Transcript Role of imaging

Regression of atherosclerosis
and related CV diseases
Jean-Claude Tardif MD, FRCPC, FACC, FCAHS
Director, MHI Research Center
Professor of Medicine
UdeM Endowed Research Chair in Atherosclerosis
Montreal Heart Institute
Université de Montréal
Change in atheroma volume in 6 weeks
in statin-naïve patients
Relative change
Nominal change
0
2
1.21
-1
-0.54 ± 0.89
0
-1.5
Median (IQR)
Adjusted mean ± SE
-0.5
-2
-2.5
-3
P = 0.002
-3.5
-2
-4
-6
P = 0.003
-4
-8
-4.5
-4.71 ± 0.96
-5
Chronic statin
therapy
prior to ACS
(n = 38)
Newly initiated
statin therapy
following ACS
(n = 36)
-9.10
-10
Chronic statin
therapy
prior to ACS
(n = 38)
Newly initiated
statin therapy
following ACS
(n = 36)
Rodes J and Tardif JC, Am J Cardiol 2009;104:750-7
Substantial Risk of CHD Events Remains for
Many Patients on Statin Therapy
Clinical eventsa
Trial (N)
Statin treatment
Risk reduction
vs placebo
Remaining
risk
WOSCOPSb (6595)
Pravastatin 40 mg
31%
69%
AFCAPS/TexCAPSb (6605)
Lovastatin 20 or 40 mg
37%
63%
ASCOT-LLAb (10,305)
Atorvastatin 10 mg
36%
64%
4Sb (4444)
Simvastatin 20 mg
26%
74%
CAREc (4159)
Pravastatin 40 mg
24%
76%
LIPIDc (9014)
Pravastatin 40 mg
24%
76%
HPSc (20,536)
Simvastatin 40 mg
27%
73%
PROSPERc (5804)
Pravastatin 40 mg
19%
81%
aNonfatal
myocardial infarction and coronary heart death; bPrimary prevention trial; cSecondary prevention trial
WOSCOPS=West of Scotland Coronary Prevention Study; AFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT-LLA=AngloScandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; 4S=Scandinavian Simvastatin Survival Study; CARE=Cholesterol and Recurrent Events; LIPID=Long-Term Intervention with
Pravastatin in Ischemic Disease; HPS=Heart Protection Study; PROSPER=Prospective Study of Pravastatin in the Elderly at Risk
Adapted from Mahley RW, Bersot TP. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill Medical Publishing Division, 2006:933–
966; Bays HE. Expert Rev Cardiovasc Ther. 2004;2:485–501; Shepherd J et al. N Engl J Med. 1995;333:1301–1307; Downs JR et al. JAMA. 1998;279:1615–1622; Sever PS et al.
Lancet. 2003;361:1149–1158; Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383–1389; Sacks FM et al. N Engl J Med. 1996;335:1001–1009; Long-Term
Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Eng J Med. 1998;339:1349–1357;
Heart Protection Study Collaborative Group. Lancet. 2002;360:7–22; Shepherd J et al. Lancet. 2002;360:1623–1630.
