Cardiovascular risk factors and pericardial fat volume as predictors of coronary atherosclerosis burden in postmenopausal women: A retrospective, single center study

Abstract

Background and Aims

Little is known about the clinical relevance of pericardial fat volume (PFV), compared to other conventional cardiovascular risk factors, as predictors of coronary atherosclerosis severity among postmenopausal women. Our main aim was to assess the association of PFV and cardiovascular risk factors with coronary atherosclerosis burden, including occlusive coronary artery disease (CAD) (luminal stenosis >50%), coronary artery calcium score (CAC) >100, and plaque types in postmenopausal women.

Methods

Patients who had chest pain of angina and referred for 64‐slice multi‐detector CT (MDCT) angiography examination to exclude occlusive CAD presence were enrolled in this retrospective study.

Results

A total of 241 women with absence of menses for more than 2 consecutive years and not taking hormone replacement therapy were enrolled in the present study. Increased PFV (OR [CI] = 1.1 [1−1.3], p = 0.004), age (OR [CI] = 1.1 [1−1.4], p = 0.002), and diabetes mellitus (OR [CI] = 2 [1−4], p = 0.025) were significant predictors of occlusive CAD presence. Increased PFV (OR [CI] = 1.1 [1−1.4], p = 0.017) and increased age (OR [CI] = 1.2 [1.1−1.4], p < 0.001) were better predictors of CAC >100 than other cardiovascular risk factors. Regarding coronary plaque types, increased age (OR [CI] = 1.1 [1.1−1.3], p = 0.001) showed a significant association with coronary calcified plaque presence while increased body mass index(OR [CI] = 1.2 [1−1.4], p = 0.018) showed a significant association with coronary non‐calcified plaque presence.

Conclusion

Higher PFV values showed an independent association with occlusive CAD and significant coronary calcification. This may imply that increased PFV is likely associated with the development of advanced and severe phenotype of coronary atherosclerosis among postmenopausal women with suspected CAD.

1. INTRODUCTION

There is significant sex‐related differences in the prevalence, presentation, and adverse outcome of coronary artery disease (CAD). ¹ , ² During menopausal transition, women undergo significant changes in the body fat composition and deposition, cardiovascular risk profiles, and vascular remodeling that increased the risk of CAD after menopause. ³ Recent clinical data demonstrate that women have a higher mortality rate than men, and with greater prevalence of non‐obstructive CAD compared with men presenting with similar symptoms. ¹ Indeed, symptomatic women with CAD usually come to medical attention 10−15 years later than symptomatic men, and they often have a higher clustering of cardiovascular risk factors, coronary microvascular disease, and endothelial dysfunction in comparison to men. ² However, recognition of CAD is often delayed and conventional cardiovascular risk factors have a limited or nonspecific role in disease prediction and risk stratification compared to men and additional clinical markers are required to refine risk‐stratification in postmenopausal women.

Recently, pericardial fat deposition is reported to be related to CAD through its close anatomical relationship with coronary artery and heart and its active secretion of several pro‐atherogenic and proinflammatory adipokines. ⁴ , ⁵ Two large clinical studies, MESA and the Framingham Heart Study, reported that increased pericardial fat deposition is a predictor for cardiovascular disease independent of conventional risk factors, including body mass index (BMI) and other measures of obesity. ⁶ , ⁷ In the literature, significant sexual dimorphism in adipose tissue deposition and distribution has been reported. After a woman goes through menopause, fat shifts toward visceral sites, correlating with a rise in cardio‐metabolic risks. ⁴ This significant fat redistribution may be connected to alterations in sex hormone concentrations after menopause. ⁴ , ⁵ , ⁶ However, little is known about the clinical relevance of pericardial fat volume (PFV), compared to other conventional cardiovascular risk factors, as a potential predictor of coronary atherosclerosis severity among postmenopausal women.

We aimed to assess the association of PFV and cardiovascular risk factors with coronary atherosclerosis burden, including occlusive CAD (luminal stenosis >50%), coronary artery calcium score (CAC) >100, and plaque types in postmenopausal women with suspected CAD.

