The role of perivascular fat in aortic atherosclerosis.

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Dr Ilias Kylintireas, Dr Cheerag Shirodaria, Dr Oliver Rider, Dr Justin Lee, Dr Ikhlef Bechar, Dr

1 UNIVERSITY OF OXFORD DEPARTMENT OF CARDIOVASCULAR MEDICINE Centre for Clinical Magnetic Resonance Research (OCMR) The role of perivascular fat in aortic atherosclerosis. Dr Ilias Kylintireas, Dr Cheerag Shirodaria, Dr Oliver Rider, Dr Justin Lee, Dr Ikhlef Bechar, Dr Janet Digby, Dr Matthew Robson, Prof. Stefan Neubauer, Dr Robin Choudhury Nothing to disclose No discussion regarding off label medication use

2 Atherosclerosis Obesity-Adiposity-Cardiovascular Disease Obesity Excess Adiposity HTN LDL /HDL /TG IR/DM Cardiometabolic Risk Inflammatory Infiltration Inflammation Thrombosis Endothelial Dysfunction CHF

3 Direct adipokine effects on vascular inflammation (Vela 2007) NEFA Resistin Leptin Adiponectin Inflammatory mediators (CRP, MCP-1 etch.) Toll-like receptor 4 (TLR4) activation adhesion molecule and MCP-1 expression foam cell transformation of macrophages (expression of CD36) macrophage production of TNF-α NFκB activation MCP-1 production inflammatory cell proliferation and activation NFκB inhibition adhesion molecule expression inhibition macrophage scavenger receptor expression reduction direct pro-inflammatory effect

4 Vascular effects of Perivascular Adipose Tissue (PVAT)? Production of cytokines (Barandier 2005, Henrichot 2005) Inflammation (Ishikawa 1997) Vasoactive factors Vasorelaxation ADRF (adventitia derived relaxation factor) Adiponectin Vasoconstriction H2O2 and reactive oxygen species (ROS) (Gao 2007)

5 Vascular effects of PVAT - MECHANISM? Paracrine route Periadventitialy applied IL-1β induces vascular inflammation (Shimokawa 1996) Transferable vasoactive products (Gao 2007) Vasocrine route vasa vasora (Virmani, 2005)

6 Turbo spin Echo for Adipose Tissue T1 relaxation TSE NFS TSE WS TSE FS

distensibility/ Pulse Wave Velocity Endothelial Dysfunction NO Elastin

7 MRI assessment of non coronary vascular function and structure. Flow Mediated Dilatation (FMD) Arterial wall imaging Arterial distensibility/ Pulse Wave Velocity Endothelial Dysfunction NO Elastin Collagen Arterial stiffening Atheromatic plaque Wall remodeling Arterial wall thickening

Adipose tissue dysfunction and the role of excess adiposity Weight gain Obesity Weight Loss Fat Accumulation Adipocyte hypertrophy and hyperplasia Increased adiposity Adipocyte hypertrophy and

8 Adipose tissue dysfunction and the role of excess adiposity Weight gain Obesity Weight Loss Fat Accumulation Adipocyte hypertrophy and hyperplasia Increased adiposity Adipocyte hypertrophy and hyperplasia Macrophage infiltration Fat reduction Adipocyte hypertrophy and hyperplasia regression Macrophage infiltration regression Adiponectin Visfatin? Atheroprotection Atheroprotection IS Insulin sensitivity Normally functional Adipose tissue= Normal Adipocytes Dysfunctional Adipose tissue= Dysfunctional Adipocytes + Macrophages/T cells Adiponectin Resistin Leptin Atherogenesis TNF-a/IL-6/IL-1/MCP-1 PAI-1/t-Fg endothelial ED/vascular dysfunction/insulin inflammation/htn/ir resistance/htn

9 Adipose tissue dysfunction Systemic adipose tissue state in obesity (Bruun, 2003, Fain 2004, Kanda 2006, Suganami, 2005, McCann 2003) Perivascular adipose tissue dysfunction Paracrine vasodilatory effect abolished in obesity(greenstein et al. 2009) Dysfunction linked to adipocyte hypertrophy and tissue inflammation(greenstein et al. 2009) Metabolic impairment associated with perivascular adipose tissue oxidative stress and inflammation and resulting in endothelial dysfunction and vascular inflammation (Marchesi et al. 2009) Hypertention and diabetes associated with a pro-atherogentic functional shift (Calabro et al. 2008;Zeng et al. 2009) Obesity associated with a shift from an anti-inflamatory to a pro-inflammatory PVAT secretory profile(takaoka et al. 2009)

