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. 2021 Apr 8;16(4):e0248884. doi: 10.1371/journal.pone.0248884

Sex differences in coronary artery calcium progression: The Korea Initiatives on Coronary Artery Calcification (KOICA) registry

Wonjae Lee 1,2, Yeonyee E Yoon 1,2,*, Sang-Young Cho 3, In-Chang Hwang 1,2, Sun-Hwa Kim 2, Heesun Lee 1,4, Hyo Eun Park 1,4, Eun Ju Chun 1,5, Hyung-Kwan Kim 1,6, Su-Yeon Choi 1,4, Sung Hak Park 7, Hae-Won Han 8, Jidong Sung 9, Hae Ok Jung 10, Goo-Yeong Cho 1,2, Hyuk-Jae Chang 11,12
Editor: Rudolf Kirchmair13
PMCID: PMC8031433  PMID: 33830992

Abstract

Even with increasing awareness of sex-related differences in atherosclerotic cardiovascular disease (ASCVD), it remains unclear whether the progression of coronary atherosclerosis differs between women and men. We sought to compare coronary artery calcium (CAC) progression between women and men. From a retrospective, multicentre registry of consecutive asymptomatic individuals who underwent CAC scoring, we identified 9,675 men and 1,709 women with follow-up CAC scoring. At baseline, men were more likely to have a CAC score >0 than were women (47.8% vs. 28.6%). The probability of CAC progression at 5 years, defined as [√CAC score (follow-up)—√CAC score (baseline)] ≥2.5, was 47.4% in men and 29.7% in women (p<0.001). When we stratified subjects according to the 10-year ASCVD risk (<5%, ≥5% and <7.5%, and ≥7.5%), a sex difference was observed in the low risk group (CAC progression at 5 years, 37.6% versus 17.9%; p<0.001). However, it became weaker as the 10-year ASCVD risk increased (64.2% versus 46.2%; p<0.001, and 74.8% versus 68.7%; p = 0.090). Multivariable analysis demonstrated that male sex was independently associated with CAC progression rate among the entire group (p<0.001). Subgroup analyses showed an independent association between male sex and CAC progression rate only in the low-risk group. The CAC progression rate is higher in men than in women. However, the difference between women and men diminishes as the 10-year ASCVD risk increases.

Introduction

Coronary artery disease (CAD) is the leading cause of death worldwide for both men and women [1]. Given the worldwide health and economic implications of atherosclerotic cardiovascular disease (ASCVD) in women, there is a strong rationale to sustain an effort to control major ASCVD risk factors and apply evidence-based therapies in women [2]. Currently, adverse trends in ASCVD risk factors among women are an ongoing concern. For example, in older adults, a higher percentage of women than men have hypertension, and the gap will likely increase in the aging society [3]. The prevalence of diabetes in women is also increasing, which exacerbates the overall risk of ASCVD [4]. Nevertheless, women are regarded as at lower risk for ASCVD than are men, and are not given aggressive preventive medications, such as statins, despite a similar benefit for both women and men [5–7].

Coronary artery calcium (CAC) is a characteristic of coronary atherosclerosis, and the detection and quantification of CAC significantly improves the risk stratification of ASCVD [8]. Especially, the importance of CAC imaging in women has been repeatedly proven, even in those with a low risk factor burden [9–12]. However, atherosclerosis is a dynamic process. While baseline CAC can be thought of as a single time point in atherosclerosis, the assessment of CAC progression provides insight into the dynamic atherosclerotic process in given individuals. Although male sex is a well-known risk factor for CAC progression [13], it has not been established whether CAC progression differs by sex. Therefore, we aimed to evaluate sex differences in CAC progression in a large cohort of asymptomatic individuals in the general population. In addition, we attempted to evaluate whether the sex difference varies according to the 10-year ASCVD risk.

Methods

Study population

This retrospective study was approved by Institutional Review Board of Seoul National University Bundang Hospital (and that of each participating institution) and conducted in accordance with the Declaration of Helsinki. The approval number was IRB No. B-1506/302-110. The need for informed consent from study participants was waived. The Korea Initiatives on Coronary Artery Calcification (KOICA) registry is an observational, retrospective, multicentre registry of Korean individuals who underwent CAC scoring as a part of a health check-up in a self-referral setting at six healthcare centres [14]. In the registry, 93,914 participants were enrolled between April 2003 and March 2017 (Fig 1). Among these, we identified 12,638 participants who underwent at least two CAC scans; however, 1,254 of these had incomplete data for the calculation of the 10-year ASCVD risk and were excluded. Finally, 11,384 participants remained for the analysis.

Fig 1. Flow chart of the study participant selection process.

Fig 1

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CAC, coronary artery calcium.

Ascertainment of risk factors

During the health check-up, sociodemographic factors, risk profiles, and medication history were collected by a detailed questionnaire. All participants underwent clinical examinations, including a physical examination and laboratory tests. The predicted 10-year ASCVD risk was estimated by using the Korean Risk Prediction Model, which is a recalibration of the Pooled Cohort Equation specifically for the Korean Population [15, 16]. The 10-year ASCVD risk takes into account the participant’s age, sex, ethnicity, total cholesterol, high-density lipoprotein (HDL) cholesterol, treatment for hypertension, systolic blood pressure, smoking, and the presence of diabetes. The study participants were classified into three groups according to their 10-year ASCVD risk: <5%, ≥5% and <7.5%, or ≥7.5% [17].

