9 | 92.9 | 0.580 |
| Variable | CAC score < 10 HU (n = 99) | CAC score ≥ 10 HU (n = 17) | p-Value |
|---|---|---|---|
Carotid intima-media thickness Maximal CIMT (cm) |
0.089 ± 0.018 | 0.103 ± 0.030 | 0.008 |
| Maximal CIMT ≥ 1 mm (%) | 49 | 69 | 0.030 |
3.4 Clinical and biochemical data of women with and without moderate coronary calcification (Tables 5 & 6)
Women who had moderate coronary calcification (CAC score ≥ 100 HU) had higher triglyceride levels compared to those with the CAC score <100 HU (Table 5). They also had thicker CIMT (p = 0.005) and a higher prevalence of thickened CIMT (p = 0.039) compared to those with the CAC score <100 HU (Table 6). There was no other significant clinical and biochemical difference between groups.
| Variable | All included patients (n = 117) | CAC score < 100 HU (n = 99) | CAC score ≥ 100 HU (n = 17) | p-Value |
|---|---|---|---|---|
| Age (years) | 59 ± 7 | 58.6 ± 6 | 61.8 ± 8 | 0.110 |
| Years of menopause | 9.5 ± 8 | 9.0 ± 7 | 12.1 ± 10 | 0.114 |
| Smoking (%) | 10.3 | 10.1 | 11.1 | 0.583 |
| Body-mass index (kg/m2) | 28.9 ± 5 | 28.7 ± 5 | 30 ± 4 | 0.220 |
| Erythrocyte sedimentation rate (mm/h) | 22.6 ± 14 | 22 ± 13 | 26.8 ± 21 | 0.376 |
| C-Reactive protein (%) | 7.1 ± 7.6 | 6.7 ± 7.1 | 8.8 ± 10 | 0.413 |
| Total calcium (mmol/L) | 2.3 ± 0.2 | 2.3 ± 0.3 | 2.3 ± 0.3 | 0.594 |
| Ionised calcium (mmol/L) | 1.5 ± 0.4 | 1.5 ± 0.4 | 1.5 ± 0.4 | 0.925 |
| Vitamin D3 (IU) | 24 ± 13 | 24 ± 13 | 25 ± 12 | 0.782 |
| Anti-CCP (μ/mL) | 7.2 ± 3.9 | 6.8 ± 2.9 | 8.6 ± 7.0 | 0.140 |
| Glucose (mmol/L) | 5.3 ± 0.9 | 5.3 ± 0.8 | 5.4 ± 0.8 | 0.411 |
| Total cholesterol (mmol/L) | 5.4 ± 0.9 | 5.4 ± 0.9 | 5.5 ± 1.1 | 0.416 |
| Triglycerides (mmol/L) | 1.7 ± 0.6 | 1.7 ± 0.6 | 2.0 ± 0.2 | 0.016 |
| Creatinine (μmol/L) | 78 ± 18 | 78 ± 20 | 77 ± 15 | 0.790 |
| Urea (mmol/L) | 6.0 ± 2 | 5.9 ± 1.9 | 6.1 ± 2.1 | 0.134 |
| Haemoglobin (g/dL) | 124 ± 14 | 124 ± 13 | 126 ± 16 | 0.467 |
| Heart rate at admission (beats/min) | 67 ± 10 | 67 ± 10 | 68 ± 13 | 0.686 |
| Use of contraceptives (%) | 12 | 10.1 | 22.2 | 0.144 |
| Using milk products (%) | 92.2 | 93 | 89 | 0.422 |
| Variable | CAC score < 100 HU (n = 99) | CAC score ≥ 100 HU (n = 17) | p-Value |
|---|---|---|---|
Carotid intima-media thickness Maximal CIMT (cm) |
0.092 ± 0.020 | 0.109 ± 0.028 | 0.005 |
| Maximal CIMT ≥ 0.10 cm (%) | 52.5 | 77.8 | 0.039 |
3.5 Predictors of subclinical atherosclerosis (CIMT > 1 mm) in postmenopausal women (Table 7)
In the univariate analysis model, age (p = 0.004), menopause years (p = 0.018), cholesterol (p = 0.018), CAC score >10 HU (p = 0.015), CAC score >100 HU (p = 0.030) predicted subclinical atherosclerosis in our postmenopausal non-diabetic women. In multivariate analysis [odds ratio 95% confidence interval], only age [1.101 (1.032–1.174), p = 0.037] and high cholesterol [2.020 (1.225–3.331), p = 0.006] independently predicted the presence of subclinical atherosclerosis in the studied cohort (Table 7). Thickened CIMT proved to be the most common manifestation of subclinical atherosclerosis in 55% of the cohort, followed by CACs >10 in only 36% (Table 8). The difference between these two variables was significant (p < 0.05).
| Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|
| Variable | OR | CI 95% | p | OR | CI 95% | p |
| Age | 1.101 | (1.032–1.174) | 0.004 | 1.152 | (1.008–1.317) | 0.037 |
| Menopause (years) | 1.064 | (1.011–1.120) | 0.018 | |||
| Cholesterol | 1.726 | (1.099–2.710) | 0.018 | 2.020 | (1.225–3.331) | 0.006 |
| CAC score >10 | 0.377 | (0.172–0.826) | 0.015 | |||
| CAC score >100 | 0.318 | (0.113–0.896) | 0.030 | |||
- Abbreviation: CAC, coronary artery calcium
| Variable | Total number | Number with presence of | Percentage (%) |
|---|---|---|---|
| Hypercholesterolaemia | 117 | 76 | 65% |
| CIMT > 0.9 mm | 117 | 64 | 55% |
| Plaque | 117 | 26 | 22% |
| CAC > 10 | 117 | 42 | 36% |
| CAC > 100 | 117 | 18 | 15.4% |
4 DISCUSSION
4.1 Findings
In this study of non-diabetic asymptomatic postmenopausal women, we found the following: (1) 38% have subclinical atherosclerosis detected by carotid ultrasound pathology in the form of thickened CIMT or plaque formation; (2) these women had higher levels of serum cholesterol and higher coronary artery calcium score, compared to those without subclinical atherosclerosis; (3) subclinical atherosclerosis correlated with the CAC score; and (4) age and cholesterol level were the two independent predictors of sub-clinical atherosclerosis.
4.2 Data interpretation
Age is a well-established association with atherosclerosis (28) with its impact on the frequency of atherosclerosis acute events in the form of acute coronary and cerebral syndromes (30, 31). This observation supports the very well-established fact of atherosclerosis starting as early as the adolescence age (32), although in most cases, it remains subclinical unless provoked by an aggressive risk factor like smoking (33) or aggressive familial hypercholesterolaemia (34, 35). In most individuals, atherosclerosis takes a slow progressive course over the years with obvious manifestations above the age of 50 years. Also, one of its well-established features is the lag of atherosclerosis manifestations in females compared to males by approximately 10 years. The latter has been explained on the basis of the protective impact of female hormones (36). With the drop of female hormone levels in the circulation at postmenopause, studies have shown a significant rise in the incidence of atherosclerosis-related events, with phenotypic pathology similar to that seen in men, particularly in the coronary circulation. The findings of this study provide an addition to the above facts. Having excluded diabetes from the studied menopausal women, we have identified an important role of hypercholesterolaemia in predicting the development of even subclinical atherosclerosis. None of our patients had a prior arterial event or symptom, but the ones found to have carotid or coronary evidence for atherosclerosis proved to have significantly higher cholesterol levels. This finding supports the impact of hypercholesterolaemia in the development of atherosclerosis irrespective of its severity; hence, it urges optimum early management to protect individuals from the development of future serious arterial events and complications. Since age and its related impact on our human arterial system cannot be altered, then the second important predictor of atherosclerosis should be a clinical target for a good preventive strategy. Finally, our findings highlight the beneficial use of carotid ultrasound scanning in detecting early atherosclerotic changes based on simple CIMT increased thickness. While some studies raised doubts about the accuracy of such simple measurement in other groups of patients (37, 38), it proved consistently diagnostic in 55% of our postmenopausal non-diabetic women, over and above the accuracy of coronary calcification. The latter does not devalue the use of CAC score in clinical practice, but in the setting of asymptomatic postmenopausal coronary arteries might have already developed microcalcification that is undetectable by the current CT algorithms, whereas CIMT is easier to measure and evaluate. It must be mentioned that the latter does not preclude spotty CIMT thickening, away from the conventional measurement segment, as an explanation for the only modest accuracy in confirming subclinical atherosclerosis.
4.3 Clinical implications
Our findings establish the presence of subclinical atherosclerosis in at least 55% of asymptomatic non-diabetic individuals who need optimum risk factors control as a means of preserving the integrity of their arterial health. In this group of postmenopausal women, hypercholesterolaemia plays an important role in the development of arterial disease and thus needs an optimum long-term hypocholesterolemic strategy. Ultrasound scanning of the carotid artery should be an integral part of atherosclerosis disease prevention in these women because of its accuracy in detecting early disease, lack of radiation, and for being patient-friendly compared to claustrophobic CT scanners, whose accuracy in disease detection is significantly lower.
4.4 Study limitations
We could not accurately ascertain the menopausal duration of the studied women. The sample volume of this study is modest, so the results should be retested in a larger cohort to identify predictors of disease as well as future events. We used conventionally recommended carotid landmarks for measuring CIMT; however, experienced operators know that some individuals might present with a variant site where pathology can be detected. The same applies to the CAC score, where we used the conventional Agatston score system and Hounsfield units, knowing that individuals might have some degree of micro-calcification not detectable by the currently available scanning algorithm.
5 CONCLUSION
Postmenopausal women have clear evidence for subclinical atherosclerosis, which is related to hypercholesterolaemia. Optimum diagnosis of such condition with carotid ultrasound should guide towards devising suitable management strategies to combat disease progression.
ACKNOWLEDGEMENTS
The authors would like to thank the staff at the Clinic of Rheumatology and Clinic of Cardiology at the University Clinical Centre of Kosova for very much appreciated help and support. This study was not supported by any research grant.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data supporting findings of this study are not publicly available because they were not included in the original consent forms. The anonymized data are available from the corresponding author upon request.