10 Hypothesis Perivascular Excess adiposity Atherosclerosis/ vascular dysfunction The association between Perivascular adiposity and atherosclerosis/ vascular dysfunction of the corresponding vessel (as assessed by MRI) Obesity Adipose tissue Dysfunction will be influenced by the degree of generalized obesity and the extent of local adiposity

Investigations Lipids-Fasting glucose-adiponectin-hscrp-insulin-homa-ir AORTIC DISTENSIBILITY 128 Patents with cardiovascular disease MRI AORTIC THICKNESS Abdominal and PERI-AORTIC ADIPOSE TISSUE

11 Investigations Lipids-Fasting glucose-adiponectin-hscrp-insulin-homa-ir AORTIC DISTENSIBILITY 128 Patents with cardiovascular disease MRI AORTIC THICKNESS Abdominal and PERI-AORTIC ADIPOSE TISSUE Measurements FMD 75 Patents with coronary artery disease (CAD) MRI Abdominal and PERI-BRACHIAL ADIPOSE TISSUE Measurements 30 healthy Obese subjects (BMI>30kg/m²) MRI AORTIC DISTENSIBILITY WEIGHT LOSS INTERVENTION 12 months 15 healthy Lean subjects (BMI<25kg/m) Abdominal and PERI-AORTIC ADIPOSE TISSUE Measurements MRI

12 Aortic TSE

13 AA PA Vascular lumen area Vs Time after R (cardiac cycle) Maximum Area DA Minimum Area Distensibility =[(max area min area)/ min area]/pulse Pressure

after cuff release baseline ED crossectional vessel area)/ baseline ED

14 MR brachial FMD Flow Mediated Dilatation (FMD)/ Endothelium Independent Dilatation (EID)= [(maximum end diastolic (ED) crossectional vessel area after cuff release baseline ED crossectional vessel area)/ baseline ED crossectional vessel area] % 5 min forearm BP cuff 400 μg GTN Cuff release FMD EID

Abdominal and PERI-AORTIC ADIPOSE TISSUE IMAGING VAT + SCAT =

(TSE) 5 transverse slices at the level of the middle of the

650/6 Breath hold in expiration T1W TSE 5 mm thick slices (in

15 Abdominal and PERI-AORTIC ADIPOSE TISSUE IMAGING VAT + SCAT = TAT Water suppression (WS) T1 weighted (T1W) Turbo Spin Echo (TSE) 5 transverse slices at the level of the middle of the body of lumbar vertebra L4/L5 Slice thickness = 6 mm TR/TE = 650/6 Breath hold in expiration T1W TSE 5 mm thick slices (in plane resolution 0.8 x 0.8 mm ) TR/TE = 750/36 Breath hold in expiration

16 Aortic turbo spin echo (TSE) imaging Peri-vascular adipose tissue (PVAT) index = Peri-vascular Fat area / vascular cross-sectional (inner) area Water Suppression (WS) TSE Fat Suppression (FS) TSE

17 PERI-AORTIC ADIPOSE TISSUE QUANTIFICATION PVAT= peri-vascular (aortic) adipose tissue area (mm²) PVAT index= PVAT /cross-sectional vessel area variability Interobserver Intraobserver variability Inter-scan variability (n=10) CV<0.06 CV<0.05 CV<0.08

PBAT /cross-sectional vessel area Inter-observer

18 Peri-brachial adipose tissue (PBAT) analysis PBAT= peri-brachial adipose tissue area (mm²) PBAT index= PBAT /cross-sectional vessel area Inter-observer variability Intra-observer variability CV<0.06 CV<0.05

19 PATIENT CHARACTERISTICS PERI-AORTIC PVAT PERI-BRACHIAL PVAT Number Age 128 CVD 62.1 (± 0.58) 75 CAD (± 0.78) Gender Male 84% Male 88% Diabetes mellitus (type 2) 27% 40 % BMI Tertiles BMI 1 st <26 (near) normal 2 nd overweight 3 rd >30 obese Hypertension 56% 77 % Smoking 46% 60 % Dyslipidemia 70% 85 % Total cholesterol 4.65 (± 0.09) 4.21 (± 0.09) LDL 2.73 (± 0.09) 2.44 (± 0.09) HDL 1.19 (± 0.03) 1.11 (± 0.03) Triglycerides 1.78 (± 0.07) 1.87 (± 0.1) Glucose 5.76(±0.08) 5.76 (± 0.07) Body Mass Index (kg/m²) (± 0.32) (± 0.41)