Cardiac computed tomography (CT) acquisition and analysis

Multi-detector CT scanners used to assess CAC had at least 16 slices (Siemens 16-slice Sensation, Philips Brilliance 256 iCT, Philips Brilliance 40 channel multi-detector CT, and GE 64-slice Lightspeed). CAC scores were calculated using the Agatston method [18]. The square root transformed difference was calculated [√CAC score (follow-up)—√CAC score (baseline)], and CAC progression was defined as a square root transformed difference of >2.5 to minimize the effect of interscan variability [19, 20]. For participants with more than two CT scans, the square root transformed difference was calculated for each follow-up CT scan, and the earliest follow-up scan with demonstrated CAC progression was included in the analysis. The CAC progression rate was calculated as the annualized difference between the square root of the baseline and last follow-up CAC scores.

Statistical analysis

Continuous variables are expressed as means ± standard deviation; categorical variables are expressed as proportions. The Student’s t-test and Wilcoxon rank-sum test were used to evaluate group differences in normally distributed and non-normally distributed continuous variables, respectively. Categorical variables were compared using the χ2 test or Fisher’s exact test, as appropriate. Kaplan-Meier curves were used to visualize and estimate the distribution of the time to CAC progression according to sex, with differences evaluated using the log-rank test. The earliest scan date of detected CAC progression was assigned as the occurrence of an event. We also evaluated Kaplan-Meier curves using a propensity matched cohort, with a matching ratio of 1:2 (women to men).

Univariable and multivariable linear regression analyses were performed to determine the effects of conventional coronary risk factors and the baseline CAC score on the annualized progression of the CAC score. The multivariable analysis was initiated with the following conventional risk factors (model 1): age, male sex, waist circumference, hypertension, dyslipidaemia, diabetes, current smoking, systolic blood pressure, low-density lipoprotein (LDL) cholesterol, HDL cholesterol, triglyceride, creatinine, high-sensitive C-reactive protein, and glycated haemoglobin (HbA1c). Body mass index, diastolic blood pressure, and estimated glomerular filtration rate were excluded from the multivariable analysis because of multicollinearity (variance inflation factor of 2). We also performed a multivariable analysis with the addition of the baseline CAC score to the conventional risk factors in model 1 (model 2). The results are expressed as regression coefficients (β) and the corresponding 95% confidence interval (CI). Stepwise regression under Akaike’s Information Criterion was performed to determine the appropriate multivariate linear regression model. For subgroup analyses, the variables that remained in the final model of the multivariable analysis were included.

All reported p-values are 2-tailed, and p≤0.050 was considered statistically significant. All statistical analyses were performed using R Statistical Software/environment (version 3.4.3, The R foundation for Statistical Computing, Vienna, Austria).

Results

Baseline characteristics

The 11,384 study participants consisted of 9,675 men and 1,709 women. Baseline characteristics of the study participants are provided in Table 1. Although age was not significantly different between men and women, men showed a higher proportion of conventional cardiovascular risk factors, and a higher 10-year ASCVD risk, compared to that in women. Therefore, women tended to be classified into lower risk groups. While the percentages of women with 10-year ASCVD risks of <5%, ≥5% and <7.5%, and ≥7.5% were 74.7%, 11.4%, and 13.9%, those of men were 69.2%, 14.3%, and 16.6%, respectively (p<0.001). Women also showed lower baseline CAC scores compared to those in men.

Table 1. Baseline characteristics.

