Endocrine Care 587
Authors
G. Iacobellis1, M. C. Zaki2, D. Garcia3, H. J. Willens2
Affiliations
1
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Miami, Miller School of Medicine, Miami, FL, USA 2 Department of Medicine, Division of Cardiology, University of Miami, Miller School of Medicine, Miami, FL, USA 3 Department of Medicine, Internal Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA
Key words ▶ epicardial fat ● ▶ atrial fibrillation ● ▶ heart failure ● ▶ echocardiography ● ▶ obesity ●
Abstract
received 17.11.2013 accepted 21.01.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1367078 Published online: February 20, 2014 Horm Metab Res 2014; 46: 587–590 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence G. Iacobellis, MD, PhD Professor of Clinical Medicine Division of Diabetes, Endocrinology and Metabolism University of Miami 1400 NW 10th Ave Dominion Tower suite 805-807 FL 33136 Miami USA Tel.: + 1/305/243 3636 Fax: + 1/305/243 9487 [email protected]
▼
Obesity is a well-known risk factor for atrial fibrillation (AF) and heart failure (HF). Epicardial fat, the true visceral fat depot of the heart, has been associated with changes in both cardiac function and morphology. In this study, we evaluated whether ultrasound-measured epicardial fat thickness is related to AF and HF. A crosssectional study was performed in 84 consecutive subjects with clinical and ECG-documented history of permanent (AF) or paroxysmal AF (PAF) who underwent echocardiographic epicardial fat thickness measurement. Sixty-four subjects had AF and 20 showed PAF. AF subjects had higher prevalence of heart failure (HF), defined by ejection fraction (EF) < 50 %, (p < 0.01). Subjects with
Introduction
▼
Epicardial adipose tissue, the true visceral fat of the heart, recently emerged as a cardiovascular risk factor [1–5]. Given its anatomical and functional contiguity to the myocardium, epicardial fat is thought to directly modulate the heart and play an active and independent role in the coronary artery disease [1, 2]. We have therefore developed a methodology through which epicardial fat can be visualized and measured using standard 2-dimensional echocardiography [6, 7]. Increase in epicardial fat thickness is significantly correlated with abnormal both left and right ventricular mass, enlarged atria, and impaired left ventricular diastolic filling, as we previously reported [8–10]. Obesity is a well-known risk factor for atrial fibrillation (AF) and heart failure (HF). Epidemiological studies have reported an association between epicardial fat and AF [11–16]. Mechanical and biochemical factors have been suggested to play a role in this association, although the mechanisms are still unclear.
AF had higher epicardial fat thickness than PAF subjects (4.8 ± 2.5 vs. 3.5 ± 2.4 mm, p < 0.05). As subjects were stratified by HF, epicardial fat thickness was lower (4.4 ± 2.2 vs. 5.4 ± 2.3 mm, p < 0.05) in those with HF as compared to subjects without HF. This study showed for the first time that echocardiographic epicardial fat thickness is significantly higher in subjects with chronic AF when compared to those with PAF. It is plausible that permanent AF is related to longterm influence of epicardial fat. Epicardial fat reduction in HF subjects may reflect the overall fat mass reduction, commonly observed in these patients. It is also possible to hypothesize that epicardial fat pad may incur in fibrotic changes during chronic cardiac failure.
Nevertheless, the relation between echocardiographic epicardial fat thickness and AF is poorly explored. Epicardial fat can be measured with echocardiography and computed tomography (CT) scan methodologies [17]. Most of the previous studies used CT to evaluate the relation of AF with pericardial fat, namely the entire fat content within the pericardial sac [11–16]. Given the fact that epicardial and pericardial fat are anatomically and biochemically very different [18], this approach could be misleading. Pericardial fat actually reflects the intra-thoracic adiposity, rather than the visceral fat depot of the heart [1, 2]. The relation of epicardial fat with AF may be affected by measuring the intra-thoracic fat. Hence, in this study we evaluated that ultrasound-measured epicardial fat thickness is related to AF and HF. Given the fact that echocardiography is an easily and routinely performed diagnostic procedure, we feel that achieving this knowledge would be of relevance and interest.