Risk of death according
to presence of metabolic syndrome
Survival (all-cause)
1.0
Survival (CV)
1.0
p < 0.0001
p < 0.0001
0.75
0.75
0.50
0.50
0.25
0.25
No WHO metabolic syndrome
WHO metabolic syndrome
0
No WHO metabolic syndrome
WHO metabolic syndrome
0
0
No at risk
No MS
23813
MS
1078
5
10
15
Time (years)
20796
877
17854
673
20
10978
388
0
5
23122
1054
10
15
Time (years)
20110
853
17233
651
20
10611
376
Nigam A, Bourassa MG, Fortier A, Guertin MC, Tardif JC. Am Heart J 2006; 151: 514-21
Lipoprotein metabolism
LDL
receptor
Liver
ACAT
MTP
FC
CE
ApoB
LPL
27-hydroxylase
LPL
E
E
ABCG1
IDL
Oxidation
LDL
VLDL
Bile
CETP
Intestine
LCAT
FC  CE
ACAT
Cholesterol
pool
PL TP
A-1
CD36
SR-A
A-1
ABC1
FC
Macrophage
ACAT
HL
HDL
CE
IBAT
Nascent
HDL
Change in plaque volume
A+
30-mm segment, intent-to-treat population
mm3 6
5.1 ± 30.0
p = 0.058 (unadjusted)
p = 0.17 (adjusted)
Mean change (±SD)
4
1.9 ± 33.1
2
1.2 ± 24.2
0
-2
-2.5 ± 26.6
-4
Placebo
(n=109)
Avasimibe
50 mg
(n = 108)
Avasimibe
250 mg
(n = 98)
Avasimibe
750 mg
(n = 117)
Tardif et al Circulation 2004; 110:3372-7
A+
Long-Term Safety of
Intravascular Ultrasound
Coronary change score
New lesions
20
0
-0.04
-0.06
p = 0.35
-0.10
(% of patients)
(mm)
-0.02
-0.08
Disease
progression
15
p = 0.27*
10
p = 0.84*
5
0
Instrumented (IVUS-related arteries)
Non-instrumented (Non-IVUS arteries)
J Am Coll Cardiol 2005;45:559-564
IVUS assessment - Atherosclerosis regression
20% reduction in plaque burden
Baseline
Follow-up
Plaque volume (mm3): 272.9
EEM volume (mm3): 609.5
Plaque volume (mm3): 197.3
EEM volume (mm3): 445.9
Correlations between changes in plaque,
vessel and lumen areas in pts with regression
 Mean vessel area (mm2)
 Mean lumen area (mm2)
6
6
n = 227
r = 0.64
p < 0.0001
4
2
2
0
0
-2
-2
-4
-4
-6
-6
-4
-3.5
-3
n = 227
r = 0.20
p = 0.0030
4
-2.5
-2
-1.5
-1
-.5
Change in mean plaque area (mm2)
0
-4
-3.5
-3
-2.5
-2
-1.5
-1
-.5
Change in mean plaque area (mm2)
Tardif et al. Am J Cardiol 2006;98-23-7
0
IVUS results in patients with angiographic progression
vs no progression by QCA in the IVUS-related artery
Mean plaque volume (mm3)
250
Progression
No progression
p = 0.05
225
200
p = 0.0089
226.8

69.9
217.2

72.1
197.1

73.6
175
196.0

71.3
150
Baseline
P-value for mean change in plaque volume: 0.0283
Follow-up
Circulation 2007;115:1851-7
Prognostic significance of angiographic
progression of coronary atherosclerosis
Any coronary event ( n = 112)
Death or MI (n = 40)
1.0
Proportion event free
Proportion event free
1.0
Non progressors
0.75
p < 0.001
0.50
Progressors
(N = 260) (N = 137)
(N = 0)
Non progressors
0.75
p < 0.001
Progressors
0.50
(N = 0)
0.25
(N = 309) (N = 192)
(N = 5)
(N = 1)
60
80
0.25
0
20
40
Months
60
80
0
20
40
Months
Circulation 1993; 87: 1067-75
Canadian Atherosclerosis Imaging Network
Clinical Translation and Practice
 Correlation of coronary and carotid atherosclerosis and their
changes over time and links with clinical outcomes
 2000 patients undergoing coronary angiography, IVUS (with
virtual histology) and carotid ultrasound (IMT and plaques) at
baseline and 24 months
 5-year follow-up for cardio/cerebrovascular events
 NIRS, PET/CT, MRI and microvascular substudies
 Genomic (including miRNAs) and biomarker biobanks
 Proteomic and metabolomic analyses
 Application of this knowledge and framework in clinical trials of
novel anti-atherosclerotic agents
Beyond statin-induced LDL-C reduction
 CETP inhibitors
 HDL infusions/mimetics
 5-LO/FLAP inhibitors
 PLA2 inhibitors
 Serpins
 Heart rate reduction?
