metabolic syndrome is a key determinant of microvascular function

Metabolic Syndrome Is A Key Determinant Of Metabolic Syndrome Is A Key Determinant Of Coronary Microvascular Function In Patients With Coronary Microvascular Function In Patients With

Stable Coronary Disease Undergoing PCIStable Coronary Disease Undergoing PCI

Narbeh MelikianNarbeh Melikian**‡‡, Ajay M Shah, Ajay M Shah**‡‡, Martyn R Thomas, Martyn R Thomas,,

Roy SherwoodRoy Sherwood|||| , Mark T Kearney , Mark T Kearney§§ , Philip A MacCarthy , Philip A MacCarthy‡‡

* * Cardiology Department, King’s College School of Medicine, LondonCardiology Department, King’s College School of Medicine, London‡‡ Cardiology & Cardiology & |||| Clinical Biochemistry Departments, King’s College Hospital, London Clinical Biochemistry Departments, King’s College Hospital, London Cardiology Department, St Thomas’ Hospital, LondonCardiology Department, St Thomas’ Hospital, London§§ The LIGHT Laboratories, University of Leeds, Leeds The LIGHT Laboratories, University of Leeds, Leeds

I have no conflicts of interest to declare

The Metabolic SyndromeThe Metabolic Syndrome

“ …“ …Collection of lipid and non-lipid risk factors for the development of Collection of lipid and non-lipid risk factors for the development of cardiovascular disease …. “cardiovascular disease …. “

Defined byDefined by

National Cholesterol Education Program Adult Treatment Panel III National Cholesterol Education Program Adult Treatment Panel III

(ATP III criteria)(ATP III criteria)

Diagnosed on the basis of > 3 of the following:Diagnosed on the basis of > 3 of the following:Abdominal obesityAbdominal obesity TriglycerideTriglyceride HDL HDL Blood pressureBlood pressure Fasting glucoseFasting glucose

men 102cm >1.7mmol/L men <1.0mmol/L SBP >130 mmHg >5.5mmol/Lmen 102cm >1.7mmol/L men <1.0mmol/L SBP >130 mmHg >5.5mmol/L

women 88cm women <1.3mmol/L DBP >85 mmHgwomen 88cm women <1.3mmol/L DBP >85 mmHg

N Melikian – ACI - 2009

Capillary network

Conduit vessels Microcirculation

Pre-arterioles [500-100m]

Arterioles [100-10m]

The Influence Of Metabolic Syndrome On Coronary Microvascular Function ?The Influence Of Metabolic Syndrome On Coronary Microvascular Function ?

Coronary microvascular function is determinant of prognosis in:

1. Stable coronary artery disease

2. Cardiomyopathy

3. ST-elevation myocardial infraction

4. Post PCI


Study IStudy ITo validate a novel technique to assess to assess endothelium-dependent coronaryTo validate a novel technique to assess to assess endothelium-dependent coronary

microvascular functionmicrovascular function

Study IIStudy IITo use the validated technique to comprehensively assess coronary microvascularTo use the validated technique to comprehensively assess coronary microvascular

function in patients with stable coronary artery disease with and without the function in patients with stable coronary artery disease with and without the

metabolic syndrome (as defined by ATP III criteria)metabolic syndrome (as defined by ATP III criteria)

…....... Conducted a series of studies to…..


Baseline Maximal

Baseline QCA Maximal QCA

APV 41 cm/s

APV 38 cm/s

Mean diameter 1.76mm

Mean diameter 1.87mm

Assessment Of Endothelium-dependent Coronary Microvascular Function Assessment Of Endothelium-dependent Coronary Microvascular Function [Doppler / QCA][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

2. QCA to derive vessel diameter and area

FLOW = [area/4] x [0.5 x velocity]


Intra-coronary Thermodilution To Assess Coronary Blood FlowIntra-coronary Thermodilution To Assess Coronary Blood Flow

Transit time (Tmn) of hand held injectate Transit time (Tmn) of hand held injectate Coronary flow

1

Baseline Tmn = 1.20

Peak Tmn = 0.32


Derived from pressure / temperature sensor-tipped guide wire (RADI wire)

Study One

Validation Of Intra-coronary Thermodilution To Assess Endothelium-Validation Of Intra-coronary Thermodilution To Assess Endothelium-Dependent Coronary Microvascular Function Dependent Coronary Microvascular Function

Transit time (Tmn) of hand held injectate Transit time (Tmn) of hand held injectate

1Coronary flow

20 patients with stable CAD undergoing elective PCI to a remote artery20 patients with stable CAD undergoing elective PCI to a remote artery

endothelium-dependent microvascular function was assessed endothelium-dependent microvascular function was assessed

Validation • Intra-coronary thermodilution• Pressure / temperature wire guide wire [Radi wire]• Substance P (20 pmol/min)