Iacobellis G et al. Epicardial Fat … Horm Metab Res 2014; 46: 587–590
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Epicardial Fat in Atrial Fibrillation and Heart Failure
588 Endocrine Care Patients and Methods
▼
Eighty-four consecutive subjects with clinical and documented history of permanent (AF) or paroxysmal AF (PAF) were recruited from an outpatient population referred to the Cardiology Department for a routine transthoracic 2D guided M-mode echocardiogram. The protocol # 20130128 was approved by University of Miami IRB and each subject signed an informed consent before the study began.
reproducibility of echocardiographic epicardial fat thickness measurement was evaluated by ICC, with values > 0.8 being considered as excellent. Comparisons between groups were calculated by unpaired nonparametric tests (Mann-Whitney test). A value of p < 0.05 was considered statistically significant.
Results
▼
The diagnosis of AF was based on 24 h electrocardiogram (ECG)Holter monitoring or single ECG. PAF was defined as recurrent (2 or more) episodes of AF that terminated spontaneously in less than 7 days. When the arrhythmia sustained more than 7 days, it was defined as AF. The category of AF also included cases of long-standing AF and cases who failed to revert to sinus rhythm on cardioversion. Diagnosis of HF was based on clinical assessment and ejection fraction (EF) lower than 50 %.
Exclusion criteria Patients with signs, symptoms or clinical history of pericardial or valve diseases, thyroid, cerebrovascular, pulmonary, renal or liver diseases, cancer, and drug abuse were excluded.
Echocardiographic measurements Each subject had a transthoracic 2D guided M-mode echocardiogram using commercially available equipment. Standard parasternal and apical views were obtained in the left lateral decubitus position. All echocardiograms were recorded and analyzed offline for epicardial fat thickness quantification, according to the method previously described and validated by Iacobellis et al. [7]. Echocardiograms were read by 2 readers who were blinded of the anthropometric features of the patients. Epicardial fat was identified as the echo-free space between the outer wall of the myocardium and the visceral layer of pericardium. Epicardial fat thickness was measured in the parasternal long-axis view, perpendicularly on the free wall of the right ventricle at end-systole in 3 cardiac cycles. Maximum epicardial fat thickness was measured at the point on the free wall of the right ventricle along the midline of the ultrasound beam, perpendicular to the aortic annulus, used as anatomical landmark for this view. The average value of 3 cardiac cycles was considered. Left atrial diameter was measured at end systole in the parasternal long-axis view. Left atrial enlargement was defined as diameter > 4.2 cm. Left ventricle (LV) systolic function was evaluated by EF calculated using the Simpson’s ellipsoid that estimates LV volumes. LV mass (LVM) was calculated with the Deveraux’s formula.
Anthropometrics and blood tests Body Mass index (BMI), was calculated as previuously described. Fasting plasma glucose, Hemoglobin A1c (HbA1c), thyroid stimulating hormone (TSH), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and blood pressure (BP) were obtained and measured as described before.
Statistical analysis Data in the text and in the tables are expressed as mean ± standard deviation (SD). Intra and inter-observer variability of the epicardial fat thickness were evaluated using paired t tests. The Iacobellis G et al. Epicardial Fat … Horm Metab Res 2014; 46: 587–590
The main characteristics of study subjects are summarized ▶ Table 1. Sixty-four subjects had AF and 20 were diagnosed in ● with PAF. AF subjects presented with higher prevalence of HF than subjects with PAF (p < 0.01). No significant differences in age, sex distribution, BMI, prevalence and severity of CAD, hypertension and blood pressure control, dyslipidemia and lipid profile, diabetes and diabetes control, blood pressure-lowering, lipid-lowering and antidiabetes medications, thyroid function, and smoking habit between subjects with AF and those with PAF were found. Patients with AF were treated with anti-arrhythmic medications, more than those with PAF (42 vs. 25 %).
Echocardiographic parameters Intra- and inter-observer reproducibility of the epicardial fat thickness measurement was excellent, ICC 0.90 and 0.88, respectively) as well as the agreement. Subjects with AF had higher epicardial fat thickness (4.8 ± 2.5 vs. 3.5 ± 2.4 mm, p < 0.05), LVM ▶ Fig. 1). (p < 0.01) and lower EF (p < 0.01) than PAF subjects (● When overall subjects (both AF and PAF) were stratified by the presence of HF, epicardial fat thickness was lower (4.4 ± 2.2 vs. 5.4 ± 2.3 mm, p < 0.05) in those with HF as compared to subjects ▶ Fig. 2). without HF (●
Table 1 Main clinical and echocardiographic parameters.
