Nutrition, Metabolism & Cardiovascular Diseases (2014) xx, 1e6

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Epicardial fat, rather than pericardial fat, is independently associated with diastolic filling in subjects without apparent heart disease S. Dabbah a,*, H. Komarov a, A. Marmor a, N. Assy b a b

Department of Cardiology, Ziv Medical Center and Bar-Ilan University, Safed, Israel Liver Disease Unit, Ziv Medical Center and Bar-Ilan University, Safed, Israel

Received 10 September 2013; received in revised form 22 January 2014; accepted 29 January 2014 Available online - - -

KEYWORDS Epicardial fat; Pericardial fat; Diastolic dysfunction; Echocardiography; Long axis; Short axis

Abstract Background and aim: Epicardial and pericardial fat are separate fat depots surrounding the heart. Previous studies found epicardial fat to be associated with diastolic dysfunction, but they had some limitations. Pericardial fat association with diastolic dysfunction was not examined. Our aim was to assess the relation of epicardial and pericardial fat with diastolic filling. Methods and results: In 73 volunteers without known heart disease or complaints, using echocardiography, we measured epicardial and pericardial fat thickness from long(LAX) and short(SAX) axis views and assessed diastolic filling: mitral inflow (E/A ratio, E wave deceleration time[DT]), pulmonary vein flow (systolic/diastolic ratio [S/D], systolic filling fraction[SFR], late retrograde velocity[Ar]), color M-mode flow propagation velocity [Vp], and tissue Doppler derived mitral early annular velocities at the septum [e0 sep] and lateral wall [e0 -lat]. By Spearman’s correlation, epicardial fat from LAX had a weak, but statistically significant correlations with several diastolic filling indices (SFR{rs Z 0.29, P Z 0.02}, Ar{rs Z 0.3, P Z 0.01}, Vp{rs Z 0.3, P Z 0.01}, e0 sep {rs Z 0.23, P Z 0.04}, e0 lat{rs Z 0.26, P Z 0.03}). In multivariate logistic regression model adjusting for age, gender, diabetes, systolic blood pressure and left ventricle mass index, epicardial fat thickness from LAX (and not from SAX) was the only independent predictor of e0 [e0 sep < 8: OR Z 1.8, 95%CI Z 1.1e2.9; e0 lat1.1 cm (1), moderate or severe valvular stenosis or regurgitation (1) and mitral annulus calcification (2). Clinical and demographic data were collected. Body mass index (BMI) was defined as weight (kilograms) divided by height squared (meters). Blood pressure was measured at rest by a sphygmomanometer. Diabetes (type 2) was defined as fasting plasma glucose >126 mg/dl. Hypertension was defined as a history of blood pressure >140/90 at rest. Hyperlipidemia was defined as total cholesterol level >240 or triglycerides >150 mg/dl. Smoking was defined as current smoking. The study protocol was approved by our institutional review board, and all subjects gave their written informed consent. Echocardiography Transthoracic echocardiography was performed by a single experienced operator, in the left lateral decubitus position

S. Dabbah et al.

according to the ASE guidelines [22], by a commercially available ultrasound machine (Philips IE 33, Bothhell WA, USA). Left atrial dimension was measured from parasternal long axis view, by M-mode. Left ventricle dimensions were measured by M-mode from parasternal short axis view at papillary muscles level. Left ventricle mass was calculated by the cubed method and ejection fraction was calculated by Teicholz formula. Measurement of epicardial and pericardial fat Epicardial fat thickness was measured perpendicularly to the myocardium, as the echo lucent space between the right ventricular epicardium and the linear echo dense parietal pericardium [2,13]. Pericardial fat was measured as the echo lucent space anterior to parietal pericardium [2]. Measurements were performed in parasternal LAX and SAX views, on the still images of the two-dimensional echocardiogram at end diastole [2,12,13]. The maximal value at each site and view was measured in three cardiac cycles and the average value considered [2] for analysis. Diastolic filling According to the ASE [22] guideline, from the apical four chamber view, diastolic filling indices were measured at end expiration after optimizing gain, sweep speed, filters and scale. Values from three cardiac cycles were averaged. The following parameters were measured: 1 Mitral inflow: by pulsed wave Doppler, with the sample volume located between the tips of mitral leaflets, guided by color Doppler for parallel alignment with mitral inflow, the peak early filling velocity (E), peak late filling velocity (A), E deceleration time (DT) were measured and the E/A ratio calculated. In cases of partial fusion of E and A (E value at onset of A >20 cm/s) absolute A velocity (peak A minus the height of E at the onset of A) was used to calculate E/A ratio. With the sample volume at the level of the mitral annulus, A duration (Adur) was measured. 2 Pulmonary venous flow: color Doppler was used to identify flow within the right upper pulmonary vein, and a sample volume was placed >1 cm deep in the vein. Measurements of pulmonary venous waveforms included peak systolic velocity (S), peak diastolic velocity (D), S/D ratio, systolic flow time velocity integral(STVI), diastolic flow time velocity integral(DTVI), systolic filling fraction (SFR) defined as STVI/ (STVI þ DTVI), peak retrograde velocity in late diastole (Ar), the time difference between Ar and mitral A-wave durations ([Ar  A]dur). 3 Color M-Mode flow propagation velocity (Vp): color flow baseline was shifted to lower the Nyquist limit, and Vp was measured from the mitral annulus distally into the left ventricle, as the slope of the first aliasing velocity. 4 Tissue Doppler imaging (TDI): as described elsewhere [22], measurement of the septal and lateral early

