Epicardial adipose tissue and its association with cardiovascular risk factors and mitral annular calcium deposits

Abstract

Introduction

Epicardial fat is a variety of visceral adipose tissue that secretes pro-inflammatory cytokines that can lead to progression of atherosclerosis. Previous studies have shown a correlation between cardiovascular risk factors and severity of mitral annular calcification. The aim of our study was to assess the correlation between epicardial fat thickness and mitral annular calcification.

Methods

This study recruited 188 patients who were considered for coronary angiography and underwent echocardiography within 24 hours of admission. Epicardial fat thickness was measured in the parasternal long axis view at the end-systole. Mitral annular calcification was visualized in the parasternal short-axis view and was grade as none, mild, moderate, and severe. Furthermore, left atrial diameter, severity of mitral regurgitation, left ventricular ejection fraction, and early diastolic velocities (E wave) determined by transmitral pulsed Doppler, the early mitral annular velocities measured by tissue Doppler (e′), and E/e′ were obtained.

Results

Patients with an epicardial fat thickness ≥7 mm had higher prevalence of hypertension and higher SYNTAX score (p value = 0.002 and 0.0014, respectively). Also, mitral annular calcification was both more prevalent and more extensive (p value = 0.007 and <0.001, respectively) and left atrial diameter was larger in these patients compared with patients with epicardial fat thickness <7 mm (p value = 0.001).

Conclusions

Our study showed significant association between increased epicardial fat thickness and calcium deposits in the mitral valve annulus that is a degenerative process associated with cardiovascular risk factors.

Keywords

Echocardiography epicardial fat thickness mitral annular calcification

Introduction

Epicardial fat is a variety of visceral adipose tissue which is located below the visceral pericardium.¹ Beyond multiple physiological roles, epicardial fat produces several pro-inflammatory cytokines that can accelerate coronary atherosclerosis via smooth muscle cell proliferation, increased oxidative stress, apoptosis, and neovascularization and is associated with insulin resistance, coronary calcium deposits, and presence and severity of coronary artery disease (CAD).^2,3 Mitral annular calcification (MAC) and atherosclerosis share common risk factors and histopathological findings. MAC has been associated with an increased risk of ischemic stroke, coronary atherosclerosis, cardiac conduction defects, coronary events, and all-cause mortality and is an important indicator of higher prevalence of severe stenosis in at least one major epicardial coronary artery and is a predictor of the presence of triple vessel disease or left main (LM) coronary artery stenosis in patients presenting with chest pain. Patients with MAC also have a higher prevalence of aortic atheroma and protruding atheroma that may explain the increased risk of stroke in these patients. There is an association between MAC with age, female sex, hypertension, diabetes mellitus, and hyperlipidemia. Echocardiography is a non-invasive, commonly used, and easily accessible diagnostic tool applied to evaluate patients with acute coronary syndrome (ACS).⁴ The two-dimensional echocardiography can clearly detect MAC as an echo-dense structure situated at the junction of the atrioventricular groove and posterior leaflet of the mitral valve, and can be helpful in estimation of ischemic risk and determining the prognosis of ACS patients.^5,6 Few studies have evaluated the association between epicardial fat thickness (EFT) and MAC.³ The aim of our study was to assess this association in patients who were considered for coronary angiography.

Methodology

Our study was a historical cohort study of 188 patients who were admitted to our hospital and considered for coronary angiography between 2017 and 2018. This study was conducted in accordance with the guidelines of Helsinki Declaration and was approved by the ethic committee of our hospital. A written informed consent was obtained from all study participants. Patients with ST segment elevation greater than 0.1 mV in leads other than V1 or aVR, mitral or aortic stenosis (AS), autoimmune or collagen vascular disorders, chronic kidney disease, left bundle branch block, atrioventricular conduction defects, and significant primary valvular heart diseases were excluded from the study. Diabetes mellitus (DM) was defined as the guidelines of the American Diabetes Association or need to take insulin or oral hypoglycemic drugs.⁷ Hypertension (HTN) was defined as a systolic blood pressure of 140 mm Hg or more and/ or a diastolic blood pressure of 90 mm Hg or more or need to take antihypertensive medication.⁸ Family history (FH) was defined as having a first-degree relative with CAD before the age of 55 years in males or before the age of 65 years in females.⁹ Hyperlipidemia (HLP) was characterized by serum cholesterol levels above 5.5 mmol/L, high-density lipoprotein-cholesterol levels below 1.0 mmol/L in men, or below 1.1 mmol/L in women.¹⁰ Cigarette smoking was determined by a face-to-face interview. Cardiac troponin-I (TnI) plasma level was determined by an electrochemiluminescence immunoassay technique and concentration of creatine kinase-MB (CKMB) in plasma was measured by an auto analyzer (Erba Mannheim) with direct measurement of its enzymatic activity.