Age (years) BMI (kg/m2) HF ( %) CAD ( %) Diabetes ( %) Hypertension ( %) Dyslipidemia ( %) HbA1c (mmol/mol) HDL-C (mg/dl) LDL-C (mg/dl) TG (mg/dl) TSH (U/I) LA (mm) LVM (g) EF ( %) Epicardial fat thickness (mm)
AF n = 64
PAF n = 20
69.2 ± 12 30 ± 7.4 73 37 30 90 70 48.6 41 ± 14 97 ± 40 140 ± 60 2.5 ± 0.8 45 ± 9 234.2 ± 82 47.8 ± 14 4.8 ± 2.5
70 ± 11.8 29.2 ± 6.6 50 30 29 90 65 43.2 43 ± 10 100 ± 45 155 ± 60 2.3 ± 0.8 43 ± 5 205.2 ± 71 57 ± 11 3.5 ± 2.4
p ns ns < 0.01 ns ns ns ns ns ns ns ns ns ns < 0.01 < 0.01 < 0.05
Data are expressed as mean ± SD. AF: Chronic atrial fibrillation; PAF: Paroxysmal atrial fibrillation; BMI: Body mass index; HF: Heart failure; CAD: Coronary artery disease; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; TG: Triglycerides; HbA1c: Hemoglobin A1C reported in mmol/mol according to IFCC recommendation; TSH: Thyroid stimulating hormone; LA: Left atrium; LVM: Left ventricle mass; EF: Ejection fraction
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Clinical features Inclusion criteria
Fig. 1 Epicardial fat thickness was higher (p < 0.05) in subjects with AF than in those with PAF; epicardial fat thickness (EAT); chronic atrial fibrillation (AF); paroxysmal atrial fibrillation (PAF).
Fig. 2 Epicardial fat thickness was lower (p < 0.05) in overall subjects (both AF and PAF) with HF than in those without HF (no HF); epicardial fat thickness (EAT); heart failure (HF).
Discussion
▼
This study showed for the first time that echocardiographic epicardial fat thickness was significantly higher in subjects with chronic AF when compared to those with paroxysmal AF. The difference was independent of potential confounding factors, such as obesity, age, sex, coronary artery disease, diabetes, dyslipidemia, or hypertension. Additionally and remarkably, epicardial fat thickness was actually lower in AF subjects with HF when compared to those without HF. An association between epicardial fat and AF has been recently suggested [11–16]. Our observation provides some novel and unique findings. First of all, most of the previous studies were performed using CT scan procedures, rather than echocardiography. Whilst CT imaging can undoubtedly provide a volumetric and therefore more accurate assessment of the epicardial fat, most of the previous reports included the pericardial fat within the measurement [11–16]. Given the fact that pericardial fat actually reflects the intra-thoracic adiposity, we argued that this measurement might be misleading [18]. Second, the difference in echocardiograhic epicardial fat thickness between chronic and paroxysmal AF was unexplored. It is plausible to hypothesize that persistent AF is related to longterm changes due to the effect of epicardial fat. Although this study cannot establish any cause-effect, it is tempting to briefly discuss some potential mechanisms [1, 19]. Epicardial fat is an extremely active paracrine adipose tissue with peculiar biomolecular and anatomic properties [1, 2]. It has been proposed that pro-inflammatory and pro-fibrotic cytokines may diffuse from epicardial fat into the adjacent myocardium and promote arrhythmogenesis [1, 20]. Free fatty acids can be also transported from the epicardial fat to the myocardium through vasocrine or paracrine pathways and lead to electromechanical changes in atrial tissue [1, 2]. Increased epicardial fat could also influence the intrinsic autonomic system, enhancing vagal tone and increasing the propensity for AF [1, 2]. Mechanical and structural factors can be also evoked. In fact, increased epicardial fat is also associated with changes in cardiac structures and specifically increased left atrial dimensions [10]. The association of epicardial fat and AF seems to be more pronounced
when AF is associated with left atrial dilation [21] and when large amount of fat is located adjacent the left atrial appendage [15]. However, whether the relation of epicardial fat with AF is always mediated by an enlarged left atrium is object of debate. In fact, CT-calculated peri-atrial epicardial fat could predict the development of new-onset AF in CAD patients, independently of left atrial enlargement [22]. Consistently with this latter finding, we did not find a statistical relation between left atrium and epicardial fat thickness. An independent and organ-specific effect of epicardial fat in contributing to the development of AF could be therefore suggested. In our study, the lack of correlation with epicardial fat thickness could also be explained by the fact that