All Men Women P value
(n = 11,384) (n = 9,675) (n = 1,709)
Age 51.4 ± 8.5 51.4 ± 8.2 51.7 ± 9.7 0.288
Body mass index, kg/m2 24.5 ± 2.7 24.8 ± 2.6 23.0 ± 3.0 <0.001
Waist circumference, cm 86.2 ± 8.0 87.5 ± 7.1 77.8 ± 8.6 <0.001
Systolic blood pressure, mmHg 119.5 ± 15.0 119.8 ± 14.8 117.5 ± 16.0 <0.001
Diastolic blood pressure, mmHg 75.0 ± 10.5 75.8 ± 10.4 71.0 ± 10.7 <0.001
Hypertension, n (%) 3534 (31.0%) 3133 (32.4%) 401 (23.5%) <0.001
Diabetes, n (%) 1371 (12.0%) 1246 (12.9%) 125 (7.3%) <0.001
Dyslipidaemia, n (%) 2483 (21.8%) 2178 (22.5%) 305 (17.8%) <0.001
Current smoking, n (%) 3248 (28.5%) 3121 (32.3%) 127 (7.4%) 0.072
Haemoglobin, g/dL 15.0 ± 1.3 15.3 ± 1.0 13.1 ± 1.1 <0.001
Total cholesterol, mg/dL 197.3 ± 33.9 197.1 ± 33.6 198.4 ± 35.5 0.163
HDL cholesterol, mg/dL 53.4 ± 16.0 52.0 ± 15.2 61.6 ± 17.9 <0.001
LDL cholesterol, mg/dL 121.9 ± 31.7 122.9 ± 31.3 116.1 ± 33.7 <0.001
Triglyceride, mg/dL 142.2 ± 88.8 149.1 ± 91.0 103.3 ± 61.9 <0.001
Creatinine, mg/dL 1.0 ± 0.2 1.0 ± 0.1 0.8 ± 0.1 <0.001
eGFR, ml/min/1.73 m2 88.6 ± 13.8 88.3 ± 13.3 90.6 ± 15.9 <0.001
hs-CRP, mg/dL 0.4 ± 1.8 0.4 ± 1.4 0.5 ± 3.1 0.089
Fasting glucose, mg/dL 97.7 ± 20.2 98.7 ± 20.7 92.1 ± 16.0 <0.001
HbA1C, % 5.7 ± 0.7 5.7 ± 0.8 5.7 ± 0.6 0.427
10-year ASCVD risk, % 4.6 ± 4.6 4.8 ± 4.6 3.9 ± 4.5 <0.001
    <5% 7,968 (70.0%) 6,691 (69.2%) 1,277 (74.7%) <0.001
    ≥5%, <7.5% 1,575 (13.8%) 1,381 (14.3%) 194 (11.4%)
    7.5%≥ 1,841 (16.2%) 1,603 (16.6%) 238 (13.9%)
Baseline CAC score 57.8 ± 187.6 62.7 ± 196.4 30.3 ± 123.3 <0.001
    0 6,271 (55.1%) 5,050 (52.2%) 1,221 (71.4%) <0.001
    >0, <100 3,508 (30.8%) 3,146 (32.5%) 362 (21.2%)
    ≥100 1,605 (14.1%) 1,479 (15.3%) 126 (7.4%)
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HDL: high density lipoprotein; LDL: low density lipoprotein; eGFR: estimated glomerular filtration rate; hs-CRP: high-sensitive C-reactive protein; CAC: coronary artery calcium; ASCVD: atherosclerotic cardiovascular disease; HbA1c, glycated haemoglobin

Sex differences in CAC progression

The median duration between the initial and last follow-up scan was 2.8 years for men (interquartile range, 1.9–4.1 years) and 2.6 years for women (interquartile range, 1.9–4.1 years) (p = 0.464). During follow-up, 3,131 of 9,675 men (32.4%) and 264 of 1,709 women (15.4%) experienced CAC progression. The absolute increase in CAC score in men and women was 49.8±143.4 and 19.1±76.5 (p<0.001), respectively (Fig 2A). The mean CAC progression rate for men and women was 0.9±2.0 and 0.4±1.3 (p<0.001), respectively (Fig 2B). Comparison of the cumulative proportion of CAC progression between men and women revealed that the chance of CAC progression was higher in men than in women (proportion of CAC progression at 5 years, 47.4% vs. 29.7%; p<0.001) (Fig 3).

Fig 2. CAC progression for men versus women according to the 10-year ASCVD risk score.

Fig 2

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(A) Absolute difference in the CAC score between the first and last scanning sessions, (B) Annualized progression rate of CAC. CAC, coronary artery calcium; ASCVD, atherosclerotic cardiovascular disease.

Fig 3. Kaplan-Meier 5-year CAC progression for men versus women in asymptomatic Korean individuals.

Fig 3

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CAC, coronary artery calcium.

In subgroup analyses according to the 10-year ASCVD risk, absolute changes in the CAC score and annualized CAC progression rate increased as the 10-year ASCVD risk increased in both men and women (Fig 2). Interestingly, the difference between men and women decreased as the 10-year ASCVD risk increased. The cumulative proportion of CAC progression was also compared according to the 10-year ASCVD risk (Fig 4). In the subgroup with a 10-year ASCVD risk <5%, a difference in the CAC progression between women and men was evident (proportion of CAC progression at 5 years, 37.6% versus 17.9%, respectively; p<0.001) (Fig 4A). However, the difference was less prominent in the subgroup with a 10-year ASCVD risk ≥5% and <7.5% (proportion of CAC progression at 5 years, 64.2% versus 46.2%, respectively; p<0.001), and was further diminished in the subgroup with a 10-year ASCVD risk ≥7.5% (proportion of CAC progression at 5 years; 74.8% versus 68.7%, respectively; p = 0.090) (Fig 4B and 4C).

Fig 4. Kaplan-Meier 5-year CAC progression for men versus women according to the 10-year ASCVD risk score.

Fig 4

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(A) 10-year ASCVD risk <5%, (B) 5%≤ 10-year ASCVD risk <7.5%, (C) 10-year ASCVD risk ≥7.5%. CAC, coronary artery calcium; ASCVD, atherosclerotic cardiovascular disease.

In the Kaplan-Meier curves from the propensity score matched cohort, men demonstrated a higher risk of CAC progression than did women (S1 Fig). In the subgroup analysis, men had a higher risk of CAC progression in the subgroups with a 10-year ASCVD risk <7.5% (S2A and S2B Fig), but the curves became similar between men and women in the subgroup with a 10-year ASCVD risk ≥7.5% (S2C Fig).

