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
N Melikian – ACI - 2009
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…..
N Melikian – ACI - 2009
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]
N Melikian – ACI - 2009
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
N Melikian – ACI - 2009
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)
N Melikian – ACI - 2009
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
N Melikian – ACI - 2009
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)
N Melikian – ACI - 2009
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
N Melikian – ACI - 2009
0
10
20
30
40
Maxim
al ch
ange
in flo
w - s
ubsta
nce P
(%)
MS present MS absent
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
MS present MS absent
N Melikian – ACI - 2009
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
N Melikian – ACI - 2009
MS present MS absent
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
N Melikian – ACI - 2009
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
N Melikian – ACI - 2009
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
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
N Melikian – ACI - 2009
This work was made possible through the British Cardiac Society
John Parker Fellowship
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
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
N Melikian – ACI - 2009
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
N Melikian – ACI - 2009
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
N Melikian – ACI - 2009
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
N Melikian – ACI - 2009
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
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
N Melikian – ACI - 2009