2. METHODS

This retrospective study was conducted at Al‐Sader Teaching Hospital between January 2013 and February 2021. Patients with chest pain suggestive of angina and low‐to‐intermediate pretest probability of CAD who were referred for multi‐detector CT (MDCT) angiography examination to rule out the presence of occlusive CAD were included in this study. A flow chart describing patients enrollment in the study is presented in Figure 1. Information related to the individual's cardiovascular risk factors was gathered at the time of MDCT examination, as in our earlier study. ⁵

Figure 1.

Flow chart for the study population. CAD, coronary artery disease; MDCT, multi‐detector CT.

Postmenopausal status was defined as an absence of menses for more than 2 consecutive years without taking hormone replacement therapy. After receiving approval from the medicine college board, patients who agreed to participate in the study were asked to provide verbal informed consent.

2.1. MDCT examination

A 64‐slice scanner was used to perform coronary angiography (Aquilon 64, v. 4.51 ER 010; Toshiba Medical Systems), with retrospective electrocardiography gating, as described in detail previously. ⁵

A CT scan without contrast dye was used to measure the CAC using the Agatston method. This involved taking sequential scans of the entire heart with a slice thickness of 3 mm. CAC >100 was categorized as significant coronary calcification. The amount of fat tissue located inside the pericardial sac was calculated three‐dimensionally using contrast‐enhanced phase imaging. Occlusive CAD was defined as a significant reduction of >50% in the diameter of at least one coronary vessel. For coronary plaque analysis, a plaque was defined as a structure of >1 mm within and/or adjacent to the coronary artery lumen. Plaques were classified, based on visual assessment, into calcified (>70% calcification) and non‐calcified (soft) plaque (without any calcification). Two radiologists with extensive experience in interpreting coronary MDCT angiograms independently analyzed the data.

2.2. Statistical analysis

A priori sample size was not determined, and the sample size equaled the number of postmenopausal women who were referred for MDCT examination during the research period. Continuous data were presented as mean ± standard deviation, and the categorical data as numbers with percentages. Kolmogorov−Smirnov test was used to measure the normal distribution of the variables. A multivariate binary regression analysis was used to assess the odds ratio and 95% confidence interval (OR [CI]) for the association of PFV and cardiovascular risk factors, including age, positive family history of CAD, diabetes mellitus, smoking, hypertension, and BMI with coronary atherosclerosis markers, including occlusive CAD presence, CAC >100, and coronary plaque types. We considered two‐sided p value less than 0.05 as significant. All statistical analyses were performed using the SPSS for Windows ver. 23.0 (SPSS Inc.).

3. RESULTS

A total of 241 women (mean age = 59 ± 6 years) with an absence of menses for more than 2 consecutive years and not taking hormone replacement therapy were enrolled in the present study. The prevalence of cardiovascular risk factors was as follows: 73% for hypertension, 56% for obesity, 28% for diabetes mellitus, 22% for family history, and 11% for smoking. The mean PFV was 126 ± 60 cm.³ The prevalence of occlusive CAD and CAC >100 were 35% and 20%, respectively. Coronary plaque was observed in 53% of postmenopausal women. The prevalence of calcified and non‐calcified plaques were 44% and 9%, respectively. The clinical characteristics are presented in Table 1.

Table 1.

Patients characteristics.

Variable	Mean ± SD or n (%) or median (IQR)
Age (years)	59 ± 6
BMI	30 ± 5
Obesity (BMI ≥ 30)	136 (56)
Hypertension	157 (73)
Smoking	27 (11)
Diabetes mellitus	68 (28)
Family history	52 (22)
Coronary calcium score	3 (0−70)
CAC > 100	49 (20)
PFV (cm)3	126 ± 60
Occlusive CAD	85 (35)
Coronary plaque
Absent plaque	113 (47)
Plaque presence	128 (53)
Non‐calcified plaque	22 (9)
Calcified plaque	106 (44)

Abbreviations: BMI, body mass index; CAC, coronary artery calcium; CAD, coronary artery disease; PFV, pericardial fat volume; SD, standard deviation.

3.1. Multivariate binary regression analyses

Increased PFV (OR [CI] = 1.1 [1−1.3], p = 0.004), increased age (OR [CI] = 1.1 [1−1.4], p = 0.002), and diabetes mellitus (OR [CI] = 2 [1−4], p = 0.025) were significant predictors of occlusive CAD presence, as in Table 2. Increased PFV (OR [CI] = 1.1 [1−1.4], p = 0.017) and increased age (OR [CI] = 1.2 [1.1−1.4], p < 0.001) were better predictors of CAC >100 than other cardiovascular risk factors, as in Table 3.

