One of the assessments for coronary atherosclerosis during cardiac computed tomography (CT) is coronary artery calcium (CAC) scoring. We conducted analysis on the determinants of high-risk coronary calcification, represented by CAC score, among women as a step to improve their outcomes and prognosis. This study involved a total of 1,129 female patients from a single centre. There were 127 patients (11.2%) classified as high risk (CAC ≥400). We found that a history of hypertension and diabetes are independent determinants of having a high-risk CAC score. Furthermore, this study demonstrated protective effects associated with physical activity and diastolic blood pressure. In conclusion, a history of hypertension, diabetes, and high uncontrolled systolic blood pressure might be used as cues for physicians to prioritise CAC assessment in women, despite the absence of chest pain or atypical symptoms.
Introduction
Recent data indicate that cardiovascular disease (CVD) remains the leading cause of mortality in women.1 Nevertheless, CVD in women worldwide is frequently underdiagnosed and undertreated compared with men.2 The cardiac symptoms in women are often misdiagnosed and dismissed as anxiety related. Moreover, South East Asian women are known to have a considerably longer delay in seeking treatment due to education level, socioeconomic reasons, and limited mobility. Consequently, these women are less likely to obtain guideline-based treatments such as statins.3
The application of non-invasive cardiac imaging techniques, notably cardiac computed tomography (CT) angiography, enables a more convenient, patient-friendly, and comprehensive investigation of intra-arterial plaques in women. One sensitive and specific assessment for coronary atherosclerosis during cardiac CT is coronary artery calcium (CAC) scoring. CAC is a screening tool, but it is most effective for patients at intermediate risk as it facilitates informed decision-making for preventive measures in women.4 However, only a few studies have investigated which cardiovascular risk factors are the main determinants of high-risk CAC scores in women. Additionally, at such a significant expense and low resources, further research is still necessary to determine which female patients should be prioritised to undergo this CAC assessment. Therefore, this study conducted analysis on the determinants of high-risk coronary calcification represented by CAC score among women as a step to improve their outcomes and prognosis.
Materials and method
Study design, settings and participants
The study design was a single-centre cross-sectional study. The study consecutively included all female patients referred to Siloam Hospital Surabaya for CAC assessment between 1 January and 31 December 2022. Female patients with complete cardiac CT imaging, clinical, and laboratory data records met the inclusion criteria. Patients with a history of vascular or cardiac interventional procedures (coronary stent or coronary bypass grafting) as documented in medical records/CT imaging were excluded. The Ethical Committee of Siloam Hospital Surabaya had approved this study (No. 15103/DIR-SHSB/III/2022) on 15 March 2022. As this study was retrospective and the analysis used anonymous medical-record data, informed consent was waived. The procedures applied in the study were made in accordance with the ethical standards of the Helsinki Declaration (2008).
Data extraction
Demographic data, CVD risk factors, physical activity, and the most recent systolic (SBP) and diastolic (DBP) blood pressure measurements were extracted from medical records using a standardised form. The CVD risk factors comprised hypertension, dyslipidaemia, diabetes mellitus, current smoking, and obesity. The definition of current/active smoking was regular tobacco smoking (duration >2 years). Patients with SBP greater than 140 mmHg or DBP greater than 90 mmHg in the most recent record, or any history of antihypertensive medication use, were defined as hypertensive.5 Dyslipidaemia was defined as low-density lipoprotein (LDL)-cholesterol >160 mg/dL, serum total cholesterol ≥240 mg/dL, triglycerides >200 mg/dL, high-density lipoprotein (HDL)-cholesterol <40 mg/dL, or history of taking lipid-lowering medication.5 Any history of a fasting glucose level ≥126 mg/dL, a random glucose level ≥200 mg/dL, a glycated haemoglobin A1c (HbA1c) level ≥7.0%, or the use of oral antidiabetic medicine or insulin was classified as diabetes. Positive familial coronary artery disease history was defined as any history of myocardial infarction in first-degree relatives. The presence of typical chest pain was defined based on three characteristics described by the European Society of Cardiology (ESC).7 Physical activity was classified based on ESC definition as active or inactive (sedentary).5 The body mass index (BMI), calculated using anthropometric measures, together with SBP and DBP (mmHg) as blood pressure control indicators, would be reported as a continuous variable.