left atrium size did not differ between subjects with AF and PAF. In fact, the majority of our patients presented with enlarged left atrium. Third, for the first time we evaluated epicardial fat thickness, as measured with ultrasound, in subjects with AF and HF. A stepwise decrease in CT- or Cardiac Magnetic Resonance (CMR)measured epicardial fat volume in patients with impaired cardiac function [23] and congestive heart failure [24, 25] was previously reported. Interestingly, LV-EF was found as the best independent determinant of CMR-calculated epicardial fat by Doesch et al. [24]. To further emphasize its potential as predictive marker, the same authors suggested that epicardial fat might serve as additional prognostic indicator for survival in subjects with HF [24]. The mechanism causing a decreased epicardial fat in patients with HF is unknown. The commonly observed lean and fat mass loss in patients with heart failure may explain the lower epicardial fat thickness in these patients. Epicardial fat reduction may reflect the overall fat mass reduction. It is also possible to hypothesize that epicardial fat pad may incur in fibrotic changes during chronic cardiac failure. Interestingly, an experimental study suggested that epicardial fat can increase the atrial arrhythmogenesis in rabbits with HF [26]. Very recently p53 mRNA expression was found higher increase in epicardial fat obtained from HF patients [27]. The presence of HF can explain the lower actual epicardial fat thickness values in our patients, when compared to our previous studies [8–10]. In conclusion, this study suggests that echocardiographic epicardial fat thickness is higher in subjects with chronic AF, but lower in AF subjects with HF. Our findings may warrant future longitudinal studies to evaluate the capacity of epicardial fat thickness to predict AF and HF.
Study Limitations
▼
Sample size of patients with PAF was relatively small. However, this sample size provided significant statistical power to detect differences between the 2 groups. We certainly recognize that CT or CMR procedures can provide a volumetric assessment of epicardial fat. However, echocardiography is undoubtedly less invasive. Moreover, echocardiography can easily distinguish between epicardial and pericardial fat. Waist circumference was not measured in our population. However, previous studies showed that epicardial fat thickness reflects body fat distribution and visceral fat accumulation better than waist circumference. HF was diagnosed only on the basis of the ejection fraction, clinical history and examination. Additional imaging tests may be necessary to confirm our preliminary findings of the lower epicardial fat thickness in patients with HF. Iacobellis G et al. Epicardial Fat … Horm Metab Res 2014; 46: 587–590
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Endocrine Care 589
Conflict of Interest
▼
The authors declare that they have no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
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15 Tsao HM, Hu WC, Wu MH, Tai CT, Lin YJ, Chang SL, Lo LW, Hu YF, Tuan TC, Wu TJ, Sheu MH, Chang CY, Chen SA. Quantitative analysis of quantity and distribution of epicardial adipose tissue surrounding the left atrium in patients with atrial fibrillation and effect of recurrence after ablation. Am J Cardiol 2011; 107: 1498–1503 16 Wong CX, Abed HS, Molaee P, Nelson AJ, Brooks AG, Sharma G, Leong DP, Lau DH, Middeldorp ME, Roberts-Thomson KC, Wittert GA, Abhayaratna WP, Worthley SG, Sanders P. Pericardial fat is associated with atrial fibrillation severity and ablation outcome. J Am Coll Cardiol 2011; 57: 1745–1751 17 Apfaltrer P, Schindler A, Schoepf UJ, Nance JW Jr, Tricarico F, Ebersberger U, McQuiston AD, Meyer M, Henzler T, Schoenberg SO, Bamberg F, Vliegenthart R. Comparison of Epicardial Fat Volume by Computed Tomography in Black Versus White Patients With Acute Chest Pain. Am J Cardiol 2014; 113: 422–428 18 Iacobellis G. Epicardial and pericardial fat: close, but very different. Obesity 2009; 17: 625 19 Wang TJ, Parise H, Levy D, D’Agostino RB Sr, Wolf PA, Vasan RS, Benjamin EJ. Obesity and the risk of new-onset atrial fibrillation. JAMA 2004; 292: 2471–2477 20 Venteclef N, Guglielmi V, Balse E, Gaborit B, Cotillard A, Atassi F, Amour J, Leprince P, Dutour A, Clément K, Hatem SN. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines. Eur Heart J Mar 22 2013 [Epub ahead of print] 21 Greif M, von Ziegler F, Wakili R, Tittus J, Becker C, Helbig S, Laubender RP, Schwarz W, D’Anastasi M, Schenzle J, Leber AW, Becker A. Increased pericardial adipose tissue is correlated with atrial fibrillation and left atrial dilatation. Clin Res Cardiol 2013; 102: 555–562 22 Nakanishi K, Fukuda S, Tanaka A, Otsuka K, Sakamoto M, Taguchi H, Yoshikawa J, Shimada K, Yoshiyama M. Peri-atrial epicardial adipose tissue is associated with new-onset nonvalvular atrial fibrillation. Circ J 2012; 6: 2748–2754 23 Khawaja T, Greer C, Chokshi A, Chavarria N, Thadani S, Jones M, Schaefle K, Bhatia K, Collado JE, Shimbo D, Einstein AJ, Schulze PC. Epicardial fat volume in patients with left ventricular systolic dysfunction. Am J Cardiol 2011; 108: 397–401 24 Doesch C, Suselbeck T, Leweling H, Fluechter S, Haghi D, Schoenberg SO, Borggrefe M, Papavassiliu T. Bioimpedance analysis parameters and epicardial adipose tissue assessed by cardiac magnetic resonance imaging in patients with heart failure. Obesity (Silver Spring) 2010; 18: 2326–2332 25 Doesch C, Streitner F, Bellm S, Suselbeck T, Haghi D, Heggemann F, Schoenberg SO, Michaely H, Borggrefe M, Papavassiliu T. Epicardial adipose tissue assessed by cardiac magnetic resonance imaging in patients with heart failure due to dilated cardiomyopathy. Obesity (Silver Spring) 2013; 21: E253–E261 26 Lin YK, Chen YC, Chang SL, Lin YJ, Chen JH, Yeh YH, Chen SA, Chen YJ. Heart failure epicardial fat increases atrial arrhythmogenesis. Int J Cardiol May 25 2012 [Epub ahead of print] 27 Agra RM, Teijeira-Fernández E, Pascual-Figal D, Sánchez-Más J, Fernández-Trasancos A, González-Juanatey JR, Eiras S. Adiponectin and p53 mRNA in epicardial and subcutaneous fat from heart failure patients. Eur J Clin Invest 2014; 44: 29–37
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590 Endocrine Care
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Authors
G. Iacobellis1, M. C. Zaki2, D. Garcia3, H. J. Willens2
Affiliations
1
Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Miami, Miller School of Medicine, Miami, FL, USA 2 Department of Medicine, Division of Cardiology, University of Miami, Miller School of Medicine, Miami, FL, USA 3 Department of Medicine, Internal Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA
Key words ▶ epicardial fat ● ▶ atrial fibrillation ● ▶ heart failure ● ▶ echocardiography ● ▶ obesity ●
Abstract
received 17.11.2013 accepted 21.01.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1367078 Published online: February 20, 2014 Horm Metab Res 2014; 46: 587–590 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence G. Iacobellis, MD, PhD Professor of Clinical Medicine Division of Diabetes, Endocrinology and Metabolism University of Miami 1400 NW 10th Ave Dominion Tower suite 805-807 FL 33136 Miami USA Tel.: + 1/305/243 3636 Fax: + 1/305/243 9487 [email protected]
▼
Obesity is a well-known risk factor for atrial fibrillation (AF) and heart failure (HF). Epicardial fat, the true visceral fat depot of the heart, has been associated with changes in both cardiac function and morphology. In this study, we evaluated whether ultrasound-measured epicardial fat thickness is related to AF and HF. A crosssectional study was performed in 84 consecutive subjects with clinical and ECG-documented history of permanent (AF) or paroxysmal AF (PAF) who underwent echocardiographic epicardial fat thickness measurement. Sixty-four subjects had AF and 20 showed PAF. AF subjects had higher prevalence of heart failure (HF), defined by ejection fraction (EF) < 50 %, (p < 0.01). Subjects with
Introduction
▼
Epicardial adipose tissue, the true visceral fat of the heart, recently emerged as a cardiovascular risk factor [1–5]. Given its anatomical and functional contiguity to the myocardium, epicardial fat is thought to directly modulate the heart and play an active and independent role in the coronary artery disease [1, 2]. We have therefore developed a methodology through which epicardial fat can be visualized and measured using standard 2-dimensional echocardiography [6, 7]. Increase in epicardial fat thickness is significantly correlated with abnormal both left and right ventricular mass, enlarged atria, and impaired left ventricular diastolic filling, as we previously reported [8–10]. Obesity is a well-known risk factor for atrial fibrillation (AF) and heart failure (HF). Epidemiological studies have reported an association between epicardial fat and AF [11–16]. Mechanical and biochemical factors have been suggested to play a role in this association, although the mechanisms are still unclear.