Please cite this article in press as: Dabbah S, et al., Epicardial fat, rather than pericardial fat, is independently associated with diastolic filling in subjects without apparent heart disease, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/ j.numecd.2014.01.019

Effect of epicardial fat on diastolic filling

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diastolic annular velocities (e0 sep and e0 lat) was performed while paying attention to minimize angulation with annular motion. The ratios E/e0 sep, E/e0 lat were then calculated. After acquiring the above mentioned parameters, the correlation of the fat depots with indices of myocardial relaxation (E/A ratio, Vp, e0 ), myocardial stiffness (DT), left ventricle (LV) end diastolic pressure (Ar, [Ar  A] dur) and LV mean filling pressure (S/D ratio, SFR, E/e0 ) was examined. Statistical analysis SPSS version 19.0 (IBM) was used for statistical analysis. Continuous variables are expressed as mean  SD. Categorical variables are expressed as number and percentage. Concordance correlation coefficient (rc) was calculated to determine intra-observer variation of echo measurements. Correlations of epicardial and pericardial fat with diastolic filling indices and other factors were examined by Spearman’s correlation analysis. Multiple logistic regressions was performed to examine association of diastolic filling indices (outcome variable) with fat thickness, age, gender, diabetes, systolic blood pressure and left ventricle mass index as independent variables. Several different analyses were constructed to include the different fat measurement and diastolic indices separately. A p-value115 g /m2 for males). We found EF-LAX to be independently correlated with SFR, but not with E/e0 sep and E/e0 lat, though they all are indices of mean LV filling pressure. Because in subjects with normal ejection fraction, as in our population, the relation of SFR to LV mean filling pressure is of limited accuracy [22], and the E/e0 ratio is the preferred method for assessing mean LV filling pressure [22], we believe epicardial fat is not independently associated with mean LV filling pressure. We did not find an independent relation between epicardial fat and indices of LV stiffness (DT) or LV end diastolic pressure (Ar, [Ar  A] duration). Cavalcante [19] and Konishi [18] found independent correlation of epicardial fat and E/e0 . This discrepancy between our and their results may be due to different imaging modalities for measuring epicardial fat (they used CT based epicardial fat volume) or different populations. For example the study by Konishi et al. included patient suspected of coronary artery disease referred for cardiac CT, so some of them may have had ischemia resulting in more advanced diastolic dysfunction. Iacobellis et al. [16] found epicardial fat thickness as measured by echocardiography in obese subjects, to be significantly related to mitral E/A ratio, even after adjustment for BMI, age and sex. We did not find significant relation between epicardial fat and mitral E/A ratio. The E/A ratio is dependent on myocardial relaxation as well as other factors such as volume status [22], and tissue Doppler derived e0 is a more accurate and sensitive [22]