Tardif JC, Heinonen T. Nature Clin Pract CV Med 2006;3:366-7
INHIBITION OF ATHEROSCLEROSIS BY HDL
HDL INHIBITS ADHESION MOLECULE EXPRESSION
Monocyte
HDL INHIBITS MCP-1 EXPRESSION
LDL
Adhesion
Molecule
MCP-1
LDL
HDL INHIBITS
OXIDATION OF LDL
Cytokines
MODIFIED LDL
Macrophage
HDL PROMOTES CHOLESTEROL EFFLUX
Foam Cell
Effects of rApo-A1 Milano
on coronary atherosclerosis
Change in atheroma volume
0
-4
Change in % atheroma volume
1
0.14 ± 3.09
-2.9 ± 23.3
0
-8
mm3
%
-12
-12.6 ± 15.3
-16
-15.1 ± 50.6
p = 0.97
p = 0.02
p = 0.007
-0.73 ± 2.75
-1
-1.06 ± 3.17
-14.1 ± 39.5
-1.29 ± 3.48
p < 0.001
-20
p = 0.03
p = 0.45
p = 0.02
15 mg/kg
(n = 21)
45 mg/kg
(n = 15)
Combined
(n = 36)
-2
Placebo
(n = 11)
15 mg/kg
(n = 21)
45 mg/kg
(n = 15)
ETC-216
Combined
(n = 36)
Placebo
(n = 11)
ETC-216
JAMA 2003; 290:2292-2300
The ERASE trial
Change in atheroma volume on IVUS
Median percent change
Median nominal change
0
0
-0.5
-1
p = 0.07
-2
-2.5
-3
-3.5
p=NS
-2.33
-2
-1.62
-1.5
%
-1
p=NS
mm3
P=0.04
-3
-4
-3.41
-5
p < 0.0001
-4
-6
CSL-111
(n = 89)
Placebo
(n = 47)
-5.34
p < 0.0001
CSL-111
(n = 89)
Placebo
(n = 47)
 Plaque volume at baseline: 146.0 mm3 for CSL-111, 151.4 mm3 for placebo
 Interval between IVUS examinations : 43 ± 6 days in both groups
Tardif et al. JAMA 2007;297:1675-82
The ERASE trial
Changes in plaque characterization indexes
Arc index
Inner perimeter index
0.02
0.0137
0.01
0
-0.0083
-0.01
Least square means
Least square means
0.02
0
-0.0097
-0.01
p = 0.01
-0.02
0.0128
0.01
p = 0.01
-0.02
CSL-111 Placebo
CSL-111
Placebo
Tardif et al. JAMA 2007;297:1675-82
The ERASE trial
Changes in coronary score on QCA
Least square means (mm)
0
-0.02
There was a significant interaction between
study treatment and baseline coronary score
(p = 0.03)
CSL-111 40 mg/kg
-0.04
p = 0.03
-0.06
Placebo
-0.08
1.76 mm
1st quartile
2.00 mm
Median
2.26 mm
3rd quartile
Coronary score at baseline
JAMA 2007;297:1675-82
Lipoprotein metabolism
LDL
receptor
Liver
ACAT
MTP
FC
CE
ApoB
LPL
27-hydroxylase
LPL
E
E
ABCG1
IDL
Oxidation
LDL
VLDL
Bile
CETP
Intestine
LCAT
FC  CE
ACAT
Cholesterol
pool
PL TP
A-1
CD36
SR-A
A-1
ABC1
FC
Macrophage
ACAT
HL
HDL
CE
IBAT
Nascent
HDL
ILLUSTRATE – Primary endpoint
Change in Percent Atheroma Volume
0,35
p = 0.72†
0,3
0,25
Change
in percent
atheroma
volume
0,2
0,19
0,15
0,12
0,1
0,05
0
Atorvastatin
monotherapy
*LS Mean change
†p value from ANCOVA
Torcetrapibatorvastatin
Nissen, Tardif, et al. N Engl J Med 2007; 356:1304-16
Event Free (%)
ILLUMINATE - Primary Endpoint
Time to First MCVE*: Kaplan-Meier Plot
Hazard Ratio 1.25
100
P=0.001
98
96
94
Atorvastatin (A) events = 373
92
Torcetrapib/Atorvastatin (T/A) events = 464
90
0
90
180
270
360
450
540
630
720
810
Days from Randomization