Established technique • Intra-coronary Doppler [Flow Wire]

& QCA• Substance P (20 pmol/min)


r=0.76, p<0.001

0

10

20

30

40

50

60

70

0 10 20 30 40 50 60 70 80

Flow-Doppler (% change)

Flow

-ther

mo

(% c

hang

e)

Panel A

-30

-20

-10

0

10

20

30

0 20 40 60 80

Average of Flow-thermo and Flow-Doppler

Flo

w-t

her

mo

- F

low

-Do

pp

ler

MEAN 1.4

- 2 SD

+ 2SD

Panel B

Study One

Validation Of Intra-coronary Thermodilution To Assess Endothelium-Validation Of Intra-coronary Thermodilution To Assess Endothelium-

dependent Coronary Microvascular Functiondependent Coronary Microvascular Function


Study Two

The Effects Of Metabolic Syndrome (MS) On Coronary Microvascular The Effects Of Metabolic Syndrome (MS) On Coronary Microvascular Function In Patients With Stable Coronary Artery DiseaseFunction In Patients With Stable Coronary Artery Disease

54 non-diabetic patients with stable coronary artery disease and an optimal lipid 54 non-diabetic patients with stable coronary artery disease and an optimal lipid profile on statinsprofile on statins

MS present MS absent

Comprehensive assessment of coronary microvascular function:Comprehensive assessment of coronary microvascular function:

1. Endothelium-dependent microvascular function1. Endothelium-dependent microvascular function Thermodilution derived changes in coronary flow in response to intra-coronary infusion Thermodilution derived changes in coronary flow in response to intra-coronary infusion infusion of substance P (20pmol/min)infusion of substance P (20pmol/min)

2. Endothelium-independent microvascular function2. Endothelium-independent microvascular function Thermodilution derived changes in coronary flow to assess Coronary Flow Reserve (CFR) Thermodilution derived changes in coronary flow to assess Coronary Flow Reserve (CFR) in response to central infusion of adenosine (140in response to central infusion of adenosine (140mol/kg/min)mol/kg/min)


Study Two

Baseline CharacteristicsBaseline Characteristics

MS present MS absent P [n = 20] [n = 34]

•Age (yrs) 61 (42-84) 65 (47-83) 0.10

•Male (%) 10 (50%) 58 (58%) 0.53

•Smoker (%) 12 (60%) 11 (32%) 0.06

•Anthropomorphic measurements

Weight (kg) 80 (51-118) 74 (42-133) 0.12

Waist (cm) 102 (80-155) 94 (70-118) 0.03

W:H ratio 1.0 (0.8-1.3) 0.9 (0.9-1.0) 0.46

•Blood pressure

SBP (mmHg) 142 (112-180) 130 (100-170) <0.01

DBP (mmHg) 81 (70-93) 70 (47-94) <0.01

•HOMA IR index 8.2 (3.5-32.6) 6.2 (2.0-12.8) 0.06

MS present MS absent P [n = 20] [n = 34]

• Full lipid profile

LDL (mmol/L) 2.0 (0.2-3.5) 2.1 (1.0-4.1) 0.58

HDL (mmol/L) 2.0 (0.2-3.5) 2.1 (1.0-4.1) 0.58

Trig (mmol/L) 2.0 (0.2-3.5) 2.1 (1.0-4.1) 0.58

• Medication

Aspirin (%) 20 (100%) 34 (100%) 1.00

Plavix (%) 20 (100%) 34 (100%) 1.00

Statin (%) 18 (90%) 32 (94%) 0.65

ACEi (%) 13 (50%) 18 (53%) 0.72

-blocker (%) 17 (85%) 19 (56%) 0.10

CCB (%) 6 (30%) 11 (32%) 0.62

Nitrate (%) 2 (10%) 5 (15%) 0.47


0

10

20

30

40

Maxim

al ch

ange

in flo

w - s

ubsta

nce P

(%)


Endothelium-dependent microvascular function

0

1

2

3

4

5

Coro

nary

Flow

Rese

rve (

CFR)

Endothelium-independent microvascular function

p < 0.001 p = 0.67

Study Two

Markers Of Coronary Microvascular FunctionMarkers Of Coronary Microvascular Function



0

20

40

60

Max

imal

ch

ang

e in

flo

w -

su

bst

ance

P (

%)

Number of ATP- III metabolic diagnostic criteria present

ZERO ONE TWO THREE FOUR or FIVE

Study Two

Endothelium-dependent Microvascular Function In Relation To ATP-III Endothelium-dependent Microvascular Function In Relation To ATP-III Diagnostic Criteria Present In Each SubjectDiagnostic Criteria Present In Each Subject