measurement of myocardial relaxation (they did not measure tissue Doppler e0 ). Moreover, perhaps with further adjustment for other factors such diabetes and hypertension, their relation would become insignificant. In contrast to EF-LAX, EF-SAX was not independently associated with any diastolic filling index after adjustment. So, epicardial fat thickness as measured in the long axis (and not in short axis) view is a predictor of diastolic filling. Relation between pericardial fat and diastolic filling Very few studies examined the relation of pericardial fat separately with cardiovascular diseases. Sicari [2] et al. found pericardial (rather than epicardial) fat to be a cardiometabolic risk marker. Other studies found thoracic fat which includes pericardial fat to be associated with cardiovascular diseases [3,4], but separation between pericardial and other fat depots was not performed. So, the role of pericardial fat in cardiovascular disease was unclear. We found pericardial fat thickness in long and short axis views to be significantly related only to e0 lat and [Ar  A] duration, respectively. These relations are much less robust than those of epicardial fat with uncertain meaning. To the best of our knowledge, our study is the first one to describe the relation of pericardial fat thickness and diastolic filling. Postulated mechanism As mentioned earlier, epicardial fat is a metabolically active tissue. It is active in energy homeostasis [23], free fatty acid metabolism [23], secretion of inflammatory adipokines [23] and has high level of oxidative stress [23]. It shares the same microcirculation [23] with, and is in close proximity to the myocardium and coronary arteries. By these properties, epicardial fat can exert a harmful effect on the coronary arteries and myocardium, thus worsening diastolic function. On the other hand, pericardial fat role as a source of adipokines is still partially unknown [24]. It is separated from the myocardium and coronary arteries by the pericardium, and is vascularized from non coronary sources [23]. These different properties of epicardial and

Please cite this article in press as: Dabbah S, et al., Epicardial fat, rather than pericardial fat, is independently associated with diastolic filling in subjects without apparent heart disease, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/ j.numecd.2014.01.019

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pericardial fats may explain the stronger association of epicardial fat with diastolic dysfunction. Conclusion Epicardial and pericardial fat thickness are easily measured by Echocardiography. Epicardial fat thickness as measured from the long axis view (and not from the short axis view) is an independent predictor of myocardial relaxation indices, but not of left ventricular stiffness or filling pressures. Pericardial fat is a predictor of much less diastolic indices making its role in diastolic dysfunction uncertain. A larger study may be needed to demonstrate a possible relation of pericardial fat to diastolic filling with more certainty. Whether these differences between epicardial Vs pericardial fat and between long axis Vs short axis are applicable for other cardiac abnormalities, such coronary artery disease needs to be examined. Study limitations The small sample size may reduce the power of our study to detect associations between fat thickness and diastolic indices not detected with this sample size. Also our population consisted mainly of middle aged men, and results may not be applicable to other populations. Though we included several co-variable in our multivariate logistic regression analyses, there are still some potential factors not included, such as ischemia. Some of our volunteers had risk factors for ischemic heart disease and may have had subclinical coronary artery disease and/ or possible silent ischemia, but the likelihood for this is low considering the absence of known cardiac disease/ complaints and segmental wall motion abnormalities on echocardiography. Further studies are needed to examine if our results are applicable to other cardiovascular conditions such as coronary disease. Another limitation of our study is the use of linear dimension of the cardiac chambers instead of volumes, but cardiac dimensions and systolic function was not of our goals. Acknowledgment The authors would like to thank Zipi Avraham for her assistance with statistical analysis. References [1] Iacobellis G, Willens HJ. Echocardiographic epicardial fat: a review of research and clinical applications. J Am Soc Echocardiogr 2009; 22(12):1311e9. [2] Sicari R, Sironi AM, Petz R, Frassi F, Chubuchny V, De Marchi D, et al. Pericardial rather than epicardial fat is a cardiometabolic risk marker: an MRI vs echo study. Am Soc Echocardiogr 2011;24(10): 1156e62.  L, Valea A, Pais R, Silaghi H. Is epicardial adipose [3] Silaghi AC, Poanta tissue, assessed by echocardiography, a reliable method for visceral adipose tissue prediction? Med Ultrason 2011;13(1): 15e20.

