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1 I have nothing to disclose.

2 Epicardial vs Pericardial Fat? Implications of this Question Thomas H Marwick MBBS, PhD, MPH Menzies Research Institute, Hobart, Australia

3 Epicardial and pericardial fat 1. Pathophysiology 2. Imaging of epicardial vs pericardial fat 3. Relevance to CAD 4. Relevance to heart failure

4 Sacks HS, Fain JN. Am Heart J 2007 Epicardial adipose tissue RCA and periadventitial epicardial fat. H+E ( 100 magnification) shows the close contact of epicardial adipocytes with the adventitia

5 Characteristics of fat depots Epicardial fat Pericardial fat Location Within visceral pericardium External to parietal pericardium Embyology Splanchnopleuric mesoderm (with omental) Thoracic mesenchyme Circulation Coronary branches Noncoronary (eventually IMA) Association Visceral fat

6 Fat very active and very close! Cellular and molecular inflammatory cascade with positive feedback loops involving VEGF and MCP-1 cause; - increased adipose tissue vascularity - enhanced accumulation of macrophages and release of cytokines - local insulin resistance, accelerated lipolysis and FFA release - decreased adiponectin production - increased leptin release by adipocytes 1. Paracrine signaling - adipokines diffuse in interstitial fluid across the adventitia, media, and intima 2. Vasocrine signaling - Adipokines transported downstream to react with media and the intima around plaques. (macrophages and lymphocytes can migrate alongside the vasa vasorum) Sacks HS, Fain JN. Am Heart J 2007

7 Metabolic risk with intrathoracic and visceral fat Age-adjusted prevalence of DM, impaired fasting glucose (IFG), HTN, and Met Synd by tertiles of intrathoracic fat within tertiles of visceral fat Significant p for trend of intrathoracic fat tertiles in; women - upper tertile of VAT in for HTN and IFG men - MetSynd p=0.009 p=0.02 p=0.02 Rosito G (Framingham). Circulation 2008

8 Association of metabolic factors with IT/PF Women Men ITF PF ITF PF Age BMI Waist circumf Visceral adipose Log TG HDL C Total cholesterol SBP * 0.10 * DBP * 0.08 Blood glucose * Phys activity 0.09 * *p<0.05; p<0.01; p< participants (age 53, 58% women) free of CVD Pericardial fat, but not intrathoracic fat, was indep a/w coronary calcification (OR 1.21 [1.005 to 1.46], p=0.04) Intrathoracic fat, but not pericardial fat, was a/w abdominal aortic calcification (OR 1.32 [1.03 to 1.67], p=0.03) Rosito G (Framingham) Circulation 2008

9 Epicardial and pericardial fat 1. Pathophysiology 2. Imaging of epicardial vs pericardial fat 3. Relevance to CAD 4. Relevance to heart failure

10 Epicardial fat measurement PLAX and PSAX Measure perpendicular to RV in systole, ao annulus landmark for LAX and mid-papillary muscles for SAX Median 7mm in men, 6.5mm in women Metabolic syndrome and IR a/w >9.5mm in men and >7.5mm in women Iacobellis & Willens JASE 2009

11 Reliability of epicardial fat measurement ICC for inter- and intra-observer variation with and (Iacobellis, JASE 2009) Intra-observer Inter-observer Accuracy Saura D. Intern J Cardiol 2010

12 Pericardial fat measurement Hypoechoic space anterior to epicardial fat and pericardium Does not deform with cardiac cycle Not hyperechoic

13 Paracardiac and thoracic fat by CT Images reconstructed using a medium sharp kernel with a 3-mm slice thickness for quantification of EpiFat volume (EFV). Contiguous 3D voxels between the Hounsfield Unit (HU) limits of -190 to -30 were defined as fat voxels by default. Tamarappoo B. J Cardiovasc CT 2011

14 Sicari R, JASE 2011;24:1156 Epicardial vs pericardial fat by CMR

15 Echo vs MRI - Epicardial vs pericardial thickness Sicari R, JASE 2011;24:1156

16 Sicari R, JASE 2011;24:1156 Epi/pericardial vs visceral fat

17 Epicardial and pericardial fat 1. Pathophysiology 2. Imaging of epicardial vs pericardial fat 3. Relevance to CAD 4. Relevance to heart failure