20 Peri-aortic adipose tissue (PVAT) associations PVAT index associations Multivariate regression analysis(r²=0.44) BMI r=0.34(p<0.001) NS Waist-hip ratio r=0.33(p<0.005) NS VAT r=0.47(p<0.0001) β=0.38(0.13) x 10 ³, P<0.01 SCAT NS NS HOMA IR r= 0.48 (P<0.0005) β=0.11(0.04), P<0.005 insulin levels r= 0.27 (P<0.005) NS fasting glucose r= 0.26 (P<0.005) NS HbA1c r= 0.26 (P<0.005) NS triglycerides r= 0.24 (P<0.005) NS (n) MS criteria (AHA/NCEP) r= 0.41 (P<0.005) β=0.07(0.02), P<0.005

21 PVAT and ATHEROMA BURDEN -Generalized adiposity- Mean aortic wall thickness (mm) PVAT index vs. aortic wall thickness (n=128) [r=0.23(p<0.05)] BMI tertiles Multivariate regression analysis 1 st (<26 kg/m²) 2 nd (26-30 kg/m²) 3 rd (>30 kg/m²) r=-0.16(p=0.3) r=0.06(p=0.7) r=0.59(p<0.0001) β=0.69(0.16) (P<0.005) (R²=0.49) 3.5 BMI>30 kg/m² r = 0.59 P< PVAT index

22 Mean aortic wall thickness (mm) PVAT and ATHEROMA BURDEN -Local adiposity- PVAT index vs. aortic wall thickness (n=128) [r=0.23(p<0.05)] PVATI tertiles Multivariate regression analysis 1 st r=-0.59(p<0.0001) β=-1.4(0.3) (P<0.0001), R²= nd r=-0.16(p=0.33) 3 rd r=0.57(p<0.0001) β=0.47(0.18) (P<0.05), R²= Lowest PVAT index tertile r = P< Highest PVAT index tertile r = r 0.57 = P<0.05 P< PVAT index PVAT index

23 PVAT and AORTIC ELASTICITY -Generalized adiposity- Aortic distensibility (x 10 ³ mmhg ¹) PVAT index vs. aortic distensibility(n=128) [NS] BMI tertiles Multivariate regression analysis 1 st (<26 kg/m²) 2 nd (26-30 kg/m²) 3 rd (>30 kg/m²) r=0.38(p<0.05) r=-0.26(p=0.13) r=-0.45(p<0.01) β=1.87(0.48) x 10 ³ (P<0.0005), R²=0.46 β=-1.7(0.7) x 10 ³ (P<0.05), R²= BMI< 26 kg/m² r = 0.38, P< BMI> 30 kg/m² r = -0.45, P< PVAT index PVAT index

24 Aortic distensibility (x 10 ³ mmhg ¹) PVAT and AORTIC ELASTICITY -Local adiposity- PVAT index vs. aortic distensibility(n=128) [NS] PVATI tertiles Multivariate regression analysis 1 st r=0.42(p<0.01) β=4.1(2) x 10 ³ (P<0.05), R²= nd r=0.22(p=0.17) 3 rd r=-0.52(p<0.001)] β=-2.2(0.8) x 10 ³ (P<0.05), R²= Low perivascular fat (1st PVAT index tertile) r = 0.42 P< High perivascular fat (3rd PVAT index tertile) r = P< PVAT index PVAT index

25 EID (%) Peri-Brachial adipose tissue (PBAT) associations PBAT index associations Partial Correlation Analysis BMI r=0.22(p<0.05) NS VAT r=0.25(p<0.05) β=0.02 (0.01), P<0.05 Waist-hip ratio SCAT NS NS PBAT index vs. Brachial arterial function FMD EID r= (P<0.005) r= (P<0.01) 25 R²= 0.154, P< R²= 0.111, P< PBAT index PBAT index

26 PBAT index vs. FMD -Generalized adiposity- BMI groups Multivariate regression analysis (near) normal weight (<26 kg/m²) Overweight and obese (>26) r=-0.102(p=0.65) r=-0.48(p<0.001) β=-3.9(1.4) (P<0.001), R²=0.37 -Local adiposity- PVATI tertiles Multivariate regression analysis 1 st r=0. 11(P=0.44) 2 nd and 3 rd r=-0.39(p<0.05) β=-5.5(2.0) (P<0.01), R²=0.43

