The brachial artery and its relationship with carotid atherosclerosis

Alexandru AndritoiuEmergency Military Hospital

Craiova-Romania

Theoretical background

• Dysfunction of the endothelium can be defined as an imbalance between relaxing and contracting factors;• This imbalance can be developed by reduced synthesis and/or release of protective factors such as EDRF(NO) or augmented synthesis and/or release of contracting, procoagulant or growth-promoting factors, or both . • Not all of the factors (smoking, atherosclerosis, direct damage of the endothelium, diabetes, lack of oestrogen, etc.) impair endothelial function in the same way. • Atherosclerosis causes dysfunction via chemical modulations inside the vessel wall. Once the endothelium is injured, it undergoes phenotypic modulation, which causes an abnormal function. This dysfunction is usually found in all vessels in the body - some show it more and some less. •Endothelial dysfunction generally contributes to thrombus and/or plaque formation, and thus in the overwhelming majority of cardiovascular diseases including atherosclerosis, vasopasm and thrombosis.

Left: The quiescent state of the endothelium, where NO (green circles) is generated by the endothelial isoform of nitric oxide synthase (eNOS) in its membrane-bound configuration.

Right: The state of endothelial activation where reactive oxygen signaling (red circles) predominates. The ROS such as H2O2 are generated from oxidases as well as the uncoupled

state of eNOS.

Evaluation of Brachial Artery reactivity (%FMD)

US• B-mode (high-frequency)

• CD-US• PWD-US

Endothelial function, defined as flow mediated dilatation (FMD), is estimated as the percentage increase in vessel diameter from baseline conditions to maximum vessel diameter during hyperaemia.

Celermajer et al 1994

Peak percentage change in brachial artery diameter post-reactive hyperemia

Vasoactive substances• Ach• NTG

Mechanical stress• Forearm ischemia

induced 4 min. by an occluding cuff

Peak vs Total hyperemia ?

Pyke KE et al. Appl Physiol 2007

Conditions associated with ED

• Aging• Hypertension• CAD• PAD• Diabetes• Hyper Cholesterolemia• Hyper -Homocysteinemia• Metabolic sdr.• Smoking• CHF

Only in population of low risk, (not in medium or high-risk populations), FMD is related to the principal CVRFs and estimate 10-year risk of CAD.

(Witte DR et al. JACC 2005)

Risk factors and ET dysfunction

• Importance of risk factors and endothelial dysfunction in early life for atherosclerosis development and later cardiovascular outcome.

• A) Impact of cardiovascular risk factor profile at age 50 years on subsequent clinical events in the Framingham Study.

• B) Association between risk factors and carotid IMT in young adults with enhanced, intermediate, and reduced FMD in the Cardiovascular Risk in Young Finns Study.

Lloyd-Jones et al. 2006; Juonala et al. 2004

The unsolved issue is the broad spectrum of %FMD reference value

-1.9 – 19.2!?!

Bots ML et al. Eur Heart J 2004

4 min

Possible explanations…

• Differences in study populations• CVRF (risk factor profile) vary considerably across

populations• Consequence of various aspects of measurement

methodology• equipment (wall track/B mode)• location of measurement (antecubital fossa/upper arm)• occlusion site (lower/upper arm)• occlusion duration (min.)• occlusion pressure• time course of FMD (time to peak diameter)• frequency of transducer (7-13 MHz)

Bots ML et al. Eur Heart J 2004; Pyke KE et al. J Physiol 2005; Black MA et al. Hypertension 2008

Shear-stress stimulusShear-stress stimulus

Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of

the FMD measurement on the FMD response Michiel L. Bots, J. Westerink, TJ Rabelink, E.J.P. de Koning

Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of

the FMD measurement on the FMD response Michiel L. Bots, J. Westerink, TJ Rabelink, E.J.P. de Koning

• The lower arm occlusion compared with upper arm occlusion was related to a significantly decreased FMD (mean difference in FMD –2.47%; 95% CI 0.55–4.39).

• An occlusion duration of 4.5 min was related to a significantly increased FMD compared with an occlusion time of 4 min (mean difference 1.30%; 95% CI 0.35–2.46).

Bots ML et al. Eur Heart J 2004

Distribution of mean FMD values among healthy populations (A), CAD populations (B) and populations with diabetes mellitus (C).

Bots ML et al. Eur Heart J 2004

Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery

A report of the International Brachial Artery Reactivity Task Force Mary C. Corretti, MD, FACC*,*, Todd J. Anderson, MD, Emelia J. Benjamin, MD, MSc, David Celermajer, MD, Francois Charbonneau, MD||, Mark A. Creager, MD¶, John Deanfield, MD#, Helmut Drexler, MD**, Marie Gerhard-Herman, MD¶, David Herrington, MD, MHS, Patrick Vallance, MD, Joseph Vita, MD and Robert Vogel, MD*

JACC 2002; 39:257-265

Relationship between FMD (BA) and CIMT (CCA)

FMD and CIMT – good surrogate markers of clinical atherosclerosis

Relationship Between Carotid Artery Intima-Media Thickness and Brachial

Artery Flow-Mediated Dilation in Middle-Aged Healthy Men

R.T. Yan, T.J. Anderson, F. Charbonneau, L. Title, S. Verma, E. Lonn, on behalf of the FATE Investigators

 

Yan RT et al- JACC 2005

• Carotid IMT and brachial artery FMD are frequently used as surrogate measures of subclinical atherosclerosis. • Whereas carotid IMT identifies early structural abnormalities, brachial artery FMD, considered a bioassay of endothelial function, measures functional vascular integrity. • The relationship between carotid IMT and brachial artery FMD has not been well studied.

In middle-aged healthy men, there is no significant correlation between carotid IMT and brachial artery FMD.

