how to detect early atherosclerosis ; focusing on techniques · fmd (endothelial function), % =...

How to detect early

atherosclerosis

; focusing on techniques

Jang-Ho Bae, MD., PhD.

Heart Center

Konyang University Hospital

Daejeon city, S. Korea

Surrogates for Atherosclerosis

Measures of endothelial function

Measures of arterial wall structure

Generalized measures of inflammation

Prognostic Value of Systemic

Endothelial Dysfunction in Patients

With Acute Coronary Syndromes

198 patients with ACS

Cardiovascular events

cardiovascular death

myocardial infarction

ischemic stroke

Assessment of systemic vasoreactivity

provides important prognostic

information

(n=31)

Fichtlscherer S et al. Circulation. 2004;110:1926-1932

Methods assessing endothelial function

Invasive

Coronary angiography using Doppler wire

Strain guage plethysmography

Noninvasive

Flow-Mediated brachial artery Dilation

first introduced in 1992 by Dr. Celermajer.

Basic principle of noninvasive method

for testing endothelial function

Hyperemic

Blood Flow

Shear stress

Endothelium

Baseline

Hyperemia

Normal Endothelial Dysfunction

NO

NO

PGI2(?)NO

Vasodilatation

FMD (endothelial function), %

=Baseline Diameter

Hyperemic Diameter – Baseline Diameter 100

Overnight fasting (8~12 hrs)

A quiet, temperature-controlled room

Medicine withheld for at least four half-lives, if possible

Consider the subject`s mestrual cycle

Affecting factors; temperature, food, drugs, sympathetic stimuli

Guidelines for FMD of the Brachial Artery

(Subject preparation)

Corretti MC et al. JACC 2002;39:257-65

Why Overnight Fasting ?

120100806040200-20-40

10

5

0

-5

-10

-15

-20

GROUP

Low-fat

High-fat

Changes of serum triglycerides

(delta mg/dl)

Ch

an

ge

s o

f %

dia

me

ter

ch

an

ge

(de

lta

%) y= 0.74x - 0.971

r= - 0.650

p= 0.002

120100806040200-20-40

3.0

2.5

2.0

1.5

1.0

.5

0.0

-.5

-1.0


(delta mg/dl)

Su

pe

rox

ide

an

ion

form

atio

n

(de

lta

nm

ol/1

06

ce

lls/m

in)

y= 0.1698x + 0.296

r= 0.798

P< 0.001

Changes of superoxide anion formation

(delta nmol/106 cells/min)

3.02.52.01.51.0.50.0-.5-1.0

10

5

0

-5

-10

-15

-20

y= - 2.608x - 0.969

r= - 0.784

P< 0.001

Bae JH et al. Atherosclerosis 2001;155:517-23

120100806040200-20

2

1

0

-1

-2

-3

GROUP

low fathigh fat


(delta mg/dl)

r = 0.664p = 0.004n = 17y = 0.198x-0.615

120100806040200-20

6

4

2

0

-2

-4

-6


(delta mg/dl)

r = -0.488p = 0.040n = 18y = -0.0302x+1.5675

Ch

an

ge

s o

f

% d

iam

ete

r c

ha

ng

e(d

elta

%)

GROUP

low fat

high fat

210-1-2-3

6

4

2

0

-2

-4

-6

r = -0.419

p = 0.094

n = 17

y = -0.9377x+0.6023

Acute Effects of Vasoactive Drug on FMD

Gokce N et al. JACC 2002;40:761-5

Recent administration of nonnitrate vasoactive drugs

has no significant effects on FMD

SBPFMD

NMD

In Normal Subjects

Measurements;

Baseline and 3 hrs after medicine Holding 24hrs 3hr

Menstrual Cycle on FMD

Gokce N et al. JACC 2002;40:761-5

Endothelium-dependent vasodilatation varies during the menstrual cycle.

The endogenous estradiol may be involved in this menstrual cycle–related vasodilatation.

Phase ... M F L

Age, y 24.8±0.6 25.1 ±0.8 ... ...