Association of sex with CAC progression rate

Univariable linear regression analyses showed that almost all conventional risk factors, including male sex, were significantly associated with the CAC progression rate (Table 2). In the multivariable model with conventional risk factors (model 1), male sex remained as a significant predictor, along with age, waist circumference, hypertension, diabetes, hyperlipidaemia, current smoking, LDL cholesterol, HDL cholesterol, triglyceride, creatinine, and HbA1c (Table 3). Similar results were observed in the multivariable model with the additional inclusion of the baseline CAC score (model 2). In subgroup analyses according to the 10-year ASCVD risk, male sex was independently associated with the CAC progression rate in the subgroup with a 10-year ASCVD risk <5% (model 1: β = 0.397; 95% CI, 0.158 to 0.636; p = 0.001 and model 2: β = 0.265; 95% CI, 0.030 to 0.500; p = 0.028). However, male sex did not remain an independent predictor in the subgroups with a 10-year ASCVD risk ≥5% and <7.5% (model 1: β = 0.324; 95% CI, -0.190 to 0.838; p = 0.217 and model 2: β = 0.264; 95% CI, -0.250 to 0.778; p = 0.313) and a 10-year ASCVD risk >7.5% (β = 0.220; 95% CI, -0.211 to 0.651; p = 0.317 and model 2: β = 0.149; 95% CI, -0.272 to 0.570; p = 0.494).

Table 2. Univariate analysis for factors associated with the CAC progression rate.

Univariate
Β 95% CI P value
Male sex 0.576 0.051 - 0.576 <0.001
Age 0.040 0.036 - 0.044 <0.001
Body mass index, kg/m2 0.074 0.060 - 0.088 <0.001
Waist circumference, cm 0.031 0.025 - 0.037 <0.001
Systolic blood pressure, mmHg 0.007 0.005 - 0.009 <0.001
Diastolic blood pressure, mmHg 0.007 0.003 - 0.011 <0.001
Hypertension 0.667 0.589 - 0.745 <0.001
Diabetes 0.846 0.736 - 0.956 <0.001
Dyslipidaemia 0.555 0.469 - 0.641 <0.001
Current smoking 0.162 0.084 - 0.240 <0.001
Haemoglobin, g/dL 0.074 0.047 - 0.101 <0.001
Total cholesterol, mg/dL 0.000 -0.002 - 0.002 0.616
HDL cholesterol, mg/dL -0.005 -0.007 - -0.003 <0.001
LDL cholesterol, mg/dL 0.003 0.001 - 0.005 <0.001
Triglyceride, mg/dL 0.002 0.002 - 0.002 <0.001
Creatinine, mg/dL 0.79 0.578 - 1.002 <0.001
eGFR, ml/min/1.73 m2 -0.011 -0.013 - -0.009 <0.001
hs-CRP, mg/dL -0.033 -0.055 - -0.011 0.003
Fasting glucose, mg/dL 0.011 0.009 - 0.013 <0.001
HbA1C, % 0.301 0.246 - 0.356 <0.001
10-year ASCVD risk 7.670 6.908 - 8.432 <0.001
Baseline CAC score 0.002 0.002 - 0.002 <0.001
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HDL: high density lipoprotein; LDL: low density lipoprotein; eGFR: estimated glomerular filtration rate; hs-CRP: high-sensitive C-reactive protein; CAC: coronary artery calcium; ASCVD: atherosclerotic cardiovascular disease; HbA1c, glycated haemoglobin

Table 3. Multivariate analysis for factors associated with the CAC progression rate.

Model 1a Model 2b
β 95% CI P value β 95% CI P value
Male sex 0.396 0.186 - 0.606 <0.001 0.270 0.079 - 0.459 <0.001
Age 0.032 0.026 - 0.038 <0.001 0.020 0.014 - 0.026 <0.001
Body mass index, kg/m2
Waist circumference, cm 0.012 0.006 - 0.018 0.002 0.010 0.004 - 0.016 0.006
Systolic blood pressure, mmHg
Diastolic blood pressure, mmHg
Hypertension 0.321 0.211 - 0.431 <0.001 0.253 0.143 - 0.363 <0.001
Diabetes 0.452 0.266 - 0.638 <0.001 0.368 0.184 - 0.552 <0.001
Dyslipidaemia 0.256 0.138 - 0.374 <0.001 0.254 0.138 - 0.370 <0.001
Current smoking 0.239 0.123 - 0.355 <0.001 0.225 0.109 - 0.341 <0.001
Haemoglobin, g/dL
Total cholesterol, mg/dL
HDL cholesterol, mg/dL 0.006 0.002 - 0.010 0.009 0.006 0.002 - 0.010 0.01
LDL cholesterol, mg/dL 0.002 0.000 - 0.004 0.044 0.002 0.000 - 0.004 0.025
Triglyceride, mg/dL 0.001 0.001 - 0.001 <0.001 0.001 0.001 - 0.001 <0.001
Creatinine, mg/dL 0.367 0.020 - 0.714 0.038 0.393 0.050 - 0.736 0.025
eGFR, ml/min/1.73 m2
hs-CRP, mg/dL
Fasting glucose, mg/dL
HbA1C, % 0.105 0.017 - 0.193 0.02 0.100 0.012 - 0.186 0.027
10-year ASCVD risk
Baseline CAC score 0.002 0.002 - 0.002 <0.001
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HDL: high density lipoprotein; LDL: low density lipoprotein; eGFR: estimated glomerular filtration rate; hs-CRP: high-sensitive C-reactive protein; CAC: coronary artery calcium; ASCVD: atherosclerotic cardiovascular disease; HbA1c, glycated haemoglobin

aModel 1 adjusted for male sex, age, waist circumference, hypertension, diabetes, hyperlipidaemia, current smoking, LDL cholesterol, HDL cholesterol, triglyceride, creatinine, and HbA1c.

bModel 2 adjusted for the baseline CAC score in addition to the variables in Model 1.

