- A study examined ruptured coronary plaques in patients with acute coronary syndrome using intravascular ultrasound (IVUS) and found ruptured plaques not just at the culprit lesion but also in other vessels. - Both culprit lesions and additional ruptured plaques showed positive arterial remodeling, where the vessel expands to accommodate plaque growth. - Positive remodeling is associated with plaque vulnerability and unstable coronary syndromes, while negative remodeling is more common in stable lesions and involves vessel constriction around plaque. - The direction of remodeling may represent different inflammatory stages of plaque development, with positive remodeling indicating early active lesions and negative remodeling indicating more stabilized advanced lesions.

1. Editorial Slides
VP Watch –August 14, 2002 - Volume 2, Issue 32
Positive Arterial Remodeling and CoronaryPositive Arterial Remodeling and Coronary
Plaque VulnerabilityPlaque Vulnerability
Paul Schoenhagen
M.D., FAHA
The Cleveland Clinic Foundation, Cleveland, Ohio, USA

2.  As reported in VP Watch of this week, Rioufol
et al. (Circulation 2002;106: 804 - 808), describe
the presence of multiple ruptured atherosclerotic
coronary plaques in patients presenting with an
acute coronary syndrome (ACS).
• Using intravascular ultrasound (IVUS), the
authors systematically examined proximal
portions of the entire coronary tree in 24
patients. Ruptured plaques were found in 9
patients (37.5%) at the “culprit lesion” but, more
importantly, distant from the culprit lesion in 19
patients (79%).

3. • These additional, ruptured plaques were
frequently multiple, located in a vessel
different from the culprit vessel in 70% of
patients and in 2 vessels not related to the
acute event in 12% of patients.
• Both culprit lesion and additional ruptured
plaques were characterized by positive
remodeling.

4. • Arterial Remodeling describes changes of
vessel size at the site of atherosclerotic
lesions.
• Vessel expansion, as shown in the upper
part of the following slide, is called
positive remodeling and vessel
constriction, as shown in the lower part, is
called negative remodeling.

5. Positive
Remodelin
g
Culprit Lesion
EEM Contour
Proximal
Reference
Proximal
Reference
Direction of Arterial RemodelingDirection of Arterial Remodeling
Schoenhagen et al. Circulation 2000; 101:598-603
Negative
Remodeli
ng
Culprit Lesion
EEM Contour
CCFIVUS

6. • Dr. Glagov and his colleagues at the University
of Chicago described positive remodeling as a
compensatory mechanism preventing lumen
loss despite plaque growth in early
atherosclerosis.
• This is shown in the following slide showing
tomographic sections through a vessel at
different times.
• Initially the plaque grows by expanding vessel
size. With further plaque growth in more severe
stages of the disease, the artery is unable to
expand further and the lumen begins to narrow.

7. Adapted from Glagov et al.Adapted from Glagov et al. N Engl J MedN Engl J Med. 1987;316:1371-1375.. 1987;316:1371-1375.
Glagov’s Coronary Remodeling
Hypothesis
NormalNormal
vesselvessel
MinimalMinimal
CADCAD
ProgressionProgression
Compensatory expansionCompensatory expansion
maintains constant lumenmaintains constant lumen
Expansion overcome:Expansion overcome:
lumen narrowslumen narrows
SevereSevere
CADCAD
ModerateModerate
CADCAD
CCFIVUS

8. • The effect of this phenomenon is exemplified in
the following slide. It shows a relative normal
appearing angiogram on the left and IVUS
images at point A and B on the right.
– At point B the IVUS catheter is surrounded by the
lumen. The vessel wall is seen as a narrow rim of
tissue bound by the adventitia.
– In panel A the lumen has similar size but a large
plaque has expanded the vessel wall. In other words,
positive remodeling allows plaque progression
concealed to angiographic detection.

9. AA
BB
AA
BB
CCFIVUS

10. AA
BB
AA
BB
Lumen vs. Vessel WallLumen vs. Vessel Wall
Lumen Plaque CCFIVUS

11. • Several recent studies have examined the
relation between arterial remodeling and
clinical presentation in different patient
populations.
• These studies consistently show that
positive remodeling is associated with
unstable coronary syndromes.

12. • We have compared the remodeling response in
85 patients presenting with unstable and 46
patients presenting with stable clinical
presentation.
• We found positive remodeling to be significantly
more common in the unstable group. It was
found in 52% of patients in the unstable but only
20% of the stable group.
• Negative remodeling was significantly more
common in the stable group. It was found in
56% of patients in the stable but only 32% of
the stable group.

13. Direction of Remodeling and Clinical
Presentation
00
2020
4040
6060
Percentof
Cohort
Positive
Remodeling
Absence of
Remodeling
Negative
Remodeling
Unstable
Stable
*p=0.000
3
*p=0.3 *p=0.006
Schoenhagen et al. Circulation 2000;101:598-603CCFIVUS

14. Unstable Presentation: Positive Remodeling
Echolucent Plaque with Plaque Rupture and
Remodeling Index of 1.42
Proximal Reference
EEM = 14.3 mm2
EEM = 20.3 mm2
Culprit Lesion
Schoenhagen et al. Circulation 2000; 101:598-603
CCFIVUS

15. • Both, positive remodeling and plaque
vulnerability are characterized by an
inflammatory response:
– Femoral artery cross-sections with larger
vessel and plaque area showed: (Pasterkamp
et al. JACC 1998;32:655)
• More CD68, CD 45 positive cells
• Less collagen
• Less alpha-actin staining MMP
– Increased presence of MMP in abdominal
aortic aneurysms.

