Metabolic Syndrome Is A Key Determinant Of Coronary Microvascular Function In Patients With Stable Coronary Disease Undergoing PCI

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1 Metabolic Syndrome Is A Key Determinant Of Coronary Microvascular Function In Patients With Stable Coronary Disease Undergoing PCI Narbeh Melikian*, Ajay M Shah*, Martyn R Thomas, Roy Sherwood, Mark T Kearney, Philip A MacCarthy * Cardiology Department, King s College School of Medicine, London Cardiology & Clinical Biochemistry Departments, King s College Hospital, London Cardiology Department, St Thomas Hospital, London The LIGHT Laboratories, University of Leeds, Leeds

2 I have no conflicts of interest to declare

3 The Metabolic Syndrome Collection of lipid and non-lipid risk factors for the development of cardiovascular disease. Defined by National Cholesterol Education Program Adult Treatment Panel III (ATP III criteria) Diagnosed on the basis of > 3 of the following: Abdominal obesity Triglyceride HDL Blood pressure Fasting glucose men 12cm >1.7mmol/L men <1.mmol/L SBP >13 mmhg >5.5mmol/L women 88cm women <1.3mmol/L DBP >85 mmhg

4 The Influence Of Metabolic Syndrome On Coronary Microvascular Function? Conduit vessels Microcirculation Pre-arterioles [5-1 m] Arterioles [1-1 m] Capillary network Coronary microvascular function is determinant of prognosis in: 1. Stable coronary artery disease 2. Cardiomyopathy 3. ST-elevation myocardial infraction 4. Post PCI

5 ... Conducted a series of studies to.. Study I To validate a novel technique to assess to assess endothelium-dependent coronary microvascular function Study II To use the validated technique to comprehensively assess coronary microvascular function in patients with stable coronary artery disease with and without the metabolic syndrome (as defined by ATP III criteria)

6 Assessment Of Endothelium-dependent Coronary Microvascular Function [Doppler / QCA] Derived from % change in coronary flow in response to an endothelial agonist using: 1. Intra-coronary Doppler [Flow Wire] to derive blood flow velocity Baseline APV 38 cm/s Maximal APV 41 cm/s 2. QCA to derive vessel diameter and area Baseline QCA Maximal QCA Mean diameter 1.76mm Mean diameter 1.87mm FLOW = [area/4] x [.5 x velocity]

7 Intra-coronary Thermodilution To Assess Coronary Blood Flow Transit time (Tmn) of hand held injectate 1 Coronary flow Derived from pressure / temperature sensor-tipped guide wire (RADI wire) Peak Tmn =.32 Baseline Tmn = 1.2

8 Study One Validation Of Intra-coronary Thermodilution To Assess Endothelium- Dependent Coronary Microvascular Function Transit time (Tmn) of hand held injectate 1 Coronary flow 2 patients with stable CAD undergoing elective PCI to a remote artery endothelium-dependent microvascular function was assessed Validation Intra-coronary thermodilution Pressure / temperature wire guide wire [Radi wire] Substance P (2 pmol/min) Established technique Intra-coronary Doppler [Flow Wire] & QCA Substance P (2 pmol/min)

9 Flow-thermo (% change) Flow-thermo - Flow-Doppler Study One Validation Of Intra-coronary Thermodilution To Assess Endotheliumdependent Coronary Microvascular Function 7 Panel A 3 Panel B SD MEAN r=.76, p< SD Flow-Doppler (% change) Average of Flow-thermo and Flow-Doppler

10 Study Two The Effects Of Metabolic Syndrome (MS) On Coronary Microvascular Function In Patients With Stable Coronary Artery Disease 54 non-diabetic patients with stable coronary artery disease and an optimal lipid profile on statins MS present MS absent Comprehensive assessment of coronary microvascular function: 1. Endothelium-dependent microvascular function Thermodilution derived changes in coronary flow in response to intra-coronary infusion infusion of substance P (2pmol/min) 2. Endothelium-independent microvascular function Thermodilution derived changes in coronary flow to assess Coronary Flow Reserve (CFR) in response to central infusion of adenosine (14 mol/kg/min)

11 Study Two Baseline Characteristics MS present MS absent P [n = 2] [n = 34] Age (yrs) 61 (42-84) 65 (47-83).1 Male (%) 1 (5%) 58 (58%).53 Smoker (%) 12 (6%) 11 (32%).6 Anthropomorphic measurements Weight (kg) 8 (51-118) 74 (42-133).12 Waist (cm) 12 (8-155) 94 (7-118).3 W:H ratio 1. (.8-1.3).9 (.9-1.).46 Blood pressure SBP (mmhg) 142 (112-18) 13 (1-17) <.1 DBP (mmhg) 81 (7-93) 7 (47-94) <.1 HOMA IR index 8.2 ( ) 6.2 ( ).6 Full lipid profile MS present MS absent P [n = 2] [n = 34] LDL (mmol/l) 2. (.2-3.5) 2.1 (1.-4.1).58 HDL (mmol/l) 2. (.2-3.5) 2.1 (1.-4.1).58 Trig (mmol/l) 2. (.2-3.5) 2.1 (1.-4.1).58 Medication Aspirin (%) 2 (1%) 34 (1%) 1. Plavix (%) 2 (1%) 34 (1%) 1. Statin (%) 18 (9%) 32 (94%).65 ACEi (%) 13 (5%) 18 (53%).72 -blocker (%) 17 (85%) 19 (56%).1 CCB (%) 6 (3%) 11 (32%).62 Nitrate (%) 2 (1%) 5 (15%).47