Discussion

The present study demonstrated a sex difference in CAC progression in a large number of asymptomatic individuals. The probability of CAC progression was higher in men than in women, and the difference grew over time. However, in subgroup analyses according to the 10-year ASCVD risk, the sex difference diminished as the 10-year ASCVD risk increased. Additionally, although male sex was independently associated with CAC progression among the entire study cohort, it maintained an independent association with CAC progression only in the subgroup with a 10-year ASCVD risk <5.0%.

Data regarding differences in CAC progression between men and women are sparse. The results of the Multi-Ethnic Study of Atherosclerosis (MESA) study suggested more rapid CAC progression in men than in women, as CAC scores were higher in men than in women and increased more rapidly with age [21]. In addition, a previous study directly showed significantly greater progression of coronary atherosclerosis (defined as progression in the CAC score or coronary atherosclerotic plaque extent/burden) in men than in women [22]. However, when CAC progression was separately analysed, no sex difference was observed. This may be due to the fact that the study population in this previous report comprised patients with suspected CAD, and the women were significantly older than the men (57.5 versus 51.9 years, p<0.001). In contrast, the present study included asymptomatic men and women, and there was not a significant sex difference in age. Additionally, we evaluated the dynamic change in CAC progression over time. The probability of CAC progression was non-linear, and the trend gradually diverged as time progressed.

In the present study, men demonstrated a higher proportion of conventional cardiovascular risk factors and higher 10-year ASCVD risk than did women. Therefore, not surprisingly, the baseline CAC score was significantly higher in men than in women. This supports the previous hypothesis that a higher burden of cardiovascular risk factors and more severe baseline coronary atherosclerosis in men contributes to the rapid progression of coronary atherosclerosis [22]. When we analysed sex differences in CAC progression according to clinical risk profiles, we found that the probability of CAC progression at 5 years in men was approximately twice that in women for the lowest 10-year ASCVD risk group. However, the gap between the probability curves was decreased in the intermediate risk group, and the curves finally merged in the highest risk group. Additionally, male sex was a significant predictor for CAC progression only in the lowest risk group. Thus, atherosclerosis progression is similar for both sexes, among those under multiple risk factors, despite an underlying sex difference. Consistent with this, the CONFIRM study reported that after propensity score matching, men and women with no or non-obstructive CAD exhibited the same rates of mortality and myocardial infarction [23]. The present data suggest that men and women at comparably high risk levels experience coronary atherosclerosis progression in a similar manner, before the onset of adverse cardiac events. Therefore, women with a high ASCVD risk profile should be screened for the presence of CAC and managed with a greater degree of attention [24].

The retrospective observational design of our study introduced several limitations. First, the present study cohort of self-referred healthy individuals may not be fully representative of the general population, and the risk of selection bias must be considered. Even though this was a large multicentre study, the number of enrolled women was smaller than that for men, and there were relatively smaller numbers of women in the higher risk groups, which may have limited the representativeness in the subgroup analyses. This reflects the fact that women seek fewer medical services than do men in this self-referred setting. Second, because of the absence of a specific study protocol guiding follow-up scanning, the interscan duration was relatively short [2.7 years (interquartile range, 1.9–4.1 years)] and was not constant. Nevertheless, the median duration between the initial and last scans did not differ between women and men. Furthermore, to minimize the potential influence of variations in the interscan duration, we analysed the association of annualized CAC progression with various cardiovascular risk factors, including male sex. Additionally, we lacked data regarding menopause and hormone replacement therapy. As postmenopausal women are under atherogenic conditions [25], it would be valuable to compare the CAC progression between postmenopausal women and age-matched men. Finally, since we lacked detailed information regarding medication use, we could not include statin use in the multivariable analysis. Considering the emerging evidence suggesting that statins impact the increase in CAC, further studies are desired to evaluate whether the prominent CAC progression in men than in women is associated with greater statin use.

Conclusion

The present study demonstrated a sex difference in CAC progression in a large number of asymptomatic individuals. Although the probability of CAC progression was higher in men than in women, subgroup analyses according to the 10-year ASCVD risk demonstrated that this difference diminished as the 10-year ASCVD risk increased.

Supporting information

S1 Fig. Kaplan-Meier 5-year CAC progression for men versus women in the propensity matched cohort.

CAC, coronary artery calcium.

(TIF)

Click here for additional data file. (58KB, tif)
S2 Fig. Kaplan-Meier 5-year CAC progression for men versus women in the propensity matched cohort according to the 10-year ASCVD risk score.