AF had higher epicardial fat thickness than PAF subjects (4.8 ± 2.5 vs. 3.5 ± 2.4 mm, p < 0.05). As subjects were stratified by HF, epicardial fat thickness was lower (4.4 ± 2.2 vs. 5.4 ± 2.3 mm, p < 0.05) in those with HF as compared to subjects without HF. This study showed for the first time that echocardiographic epicardial fat thickness is significantly higher in subjects with chronic AF when compared to those with PAF. It is plausible that permanent AF is related to longterm influence of epicardial fat. Epicardial fat reduction in HF subjects may reflect the overall fat mass reduction, commonly observed in these patients. It is also possible to hypothesize that epicardial fat pad may incur in fibrotic changes during chronic cardiac failure.
Nevertheless, the relation between echocardiographic epicardial fat thickness and AF is poorly explored. Epicardial fat can be measured with echocardiography and computed tomography (CT) scan methodologies [17]. Most of the previous studies used CT to evaluate the relation of AF with pericardial fat, namely the entire fat content within the pericardial sac [11–16]. Given the fact that epicardial and pericardial fat are anatomically and biochemically very different [18], this approach could be misleading. Pericardial fat actually reflects the intra-thoracic adiposity, rather than the visceral fat depot of the heart [1, 2]. The relation of epicardial fat with AF may be affected by measuring the intra-thoracic fat. Hence, in this study we evaluated that ultrasound-measured epicardial fat thickness is related to AF and HF. Given the fact that echocardiography is an easily and routinely performed diagnostic procedure, we feel that achieving this knowledge would be of relevance and interest.
Iacobellis G et al. Epicardial Fat … Horm Metab Res 2014; 46: 587–590
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Epicardial Fat in Atrial Fibrillation and Heart Failure
588 Endocrine Care Patients and Methods
▼
Eighty-four consecutive subjects with clinical and documented history of permanent (AF) or paroxysmal AF (PAF) were recruited from an outpatient population referred to the Cardiology Department for a routine transthoracic 2D guided M-mode echocardiogram. The protocol # 20130128 was approved by University of Miami IRB and each subject signed an informed consent before the study began.
reproducibility of echocardiographic epicardial fat thickness measurement was evaluated by ICC, with values > 0.8 being considered as excellent. Comparisons between groups were calculated by unpaired nonparametric tests (Mann-Whitney test). A value of p < 0.05 was considered statistically significant.
Results
▼
The diagnosis of AF was based on 24 h electrocardiogram (ECG)Holter monitoring or single ECG. PAF was defined as recurrent (2 or more) episodes of AF that terminated spontaneously in less than 7 days. When the arrhythmia sustained more than 7 days, it was defined as AF. The category of AF also included cases of long-standing AF and cases who failed to revert to sinus rhythm on cardioversion. Diagnosis of HF was based on clinical assessment and ejection fraction (EF) lower than 50 %.
Exclusion criteria Patients with signs, symptoms or clinical history of pericardial or valve diseases, thyroid, cerebrovascular, pulmonary, renal or liver diseases, cancer, and drug abuse were excluded.
Echocardiographic measurements Each subject had a transthoracic 2D guided M-mode echocardiogram using commercially available equipment. Standard parasternal and apical views were obtained in the left lateral decubitus position. All echocardiograms were recorded and analyzed offline for epicardial fat thickness quantification, according to the method previously described and validated by Iacobellis et al. [7]. Echocardiograms were read by 2 readers who were blinded of the anthropometric features of the patients. Epicardial fat was identified as the echo-free space between the outer wall of the myocardium and the visceral layer of pericardium. Epicardial fat thickness was measured in the parasternal long-axis view, perpendicularly on the free wall of the right ventricle at end-systole in 3 cardiac cycles. Maximum epicardial fat thickness was measured at the point on the free wall of the right ventricle along the midline of the ultrasound beam, perpendicular to the aortic annulus, used as anatomical landmark for this view. The average value of 3 cardiac cycles was considered. Left atrial diameter was measured at end systole in the parasternal long-axis view. Left atrial enlargement was defined as diameter > 4.2 cm. Left ventricle (LV) systolic function was evaluated by EF calculated using the Simpson’s ellipsoid that estimates LV volumes. LV mass (LVM) was calculated with the Deveraux’s formula.