Echocardiography

Transthoracic echocardiography was performed in all patients within 24 hours of admission by a Vivid S5 (GE Healthcare, Wauwatosa, WI). The images were stored on a hard disk for better off-line analysis and were interpreted by one experienced echocardiographer blinded to the patients' data. Left ventricular ejection fraction (LVEF) was calculated by subtracting left ventricular end-diastolic volume (LVEDV) from left ventricular end-systolic volume divided by LVEDV using the biplane Simpson's method in both apical four-chamber and two-chamber views.¹¹ Pulse Doppler early (E wave) and late (A wave) transmitral peak flow velocities and the ratio of early to late transmitral diastolic velocity (E/A) were obtained by placing cursor at the mitral leaflet tips from the apical four-chamber view. Early diastolic mitral annular velocity (e′) was measured by placing cursor at the septal and lateral sides of the mitral annuli and their average in the apical four-chamber view. Tissue Doppler E/e′ was calculated by dividing pulse Doppler E wave velocity to tissue Doppler e′ velocity.¹² Mitral regurgitation (MR) severity as grade as none, mild, moderate, and severe according to guidelines of American society of cardiology.¹³ Left atrial (LA) antero-posterior diameter was defined as the vertical distance between LA anterior and posterior walls in the para-sternal long axis view at the end of systole. Epicardial fat was defined as a hypoechoic space located anterior to the right ventricular wall between the outer wall of the myocardium and the visceral pericardium, its thickness was measured at the point vertical to the aortic annulus in para sternal long-axis view at the end-systole in an average of three cardiac cycle (Figure 1).¹⁴ Previous studies showed that the risk of coronary atherosclerosis is higher in patients with EFT 7 mm or more compared with patients with a lower thickness.¹⁵ Therefore, we divide patients into two groups according to the EFT: a group with a thickness of less than 7 mm and other group with 7 mm or more. MAC was defined as an echo-dense structure with an irregular, rough appearance located at the junction of the atrioventricular groove and posterior mitral leaflet in parasternal short-axis view at the level of the mitral annulus and was grade as mild (involves less than one-third of the annulus), moderate (affects between one-third and two-third of the annulus), and severe (involves more than two-third of the annulus circumference; Figure 2).¹⁶

Figure 1.

Transthoracic two-dimensional echocardiography in the parasternal long-axis view, demonstrating epicardial fat thickness (arrow).

Figure 2.

Transthoracic two-dimensional echocardiography in the parasternal short-axis view, demonstrating different degrees of mitral annular calcification (MAC) including mild, moderate, and severe.

Angiography

All patients underwent coronary angiography within 48 hours after hospitalization by a Siemens AG (Medical Solutions; Erlangen, Germany). The angiograms were interpreted by an experienced cardiologist blinded to the patients' data. Significant CAD was defined as 50% or greater coronary lumen stenosis in the LM or greater than 70% in other epicardial coronary arteries.¹⁷ Furthermore, we assess the complexity of CAD using the SYNTAX score.¹⁸