(A) 10-year ASCVD risk <5%, (B) 5%≤ 10-year ASCVD risk <7.5%, (C) 10-year ASCVD risk ≥7.5%. CAC, coronary artery calcium; ASCVD, atherosclerotic cardiovascular disease.

(TIF)

Click here for additional data file. (86.3KB, tif)

Data Availability

Due to ethical restrictions by the institutional review board committees of each participating healthcare center, the Korea Initiatives on Coronary Artery Calcification (KOICA) registry data underlying this study cannot be made publicly available, as public availability would compromise patient confidentiality and participant privacy. Therefore, access to aggregated data will be granted following review by the KOICA steering committee; data access requests can be sent to onlylhw1230@yuhs.ac.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Rudolf Kirchmair

23 Nov 2020

PONE-D-20-28584

Sex Differences in Coronary Artery Calcium Progression: the Korea Initiatives on Coronary Artery Calcification (KOICA) Registry

PLOS ONE

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Reviewer #1: Yes

**********

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Reviewer #1: Yes

**********

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Reviewer #1: This is an interesting study examining sex differences in CAC progression. The study has a number of strengths including large sample size of 9,675 men and 1,709 women with follow-up CAC scores. The authors did multivariate analysis as well as propensity matching to examine CAC progression rate in men vs women.

An important finding is that among the high-risk groups by ASCVD score, that men and women had similar rates of CAC progression, and the male predominance of progression was only more pronounced in the lower risk groups

Overall I liked this paper and think the findings are important in adding to our understanding of CAC progression among men and women

A few comments.

1. Abstract – please state how progression of CAC is defined. As progression is likely more to occur among those with baseline disease, please also state prevalence of baseline CAC >0 among men and women, or median CAC score in abstract. Men might be more likely to progress is they have more disease to start with at baseline.

2. Did you exclude people with known clinical ASCVD? Was this a population of asymptomatic individuals? I would assume so, as the 10-year risk score applies in primary prevention not secondary prevention, but it does not explicitly state that this was a population without known clinical ASCVD.

3. Time is a big risk factor for progression, need to account for time between CT scans. Individuals who had the 2 CTs close together will be less likely to have progression than if CTs were farther apart. The authors used annualized difference which I think is appropriate as it adjusts for time.

4. I am also glad the adjusted for baseline CAC, because presence or absence of baseline CAC is a driver of CAC progression.

5. Can the authors add use of statins to Table 1? What was the use of statins in this population. Statin use has been shown to actually increase the CAC score despite its known risk reduction in CVD events (statins likely transform softer plaques into more stable dense plaques). The models should adjust for statin use.

6. Table 3 – change Male gender to Male sex. Sex is the more appropriate term here than gender since you are referring to likely biological differences related to sex hormones and other biological factors.

7. Also for table 3, include a footnote about what Model 1 and Model 1 adjusted for.

8. It is disappointing that there was no menopause data in this cohort, but this was appropriately acknowledged as limitation by the authors.

9. A major limitation of the study design is that this is self-referral cohort not a population based study, so there is referral bias – but this was acknowledged by authors. Men might be more likely to be referred for a second CAC scan compared to men, and indeed

10. Another limitation that should be mentioned is the relatively short followup time between scans, and sex differences in CAC progression over a longer period (i.e >10 years) could not be examined but would be of interest.

11. This is likely beyond the scope of this paper- but perhaps for the next paper, I am interested in knowing whether CAC progression is associated with incident ASCVD events incremental to risk conferred by baseline CAC, and if so, whether that association differed by sex. Some studies but not all have shown that an elevated CAC score in women confers greater CVD risk than it does in men. So is CAC progression in women also associated with greater CVD risk than in men?

**********

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PLoS One. 2021 Apr 8;16(4):e0248884. doi: 10.1371/journal.pone.0248884.r002

Author response to Decision Letter 0

4 Jan 2021

Review Comments to the Author

Reviewer #1

This is an interesting study examining sex differences in CAC progression. The study has a number of strengths including large sample size of 9,675 men and 1,709 women with follow-up CAC scores. The authors did multivariate analysis as well as propensity matching to examine CAC progression rate in men vs women. An important finding is that among the high-risk groups by ASCVD score, that men and women had similar rates of CAC progression, and the male predominance of progression was only more pronounced in the lower risk groups. Overall I liked this paper and think the findings are important in adding to our understanding of CAC progression among men and women

1. Abstract – please state how progression of CAC is defined. As progression is likely more to occur among those with baseline disease, please also state prevalence of baseline CAC >0 among men and women, or median CAC score in abstract. Men might be more likely to progress is they have more disease to start with at baseline.

Re: Thank you for your valuable suggestion. As recommended, we have added the definition of CAC progression and the prevalence of baseline CAC>0 at baseline to the abstract as follows:

Page 3, lines 53-56: At baseline, men were more likely to have a CAC score >0 than were women (47.8% vs. 28.6%). The probability of CAC progression at 5 years, defined as [√CAC score (follow-up) - √CAC score (baseline)] ≥2.5, was 47.4% in men and 29.7% in women (p<0.001).

2. Did you exclude people with known clinical ASCVD? Was this a population of asymptomatic individuals? I would assume so, as the 10-year risk score applies in primary prevention not secondary prevention, but it does not explicitly state that this was a population without known clinical ASCVD.