*Major cardiovascular event: CHD death, non-fatal MI, stroke or hospitalization for unstable angina
NEJM 2007;357:2109-2122
Post-hoc Exploratory Analyses in the Torcetrapib/Atorvastatin
Group
CHD Death or Non-Fatal MI
(Hazard Ratio)
Hazard ratios for CHD Death or Non-Fatal MI
by quintile of on-trial HDL-C
(referent group is HDL-C < 60 mg/dL stratum)
1.0
0.8
0.6
1.00
0.67
0.47 *
*P<0.05
0.57 *
0.43*
0.4
0.2
0
<60
60-70 71-80 81-93
>93
Quintiles of HDL-C (mg/dL) at Month 3
Cox proportional hazard model adjusted for age, gender and baseline HDL-C. Excludes 265 patients with missing month 3
HDL-C. Preliminary analysis initiated and authorised by P Barter and conducted by Pfizer
Lack of Effect of Dalcetrapib vs Torcetrapib
on Aldosterone Secretion
700
600
RO4607381
Aldosterone
fmole/µg protein
500
Torcetrapib
400
300
200
100
0
0
0,001
0,005
0,01
0,025
0,1
1
2,5
5
7,5
Concentration of Torcetrapib or RO4607381 (µM)
10
AngII
100 nM
The dal-HEART Program
dalcetrapib HDL Evaluation, Atherosclerosis & Reverse cholesterol Transport
The dal-HEART Program tests a novel hypothesis: enhancing HDL efficacy through
CETP modulation treats the underlying disease of atherosclerosis and will
attenuate CV risk
dal1
OUTCOMES
15,600 patients
recently hospitalized
for ACS
To evaluate the effect
of dalcetrapib on CV
outcomes
RECRUITMENT
COMPLETE
dal-VESSEL
450 patients with
CHD or CHD risk
equivalent
To evaluate the effect
of dalcetrapib on
endothelial function
and blood pressure,
measured by FMD and
ABPM
RECRUITMENT
COMPLETE
1Schwartz
2
3
4
dal-PLAQUE
dal-PLAQUE-2
130 patients with
CHD
To evaluate the effect
of dalcetrapib on
inflammation, plaque
size and burden,
measured by PET/CT
and MRI
900 patients with
CAD
To evaluate the effect
of dalcetrapib on
atherosclerotic disease
progression, assessed
by IVUS and carotid
B-mode ultrasound
RECRUITMENT
COMPLETE
RECRUITING
et al. Am Heart J 2009;158:896-901; 2http://clinicaltrials.gov/ct2/show/NCT00655538 Accessed April 1st 2010;
3http://clinicaltrials.gov/ct2/show/NCT00655473 Accessed April 1st 2010;
4http://clinicaltrials.gov/ct2/show/NCT01059682 Accessed April 1st 2010
DAL-OUTCOMES Study Design
A double-blind, randomized, placebo-controlled, parallel group,
multi-centre study in 15,600 patients recently hospitalized for ACS
Double-blind
Single-blind Placebo
Run-in
4-12 Weeks
Visit 1
Visit 2
Visit 3
randomization
1:1
Dalcetrapib 600 mg
Placebo
Follow up
1st year: every 3 months
Following years: every 4 months
Until 1600
events occur
but at least a
minimum of
2 years
dal-PLAQUE-2: Study Design
•
Objective: to assess the effect of dalcetrapib versus placebo on
atherosclerotic disease progression in patients with CAD
•
A double-blind, randomized, placebo-controlled, parallel-group multicenter
