How to detect early atherosclerosis ; focusing on techniques

Transcription

1 How to detect early atherosclerosis ; focusing on techniques Jang-Ho Bae, MD., PhD. Heart Center Konyang University Hospital Daejeon city, S. Korea

2 Surrogates for Atherosclerosis Measures of endothelial function Measures of arterial wall structure Generalized measures of inflammation

3 Prognostic Value of Systemic Endothelial Dysfunction in Patients With Acute Coronary Syndromes (n=31) 198 patients with ACS Cardiovascular events cardiovascular death myocardial infarction ischemic stroke Assessment of systemic vasoreactivity provides important prognostic information Fichtlscherer S et al. Circulation. 2004;110:

4 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.

5 Basic principle of noninvasive method for testing endothelial function Endothelium Baseline Hyperemic Blood Flow Shear stress NO NO Vasodilatation NO PGI2(?) Hyperemia Normal Endothelial Dysfunction FMD (endothelial function), % = Hyperemic Diameter Baseline Diameter Baseline Diameter 100

6 Guidelines for FMD of the Brachial Artery (Subject preparation) 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 Corretti MC et al. JACC 2002;39:257-65

7 Changes of % diameter change (delta %) Superoxide anion formation (delta nmol/10 6 cells/min) Why Overnight Fasting? GROUP Low-fat High-fat y= 0.74x r= p= Changes of serum triglycerides (delta mg/dl) y= x r= P< y= x r= P< Changes of superoxide anion formation Changes of serum triglycerides (delta nmol/10 6 cells/min) (delta mg/dl) Bae JH et al. Atherosclerosis 2001;155:517-23

8 Changes of % diameter change (delta %) GROUP low fat high fat r = p = n = 18 y = x r = p = n = 17 y = x GROUP r = low fat p = high fat n = 17 y = 0.198x Changes of serum triglycerides (delta mg/dl) Changes of serum triglycerides (delta mg/dl)

9 Acute Effects of Vasoactive Drug on FMD SBP FMDNMD In Normal Subjects Measurements; Baseline and 3 hrs after medicine Holding 24hrs 3hr Recent administration of nonnitrate vasoactive drugs has no significant effects on FMD Gokce N et al. JACC 2002;40:761-5

10 Menstrual Cycle on FMD Phase... M F L Age, y 24.8± ± Body mass index, kg/m ± ± Total cholesterol, mmol/l 4.37± ± ± ±0.19 HDL cholesterol, mmol/l 1.63± ± ± ±0.08 LDL cholesterol, mmol/l 2.35± ± ± ±0.13 Triglyceride, mmol/l 1.94± ± ± ±0.10 Estradiol, pmol/l ± ± ± ± Progesterone, nmol/l 1.6± ± ± ±4.8 4 Endothelium-dependent vasodilatation varies during the menstrual cycle. The endogenous estradiol may be involved in this menstrual cycle related vasodilatation. Gokce N et al. JACC 2002;40:761-5

11 Guidelines for FMD of the Brachial Artery (Equipment) 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) Corretti MC et al. JACC 2002;39:257-65

12 Guidelines for FMD of the Brachial Artery (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 Corretti MC et al. JACC 2002;39:257-65

13 Guidelines for FMD of the Brachial Artery (Endothelium-dependent FMD) To create a flow stimulus in the brachial artery Baseline 5 minutes of upper (lower) arm arterial occlusion s after cuff deflation Hyperemic Baseline diameter Blood flow by PW Doppler Velocity signal Cuff inflation; at least 50mmHg above SBP Ischemia and consequent dilation of downstream resistance vessel via autoregulation Corretti MC et al. JACC 2002;39:257-65

14 Guidelines for FMD of the Brachial Artery (Endothelium-dependent FMD) 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 Corretti MC et al. JACC 2002;39:257-65

15 Guidelines for FMD of the Brachial Artery (Endothelium-dependent FMD) 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 Corretti MC et al. JACC 2002;39:257-65

16 Guidelines for FMD of the Brachial Artery (Endothelium-dependent FMD) Measurement of hyperemic flow in hyperemic phase 5 minutes of upper (lower) arm arterial occlusion Hyperemic Flow; no later than 15 s after deflation Hashimoto M et al. J Pharmacol Sci. 2003;93:405-8.