Re: Thank you for your valuable comment. First, we would like to explain how Korean health check-up centres work. Once every two years, Koreans may undergo health check-ups that are fully covered by the national health insurance system; however, if they wish, they can undergo the health check-up at specialized health check-up centres that do not receive any insurance coverage. In the former case, CAC scoring is not included in the health check-up program, whereas, in the latter case, individuals can choose the tests performed, including CAC scoring, and the costs are borne by the patients or their employer. Of course, patients with prior ASCVD can visit health check-up centres in a self-referral setting. However, most health check-up centres do not recommend CAC scoring in patients with known or suspected ASCVD, referring such patients to specialists. Therefore, the KOICA registry, with participants recruited from six healthcare centres, comprises apparently healthy individuals who underwent CAC scanning as a part of a health check-up.

When we evaluated prior ASCVD based on the responses to self-administered questionnaires, 683 (6.0%) participants indicated that they were diagnosed with ASCVD. However, considering the real clinical situation in Korea, these self-reported ASCVDs usually do not refer to the presence of angiographically proven significant CAD or ischemic stroke diagnosed based on brain MRI, but rather refer to the experience of atypical chest pain, facial palsy, or numbness, etc. Furthermore, considering that most health check-up centres do not recommended CAC scoring for patients with clinically significant ASCVD, we did not exclude patients with self-reported ASCVD. Nevertheless, when we performed the primary statistical analyses after the exclusion of participants with self-reported ASCVD (n=683) and those who did not indicate whether or not they had prior ASCVD (n=292), the results were not significantly changed. The figures corresponding to Fig 3 and Fig 4-C in the manuscript file, as well as the table corresponding to Table 3, are shown below. Therefore, we consider our decision to include these individuals to be reasonable.

 

Response Letter Figure 1 (corresponding to Fig 3 in the manuscript). Kaplan-Meier 5-year CAC progression for men versus women in asymptomatic Korean individuals -> refer to the attached file

Response Letter Figure 2 (corresponding to Fig 4A-C in the manuscript). Kaplan-Meier 5-year CAC progression for men versus women according to the 10-year ASCVD risk score. (A) 10-year ASCVD risk <5%, (B) 5%≤ 10-year ASCVD risk <7.5%, (C) 10-year ASCVD risk ≥7.5%. -> refer to the attached file

Response Letter Table 1 (corresponding to Table 3 in the manuscript). Multivariate analysis for factors associated with the CAC progression rate -> refer to the attached file

HDL: high density lipoprotein; LDL: low density lipoprotein; eGFR: estimated glomerular filtration rate; hs-CRP: high-sensitive C-reactive protein; CAC: coronary artery calcium; ASCVD: atherosclerotic cardiovascular disease; HbA1c, glycated haemoglobin

aModel 1 adjusted for male sex, age, waist circumference, hypertension, diabetes, hyperlipidaemia, current smoking, LDL cholesterol, HDL cholesterol, triglyceride, creatinine, and HbA1c.

bModel 2 adjusted for the baseline CAC score in addition to the variables in Model 1.

3. Time is a big risk factor for progression, need to account for time between CT scans. Individuals who had the 2 CTs close together will be less likely to have progression than if CTs were farther apart. The authors used annualized difference which I think is appropriate as it adjusts for time.

Re: We share the reviewer’s concern regarding the potential effect of variations in the interscan duration. Although the interscan duration in men [median 2.8 years, (IQR 1.9-4.1)] was similar to that in women [median 2.6 years (IQR 1.9-4.1)], we took great care to minimize the effect of variations in the interscan duration. Specifically, we calculated the annualized CAC progression rate and evaluated the association between the annualized CAC progression rate and various cardiovascular risk factors, including male sex. This information has been added to the limitations section.

Page 21, lines 314-321: Furthermore, to minimize the potential influence of variations in the interscan duration, we analysed the association of annualized CAC progression with various cardiovascular risk factors, including male sex.

4. I am also glad the adjusted for baseline CAC, because presence or absence of baseline CAC is a driver of CAC progression.

Re: Thank you for pointing out this oversight. As you have pointed out, previous studies demonstrated that baseline CAC independently predicts CAC progression. (Atherosclerosis 2014;232:339–345). In the current study, there was a difference in baseline CAC score between men and women. Furthermore, baseline CAC was independently associated with the annualized CAC progression rate, as expected. Considering the effect of the baseline CAC score, we used two different multivariate models, with and without the baseline CAC score, to evaluate whether the association between male sex and CAC progression was affected by the baseline CAC score (Table 3). We have added footnotes to Table 3 to clarify the two models (see the response to #7).

5. Can the authors add use of statins to Table 1? What was the use of statins in this population. Statin use has been shown to actually increase the CAC score despite its known risk reduction in CVD events (statins likely transform softer plaques into more stable dense plaques). The models should adjust for statin use.