Anthropometrics and blood tests Body Mass index (BMI), was calculated as previuously described. Fasting plasma glucose, Hemoglobin A1c (HbA1c), thyroid stimulating hormone (TSH), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and blood pressure (BP) were obtained and measured as described before.
Statistical analysis Data in the text and in the tables are expressed as mean ± standard deviation (SD). Intra and inter-observer variability of the epicardial fat thickness were evaluated using paired t tests. The Iacobellis G et al. Epicardial Fat … Horm Metab Res 2014; 46: 587–590
The main characteristics of study subjects are summarized ▶ Table 1. Sixty-four subjects had AF and 20 were diagnosed in ● with PAF. AF subjects presented with higher prevalence of HF than subjects with PAF (p < 0.01). No significant differences in age, sex distribution, BMI, prevalence and severity of CAD, hypertension and blood pressure control, dyslipidemia and lipid profile, diabetes and diabetes control, blood pressure-lowering, lipid-lowering and antidiabetes medications, thyroid function, and smoking habit between subjects with AF and those with PAF were found. Patients with AF were treated with anti-arrhythmic medications, more than those with PAF (42 vs. 25 %).
Echocardiographic parameters Intra- and inter-observer reproducibility of the epicardial fat thickness measurement was excellent, ICC 0.90 and 0.88, respectively) as well as the agreement. Subjects with AF had higher epicardial fat thickness (4.8 ± 2.5 vs. 3.5 ± 2.4 mm, p < 0.05), LVM ▶ Fig. 1). (p < 0.01) and lower EF (p < 0.01) than PAF subjects (● When overall subjects (both AF and PAF) were stratified by the presence of HF, epicardial fat thickness was lower (4.4 ± 2.2 vs. 5.4 ± 2.3 mm, p < 0.05) in those with HF as compared to subjects ▶ Fig. 2). without HF (●
Table 1 Main clinical and echocardiographic parameters.
Age (years) BMI (kg/m2) HF ( %) CAD ( %) Diabetes ( %) Hypertension ( %) Dyslipidemia ( %) HbA1c (mmol/mol) HDL-C (mg/dl) LDL-C (mg/dl) TG (mg/dl) TSH (U/I) LA (mm) LVM (g) EF ( %) Epicardial fat thickness (mm)
AF n = 64
PAF n = 20
69.2 ± 12 30 ± 7.4 73 37 30 90 70 48.6 41 ± 14 97 ± 40 140 ± 60 2.5 ± 0.8 45 ± 9 234.2 ± 82 47.8 ± 14 4.8 ± 2.5
70 ± 11.8 29.2 ± 6.6 50 30 29 90 65 43.2 43 ± 10 100 ± 45 155 ± 60 2.3 ± 0.8 43 ± 5 205.2 ± 71 57 ± 11 3.5 ± 2.4
p ns ns < 0.01 ns ns ns ns ns ns ns ns ns ns < 0.01 < 0.01 < 0.05
Data are expressed as mean ± SD. AF: Chronic atrial fibrillation; PAF: Paroxysmal atrial fibrillation; BMI: Body mass index; HF: Heart failure; CAD: Coronary artery disease; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; TG: Triglycerides; HbA1c: Hemoglobin A1C reported in mmol/mol according to IFCC recommendation; TSH: Thyroid stimulating hormone; LA: Left atrium; LVM: Left ventricle mass; EF: Ejection fraction
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Clinical features Inclusion criteria
Fig. 1 Epicardial fat thickness was higher (p < 0.05) in subjects with AF than in those with PAF; epicardial fat thickness (EAT); chronic atrial fibrillation (AF); paroxysmal atrial fibrillation (PAF).
Fig. 2 Epicardial fat thickness was lower (p < 0.05) in overall subjects (both AF and PAF) with HF than in those without HF (no HF); epicardial fat thickness (EAT); heart failure (HF).