Body mass index, kg/m2 22.4±0.41 20.5 ±0.5 ... ...

Total cholesterol, mmol/L 4.37±0.19 4.45±0.17 4.50±0.17 4.22±0.19

HDL cholesterol, mmol/L 1.63±0.15 1.68 ±0.08 1.78±0.09 1.70±0.08

LDL cholesterol, mmol/L 2.35±0.15 2.53±0.11 2.49±0.13 2.26±0.13

Triglyceride, mmol/L 1.94±0.182 1.24 ±0.07 1.20±0.09 1.29±0.10

Estradiol, pmol/L 114.5 ±9.9 121.9±12.5 632.1±74.53 533.8±33.43

Progesterone, nmol/L 1.6±0.16 1.6±0.19 3.2 ±0.60 48.7±4.84

http://circ.ahajournals.org/content/vol92/issue12/images/large/hc2452135002.jpeg

Vascular software (2D-imaging, color and

spectral Doppler, an internal ECG monitor) and

a high-frequency vascular transducer)

For sufficient resolution, a minimum frequency

of 7 MHz

Image resolution is enhanced with broad-band

(7 to 12 MHz)


(Equipment)



(Image Acquisition)


Cross-sectional imaging

; can not be used

; inadequate lat wall definition

; skew artifact

M mode and A mode (wall tracking)

; more error owing to tracking drift

Anatomic landmarks

; veins and fascial planes


(Endothelium-dependent FMD)


To create a flow stimulus in the brachial artery

Baseline5 minutes of upper (lower)

arm arterial occlusionHyperemic

45-60 s after

cuff deflation

Cuff inflation; at least 50mmHg

above SBP

Baseline diameter

Blood flow by PW

Doppler Velocity signal

Ischemia and consequent dilation

of downstream resistance vessel

via autoregulation




Position of cuff inflation; no concensus

On the upper arm;

Greater percent change in diameter

due to a greater flow stimulus resulting from

recruitment of more resistance vessels or

to direct effects of ischemia on the brachial artery

Less reliable due to image distortion by collapse of the

brachial artery and shift in soft tissue




Duration of cuff inflation

The change of BA diameter increases

as the duration of cuff inflation increases

from 30 s to 5 min.

The change in diameter is similar

after 5 and 10 min of occlusion.

Therefore, the more easily tolerated 5-min occlusion



Hashimoto M et al. J Pharmacol Sci. 2003;93:405-8.

Measurement of hyperemic flow in hyperemic phase

5 minutes of upper (lower)

arm arterial occlusion Hyperemic

Flow; no later than 15 s after deflation




Measurement of BA diameter in hyperemic phase

5 minutes of upper (lower)

arm arterial occlusionHyperemic

45-60 s after

cuff deflation

Why 45-60 s after cuff deflation

Image of BA in hyperemic phase;

recording continuously

from 30 s before to 2 min after deflation

Most studies; 1 min after cuff deflation



Why brachial artery ?

876543

16

14

12

10

8

6

4

2

0

-2

Baseline BA diameterF

MD

r=-0.492

p<0.001

n=884

Arteries <2.5mm in diameter; difficult to measure (Radial artery)

Arteries >5.0mm in diameter; FMD is less difficult to perceive (Femoral artery)

Baseline Hyperemic

FMD=

Base BAD

Hyper BAD-Base BAD

100

Bots ML et al. EHJ 2005;26:363-8

FMD, in general

Guidelines for NMD of the Brachial Artery

(Endothelium-independent vasodilation with NTG)

Test sequence


Baseline 4 min after NTG

At least 10 min

rest after FMD

Exogenous NO donor

Single high dose (0.4mg)

Spray or SL NTG

To measure max vasodilatory response

Reflecting vascular smooth m function

Peak vasodilation (3-4 min)

Image; continuous recording

3-4 min after NTG

Guidelines for NMD of the Brachial Artery

(Endothelium-independent vasodilation with NTG)