Statistical analysis

We represented continuous variables as mean ± standard deviation, and categorical variables as frequency and percentile. An independent t test was used to compare continuous variables, and chi-square and Fisher's exact tests were utilized to compare categorical variable. Again, we used a logistic regression model to determine independent effect of different variables in predicting MAC. A p value less than 0.05 was considered significant. All statistical analyses were done by SPSS/PASW (Predictive Analytics SoftWare) Statistics 18 (SPSS Inc., Chicago, IL). Sample size was determined by previous studies and following statistical formula¹⁹

\begin{matrix} n 1 = n 2 = \frac{(z_{1 - \frac{α}{2}} + z_{1 - β}) 2 [σ_{1}^{2} + σ_{2}^{2}]}{(m_{1} - m_{2}) 2} = 84, \\ σ_{1}^{2} = 529 σ_{2}^{2} = 2209 α = 0.05 β = 0.2 \end{matrix}

Results

We included 188 patients, 96 males and 92 females who were considered for coronary angiography. The most common CAD risk factor was HTN (97 patients, 51%) that was followed by DM (70 patients, 37%), HLP (61 patients, 32%), smoking (22 patients, 12%), and FH (10 patients, 5%), respectively. We divided patients into two groups, one group with an epicardial fat <7 mm and other group with ≥7 mm. MAC was grade as: none (1), mild (2), moderate (3), and severe (4). Patients with an epicardial fat ≥7 mm had higher prevalence of HTN and higher SYNTAX score compared with patients with EFT <7 mm (p value = 0.002 and 0.0014, respectively Table 1). Among echocardiographic variables, both groups had mildly reduced LVEF; MAC was both more prevalent and more extensive in patients with epicardial fat ≥7 mm than patients with EFT <7 mm (p value = 0.007 and <0.001, respectively). Also, LA diameter was larger in these patients compared with other patients (p value = 0.001, Table 2, Figure 3). Again, relationships between epicardial fat with different degrees of MAC were qualitatively evaluated. This analysis showed that MAC was more prevalent in patients with EFT >7 mm than those with EFT <7 mm (p value < 0.001). However, there was no difference in prevalence of moderate and severe MAC between two groups (p value = 0.603 and 0.193, respectively, Table 3). A logistic regression model was conducted to determine independent association of different variables with MAC. Among these variables, epicardial fat and LM or three-vessel CAD were significantly associated with the presence of MAC (Table 4).

Figure 3.

Correlation between epicardial fat thickness and the severity of mitral annular calcification (MAC; p value = 0.007).

Table 1.

Demographic, cardiac enzymes, and angiographic variables of study population categorized by epicardial fat thickness ≥7 mm or <7 mm.

	Epicardial fat < 7 mm (111 patients)	Epicardial fat ≥ 7 mm (77 patients)	p value
Age (years)	61.74 ± 10.14	63.18 ± 9.62	0.324
Gender
Male	63 (56.8%)	33 (42.9%)	0.061
Female	48 (43.2%)	44 (57.1%)	0.061
BMI (kg/m²)	28.39 ± 10.66	28.47 ± 4.17	0.948
Diabetes mellitus	43 (38.7%)	27 (35.1%)	0.608
Hypertension	47 (42.3%)	50 (64.93%)	0.002*
Hyperlipidemia	32 (28.8%)	29 (37.7%)	0.203
Smoking	13 (11.7%)	9 (11.7%)	0.996
Family history	3 (2.7%)	7 (9.1%)	0.095
History of CABG	0 (0%)	1 (1.3%)	0.410
CKMB (ng/mL)	34.38 ± 37.18	36.34 ± 33.44	0.735
TnI (ng/mL)	9.99 ± 16.04	8.45 ± 8.50	0.797
Left main and three-vessel CAD	49 (44.1%)	40 (51.9%)	0.292
SYNTAX score	13.05 ± 10.19	16.58 ± 8.81	0.014*

CKMB: creatine kinase-MB; TnI: troponin-I; BMI: body mass index; CAD: coronary artery disease.

Table 2.

Echocardiographic variables of study population categorized by epicardial fat thickness ≥7 mm or <7 mm.