16. • We examined pre-interventional intravascular
ultrasound images of 35 patients for extent and
direction of remodeling
• Histologic samples were obtained with
directional atherectomy (DCA)
• Immuno-Staining for: MMP 1,2,3,9
• We found a significant relation between MMP3
presence and direction of remodeling. Intense
MMP 3 presence was associated with positive
remodeling and mild MMP 3 presence with
negative remodeling.

17. MMP3 Presence and Direction of
Remodeling
58
42
17
83
0
10
20
30
40
50
60
70
80
90
Percent of
Cohort
Positive Remodeling Negative/Intermediate
Remodeling
Direction of Remodeling
Intense
Mild
Schoenhagen et al. Am J Cardiol. 2002;89:1354-9

18. Positive Remodeling and Heavy MMP3 Presence
Remodeling Index = 1.40
LesionProximal Reference
EEM = 10.5 mm2
Lesion
EEM = 7.5 mm2
Schoenhagen et al. Am J Cardiol. 2002;89:1354-9
CCFIVUS

19. Negative Remodeling and Mild MMP3
Presence
Remodeling Index = 0.71
LesionProximal Reference
EEM = 10.5 mm2
Lesion
EEM = 7.5 mm2
Schoenhagen et al. Am J Cardiol. 2002;89:1354-9
CCFIVUS

20. • Arterial remodeling could therefore be a
characteristic of vulnerable lesions, at risk to
rupture.
• The association between positive remodeling
and plaque vulnerability has been explored in a
recent prospective study:
• Dr. Yamagichi et al. at the National
Cardiovascular Center in Osaka, Japan have
examined mildly stenotic plaques prospectively
with intravascular ultrasound.
• Plaques causing acute coronary syndromes
during follow up more frequently exhibited
positive remodeling at baseline.

21. • 114 sites <50% diameter stenoses
• Follow-up after 21.8 months
• 12 acute coronary syndromes
• Ruptured plaques at baseline showed:
– Greater percent plaque area (67% vs. 57%)
– Similar lumen area (6.7mm2
vs. 7.5mm2
)
– Frequent echolucent zones
Yamagichi et al. JACC 2000; 35:106-11

22. • It is an attractive hypothesis to describe positive
and negative remodeling as temporary stages
of plaque development.
• Positively remodeled lesions may represent
early active lesions with increased inflammatory
response. Matrix degradation may lead to
vessel expansion but also to increased plaque
vulnerability and plaque rupture.
• Negative remodeling may be associated with
advanced lesions characterized by fibrosis and
decreased inflammation. These changes may
lead to vessel shrinkage but also plaque
stabilization.

23. Conclusion:
• The findings of Rioufol et al. support the
growing body of evidence that coronary
artery disease is a systemic disease of
the entire coronary tree. Further research
is needed to illuminate the complex
relation between focal manifestation and
overall disease burden.

24. • Rioufol G, Finet G, Andre-Fouet X, et al. Multiple atherosclerotic plaque rupture in acute coronary syndrome: A
three-vessel intravascular ultrasound study. Circulation 2002;106:804-808
• Goldstein JA, Demetriou D, Grines CL, et al. Multiple complex coronary plaques in patients with acute
myocardial infarction. N Engl J Med 2000;343:915-22 3. Burke AP, Farb A, Malcom GT, et al. Coronary risk
factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997;336:1276-
82
• Asakura M, Ueda Y, Yamaguchi O, et al. Extensive development of vulnerable plaques as a pan-coronary
process in patients with myocardial infarction: An angioscopic study. J Am Coll Cardiol 2001;37:1284-8
• Burke AP, Kolodgie FD, Farb A, et al. Healed plaque ruptures and sudden coronary death: evidence that
subclinical rupture has a role in plaque progression. Circulation 2001;103:934-40
• Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability.
Circulation 2002;105:939-943
• Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001;104:365-372
• Casscells W, Hathorn B, David M, et al. Thermal detection of cellular infiltrates in living atherosclerotic plaques:
possible implications for plaque rupture and thrombosis. Lancet 1996;347:1447-51
• Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary
arteries. N Engl J Med 1987;316:1371-53
• Schoenhagen P, Ziada KM, Kapadia SR, et al. Extent and direction of arterial remodeling in stable and
unstable coronary syndromes. Circulation 2000;101:598-603
• Schroeder S, Kopp AF, Baumbach A, et al. Non-invasive characterization of coronary lesion morphology by
multi-slice computed tomography: a promising new technology for risk stratification of patients with coronary
artery disease. Heart 2001;85:576-577
• Fayad ZA, Fuster V. Clinical imaging of the high-risk or vulnerable atherosclerotic plaque. Circ Res
2001;89:305-16
References