27 Peri-aortic adipose tissue (PVAT) associations Healthy obese (BMI>30) (n=30) Healthy lean (BMI<25) (n=15) PVAT index associations BMI NS Waist-hip ratio NS VAT r=0.6(p<0.001) SCAT NS HOMA IR r=0.5(p<0.005) insulin levels r=0.48(p<0.01) fasting glucose r=0.54(p<0.005) Total cholesterol r=0.51(p<0.005) triglycerides r=0.59(p<0.005) age r=0.58(p<0.001) Mean blood pressure r=0.4(p<0.05) Obese Lean PVAT index associations BMI Waist-hip ratio VAT SCAT r=0.57(p<0.001) NS NS NS PVATI vs. Aortic elastisity r= (P<0.005) r= 0.63 (P<0.005) β=-0.9(0.4) x 10 ³ (P<0.05), R²=0.78

28 Weight loss intervention outcome (follow up at 12 months) baseline Follow up Weight (kg) 109.9(23.1) 93.5(16.3) P< BMI (kg/m²) 38.8(1.4) 33.1(0.9) P< Waist-hip ratio 0.95(0.02) 0.9(0.02) P<0.05 VAT (ml) 726(57) 532(61) P<0.001 PVATI 0.88(0.04) 0.81(0.05) P<0.005 PVATI LOSS associations Weight % Loss r=0.43(p<0.05) BMI % Loss r=0.44(p<0.05) VAT % Loss r=0.46(p<0.05) β=1.7(0.6) x 10 ³, P<0.05

29 Perivascular adipose tissue reduction vs. Aortic elasticity improvement Aortic elasticity improvement (associations) Multivariate regression analysis (R²=0.79) Weight % Loss BMI % Loss NS NS VAT % Loss r=0.46(p<0.05) β=1.7(0.6) x 10 ³, P<0.05 PVATI loss r=0.56(p<0.005) β=7.3(2.6) x 10 ³, P< r = 0.56, P<0.05 PVAT index vs. Aortic distensibility at Follow up :NS PVAT index change

Conclusions: use MRI to measure peri-vascular fat by a highly effective, reproducible and repeatable technique Perivascular (periaortic and peribrachial) adiposity is independently associated with

30 Conclusions: use MRI to measure peri-vascular fat by a highly effective, reproducible and repeatable technique Perivascular (periaortic and peribrachial) adiposity is independently associated with visceral adiposity and insulin resistance (Rittig 2009) [body size for lean healthy individuals?] Bimodal association between PVAT and markers of vascular disease (atheroma burden, vascular stiffness, endothelial dysfunction) (positive association in obesity and in the presence of excess perivascular fat accumulation, negative or no association in the absence of these parameters) Perivascular adiposity changes follow visceral adipose tissue changes and are independently associated with functional changes of the underlying vessel. Both generalized and regional excess adiposity influence on the functional state and the effects of perivascular adipose tissue on vascular disease?

31 Department of Cardiovascular Medicine Dr Robin Choudhury Prof. Stefan Neubauer Dr Oliver Rider Dr Steffen Petersen Dr Charalambos Antoniades Dr Paul Leeson Dr Cheerag Shirodaria Dr Justin Lee Dr Janet Digby OCMR Dr Matthew Robson Dr Iklef Behar

32 Aortic distensibility (mmhg ¹ x10³) 3.5 P < P < Peri-aortic adipose tissue tertiles Periaortic fat tertrtiles Linear regression analysis Model 1 Prediction of aortic thickness (R² = 0.64) β (SE) P PVAT index β=1.47 (±0.54) <0.05 Model 1 Prediction of aortic distensibility (R² = 0.64) β (SE) P PVAT index β=-1.97 (±0.55) <0.01

33 Visceral Adipose Tissue and systemic inflammation Van Gaal et al, Nature 2006

34 Epicardial adipose tissue Standard views SA TSE FS SA TSE NFS SA TSE WS

36 Epicardial adipose tissue TSE Adipose Tissue imaging WS T1W TSE - HLA, VLA, RVIT, SA base/mid/apical +/- I-PAT

37 SSFP cine (measurement of local compliance)

38 Flow (transit time method of measuring pulse wave velocity) Examples of flow images obtained magnitude (left column) and phase velocity images (right column).position 1 (level of pulmonary artery) is shown at top. Position 2 (upper abdominal aorta) is shown below.