	Epicardial fat < 7 mm	Epicardial fat ≥ 7 mm	p value
Average MAC grading	1.60 ± 0.92	2.00 ± 1.00	0.007*
Presence of MAC	40 (36%)	48 (62.3%)	<0.001*
E wave	0.89 ± 0.38	0.96 ± 0.67	0.379
A wave	0.91 ± 0.5	1.16 ± 0.73	0.012*
E/A	1.19 ± 1.19	0.99 ± 0.84	0.199
LA diameter	3.50 ± 0.41	3.75 ± 0.51	0.001*
e′	7.43 ± 2.35	7.38 ± 2.63	0.893
E/e′	12.93 ± 6.18	13.71 ± 8.92	0.485
MR (more than mild)	22 (28.6%)	19 (32.8%)	0.600
LVEF	45.49 ± 7.47	45.39 ± 7.38	0.927

MAC: mitral annular calcification; E wave: pulse Doppler transmitral early velocity; A wave: pulse Doppler late transmitral peak flow velocity; e′: early diastolic mitral annular velocity; LA: left atrium; MR: mitral regurgitation; LVEF: left ventricular ejection fraction.

Table 3.

The severity of MAC in two study groups categorized by epicardial fat thickness ≥7 mm or < 7 mm.

	Epicardial fat <7 mm	Epicardial fat ≥7 mm	p value
MAC
1.00 (no)	71 (64.0%)	29 (37.7%)	<0.001*
2.00 (mild)	20 (18.0%)	28 (36.4%)	0.005*
3.00 (moderate)	13 (11.7%)	11 (14.3%)	0.603
4.00 (severe)	7 (6.3%)	9 (11.7%)	0.193

MAC: mitral annular calcification.

Table 4.

Logistic regression analysis results on the association between the presence of MAC and other variables.

	Variables in the equation
	B	SE	Wald	df	Sig.	Exp(B)	95% CI for Exp(B)
	B	SE	Wald	df	Sig.	Exp(B)	Lower	Upper
Step 1
Age	.006	.017	.143	1	.706	1.006	.974	1.040
Hypertension	−.237	.342	.480	1	.488	.789	.404	1.542
Epicardial fat	1.054	.341	9.531	1	.002*	2.870	1.470	5.604
Hyperlipidemia	−.184	.350	.275	1	.600	.832	.419	1.653
Cigarette Smoking	.298	.569	.275	1	.600	1.348	.442	4.114
Diabetes mellitus	−.615	.350	3.083	1	.079	.541	.272	1.074
Left main and three-vessel CAD	1.092	.336	10.555	1	.001*	2.980	1.542	5.759
Constant	−2.551	1.806	1.995	1	.158	.078

B: coefficient for the constant; SE: standard error for the constant, df: degrees of freedom; Exp(B): exponentiation of the B constant, Wald: wald chi-square test; Sig: p value (<0.05 is significant); CAD: coronary artery disease. *: significant p values.