12 Maximal change in flow - substance P (%) Coronary Flow Reserve (CFR) Study Two Markers Of Coronary Microvascular Function Endothelium-dependent microvascular function Endothelium-independent microvascular function 4 5 p <.1 p = MS present MS absent MS present MS absent

13 Maximal change in flow - substance P (%) Study Two Endothelium-dependent Microvascular Function In Relation To ATP-III Diagnostic Criteria Present In Each Subject 6 F = 2.95, P = ZERO ONE TWO THREE FOUR or FIVE Number of ATP- III metabolic diagnostic criteria present

14 Adiponectin (microg/ml) Resistin (ng/ml) CRP (mg/l) Leptin (ng/ml) Study Two Markers Of Systemic Inflammation And Adipocytokines C-reactive protein Leptin p =.77 p =.48 p = MS present MS present MS absent MS absent 5 MS present MS absent Adiponection Resistin 15 p = p = MS present MS absent MS absent MS present MS absent

15 Study Two Stepwise Multivariate Regression Model To Assess Factors Independently Influencing Coronary Microvascular Function Endothelium-dependent Endothelium-independent MODEL A MODEL B MODEL C Beta P Beta P Beta P Gender Smoking Age LDL cholesterol CRP Adiponectin Leptin Resistin Presence / absence MS

16 Study Two The Effects Of Metabolic Syndrome (MS) On Coronary Microvascular Function In Patients With Stable Coronary Artery Disease SUMMARY 1. An intra-coronary thermodilution technique can be used to assess endotheliumdependent coronary microvascular function. 2. The metabolic syndrome (as defined by ATP III criteria) remains an important determinant of coronary endothelium-dependent microvascular function in patients with stable coronary disease despite adequate LDL cholesterol control and statin treatment. 3. The metabolic syndrome (as defined by ATP III criteria) does not appear to influence endothelium-independent coronary microvascular function.

17 This work was made possible through the British Cardiac Society John Parker Fellowship

18 Study Two The Effects Of Metabolic Syndrome (MS) On Coronary Microvascular Function In Patients With Stable Coronary Artery Disease SUMMARY 1. An intra-coronary thermodilution technique can be used to assess endotheliumdependent coronary microvascular function. 2. The metabolic syndrome (as defined by ATP III criteria) remains an important determinant of coronary endothelium-dependent microvascular function in patients with stable coronary disease despite adequate LDL cholesterol control and statin treatment. 3. The metabolic syndrome (as defined by ATP III criteria) does not appear to influence endothelium-independent coronary microvascular function.

19 Coronary Flow Reserve (ratio hyperemic to baseline blood flow - adenosine) Correlation between coronary endothelium-dependent microvascular function and CFR 1 8 r=.8, p= Endothelial Function (ratio maximal to baseline blood flow - substance P)

20 Endothelial Function ( % change in blood flow in response to substance P) Coronry Flow Reserve (ratio hyperemic to baseline blood flow in response to adenosine) Correlation between coronary endothelium-dependent microvascular function (PANEL A) and CFR (PANEL B) and Framingham Risk Score 1 PANEL A 1 PANEL B r= _.48, p<.1 r=.14, p= Framingham Risk Score Framingham Risk Score

21 Endothelial Function (% change in blood flow - substance P) Coronary Flow Reserve (ratio hyperemic to baseline blood flow - adenosine) Differences in endothelial function (PANEL A) and CFR (PANEL B) in patients with and without diabetes 4 PANEL A 4 PANEL B p =.1 3 p < Non-diabetic Diabetic Non-diabetic Diabetic

22 Study Two The Effects Of Metabolic Syndrome (MS) On Coronary Microvascular Function In Patients With Stable Coronary Artery Disease SUMMARY 1. An intra-coronary thermodilution technique can be used to assess endotheliumdependent coronary microvascular function. 2. The metabolic syndrome (as defined by ATP III criteria) remains an important determinant of coronary endothelium-dependent microvascular function in patients with stable coronary disease despite adequate LDL cholesterol control and statin treatment. 3. The metabolic syndrome (as defined by ATP III criteria) does not appear to influence endothelium-independent coronary microvascular function.