18 Ding J et al (MESA). Am J Clin Nutr 2009;90: Association of paracardiac fat with CAD Case-cohort study in 998 individuals (45 84 y, 42% men), randomly selected from 6814 MESA participants, 26 of whom developed incident CAD from 2000 to Pericardial fat was positively correlated with BMI (r=0.45, p<0.0001) and waist circumference (r=0.57, p<0.0001). CAD associated with pericardial fat (RR per 1-SD increment: 1.33 [1.15 to 1.54], but not BMI (RR 1.00 [0.84 to 1.18]) or waist circumference (RR 1.14 [0.97 to 1.34]; p=0.10)

19 Case-control study of 73 pts with ischemia by SPECT (cases) with 146 controls (from 1,777 consecutive pts having noncontrast CT and SPECT without known CAD) PFV and TFV remained strong predictors of ischemia after adjustment for CCS (OR 2.91 [1.53 to 5.52], p = for each doubling of PFV) Tamarappoo BK et al. ijacc 2010;3: Pericardial fat and ischemia p=0.04 p=0.04

20 Epicardial and pericardial fat 1. Pathophysiology 2. Imaging of epicardial vs pericardial fat 3. Relevance to CAD 4. Relevance to heart failure

21 Stages in HF development HF history HF signs Abn structure function Normal No No No No Stage A No No No Yes Stage B No No Yes Yes Stage C1 No Yes Yes Yes Stage C2 Yes No Yes Yes Stage D Yes Yes Yes Yes RF for HF ACC/AHA Heart Failure Guidelines 2005

22 Obesity and heart failure Association of heart failure with obesity (He et al. 2001; Hubert et al. 1983; Kenchaiah et al. 2002) No identifiable cause of HF in 80% cases of obese subjects (Kasper AJC 1992) Predominantly a/w abnormal LV diastolic function (Chakko S 1998; Zarich et al. 1991), without consistent association with LV systolic dysfunction (Alexander 1985; Scaglione et al. 1992; Pascual et al. 2003)

23 Heart failure, obesity and MS Association of heart failure with obesity (He et al. 2001; Hubert et al. 1983; Kenchaiah et al. 2002) No identifiable cause in 80% of HF in obese subjects (Kasper AJC 1992) Predominantly a/w LV diastolic dysfunction (Chakko S 1998; Zarich et al. 1991), no consistent a/w LV systolic dysfunction (Alexander 1985; Scaglione et al. 1992; Pascual et al. 2003) Voulgari C. J Am Coll Cardiol 2011;58:

24 Obesity is an ubiquitous problem with strong association with cardiovascular disease. Myocardial dysfunction of obesity Overweight subjects without overt heart disease have subclinical changes of LV structure and function (diastology and strain) even after adjustment for mean arterial pressure, age, gender and LV mass. Wong CY, Marwick TH. Circulation 2004;110:

25 Mechanisms 1. Myocyte metabolism (FFA, insulin resistance) 2. Structural - Myocardial ECM changes 6. Metabolic effects of epicardial fat Obesity heart disease 3. Structural - Myocardial fibrosis 5. Abnormal load due to arterial disease 4. Reduced perfusion due to small vessel disease Assuming subclinical CAD and LVH excluded Fang et al. Endocr Rev 2004

26 Predictors of mean e velocities Variables Univariable Multivariable* R 2 B p B p Age (per year) < <0.001 Epi fat volume (per cm 3 ) < SBP (mmhg) BMI (per kg/m 2 ) Waist circumference (cm) Total Agatston score LV mass (g) pts (55±13y, 65% men) without CAD, valve disease, LVD EFV independently a/w e after adjusting for age, LV mass, SBP and BMI Cavalcante J. Am J Cardiol 2012

27 Contribution of fibrosis- Mediators ATII Aldo RAGE TGFβ Collagen destructn MMPs Collagen production via 2 nd messengers Smads MAP kinase Pro-fibrotic proteins Conn tissue GF Platelet DGF

28 Conclusions 1. Epicardial fat may have an important pathophysiologic role in relation to CAD and LVD 2. Epi- and pericardial fat may be identified by echo, CT and MRI 3. Multiple studies have linked epi fat and CAD 4. Epi fat is likely relevant to heart failure; EpiFat is associated with lower e mean velocities. The stronger association of EpiFat compared to waist circumference and BMI suggests that the effects are likely direct (paracrine) rather than visceral adiposity mediated