Table 2.

Multivariate binary logistic regression analysis to assess predictors of occlusive CAD.

	Occlusive CAD
Predictor	OR (CI)	p Value
PFV	1.1 (1−1.3)	0.004
BMI	1 (0.9−1.1)	0.077
Age	1.1 (1−1.4)	0.002
Hypertension	0.7 (0.3−1.4)	0.415
Smoking	1.1 (0.4−3)	0.724
Diabetes mellitus	2 (1−4)	0.025
Family history	1.5 (0.7−3)	0.225

Abbreviations: BMI, body mass index; CAD, coronary artery disease; PFV, pericardial fat volume.

Table 3.

Multivariate binary logistic regression analysis to assess predictors of CAC (coronary calcium score >100).

	CAC
Predictor	OR (CI)	p Value
PFV	1.1 (1−1.4)	0.017
BMI	1 (0.9−1.1)	0.435
Age	1.2 (1.1−1.4)	<0.001
Hypertension	0.7 (0.3−1.6)	0.460
Smoking	0.8 (0.2−2.5)	0.707
Diabetes mellitus	1.5 (0.7−3)	0.283
Family history	0.7 (0.3−1.9)	0.596

Abbreviations: BMI, body mass index; OR, odds ratio; PFV, pericardial fat volume.

Regarding coronary plaque types, we observed a statistically significant association between increased age (OR [CI] = 1.1 [1.1−1.3], p = 0.001) and coronary calcified plaque presence while increased BMI (OR [CI] = 1.2 [1−1.4], p = 0.018), but not PFV or other cardiovascular risk factors, exhibited a statistically significant association with coronary non‐calcified plaque presence, as in Tables 4 and 5.

Table 4.

Multivariate binary logistic regression analysis to assess predictors of coronary calcified plaque presence.

	Coronary calcified plaque
Predictor	OR (CI)	p Value
PFV	1 (0.9−1.1)	0.302
BMI	1 (0.9−1.2)	0.207
Age	1.1 (1.1−1.3)	0.001
Hypertension	1 (0.6−2)	0.701
Smoking	1.8 (0.7−4)	0.199
Diabetes mellitus	1.3 (0.7−2.5)	0.385
Family history	1.4 (0.6−2)	0.370

Abbreviations: BMI, body mass index; OR, odds ratio; PFV, pericardial fat volume.

Table 5.

Multivariate binary logistic regression analysis to assess predictors of coronary non‐calcified (soft) plaque presence.

	Coronary non‐calcified plaque
Predictor	OR (CI)	p Value
PFV	1 (0.9−1.2)	0.552
BMI	1.2 (1−1.4)	0.018
Age	0.9 (0.9−1.1)	0.767
Hypertension	0.8 (0.3−2)	0.677
Smoking	0.3 (0.1−2.6)	0.297
Diabetes mellitus	1.7 (0.6−4.6)	0.236
Family history	1.4 (0.5−4)	0.456

Abbreviations: BMI, body mass index; OR, odds ratio; PFV, pericardial fat volume.

4. DISCUSSION

The findings of this study indicated that increased PFV and age were significant predictors for obstructive CAD and CAC >100 in postmenopausal women with suspected CAD. Additionally, there was an independent association between increased BMI, but not PFV or other cardiovascular risk factors, and non‐calcified plaque presence.

Women during the menopausal transition may experience significant metabolic changes such as increased central fat deposition and reduced muscle mass, as well as bone resorption, all of which could raise the risk of CAD. Previous clinical studies have reported that postmenopausal women tend to have expanded PFV, which can lead to cardiac and coronary abnormalities regardless of age, hypertension, diabetes, dyslipidemia, menopausal age, and BMI. The deleterious effects of increased pericardial fat deposition could be a result of systemic inflammation caused by altering the balance of secreting adipokines and cytokines toward pro‐atherogenic and proinflammatory conditions through the paracrine and vasocrine routes. ⁸ , ⁹

Consistent with our results, de Vos et al. and Bettencourt et al. reported a significant association between pericardial fat deposition and coronary calcification. Moreover, PFV and intrathoracic fat volume, as assessed by coronary CT angiography, was found to have a statistically significant relationship with CAC and occlusive CAD in women with suspected CAD, but not in men. The authors proposed that PFV may provide a better predictive value beyond traditional cardiovascular risk factors, particularly in older women. ¹⁰ , ¹¹