This finding suggests that these are independent surrogates that measure different aspects and stages of early atherosclerosis.

Further studies are needed to define their role in clinical research and in cardiovascular risk assessment.

Yan RT et al. JACC 2005

Correlation between brachial artery reactivity and CIMT (Intima–Media Thickness) of the Common Carotid Artery in 40 subjects with a parental history of premature myocardial infarction.

Correlation between brachial artery reactivity and CIMT (Intima–Media Thickness) of the Common Carotid Artery in 40 subjects with no parental history of premature myocardial infarction

Gaeta G et al. NEJM 2000

Carotid Artery Intima-Media Thickness and Brachial Artery Flow-Mediated Vasodilation in Asymptomatic Japanese Male Subjects amongst Apolipoprotein E phenotypes.

Haraki T, Takegoshi T, Kitoh C, Wakasugi T, Saga T, Hirai JI, Aoyama T, Inazu A, Mabuchi H.

J Intern Med 2002;252:114-20

There is no difference between brachial-FMD and apoE phenotypes (P=0.15).

A negative correlation between brachial-FMD and CCA-IMT was also found in all subjects (r = - 0.21, P < 0.05), being most apparent in the E3E4 subjects (r = - 0.53; P < 0.02).

Correlation between Flow-Mediated Vasodilatation of the Brachial Artery and

Inima-Media Thickness in the Carotid Artery in Men

• 34 M with ATS vs controls

• 61+/- 2 yr

• B-mode US

%FMD

CIMT

5.1+/-0.6%

2.8+/-0.4%

ATS Control

Hashimoto M et al. Arteriosclerosis, Thrombosis and Vascular Biology 1999

P<0.01

%FMD showed a significant negative correlation with IMT of CCA

%FMD

FMD – CIMT - PWV

135 pts• 110 pts - CVRFs• 33 pts. -CAD, stroke,

PADMETHODo USo CIMT/plaqueso BA-FMD%o PWV (brachial-ankle)

• All measurements are related each other !

• All measurements had a markedly higher prevalence of ATS disease and carotid plaques !

• The combination of these measurements will be of stronger clinical relevance !

Kobayashi K et al. Atherosclerosis 2004

Some personal observations…

AIM

• Evaluation of US (spectral-wave Doppler) parameters of BA in a group of subjects confirmed with carotid ATS lesions in different stages of severity;

• Finding the relation between the envelope spectral profile of BA and carotid ATS severity

STUDY GROUP

• 129 pts (45-80 yr; M/F = 1.7) • confirmed by US with carotid ATS

(plaque, stenosis, CIMT > 0.5mm) • Clinical profile: HBP – 68.4% high TC – 42% CAD – 31.6% Stroke – 26% NIDM – 21%

METHODS (B-mode, Color & Spectral Doppler)

• CAROTID ARTERY

mean CIMT, max CIMT

ATS plaques

stenosis degree (1-6 stages)• BRACHIAL ARTERY

diameter / area

PI, RI, S (m/s), D (m/s), S/D, TAMx , TAV

spectral broadening (score 1-3 p.)

Spectral broadening grading

(A) 1 p.

(B) 2 p.

(C) 3 p.

A

B

C

Brachial arteryNormal blood-flow envelope

1

2

3

RESULTS

• Mean CIMT = 0.4-1.2 mm (0.74+/-0.23)

• Max CIMT = 0.4 – 1.5 mm • ( 0.90+/-0.31)

84%

58%

max CIMT >0.5 mm CAR plaques

DISTRIBUTION OF ATHEROMATOSIS / CAROTID STENOSIS

GRADING

Mild

• Grade I – 38% pts

• Grade II – 31%

Moderate

• Grade III – 21%

• Grade IV – 5%

Severe

• Grade V – 5%

• Grade VI (occlusion ) – 0%

BA parameters

• Max Diameter 4.05+/-0.71 mm• Max Area 13.6+/-4.86 mm2

• PI 5.2+/-1.3• S 0.51+/-0.17 m/s• D 0.007+/-0.02 m/s• TAMx 0.10+/-0.038 m/s• TAV 0.05+/-0.04 m/s• Spectral broadening score: 1.58+/-0.51

STATISTICS(Pearson ecuation)

• Mean CIMT - CA ATS stage r = 0.74; p<0.001• Max CIMT - CA ATS stage r = 0.51; p<0.01• Mean CIMT - BA area r = 0.40; p<0.05• Max CIMT - BA area r = 0.32; p<0.05• BA area - CA ATS stage r = 0.47; p<0.01• BA TAMx - BA spectral-broad. score r = 0.73; p<0.001• BA TAV - BA spectral-broad. score r = 0.66; p<0.01

Spectral envelope of BA blood-flow obtained in a patient with mild carotid atherosclerosis (II/6 degree)

Spectral envelope of BA blood-flow obtained in a patient with severe carotid atherosclerosis (stage V/6).

Clinical Case

• NE, 56y, F

• High-TC

• HBP

• Car ATS 2/6

• FMD =12%

BA with broad spectral envelope

Mechanical stress (cuff)

• AI, 52y, M

• Smoker

• High-TC

• Hypertension

• FMD = 6.6%

Clinical Case

• MV, 51y, F• Hypertension• LDL 167 mg/dl• Non - Carotid ATS • FMD = 9%

CONCLUSIONS

• Carotid ATS is frequently associated with alteration of BA spectral velocity envelope and BA diameter or area;

• FMD must be regarded as a valuable clinical and physiological research tool for the study of endothelial function and early atherosclerosis, but his cut-off values are not yet clarified; Certainly, it must not be used for population screening or for clinical decision-making!

• The alteration of BA blood-flow spectral envelope profile may be associated with large arteries atherosclerosis and also, being used as a surrogate view of endothelial dysfunction.