F = 2.95, P = 0.03



C-reactive protein

p = 0.002

Study Two

Markers Of Systemic Inflammation And AdipocytokinesMarkers Of Systemic Inflammation And Adipocytokines

MS absent

0

5

10

15

Adip

onec

tin (m

icro

g/m

l)

Adiponection

0

5

10

15

Resi

stin

(ng/

ml)

0

5

10

15

20

Lept

in (

ng/m

l)

0

0.5

1

1.5

2

CR

P (m

g/L)

Resistin

Leptin

MS absent

MS absent MS absent

MS absent

MS present

MS present

MS present

MS present

p = 0.77 p = 0.48

p = 0.39 p = 0.64


Study Two

Stepwise Multivariate Regression Model To Assess Factors Stepwise Multivariate Regression Model To Assess Factors Independently Influencing Coronary Microvascular FunctionIndependently Influencing Coronary Microvascular Function

Endothelium-dependent Endothelium-independent

MODEL A MODEL B MODEL C

Beta P Beta P Beta P

Gender 0.08 0.61 0.14 0.39 0.09 0.54

Smoking - 0.28 0.36 - 0.34 0.18 - 0.36 0.10

Age - 0.09 0.52 0.003 0.98 - 0.01 0.96

LDL cholesterol - 0.07 0.58 - 0.05 0.71 - 0.19 0.15

CRP 0.21 0.18 0.19 0.23 - 0.23 0.13

Adiponectin - 0.04 0.83 0.02 0.92 - 0.42 0.18

Leptin 0.05 0.73 0.08 0.62 - 0.32 0.41

Resistin - 0.24 0.12 - 0.19 0.24 - 0.01 0.96

Presence / absence MS - 0.40 0.04 ----------------------- - 0.12 0.37


SUMMARYSUMMARY

1.1. An intra-coronary thermodilution technique can be used to assess endothelium-An intra-coronary thermodilution technique can be used to assess endothelium-

dependent coronary microvascular function.dependent coronary microvascular function.

2.2. The metabolic syndrome (as defined by ATP III criteria) remains an important The metabolic syndrome (as defined by ATP III criteria) remains an important

determinant of coronary endothelium-dependent microvascular function in patients determinant of coronary endothelium-dependent microvascular function in patients

with stable coronary disease despite adequate LDL cholesterol control and statin with stable coronary disease despite adequate LDL cholesterol control and statin

treatment.treatment.

3.3. The metabolic syndrome (as defined by ATP III criteria) does not appear to influence The metabolic syndrome (as defined by ATP III criteria) does not appear to influence

endothelium-independent coronary microvascular function.endothelium-independent coronary microvascular function.

Study Two



This work was made possible through the British Cardiac Society

John Parker Fellowship

SUMMARYSUMMARY









Study Two



Correlation between coronary endothelium-dependent microvascular Correlation between coronary endothelium-dependent microvascular function and CFRfunction and CFR

0

2

4

6

8

10

1 2 3 4 5

Endothelial Function (ratio maximal to baseline blood flow - substance P)

C

oro

nary

Flo

w R

eserv

e(r

ati

o h

yp

ere

mic

to

baselin

e b

loo

d f

low

- a

den

osin

e)

r=0.08, p=0.5


Correlation between coronary endothelium-dependent microvascular Correlation between coronary endothelium-dependent microvascular function (PANEL A) and CFR (PANEL B) and Framingham Risk Scorefunction (PANEL A) and CFR (PANEL B) and Framingham Risk Score

r= _0.48, p<0.001

0

20

40

60

80

100

0 5 10 15 20

Framingham Risk Score

En

do

thel

ial

Fu

nct

ion

(

% c

han

ge

in b

loo

d f

low

in r

esp

on

se t

o s

ub

stan

ce P

)

PANEL A

0

2

4

6

8

10

0 5 10 15 20

Framingham Risk Score

Co

ron

ry F

low

Re

se

rve

(r

atio

hyp

erem

ic t

o b

asel

ine

blo

od

flo

w in

res

po

nse

to

ad

eno

sin

e)

PANEL B

r=0.14, p=0.25


Differences in endothelial function (PANEL A) and CFR (PANEL B) in Differences in endothelial function (PANEL A) and CFR (PANEL B) in patients with and without diabetespatients with and without diabetes

0

10

20

30

40

Endo

thel

ial F

unct

ion

(% c

hang

e in

blo

od fl

ow -

subs

tanc

e P)

Non-diabetic Diabetic

PANEL A

p < 0.001

0

1

2

3

4

Coro

nary

Flo

w Re

serv

e (ra

tio h

yper

emic

to b

aseli

ne b

lood

flow

- ad

enos

ine)

PANEL B

Non-diabetic Diabetic

p = 0.10


SUMMARYSUMMARY









Study Two



metabolic syndrome is a key determinant of microvascular function

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