39 Blood Sample Protocol Vacuteiners (in order) Routine Research Inversion 1 Blue (citrate P) (2,7ml) 3 5,4ml 2 Blue (citrate P) (2,7ml) ml 2 Golden (SST S) (5ml) 5 1 Green (LH P) (3ml) 3 9ml 2 Green (Li P) (3ml) Purple (EDTA P) (4ml) 4 16ml 2 Purple (EDTA P) (4ml) Grey (oxalate fluoride P)(4ml) 1 4ml ,5ml 1 Green (LH P) (3ml) LFTs, TC/HDL/LDL/TG, U+E, CK, Urate 1 Purple (EDTA P) (4ml) HbA1c 1 Grey (oxalate fluoride P)(4ml) Glucose 1 Blue (citrate P) (2,7ml) PTT/INR clotting screen 1 Purple (EDTA P) (4ml) FBC Green form Red form Biochemistry Haematology 2 Blue (citrate P) (2,7ml) Centrifugation 6 (23-28) White cap aliquots (500 μl) store at -80 C. Avoid within 30 min repeated freeze/thaw 2 Green (Li P) (3ml) 6 (17-22) Green cap aliquots (500 μl) Program 2: cycles 2 Purple (EDTA P) (4ml) 4000 c/min x 20min 8(1-8 E) Purple cap aliquots (500 μl) 2 Golden (SST S) (5ml) allow samples to clot for 30 minutes Centrifugation Program 2: 4000 c/min x 20min 8 (9-16) Golden cap aliquots (500 μl) store at -80 C. Avoid repeated freeze/thaw cycles

40 Vascular lumen area Vs Time after R (cardiac cycle) Maximum Area Minimum Area

41 1. RNA expression profiling Quantitative RTPCR (IL-6, TNF-α, MCP-1, IL-1, MCSF, resistin, adiponectin, leptin,visfatin etch.) Gene expression array 2. Protein Product assays Cytokine and chemokine secretion -ELISAs (IL-6, TNF-α, MCP-1, IL-1, MCSF, resistin, adiponectin, leptin,visfatin etch.) Chemotaxis Assay (THP-1) Endothelial cell activation (qrtpcr for VCAM-1 on send culture) 3. Histological examination Macrophages (anti-cd68) / vascular elements (anti-pecam-1)

42 Aortic Plaque Index (API) * OSA patients Control subjects ** P < OSA Controls * P < ** 4.00 * Ascending Aorta Proximal Descending Aorta * Distal Descending Aorta

43 Adiponectin Adiponectin Normally functional Adipose tissue= Normal Adipocytes Dysfunctional Adipose tissue= Dysfunctional Adipocytes + Macrophages/Tcells Resistin Leptin TNF-a/IL-6/IL-1/MCP-1 PAI-1/t-Fg Atheroprotection Insulin sensitivity Atherogenesis endothelial dysfunction/insulin resistance/htn

44 Adiponectin (ng/ml) 11.4 ( ) PATIENT CHARACTERISTICS Number Age (± 0.58) Gender Male 84% Diabetes mellitus (type 2) 27% Hypertension 56% Smoking 46% Dyslipidemia 70% Total cholesterol 4.65 (± 0.09) LDL 2.73 (± 0.09) HDL 1.19 (± 0.03) Triglycerides 1.78 (± 0.07) Glucose 5.76(0.08) Body Mass Index (kg/m²) (± 0.32)

45 PATIENT CHARACTERISTICS Age (± 0.78) Cerebrovascular accident (CVA) 1 % Peripheral vascular disease (PVD) 17 % Diabetes mellitus (I or II) 40 % Hypertension 77 % Hyperlipidemia 86 % Total cholesterol 4.21 (± 0.09) LDL 2.44 (± 0.09) HDL 1.11 (± 0.03) Triglycerides 1.87 (± 0.1) Family history 51 % Myocardial infraction (MI) 31 % Smoking 60 % Body Mass Index (BMI) (± 0.41) Sex 88 %, 22 % Aspirin 91 % Clopidegrel 33 % Statins 96 % ACE inhibitors/arbs 62 % Beta blockers 86 % Diuretics 26 % Nitrates 13 % Calcium channel blockers 28 % Insulin /Oral hypoglycemics 13 % /26%

46 Vascular inflammation and atherosclerosis Dyslipidemia, hypertension, smoking and diabetes mellitus as triggers of vessel inflammation (Baynes1999, Tummala 1999, Witztum1998, Yudkin, 1999) Vessel wall infiltration by inflammatory cells (Libby 2001). Circulating inflammatory factors (Deo et al. 2004;Ridker et al. 2002). Rheumatoid arthritis and systemic lupus erythematosus (Roman et al. 2003).

Adipose Tissue as an Endocrine Organ. Abdel Moniem Ibrahim, MD Professor of Physiology Cairo University

Adipose Tissue as an Endocrine Organ Abdel Moniem Ibrahim, MD Professor of Physiology Cairo University Functions of Adipose Tissue Adipose tissue expresses and secretes a variety of bioactive peptides,