study in 900 patients with CAD
Double-blind
Pre-rando phase
Screening phase up to
8 weeks
Baseline IVUS, QCA
and CIMT
dalcetrapib 600 mg
placebo
Background of contemporary evidence-based
therapy for CAD and CV risk factors
Randomization
Primary endpoints: IVUS and CIMT at 24 months
Other assessments: CIMT at 6+12 months; QCA at 24 months
24 months
dal-PLAQUE-2
Primary endpoints
Co-primary endpoints
• Nominal change from baseline to study end in coronary percent atheroma
volume (PAV) for all anatomically comparable slices in a 30-mm segment of the
target coronary artery assessed by IVUS
• Rate of change from baseline to study end in intima-media thickness (IMT),
defined as the per scan average of the far wall MEAN IMT values of the right
and left common carotid, carotid bulb and internal carotid arterial segments as
assessed by carotid B-mode ultrasound
British Journal of Pharmacology 2008; 154:765-773
Aortic valve area (mm2)
Aortic valve area during treatment
Control
26
25
**
Treated
*p<0.05
**p<0.01
*
*
24
23
22
21
20
19
18
17
Days
0
5
10
15
Stop cholesterol diet + Vit D2
Start ApoA-I mimetic peptide treatment
29
Br J Pharmacol 2008;154:765-773
The dual PPAR agonist aleglitazar and change in HDL-C
35
Placebo
0.05
% Δ BL of HDL - C
30
0.15
0.3
0.6
p< 0.0001
p< 0.0001
Pioglitazone
p< 0.0001
25
p<0.0014
20
p=0.0312
15
10
5
0
54
BC22140 Investigator Meeting
54
54
53
54
57
n
Aleglitazar 150 μg Provides Beneficial Effects on
Cardiovascular Biomarkers
Aleglitazar 150 μg
Placebo
Pioglitazone 45 mg
Mean Absolute Change From Baseline
20
15
1
9
10
5
1,1
0
0
0
-0,1
-5
-10
-1
-15
-3,7
-5
-20
-1,6
-25
-5
-1,7
-2
-30
-7,3
-35
-35,4
-10
-3
-40
hsCRP (mg/dL)
Fibrinogen (mg/dL)
PAI-1 (μg/mL)
Placebo
Aleglitazar 150 µg
Pioglitazone 45 mg
337.25
342.92
328.67
hsCRP baseline (mg/dL)
4.97
3.85
4.00
PAI-1 baseline (μg/mL)
22.26
22.67
22.30
Fibrinogen baseline (mg/dL)
ALECARDIO Study Design
Screened Patients
Index ACS Event
Run-in Period
2–6 (+ 6) weeks
Treatment Period
at least 2.5 years
Aleglitazar 150 µg
Placebo
Standard of care (diabetes and other CV risk factors)
BC22140 Investigator Meeting
4 weeks
Follow-up
Potential therapeutic targets in CV diseases
Mean LTB4 Production [pg/ml]
VIA-2291 Decreases ex Vivo Whole Blood LTB4
Production from Baseline through Week 12
160,000.00
** p < 0.0001 ANCOVA Change from Baseline
140,000.00
Placebo
25mg
50mg
100mg
120,000.00
100,000.00
80,000.00
60,000.00
**
**
**
40,000.00
20,000.00
0.00
-2
0
2
4
6
8
10
12
14
Study Weeks
Error Bars represent 95% CI
Tardif et al. Circulation Cardiovasc Imaging 2010;3:298-307
Significant Decrease in hs-CRP in VIA-2291 100 mg Group
versus Placebo at 24 Weeks
Change in non-calcified plaque volume and patients with new
plaque lesions on serial coronary CT scans in the VIA-2291