17 Guidelines for FMD of the Brachial Artery (Endothelium-dependent FMD) Measurement of BA diameter in hyperemic phase 5 minutes of upper (lower) arm arterial occlusion s after cuff deflation Hyperemic Why 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 Corretti MC et al. JACC 2002;39:257-65

18 Guidelines for FMD of the Brachial Artery (Endothelium-dependent FMD) FMD Why brachial artery? Arteries <2.5mm in diameter; difficult to measure Baseline BA diameter (Radial artery) 6 r= p<0.001 n= Arteries >5.0mm in diameter; FMD is less difficult to perceive (Femoral artery)

19 Baseline Hyperemic FMD= 100 Hyper BAD-Base BAD Base BAD

20 FMD, in general Bots ML et al. EHJ 2005;26:363-8

21 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 Peak vasodilation (3-4 min) Image; continuous recording 3-4 min after NTG To measure max vasodilatory response Reflecting vascular smooth m function Corretti MC et al. JACC 2002;39:257-65

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

23 Korean IMT Study Normal Risk Factor Total n=227 Total n= ± ± ± p<0.001 p= ± ± ± ± ± ± ± ±0.10 p=0.197 p=0.912 p=0.334 SEX female ±0.1 p= N = Age (yrs) 44 35~ ~ ~64 male.5 N = Age (yrs) 31 35~ ~ ~64 Bae JH et al. Korean Society of Hypertension (supp) 2004:124-5

24 Cumulative Event-Free Rate (%) Systemic Atherosclerosis: Carotid Disease as a Marker of CV Risk Cumulative Event-Free Rates for MI or Stroke, According to Quintile of Combined IMT (n=4476), 65 years of age or older st Quintile IMT 2nd Quintile IMT 3rd Quintile IMT 4th Quintile IMT Years 5th Quintile IMT O Leary et al. N Engl J Med. 1999;340:14-22.

25 Carotid IMT 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: Chan SY et al. J Am Coll Cardiol 2003;42:

26 Measures of Arterial Wall Intima Media Thickness (QIMT) Safe standardized and validated method Direct assessment of disease Reproducible Easy to learn Relatively inexpensive

27 Measures of Arterial Wall 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

28 Manual measurement of carotid IMT 1 cm CCA

29 Example of carotid plaque

30 IMT : Semi Automatic Measurement

31 Background of Korean software (KS) development for IMT measurement Good detection Poor detection

32 Korean software (KS) for IMT measurement

33 Korean software (KS) for IMT measurement

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35 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) 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

36 IMT by M`ATH IMT by KS Korean software (KS) for IMT measurement y= x r=0.616 p<0.001 n= y= x r=0.537 p<0.001 n= Age (yrs) Age (yrs) Comparison of Pearson correlation coefficients by both methods

37 Intima thickness by KS Media thickness by KS Korean software for IMT measurement y= x r=0.507 p<0.05 n= Age (yrs) Age (yrs) Correlation between age and intima or media thickness

38 FMD, IMT, and PWV 8 7 p= p= p= N = 18 normal p= risk factor CAD.7 N = 18 normal 15 risk factor 43 CAD N = 18 normal 16 p=0.023 risk factor 43 CAD Age- and sex- matched study population Bae JH et al. Korean Circulation J 2004;34:845-55

39 FMD, IMT, and PWV 10 n=75 p=0.007 r= n=76 p=0.000 r= n=76 p=0.007 r= PWV (cm/sec) PWV (cm/sec) Bae JH et al. Korean Circulation J 2004;34: FMD (%) These are related to each other, the combination of these measurement will be of stronger clinical relevance 8 10

40 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

41 The Relative Importance of Vascular Structure and Function in Predicting Cardiovascular Events Kaplan-Meier curves for event-free survival IMT LV Mass FMD <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. Fathi R et al. J Am Coll Cardiol 2004;43:616-23

42 FMD (%) Can We Restore the Endothelial Dysfunction in Patients with Essential Hypertension with Calcium Channel Blockers? P< P<0.001 NS 15 P< Control HBP CAD Baseline Follow up Bae JH et al. Korean Circulation J 2000;30:1010-6

43 The Difference of Endothelial Function According to the Presence of Restenosis in Patients Undergoing PCI P= Restenosis Patent Bae JH et al. Korean Circulation J 2001;31:

44 Impaired flow-mediated dilation and risk of restenosis in patients undergoing coronary stent implantation. 136 patients undergoing stenting ISR; 20 pts (15%) Patti G et al. Circulation 2005;11:7005

45 Time Sequence of Atherosclerosis Surrogates Abnormality 31 diabetic children (15 yrs old, 6.8 yrs DM duration), 35 age-matched healthy children No difference in carotid IMT Endothelial dysfunction precedes an increase in carotid IMT Singh TP et al. J Am Coll Cardiol 2003;41:661-5

46 FMD (%) IMTcca (mm) Time Sequence of the Improvement of Atherosclerosis Surrogates Abnormality P=0.008 P= P=0.435 P= Statins Control 0.5 Statins Control 105 statin group and 100 control group undergoing stenting 6 months follow up Statin improves endothelial dysfunction, not carotid IMT in patients undergoing stenting Bae JH et al. J Cardiovasc Pharmacol Ther. 2004;9:185-92