Dose-response

Max vasodilatory response

at the plateau – similar

The dose required to produce

50% of the max response

- greater in patients (p<0.002)

(181ug vs.115ug)

Raitakari OT et al. AJC 2001;87:217-9

Most previous studies

; impaired FMD in atherosclerotic Pt

but preserved NMD

however, FMD associated with NMD

Impaired dilator response to NTG in CAD Pt; smooth m dysfunction

373839 343544N =

55~6445~5435~44

.8

.7

.6

.5

SEX

female

male

Normal Risk Factor

Age (yrs)

0.58±0.090.58±0.10

p=0.912

0.61±0.11

0.65±0.12

p=0.197

0.68±0.09

0.71±0.12

p=0.334

Total n=227

.9

.8

.7

.6

.5

413742 504231N =

55~6445~5435~44Age (yrs)

Total n=243

p=0.003

p<0.001

0.61±0.1

0.69±0.1

0.72±0.1

0.67±0.2

0.72±0.1

0.77±0.1

p=0.014

Korean IMT Study

Bae JH et al. Korean Society of Hypertension (supp) 2004:124-5

100

95

90

85

80

75

70

0 1 2 3 4 5 6 7

Years

Cu

mu

lati

ve

Eve

nt-

Fre

e R

ate

(%)

O’Leary et al. N Engl J Med. 1999;340:14-22.

Systemic Atherosclerosis: Carotid

Disease as a Marker of CV Risk

1st Quintile IMT

2nd Quintile IMT

3rd Quintile IMT

4th Quintile IMT

5th Quintile IMT

Cumulative Event-Free Rates for MI or Stroke, According

to Quintile of Combined IMT (n=4476), 65 years of age or older.

AHA recommendation for evaluation of risk in primary prevention out of the various noninvasive imaging

; Carotid intima-media thickness (IMT)

Carotid IMT

; independent assessment of coronary risk

;independent predictor of coronary events in patients with CAD.

Smith SC et al. AHA conference proceedings. 2000;101:111-116

Chan SY et al. J Am Coll Cardiol 2003;42:1037-43.

Carotid IMT

Measures of Arterial Wall

Intima Media Thickness (QIMT)

Safe standardized and validated method

Direct assessment of disease

Reproducible

Easy to learn

Relatively inexpensive

CLAS colestipol and niacin IMT 1cm below bulb is

(1994) reproducible and has

correlation with CV events

MARS lovastatin confirmed above

(1994)

PLAC II pravastatin established that the most

(1995) reliable part to measure is the

far wall of the common carotid

Measures of Arterial Wall

CCA

1 cm

Manual measurement of carotid IMT

Example of carotid plaque

IMT : Semi Automatic Measurement

Good detection

Poor detection

Background of Korean

software (KS) development

for IMT measurement

Korean software (KS) for IMT measurement

Korean software for IMT measurement

Number

Age

Sex (M/F)

Height (cm)

Weight (kg)

BMI

HBP

DM

Hyperlipidemia

Smoking

Diagnosis

No atherosclerotic disease

Patients with risk factors

Atherosclerotic disease

Total cholesterol (mg/dL)

Triglyceride (mg/dL)

HDL-cholesterol (mg/dL)

LDL-cholesterol (mg/dL)

Random glucose (mg/dL)

Uric acid (mg/dL)

BUN (mg/dL)

Creatinine (mg/dL)

60

58.516

18342

14077

43.810.0

10630

13666

4.631.98

17.310.3

1.030.58

Subjects: 60 consecutive

subjects undergoing

routine TTE

IMT: by M`ATH

(blinded examiner)

by Korean software

(KRISS)

Compare Pearson correlation

coefficients between age and

the data of M`ATH and Korean

software

Korean software (KS) for IMT measurement

908070605040302010

1.1

1.0

.9

.8

.7

.6

.5

.4

y=0.3925 + 0.0059x

r=0.616

p<0.001

n=60

IMT

by M

`AT

H

Age (yrs)