groups versus placebo at 24 Weeks
Plaque volume (mm3)
7
Pts with new plaques (%)
30
5
p < 0.01
25
3
20
1
15
-1
10
-3
5
-5
p < 0.01
0
Placebo
All VIA-2291
Placebo
All VIA-2291
Tardif et al. Circulation Cardiovasc Imaging 2010;3:298-307
Serp-1 Phase 2a Results: Myocardial Enzymes
Troponin I: Adjusted Geometric Mean
CK-MB: Adjusted Geometric Mean
1
7
0.8
5 µg/kg Dose
0.7
15 µg/kg Dose
5 µg/kg Dose
6
CK-MB (ng/ml)
0.9
Troponin I (ng/ml)
Placebo
Placebo
0.6
0.5
0.4
15 µg/kg Dose
5
4
3
0.3
0.2
2
0.1
0
1
Predose
VT
8 hr
16 hr
24 hr
VT
48 hr
54 hr
Day 14
VT
=statistically significant (p<0.05 vs control)
Day 28
Predose
8 hr
16 hr
VT
24 hr
VT
VT
48 hr
54 hr
Day 14
Day 28
VT
= timing of doses
Dose-dependent reduction in biomarkers of cardiac damage observed in
the first 24 hours
Tardif et al. Circulation Cardiovasc Interventions 2010 (in press)
37
Mortality by resting heart rate
Cumulative survival
Overall mortality
CV mortality
1.0
1.0
0.9
0.9
0.8
0.8
RHR in quintiles
 62 bpm
63 - 70 bpm
71 - 76 bpm
77 - 82 bpm
≥ 83 bpm
0.7
0.6
0.7
0.6
0.5
0.5
0
5
10
15
Years after enrolment
20
0
5
10
15
Years after enrolment
20
Adjusted for age, gender, hypertension, diabetes, smoking, NDCV, ejection fraction,
recreational activity, medications including -blockers, plus BMI for CV mortality
Diaz A, Bourassa MG, Guertin MC, Tardif JC. Eur Heart J 2005; 26: 967-74
Ivabradine prevents endothelial dysfunction
associated with dyslipidemia in mice
100
90
CEREBRAL
60
Wild
WT type
Wild
WT type
80
70
DL
Dyslipidemia
#
DL + IVA
DL+Ivabradine
60
50
‡
*
40
30
*
20
10
0
Dilation
(% of maximal dilation)
Dilation
(% of maximal dilation)
RENAL
50
Dyslipidemia
DL
40
DL+Ivabradine
DL + IVA
#
30
‡
20
10
0
0.001
0.01
0.1
1
10
ACh (M)
Emax: ‡ P < 0.05 vs. to WT; # P < 0.05 vs. to DL
Drouin et al. Br J Pharmacol. 2008;154:749-757.
0.0001 0.001 0.01
0.1
1
10
ACh (M)
pD2: * P < 0.05 vs. WT and DL
TED at trough of drug activity
INITIATIVE
Ivabradine vs atenolol
n
Favors ATE
E (95% CI)
P for non inferiority
Favors IVA
IVA 5 mg bid
vs ATE 50 mg od
at M1
595
286
6.7 (-7.4; 20.8)
p < 0.0001
IVA 7.5 mg bid
vs ATE 100 mg od
at M4
300
286
10.3 (-8.3; 28.8)
p < 0.0001
IVA 10 mg bid
vs ATE 100 mg od
at M4
298
286
15.7 (-2.9; 34.3)
p < 0.0001
0
- 35 sec
Equivalence interval
+ 35 sec
Tardif JC et al. Eur Heart J 2005; 26:2529-36
Ivabradine increases all ETT parameters in
patients already receiving beta-blockers
889 stable angina patients, 20 countries
60
Ivabradine + atenolol
P<0.001
P<0.001
Placebo + atenolol
50
40
P<0.001
P<0.001
30
20
10
0
Total exercise duration
Time to limiting
angina
Time to angina onset
Time to 1mm ST
segment depression
*Evaluated at trough of drug activity
Tardif JC, et al. Eur Heart J. 2009;30:540-548.