Measurement of CAC
A 64-detector CT scanner was used to obtain the CT angiography (CTA) images (Philips Medical Systems, Netherlands) with a procedure previously reported in a study by Chen et al. The Agatston method was used to determine the presence of calcification. Coronary calcium scores (total and vessel-based) were calculated for all calcified lesions larger than 1 mm2. The Agatston score was then classified into high-risk (≥400) and non-high-risk (<400) for the purpose of our analysis. Two experienced cardiologists used a dedicated workstation to evaluate the CT scans in consensus to minimise the bias.
Statistical analysis
The study presented the data as follows: continuous data were expressed as mean ± standard deviation (SD) or median (interquartile range [IQR]), while categorical data were reported as number (%). The differences between these groups regarding baseline characteristics were analysed using the independent t-test or Mann-Whitney U test and the χ2 (depending on data types and distribution). To identify the determinants of high-risk CAC scores, this study conducted unadjusted and adjusted logistic-regression model analyses. Independent predictors of high-risk CAC score (CAC ≥400) were determined using fully adjusted logistic-regression models, including the following covariates: age, hypertension, dyslipidaemia, diabetes, current smoking, physical activity, chest pain, BMI, SBP, and DBP. Continuous variables were standardised and outliers removed. This study presented odds ratio (OR) with a 95% confidence interval (CI) as estimations of coefficient effects. All analyses were performed using SPSS version 26 (IBM Inc., Armonk, NY, USA).
Results
This study involved a total of 1,129 female patients. There were 127 patients (11.2%) classified as high risk (CAC ≥400). In the high-risk CAC group, the proportion of patients with hypertension, diabetes, and increased SBP was substantially higher. The patients in the high-risk group were significantly older than the non-high-risk patients (table 1).
Table 1. Baseline characteristics of patients with and without high-risk coronary artery calcium (CAC) score ≥400
| Non-high risk (n=1,002) |
High risk (n=127) |
p value | |
|---|---|---|---|
| Median age (IQR), years* | 59 (35–84) | 68 (44–92) | <0.001 |
| Smoking, n (%) | 26 (2.6) | 3 (2.3) | 0.876 |
| Hypertension, n (%) | 386 (38.5) | 82 (64.5) | <0.001 |
| Diabetes, n (%) | 167 (16.7) | 48 (37.8) | <0.001 |
| Physically active, n (%) | 432 (43.1) | 44 (34.6) | 0.069 |
| Dyslipidaemia, n (%) | 642 (64.0) | 83 (65.4) | 0.776 |
| Family history, n (%) | 150 (14.9) | 19 (14.9) | 0.998 |
| Chest pain, n (%) | 308 (30.7) | 46 (36.2) | 0.210 |
| Mean BMI ± SD, kg/m2 | 24.79 ± 3.73 | 25.01 ± 3.96 | 0.547 |
| Mean SBP ± SD, mmHg* | 125 ± 100 | 130 ± 90 | <0.001 |
| Mean DBP ± SD, mmHg | 78.68 ± 10.4 | 76.61 ± 40 | 0.042 |
| *Not normally distributed, Mann-Whitney U test Key: BMI = body mass index; DBP = diastolic blood pressure; IQR = interquartile range; SBP = systolic blood pressure; SD = standard deviation |
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The odds ratios demonstrating the determinants of high-risk CAC scores are presented in table 2. The unadjusted regression model observed that diabetes mellitus, hypertension, SBP, and DBP were significantly associated with CAC score classification. However, when adjusted for age, physical activity also became associated with CAC score, while the ORs of previous significant factors (hypertension, diabetes, SBP, and DBP) lowered.