IMT

by K

S908070605040302010

1.2

1.1

1.0

.9

.8

.7

.6

.5

.4

y=0.4056 + 0.0054x

r=0.537

p<0.001

n=56

Age (yrs)

Comparison of Pearson correlation coefficients by both methods

Korean software for IMT measurement

Intim

a th

ickness b

y K

S

Age (yrs)

Media

thic

kness

by K

S90807060504030

.8

.7

.6

.5

.4

.3

90807060504030

.42

.40

.38

.36

.34

.32

Age (yrs)

y=0.2416 + 0.0040x

r=0.507

p<0.05

n=17

Correlation between age and intima or media thickness

FMD, IMT, and PWV

421518N =

CADrisk factornormal

8

7

6

5

4

3

2

p=0.000

p=0.003

431518N =


1.0

.9

.8

.7

p=0.005

Bae JH et al. Korean Circulation J 2004;34:845-55

Age- and sex- matched study population

431618N =


1700

1600

1500

1400

1300

1200

1100

p=0.000

p=0.023

FMD, IMT, and PWV


2200200018001600140012001000800

10

8

6

4

2

0

PWV (cm/sec)

n=75

p=0.007

r=-0.329

2200200018001600140012001000800

1.3

1.2

1.1

1.0

.9

.8

.7

.6

n=76

p=0.000

r=0.396

n=76

p=0.007

r=0.310

1086420

1.3

1.2

1.1

1.0

.9

.8

.7

.6

FMD (%)PWV (cm/sec)

These are related to each other,

the combination of these measurement will be of stronger clinical relevance

In Conclusion

FMD, IMT, and PWV are functional and structural surrogates of the atherosclerotic process.

Limitations of FMD; variable reproducibility, influenced by exogenous factors.

Future; need to reveal an association of improvement in response to treatment with improvement in prognosis

Fathi R et al. J Am Coll Cardiol 2004;43:616-23

The Relative Importance of Vascular Structure

and Function in Predicting Cardiovascular Events

IMT LV Mass FMD

Kaplan-Meier curves for event-free survival

<0.62mm

>0.71mm

<181g

>276g

>6.3%

<2%

CV events; death, MI, admission with ACS, stroke, revascularization

444 patients with CAD, dialysis, or multiple risk factors

Follow-up; 24 months

IMT was the independent vascular factor

for mortality, even in the subgroup with

no CAD and low risk.

Can We Restore the Endothelial Dysfunction in

Patients with Essential Hypertension with

Calcium Channel Blockers?


0

5

10

15

20

Control HBP CAD

FM

D (

%)

NSP<0.001

P<0.001

0

5

10

15

Baseline Follow up

P<0.01

The Difference of Endothelial Function

According to the Presence of Restenosis

in Patients Undergoing PCI


0

2

4

6

8

10

12

14

Restenosis Patent

P=0.013

Impaired flow-mediated dilation and risk

of restenosis in patients undergoing

coronary stent implantation.

Patti G et al. Circulation 2005;11:7005

136 patients undergoing stenting

ISR; 20 pts (15%)

Singh TP et al. J Am Coll Cardiol 2003;41:661-5

Time Sequence of Atherosclerosis

Surrogates Abnormality

Endothelial dysfunction precedes an

increase in carotid IMT

31 diabetic children (15 yrs old, 6.8 yrs DM duration), 35 age-matched healthy children

No difference in carotid IMT

0.85 0.89 0.880.86

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

Statins Control

Bae JH et al. J Cardiovasc Pharmacol Ther. 2004;9:185-92

105 statin group and 100 control group undergoing stenting

6 months follow up

Statin improves endothelial

dysfunction, not carotid IMT in patients

undergoing stenting

3.94 4.224.84 4.34

0

1

2

3

4

5

6

7

Statins Control

P=0.008 P=0.435

FM

D (

%)

P=0.435 P=0.530

IMTcca

(m

m)

Time Sequence of the Improvement of

Atherosclerosis Surrogates Abnormality

how to detect early atherosclerosis ; focusing on techniques · fmd (endothelial function), % =...

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