Discussion
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This study showed for the first time that echocardiographic epicardial fat thickness was significantly higher in subjects with chronic AF when compared to those with paroxysmal AF. The difference was independent of potential confounding factors, such as obesity, age, sex, coronary artery disease, diabetes, dyslipidemia, or hypertension. Additionally and remarkably, epicardial fat thickness was actually lower in AF subjects with HF when compared to those without HF. An association between epicardial fat and AF has been recently suggested [11–16]. Our observation provides some novel and unique findings. First of all, most of the previous studies were performed using CT scan procedures, rather than echocardiography. Whilst CT imaging can undoubtedly provide a volumetric and therefore more accurate assessment of the epicardial fat, most of the previous reports included the pericardial fat within the measurement [11–16]. Given the fact that pericardial fat actually reflects the intra-thoracic adiposity, we argued that this measurement might be misleading [18]. Second, the difference in echocardiograhic epicardial fat thickness between chronic and paroxysmal AF was unexplored. It is plausible to hypothesize that persistent AF is related to longterm changes due to the effect of epicardial fat. Although this study cannot establish any cause-effect, it is tempting to briefly discuss some potential mechanisms [1, 19]. Epicardial fat is an extremely active paracrine adipose tissue with peculiar biomolecular and anatomic properties [1, 2]. It has been proposed that pro-inflammatory and pro-fibrotic cytokines may diffuse from epicardial fat into the adjacent myocardium and promote arrhythmogenesis [1, 20]. Free fatty acids can be also transported from the epicardial fat to the myocardium through vasocrine or paracrine pathways and lead to electromechanical changes in atrial tissue [1, 2]. Increased epicardial fat could also influence the intrinsic autonomic system, enhancing vagal tone and increasing the propensity for AF [1, 2]. Mechanical and structural factors can be also evoked. In fact, increased epicardial fat is also associated with changes in cardiac structures and specifically increased left atrial dimensions [10]. The association of epicardial fat and AF seems to be more pronounced
when AF is associated with left atrial dilation [21] and when large amount of fat is located adjacent the left atrial appendage [15]. However, whether the relation of epicardial fat with AF is always mediated by an enlarged left atrium is object of debate. In fact, CT-calculated peri-atrial epicardial fat could predict the development of new-onset AF in CAD patients, independently of left atrial enlargement [22]. Consistently with this latter finding, we did not find a statistical relation between left atrium and epicardial fat thickness. An independent and organ-specific effect of epicardial fat in contributing to the development of AF could be therefore suggested. In our study, the lack of correlation with epicardial fat thickness could also be explained by the fact that left atrium size did not differ between subjects with AF and PAF. In fact, the majority of our patients presented with enlarged left atrium. Third, for the first time we evaluated epicardial fat thickness, as measured with ultrasound, in subjects with AF and HF. A stepwise decrease in CT- or Cardiac Magnetic Resonance (CMR)measured epicardial fat volume in patients with impaired cardiac function [23] and congestive heart failure [24, 25] was previously reported. Interestingly, LV-EF was found as the best independent determinant of CMR-calculated epicardial fat by Doesch et al. [24]. To further emphasize its potential as predictive marker, the same authors suggested that epicardial fat might serve as additional prognostic indicator for survival in subjects with HF [24]. The mechanism causing a decreased epicardial fat in patients with HF is unknown. The commonly observed lean and fat mass loss in patients with heart failure may explain the lower epicardial fat thickness in these patients. Epicardial fat reduction may reflect the overall fat mass reduction. It is also possible to hypothesize that epicardial fat pad may incur in fibrotic changes during chronic cardiac failure. Interestingly, an experimental study suggested that epicardial fat can increase the atrial arrhythmogenesis in rabbits with HF [26]. Very recently p53 mRNA expression was found higher increase in epicardial fat obtained from HF patients [27]. The presence of HF can explain the lower actual epicardial fat thickness values in our patients, when compared to our previous studies [8–10]. In conclusion, this study suggests that echocardiographic epicardial fat thickness is higher in subjects with chronic AF, but lower in AF subjects with HF. Our findings may warrant future longitudinal studies to evaluate the capacity of epicardial fat thickness to predict AF and HF.
Study Limitations
▼
Sample size of patients with PAF was relatively small. However, this sample size provided significant statistical power to detect differences between the 2 groups. We certainly recognize that CT or CMR procedures can provide a volumetric assessment of epicardial fat. However, echocardiography is undoubtedly less invasive. Moreover, echocardiography can easily distinguish between epicardial and pericardial fat. Waist circumference was not measured in our population. However, previous studies showed that epicardial fat thickness reflects body fat distribution and visceral fat accumulation better than waist circumference. HF was diagnosed only on the basis of the ejection fraction, clinical history and examination. Additional imaging tests may be necessary to confirm our preliminary findings of the lower epicardial fat thickness in patients with HF. Iacobellis G et al. Epicardial Fat … Horm Metab Res 2014; 46: 587–590
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Endocrine Care 589
Conflict of Interest
▼
The authors declare that they have no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
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