S. Dabbah et al. [4] Dey D, Wong ND, Tamarappoo B, Nakazato R, Gransar H, Cheng VY, et al. Computer-aided non-contrast CT-based quantification of pericardial and thoracic fat and their associations with coronary calcium and Metabolic Syndrome. Atherosclerosis 2010;209(1):136e41. [5] Iacobellis G, Barbaro G. The double role of epicardial adipose tissue as pro- and anti-inflammatory organ. Horm Metab Res 2008; 40(7):442e5. [6] Liu J, Fox CS, Hickson DA, May WL, Ding J, Carr JJ, et al. Pericardial fat and echocardiographic measures of cardiac abnormalities: the Jackson Heart Study. Eur J Radiol 2012;81(4):749e56. [7] Fox CS, Gona P, Hoffmann U, Porter SA, Salton CJ, Massaro JM, et al. Pericardial fat, intrathoracic fat, and measures of left ventricular structure and function: the Framingham Heart Study. Circulation 2009;119(12):1586e91. [8] Al Chekakie MO, Welles CC, Metoyer R, Ibrahim A, Shapira AR, Cytron J, et al. Pericardial fat is independently associated with human atrial fibrillation. J Am Coll Cardiol 2010;56(10):784e8. [9] Aydin H, Toprak A, Deyneli O, Yazici D, Tarçin O, Sancak S, et al. Epicardial fat tissue thickness correlates with endothelial dysfunction and other cardiovascular risk factors in patients with metabolic syndrome. Metab Syndr Relat Disord 2010;8(3):229e34. [10] Sengul C, Cevik C, Ozveren O, Oduncu V, Sunbul A, Akgun T, et al. Echocardiographic epicardial fat thickness is associated with carotid intima-media thickness in patients with metabolic syndrome. Echocardiography 2011;28(8):853e8. [11] Tamarappoo B, Dey D, Shmilovich H, Nakazato R, Gransar H, Cheng VY, et al. Increased pericardial fat volume measured from noncontrast CT predicts myocardial ischemia by SPECT. JACC Cardiovasc Imaging 2010;3(11):1104e12. [12] Eroglu S, Sade LE, Yildirir A, Bal U, Ozbicer S, Ozgul AS, et al. Epicardial adipose tissue thickness by echocardiography is a marker for the presence and severity of coronary artery disease. Nutr Metab Cardiovasc Dis 2009;19(3):211e7. [13] Ahn SG, Lim HS, Joe DY, Kang SJ, Choi BJ, Choi SY, et al. Relationship of epicardial adipose tissue by echocardiography to coronary artery disease. Heart 2008;94(3):e7. [14] Jeong JW, Jeong MH, Yun KH, Oh SK, Park EM, Kim YK, et al. Echocardiographic epicardial fat thickness and coronary artery disease. Circ J 2007;71(4):536e9. [15] Iwasaki K, Matsumoto T, Aono H, Furukawa H, Samukawa M. Relationship between epicardial fat measured by 64-multidetector computed tomography and coronary artery disease. Clin Cardiol 2011;34(3):166e71. [16] Iacobellis G, Leonetti F, Singh N, M Sharma A. Relationship of epicardial adipose tissue with atrial dimensions and diastolic function in morbidly obese subjects. Int J Cardiol 2007;115(2):272e3. [17] Kazlauskaite R, Doukky R, Evans A, Margeta B, Ruchi A, Fogelfeld L, et al. Predictors of diastolic dysfunction among minority patients with newly diagnosed type 2 diabetes. Diabetes Res Clin Pract 2010;88(2):189e95. [18] Konishi M, Sugiyama S, Sugamura K, Nozaki T, Matsubara J, Akiyama E, et al. Accumulation of pericardial fat correlates with left ventricular diastolic dysfunction in patients with normal ejection fraction. J Cardiol 2012;59(3):344e51. [19] Cavalcante JL, Tamarappoo BK, Hachamovitch R, Kwon DH, Alraies MC, Halliburton S, et al. Association of epicardial fat, hypertension, subclinical coronary artery disease, and metabolic syndrome with left ventricular diastolic dysfunction. Am J Cardiol 2012;110(12):1793e8. [20] Oyama N, Goto D, Ito YM, Ishimori N, Mimura R, Furumoto T, et al. Single-slice epicardial fat area measurement: do we need to measure the total epicardial fat volume? Jpn J Radiol 2011;29(2): 104e9. [21] Saremi F, Mekhail S, Sefidbakht S, Thonar B, Malik S, Sarlaty T. Quantification of epicardial adipose tissue: correlation of surface area and volume measurements. Acad Radiol 2011;18(8):977e83. [22] Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. Eur J Echocardiogr 2009;10(2):165e93. [23] Iacobellis G, Bianco AC. Epicardial adipose tissue: emerging physiological, pathophysiological and clinical features. Trends Endocrinol Metab 2011;22(11):450e7. [24] Iacobellis G. Epicardial and pericardial fat: close, but very different. Obesity 2009 Apr;17(4):625.

Please cite this article in press as: Dabbah S, et al., Epicardial fat, rather than pericardial fat, is independently associated with diastolic filling in subjects without apparent heart disease, Nutrition, Metabolism & Cardiovascular Diseases (2014), http://dx.doi.org/10.1016/ j.numecd.2014.01.019