The potential mechanisms for the association between obesity and coronary atherosclerosis in older women remain elusive. Estrogen may have a potential role both in the atherosclerosis process and obesity in postmenopausal women. Several clinical reports have suggested a possible role of menopause‐related changes in sex hormones balance in the development of coronary atherosclerosis and obesity. ⁴ Estrogen receptor is expressed in subcutaneous, visceral fatty tissues, and endothelial cells of blood vessels. The activation of these receptors is associated with decreased levels of several proinflammatory and pro‐atherogenic adipokines involved in the process of atherosclerosis. Hence, lower levels might lead to obesity and coronary atherosclerosis among postmenopausal women through increases in the deposition of visceral and subcutaneous fat deposition and changes in energy expenditure. ⁴ , ¹²

Compared to men, women have smaller coronary luminal area and more non‐calcified (soft) plaques, which may lead to acute non‐ST segment elevation myocardial infarction. ² , ¹³ , ¹⁴

In the MESA study, non‐calcified plaques, which cannot be detected on coronary calcium score scan or conventional coronary angiography, are associated with acute coronary events and worse prognosis than calcified plaque. ¹⁵ Data from another MESA Study reported that increased pericardial fat deposition was associated with plaque eccentricity, as a marker of coronary atherosclerosis, and plaque burden in men but not in women, suggesting that sex‐specific factors and coronary plaque type can have an impact on the risk level in women, that is, different from the traditional male pattern. ² , ¹⁶

Furthermore, a prospective study consisting of 224 asymptomatic patients (103 women with mean age, 61.8 years) who underwent coronary CT angiography was conducted to assess the relationship between coronary plaque burden and cardiovascular risk factors. The findings reported that non‐calcified plaques were associated with shorter disease duration and increased BMI, similar to findings in the present study. ¹⁷

Taken together, our findings, in addition to the results from previous studies, may suggest that PFV and BMI are linked to CAD risk in postmenopausal women by different pathways. Increased PFV is likely associated with the development of advanced and severe coronary atherosclerosis. On the other hand, increased BMI is likely to increase the risk of acute coronary events before plaque calcification among postmenopausal women.

The present study has some limitations that need to be addressed. The findings of this retrospective study do not provide information regarding the cause‐effect relationship between PFV and cardiovascular risk factors with coronary atherosclerosis burden. Hyperlipidemia, as a cardiovascular risk factor, was not included in the statistical analysis due to the absence of lipid profile data or because women were already on lipid‐lowering drugs. We do not know if the lack of an association between PFV and non‐calcified plaque is a result of type II error because of the low prevalence of non‐calcified plaque in our study. Additionally, the significant association between increased BMI and non‐calcified plaque presence should be interpreted with caution, given the high prevalence of obesity among postmenopausal women in our study.

Conclusion, higher PFV values were an independent predictor of occlusive CAD and significant coronary calcification. BMI showed a significant association with coronary non‐calcified plaque presence. These results may suggest that increased PFV is likely associated with the development of advanced and severe phenotype of coronary atherosclerosis among postmenopausal women with suspected CAD.

AUTHOR CONTRIBUTIONS

Conceptualization: Hussein Nafakhi, Abdulameer A. Al‐Mosawi, and Qais Q. Malik Alkhalil. Formal analysis: Hussein Nafakhi, Abdulameer A. Al‐Mosawi, and Qais Q. Malik Alkhalil. Data collection: Hussein Nafakhi and Abdulameer A. Al‐Mosawi. Writing—review and editing: Hussein Nafakhi and Abdulameer A. Al‐Mosawi. Writing—original draft: Hussein Nafakhi. All authors have read and approved the final version of the manuscript. Corresponding author had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

TRANSPARENCY STATEMENT

The lead author Hussein Nafakhi affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Nafakhi H, Al‐Mosawi AA, Alkhalil QQM. Cardiovascular risk factors and pericardial fat volume as predictors of coronary atherosclerosis burden in postmenopausal women: a retrospective, single center study. Health Sci Rep. 2023;6:e1155. 10.1002/hsr2.1155

DATA AVAILABILITY STATEMENT

The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.