Effect of Ivabradine on hospitalisation
for fatal and non-fatal MI (HR ≥ 70 bpm)
% with hospitalisation for fatal and non-fatal MI
8
Hazard ratio = 0.64 (0.49 – 0.84)
Placebo
RR = -36%
6
P = 0.001
4
2
Ivabradine
0
0
0.5
1
1.5
Years
Lancet Online August 31, 2008.
2
Primary composite endpoint
(CV death or hospital admission for worsening HF)
43
Cumulative frequency (%)
40
HR = 0.82 (0.75–0.90)
P < 0.0001
Placebo
18%
30
Ivabradine
20
10
0
0
6
12
18
Months
Swedberg K, et al. Lancet. 2010;online August 29.
24
30
Population
Outpatients with stable CAD without LVSD (EF > 40%) or clinical signs of HF, with
appropriate CV medication
Ivabradine
Starting dose 7.5 mg bid
Run in
2 - 4 weeks
Target HR: 55-60 bpm
Placebo bid
M000
M003
M006
Every 6 months
Methods
Events: 4.5% per year in the placebo group
1070 primary composite endpoints (cardiovascular death and non fatal MI
N = 11 330, mean follow up = 2.5 years; RRR = 18%, α bilateral 5%, power 90%
Canadian Atherosclerosis Imaging Network
“Hearts and Minds”
 Stems from CIHR’s 2007 consensus conference on imaging
 Five-year (2008-2013) 10M$ operating grant from CIHR
 Infrastructure grant 25M$ from CFI in June 2009
 Unique network combining in vivo imaging of vessel wall disease, endorgan disease, clinical and pathological endpoints
 Enables cross-sectional and longitudinal clinical studies of coronary,
carotid and peripheral vascular beds
 International resource for studying the natural history of
atherosclerosis and novel therapeutic interventions
Canadian Atherosclerosis Imaging Network
CAIN – one imaging network for one entire country
 Imaging Core Analysis Laboratories (vascular)
 IVUS, 3-D US, QCA, MDCT, MRI, PET/CT, SPECT
 Imaging Core Analysis Laboratories (end-organ)
 Pan-canadian network of 45 partner sites
 Data coordinating and image repository center (MHICC)
 Genetic, pharmacogenomic and biomarker biobanks
 Proteomic and metabolomic analyses
 Tissue samples
CAIN
Research themes
 Vascular biology of atherosclerotic plaque
Hearts
and
Minds
 Vascular imaging technology development
and assessment
 Translation to clinical research and clinical
practice
Canadian Atherosclerosis Imaging Network
1- Vascular Biology of Atherosclerotic Plaque
 Assess natural history of the plaque from 3 time points (MRI):
 Plaque initiation, progression and complication
 Evaluate inflammation, neovascularization and hemorrhage
 Determine the role of stimuli such as Db and hyperlipidemia
 Study the genetics of atheroma
 Assess the role of hypertension, hemodynamics and the interaction with
blood constituents at the site of plaque rupture
Canadian Atherosclerosis Imaging Network
2- Vascular Imaging Technology
Development and Assessment
 Validation of developing technologies through quantitative
histological examination of surgical specimens
 Includes:
 Carotid ultrasound - surface morphology, plaque vulnerability
and plaque volume
 18FDG-PET – metabolic activity and inflammation
 Ultrasound microbubbles – plaque neovascularity
Canadian Atherosclerosis Imaging Network
3- Translation to Clinical Research/Practice
 Correlation of coronary and carotid atherosclerosis and their
changes over time and links with clinical outcomes
 2000 patients undergoing coronary angiography, IVUS (with
virtual histology) and carotid ultrasound (IMT and plaques) at
baseline and 24 months
 5-year follow-up for cardio/cerebrovascular events
 NIRS, PET/CT, MRI and microvascular substudies
 Genomic (including miRNAs) and biomarker biobanks
 Proteomic and metabolomic analyses
 Application of this knowledge and framework in clinical trials of
novel anti-atherosclerotic agents
Canadian Atherosclerosis Imaging Network
CAIN – one imaging network for one entire country

www.canadianimagingnetwork.org
 [email protected]
www.gainresearch.net
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