Table 2. Logistic-regression models for high-risk CAC score
| Unadjusted | Simple adjusted modela | Fully adjusted modelb | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Variables | OR | 95%CI | p value | OR | 95%CI | p value | OR | 95%CI | p value |
| Hypertension | 2.91 | 1.98 to 4.28 | <0.001 | 2.10 | 1.41 to 3.14 | <0.001 | 1.83 | 1.18 to 2.84 | 0.007 |
| Dyslipidaemia | 1.06 | 0.72 to 1.56 | 0.776 | 0.95 | 0.63 to 1.42 | 0.799 | 0.87 | 0.57 to 1.33 | 0.530 |
| Familial history | 0.99 | 0.59 to 1.68 | 0.998 | 1.18 | 0.69 to 2.03 | 0.528 | 1.12 | 0.63 to 1.99 | 0.692 |
| Diabetes | 3.04 | 2.05 to 4.51 | <0.001 | 2.32 | 1.53 to 3.50 | <0.001 | 1.89 | 1.22 to 2.93 | 0.004 |
| Physically active | 0.69 | 0.47 to 1.02 | 0.070 | 0.65 | 0.43 to 0.96 | 0.032 | 0.63 | 0.41 to 0.95 | 0.029 |
| Current active smoking | 0.90 | 0.27 to 3.04 | 0.876 | 1.16 | 0.33 to 4.08 | 0.817 | 1.03 | 0.27 to 3.91 | 0.966 |
| Chest pain | 1.28 | 0.87 to 1.88 | 0.211 | 1.29 | 0.87 to 1.94 | 0.206 | 1.41 | 0.92 to 2.16 | 0.119 |
| BMI | 1.02 | 0.97 to 1.07 | 0.527 | 1.02 | 0.97 to 1.07 | 0.461 | 0.99 | 0.95 to 1.05 | 0.964 |
| SBP | 1.02 | 1.01 to 1.04 | <0.001 | 1.01 | 1.00 to 1.02 | 0.039 | 1.02 | 1.01 to 1.04 | 0.003 |
| DBP | 0.98 | 0.96 to 0.99 | 0.037 | 0.98 | 0.96 to 0.99 | 0.022 | 0.95 | 0.93 to 0.97 | <0.001 |
| a Simple regression models were adjusted only for age. b Fully adjusted regression models were adjusted for age, hypertension, dyslipidaemia, familial history, diabetes, physical activity, smoking, chest pain, BMI, SBP and DBP. Key: BMI = body mass index; CI = confidence interval; DBP = diastolic blood pressure; OR = odds ratio; SBP = systolic blood pressure |
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The logistic-regression model was statistically significant with χ2(11)=123.064, p<0.001. The fully adjusted model explained 10.3% (Cox and Snell R2) to 20.4% (Nagelkerke R2) of the variance in high-risk CAC and classified 88.4% of cases correctly. The Hosmer-Lemeshow tests indicated the data fitted well for this model. The odds of high-risk CAC increased with a history of hypertension (OR 1.830, 95%CI 1.179 to 2.843) or diabetes (OR 1.982, 95%CI 1.295 to 3.305). Elevated SBP was associated with an increased incidence of high-risk CAC (OR 1.023, 95%CI 1.008 to 1.038), while physical activity and DBP lower the likelihood of exhibiting a high-risk CAC score. Meanwhile, even after adjusting for all factors, dyslipidaemia, familial history, smoking, chest pain, and BMI were not associated with a high-risk CAC score.
Discussion
The current study found that a history of hypertension and diabetes are independent determinants of having a high-risk CAC score. Furthermore, this study demonstrated protective effects associated with physical activity and DBP. Each 1 mmHg increase in SBP raised the odds of having high-risk CAC by 2.3%, while each 1 mmHg increase in DBP decreased the odds by 5%.