Discussion

In our study, HTN was more prevalent and SYNTAX score was higher in patients with EFT ≥7 mm compared with patients with EFT <7 mm. Also, these patients had higher prevalence and higher degree of MAC and larger LA diameter than those with EFT <7 mm. Epicardial fat is the true visceral fat located under visceral layer of the pericardium that, under physiologic condition, plays multiple biochemical, mechanical, and thermogenic cardioprotective roles. However, it can be a rich source of free fatty acids and has been proposed as a marker of cardiovascular risk that under pathological conditions, secretes pro-inflammatory cytokines that can lead to progression of atherosclerosis.^2,19 It is also independently associated with high blood pressure, low-density lipoprotein cholesterol, fasting glucose, and inflammatory markers.¹⁴ In our study, HTN was more prevalent and SYNTAX score was higher in patients with EFT ≥7 mm with respect to other group. The SYNTAX score is an angiographic tool to characterize the coronary vasculature with respect to the number, functional impact, location, and complexity of involving lesions that higher SYNTAX scores are indicative of more complex disease.¹⁸ Although we found a statistically significant difference in SYNTAX score between the two EFT groups, the difference was very small and would not affect clinical management; both <7 mm and >7 mm groups would be considered low-risk for revascularization. On the other hand, MAC is a chronic degenerative process associated with advanced age, HTN, and radiation heart disease.²⁰ Previous studies have shown a correlation between cardiovascular risk factors and severity of MAC. Patients with MAC are more likely to have significant CAD, cerebrovascular accident, cardiac arrhythmia, and cardiovascular mortality.¹⁶ In our study, patients with EFT ≥7 mm had higher prevalence and higher degree of MAC compared with patients with EFT <7 mm. In 2016, Alnabelsi et al. evaluated the association between epicardial fat and aortic valve and MAC determined by computed tomography on 294 patients aged ≥ 65 years who had noncontrast computed tomography scans of the chest. EFT was measured at various locations and MAC and aortic valve calcification were quantified by Agatston technique. Subjects were divided into two groups: no cardiac calcification and cardiac calcification group. They found significant association between epicardial fat with calcium deposits of the mitral annulus and aortic valve.³ In 2018, Nabati et al. evaluated the association between EFT and aortic valve sclerosis on 225 patients who were admitted for coronary angiography due to new-onset angina. They underwent transthoracic echocardiography and EFT was determined. The sclerosis scoring of each aortic cusp and average aortic valve sclerosis score index were determined. They found patients with EFT ≥7 mm had higher average aortic valve sclerosis score index with respect to patients with EFT <7 mm (p value = 0.001).²¹ In 2015, Parisi et al. evaluated 95 patients with severe, isolated, calcific AS, referred to cardiac surgery for aortic valve replacement. They measured EFT by echocardiography in AS patients and in a control group of 44 healthy subjects. They found EFT was markedly increased in patients with AS compared with controls (9.85 ± 2.78 vs. 4.91 ± 1.27 mm; p value < 0.001).²² Previous studies showed LA diameter measured using two-dimensional echocardiography, from the posterior aortic wall to the posterior LA wall, in the parasternal long-axis view at the end-ventricular systole has a direct and independent association with all-cause mortality in both sexes and with ischemic stroke in women.²³ Although we found that LA diameter was larger in the EFT >7 mm group, this group was largely (65%) hypertensive, a known risk-factor for diastolic dysfunction and consequently LA dilation. In our study, there was no difference in prevalence of moderate and severe MAC between two groups. This can be explained by the small number of patients with moderate or severe MAC in this study. Also, there was no difference between groups for LM and three-vessel disease. It may be due to the fact that all the patients included in this study were suspected of having CAD and they were not selected from general population. Women outnumbered men in the group with EFT ≥7 mm. It is consistent with previous studies that showed larger EFT in females than in males.²⁴ To the best of our knowledge, no studies have evaluated association between EFT and the presence and severity of MAC using echocardiography.

Conclusion

Our study showed significant association between increased EFT and calcium deposits in the mitral valve annulus that is a degenerative and inflammatory process of the mitral fibrous region associated with cardiovascular risk factors. There may be some association to atherosclerosis but future studies are needed. We did not find a statistically significant difference between the two EFT groups for LM and three-vessel disease and the difference in SYNTAX score was very small and would not affect clinical management. However, there was an association between MAC with LM and three-vessel disease.

Limitation

The limitations of this study were the small sample size from a single center, and the fact that it was a retrospective cohort study which the patients' clinical outcomes or mortality were not included. All the patients included in our study were suspected of having CAD. A better study design would have been to recruit participants based on the EFT (epicardial fat ≥7 mm and <7 mm) and then determine the prevalence and complexity of CAD in each group. By recruiting patients with suspected CAD, we only compared the complexity and severity of CAD, and the likelihood of the presence of CAD between the two groups has not been investigated.

Footnotes

Acknowledgments

The present study was undergraduate thesis of Alireza Salehi. We would like to thank all patients and hospital staff who contributed in this study.

Contributors

Maryam Nabati designed the study, did echocardiograms and wrote manuscript; Alireza Salehi collected data; Ghazal Hatami recruited patients and measured variables; Jamshid Yazdani analyzed date; Mozhdeh Dabirian contributed to the study by collecting data from questionnaire; Homa Parsaee prepared SPSS sheets.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics Approval

This study was approved by ethic committee of cardiovascular research center of the Mazandaran University of Medical Sciences.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by a grant from the cardiovascular research center of the Mazandaran University of Medical Sciences.

Guarantor

Maryam Nabati.

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