Re: We greatly appreciate your comment. We completely agree that it is very important to consider statin’s effect on CAC progression. However, unfortunately, as the questionnaire was self-administered, the collected medication history was incomplete; only 20% of study participants answered the question regarding statin use. Considering the low response rate reading medication usage, we did not include statin use in the analysis in the current study. Nevertheless, as this is an important issue, we have added the following sentence to the limitations section:

Page 21, lines 318-322: Finally, since we lacked detailed information regarding medication use, we could not include statin use in the multivariable analysis. Considering the emerging evidence suggesting that statins impact the increase in CAC, further studies are desired to evaluate whether the prominent CAC progression in men than in women is associated with greater statin use.

6. Table 3 – change Male gender to Male sex. Sex is the more appropriate term here than gender since you are referring to likely biological differences related to sex hormones and other biological factors.

Re: Thank you for your valuable comment. We agree with the reviewer and prefer “male sex” over “male gender”. We have modified Table 3 accordingly (see the response to comment #7).

7. Also for table 3, include a footnote about what Model 1 and Model 1 adjusted for.

Re: Thank you for your suggestion. We have added footnotes as follows:

Table 3. Multivariate analysis for factors associated with the CAC progression rate -> refer to the attached file

HDL: high density lipoprotein; LDL: low density lipoprotein; eGFR: estimated glomerular filtration rate; hs-CRP: high-sensitive C-reactive protein; CAC: coronary artery calcium; ASCVD: atherosclerotic cardiovascular disease; HbA1c, glycated haemoglobin

aModel 1 adjusted for male sex, age, waist circumference, hypertension, diabetes, hyperlipidaemia, current smoking, LDL cholesterol, HDL cholesterol, triglyceride, creatinine, and HbA1c.

bModel 2 adjusted for the baseline CAC score in addition to the variables in Model 1.

　

10. Another limitation that should be mentioned is the relatively short follow-up time between scans, and sex differences in CAC progression over a longer period (i.e >10 years) could not be examined but would be of interest.

Re: Thank you for your valuable comment. We agree that examining the long-term trend in CAC progression, as well as sex differences in this trend, would be a very interesting topic. Therefore, we have added the following sentence to the limitations section:

Page 21, lines 308-314: Second, because of the absence of a specific study protocol guiding follow-up scanning, the interscan duration was relatively short [2.7 years (interquartile range, 1.9-4.1 years)] and was not constant. Nevertheless, the median duration between the initial and last scans did not differ between women and men. Furthermore, to minimize the potential influence of variations in the interscan duration, we analysed the association of annualized CAC progression with various cardiovascular risk factors, including male sex.

11. This is likely beyond the scope of this paper- but perhaps for the next paper, I am interested in knowing whether CAC progression is associated with incident ASCVD events incremental to risk conferred by baseline CAC, and if so, whether that association differed by sex. Some studies but not all have shown that an elevated CAC score in women confers greater CVD risk than it does in men. So is CAC progression in women also associated with greater CVD risk than in men?

Re: We appreciated the opportunity to discuss this interesting topic with you. To our knowledge, CAC progression is known to be associated with incident ASCVD events, even after adjustment for baseline CAC (JACC Cardiovascular Imaging 2016;9(12):1420-1429). However, as you mentioned, whether the association differs by sex was not evaluated. It would be noteworthy to investigate whether CAC progression in women has a similar impact on the risk of ASCVD to that in men. In fact, KOICA investigators are currently preparing an outcome study; thus, we hope that we will be able to answer your question in our next project.

Attachment

Submitted filename: Review_Comments_to_the_Author_editing_final.docx

Click here for additional data file. (1.9MB, docx)

Decision Letter 1

Rudolf Kirchmair

8 Mar 2021

Sex Differences in Coronary Artery Calcium Progression: the Korea Initiatives on Coronary Artery Calcification (KOICA) Registry

PONE-D-20-28584R1

Dear Dr. Yoon,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Rudolf Kirchmair

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: All of my prior comments have been sufficiently addressed by authors. Thank you. No further comments from me at this time.

The authors have indicated that data would be made available upon request after review by IRB and with data sharing agreement, and I agree with that. Many other cohorts (such as MESA) have similar restrictions about sharing data. I do not see a problem with this approach.

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Acceptance letter

Rudolf Kirchmair

31 Mar 2021

PONE-D-20-28584R1

Sex differences in coronary artery calcium progression: the Korea Initiatives on Coronary Artery Calcification (KOICA) registry

Dear Dr. Yoon:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Fig. Kaplan-Meier 5-year CAC progression for men versus women in the propensity matched cohort.

    CAC, coronary artery calcium.

    (TIF)

    Click here for additional data file. (58KB, tif)
    S2 Fig. Kaplan-Meier 5-year CAC progression for men versus women in the propensity matched cohort according to the 10-year ASCVD risk score.

    (A) 10-year ASCVD risk <5%, (B) 5%≤ 10-year ASCVD risk <7.5%, (C) 10-year ASCVD risk ≥7.5%. CAC, coronary artery calcium; ASCVD, atherosclerotic cardiovascular disease.

    (TIF)

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    Data Availability Statement

    Due to ethical restrictions by the institutional review board committees of each participating healthcare center, the Korea Initiatives on Coronary Artery Calcification (KOICA) registry data underlying this study cannot be made publicly available, as public availability would compromise patient confidentiality and participant privacy. Therefore, access to aggregated data will be granted following review by the KOICA steering committee; data access requests can be sent to onlylhw1230@yuhs.ac.

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