This study found that hypertension was independently associated with high CAC scores in our cohort, similar to a prior investigation on the general population.5 Hypertension and CAC were suggested to be parts of a vicious cycle: calcification reduces tunica media flexibility contributing to hypertension development. Hypertension causes arterial wall trauma as a result of increased arterial pressure, or the presence of concurrent shearing events, that eventually induce calcification.6,7 To further confirm our finding on the hypertension association with CAC, we found that higher SBP independently increased the risk of having a high-risk CAC score. Our finding on SBP supported Nielsen et al.’s study result that uncontrolled hypertension increased the odds of calcification by almost two times.8
A subanalysis of the Women’s Health Initiative (WHI) trial suggested that postmenopausal women who had increased DBP had decreased odds of CAC prevalence.9 Per the Multiethnic Study of Atherosclerosis data in the general population, DBP ≤60 mmHg at baseline was related to an elevated risk of cardiovascular events and mortality.10 DBP is predominantly related to coronary blood flow and has a J-curve association with cardiovascular events.11 Our current findings matched these earlier studies. The findings of our study further confirm that women with diabetes have 1.8 times higher odds of having a high-risk CAC, similar to Hoff et al.12
Previous studies have evaluated the benefit of physical activity to the CAC scores. A study conducted by Weinberg et al. enrolling women aged 50 to 80 years found that CAC severity decreased along with increased physical activity.13 Another study comparing 26 women marathon runners and 28 sedentary controls found that women who completed marathons annually had lower CAC and smaller calcified plaque.14 Thus, our finding supported the inverse association between physical activity and high-risk CAC score.
As mentioned above, the effect of hypertension, diabetes mellitus, and SBP lowered when adjusted for age. The finding that hypertension increased along with age was reasonable and in concordance with several studies on women and global populations.15,16
In our study, dyslipidaemia was not associated with high-risk CAC scores. This finding was a contradiction to other studies. CAC score in the Dutch women population was closely associated with hypercholesterolaemia, similar to a US study.5,12 The number of smoking women included in this study might be too small to represent any result. Previous studies also presented a similar percentage of current female smokers.17,18 Therefore, it could be interpreted that active smoking might not affect the high CAC score result in Indonesian women, as the smoking prevalence in Indonesian women is low. We also found no association between high-risk CAC score and BMI in our cohort. Studies examining the connections between overweight/obesity and coronary heart disease, CVD, and all-cause mortality revealed contradictory findings.5,19 Our insignificant result might be due to both groups showing similar BMI distribution, comprising mostly normal weight and overweight women. The finding should be interpreted carefully, considering the possibility that these women may have limited knowledge and awareness of heart diseases, particularly in their family history.20
Finally, our study confirmed that only one-third of women complained of chest pain, even with high-risk CAC. Chest pain was shown not to be associated with the high-risk CAC score. Previously, women are observed to have more atypical chest pain than men.21 Thus, it can be stated that, even in the absence of typical chest pain symptoms, physicians should remain vigilant on the presence of other risk factors to provide additional examination, such as a CAC assessment.
This study’s cross-sectional and single-centered nature was a significant limitation. The available data were not designated specifically for the current study. There was also frequently a paucity of data on potential confounding factors: ethnicity, socioeconomic status, or educational level. The result also could not conclude any effect of passive smoking due to a lack of data. Despite the limitation, our study involved a large number of participants and used well-measured and standardised definitions of cardiovascular risk factors.
Conclusion
In summary, this single-centre study among women found that a history of hypertension, diabetes, and high uncontrolled SBP might be used as cues for a physician to prioritise CAC assessment, despite the absence of chest pain or atypical symptoms. Further prospective studies confirming our findings would be needed in the future.
Key messages
- One of the assessments for coronary atherosclerosis during cardiac computed tomography (CT) is coronary artery calcium (CAC) scoring
- This study conducted analysis on the determinants of high-risk coronary calcification, represented by CAC score, among women as a step to improve their outcomes and prognosis
- In women, a history of hypertension, diabetes, and high uncontrolled systolic blood pressure, might be used as cues for physicians to prioritise CAC assessment, despite the absence of chest pain or atypical symptoms
Conflicts of interest
None declared.
Funding
None.
Study approval
The Ethical Committee of Siloam Hospital Surabaya had approved this study (No. 15103/DIR-SHSB/III/2022) on 15 March 2022. As this study was retrospective and the analysis used anonymous medical-record data, informed consent was waived.
Acknowledgement
The authors would like to thank Gabrielle J Kembuan, Harvard Medical School, Boston, for providing language help and proofreading the article.
References
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