1. Coronary disease in the United States
Content Points:
It is important to re-emphasize the enormity of the problem posed by coronary heart disease (CHD) in this country.
It is the single largest killer of men and women in this country.1
According to current American Heart Association (AHA) estimates, 12 million individuals have a history of myocardial infarction (MI) or angina.1
It was also estimated that, in 1999, 1.1 million individuals would have an MI and would die on the event, within 1 hour.1
1984 data from the Framingham study suggest that by age 60, every 5th male and every 17th female may develop CHD.2 We will see from data presented in this slide kit that this may be an underestimation.
The estimated direct and indirect costs of CHD in 1999 total $99.8 billion.1

2. Cardiovascular disease: Leading cause of death in US women
Content Points:
Cardiovascular disease accounts for greater mortality among women than all other causes combined.3 This is an important point and should be stressed.
For example, heart disease accounts for 8.6-times more deaths than breast cancer. Many of these women do not experience any symptoms of CHD prior to a fatal cardiovascular event.

3. Normal trilaminar coronary morphology
Content Points:
Briefly, IVUS uses an ultrasound transducer mounted at the tip of a catheter and interfaced with a scanner.4-6 A steerable angioplasty guide wire is advanced through the IVUS catheter and fluoroscopically guided into the target artery. The IVUS catheter is then advanced over the guide wire into the artery. The images are digitalized and then displayed.
This slide provides a magnified view of the morphologic features as viewed by IVUS in a left anterior descending (LAD) coronary artery. The media can always be identified by the dark or sonolucent (acoustically less reflective) band.
The arrows indicate the position of the intimal leading edge. As shown, in normal subjects, the intima is relatively thin (< 0.25 mm).

4. Atherosclerosis: Traditional vs contemporary model
Content Points:
The traditional, angiographic-based view of the atherosclerotic process held that the principal response to plaque accumulation was a gradual narrowing of the lumen, with eventual stenosis development. Diminished flow at a stenosis caused stable angina. Plaque rupture and thrombosis led to unstable angina or MI. It is now known that this model of the disease is wrong.
In the new model of atherosclerosis, supported by IVUS research, early disease results in plaque accumulation in the arterial wall without significant luminal narrowing. The adventitia or elastic external membrane (EEM) enlarges to accommodate the growing atheroma.
This process is known as compensatory enlargement or remodeling.

5. Glagov’s coronary remodeling hypothesis
Content Points:
The groundwork for the new model of atherosclerosis was a histological analysis of coronary artery sections reported by Glagov et al in The work they described showed that the early part of the disease was marked by plaque accumulation in the vessel wall, with subsequent enlargement of the EEM but no change in lumen size.
In Glagov’s original hypothesis, plaque development is extra-luminal until the lesion occupies approximately 40% of the area within the EEM. Only then does the lumen begin to shrink.

6. Remodeling in an angiographically “normal” artery
Content Points:
The slides shows angiographic and IVUS images of the LAD.8
Note that on the angiogram, the intima is thin and no luminal narrowing is apparent. These findings suggest an absence of disease in both segments.
The upper IVUS image (A) shows the segment indicated by the upper arrow on the angiogram. It shows a bright, sonogenic (acoustically reflective), crescent-shaped area. This is an atheroma causing outward remodeling of the EEM.
The lower IVUS image (B) shows the segment indicated by the lower arrow on the angiogram. Only this segment is disease-free.

7. Remodeling preserves lumen size
Content Points:
This slide shows the same images as the previous slide. For clarity, the luminal areas are outlined and quantified.
Note that the upper and lower segments have almost identical luminal areas, 5.07 mm2 and 5.18 mm2, respectively, confirming that no matter which projection angle you chose, it would be very difficult to identify an atheroma from the angiogram.
IVUS studies indicate that most plaque in the early stages of CAD is angiographically invisible. The example shown on this slide is the rule, not the exception.

8. Mechanisms of false-negative angiography
Content Points:
Remodeling is only one mechanism by which coronary angiography underestimates disease presence or severity.
If diffuse disease develops in a concentric, symmetrical manner, the entire artery will have the angiographic appearance of a small but normal vessel.
Diffuse disease was first observed in necropsy studies.9-11 IVUS studies in living patients show that it is particularly common in diabetic patients and can also occur in nondiabetics.
Because so much of atherosclerotic disease is invisible on the angiogram, the tendency is to view large, stenotic lesions as representing the bulk of the disease burden. In fact, dilating these stenotic lesions only addresses a small part of the problem.

9. Angiographically inapparent coronary atherosclerosis:
Diffuse symmetrical disease
Content Points:
The angiogram of the proximal LAD shown on this slide shows a minor luminal irregularity indicated by the arrow.
However, the angiogram provides no indication that throughout the length of the artery there is diffuse, concentric disease illustrated by the IVUS image on the right.
In addition, note the darker area on the lower left of the IVUS image. This marks an area of calcified plaque.

10. Disease burden in angiographically “normal” arteries
Content Points:
The confounding effects of remodeling and diffuse disease are illustrated by an IVUS study conducted at the Cleveland Clinic. The study population primarily consisted of patients with single-vessel disease (a small percentage had double-vessel disease) who were scheduled to undergo PCI.
The interventional cardiologist was asked to identify the arterial segment with the most normal angiographic appearance. This segment was then examined via IVUS.
As shown on the slide, the mean percent of EEM area occupied by atheroma at these angiographically normal segments was found to be 38.9 ± 16.6%. That is, the reference site used by an interventional cardiologist to size a stent is, on the average, approximately 40% occupied by plaque.
Thus, it is appropriate to dilate a stenotic lesion and, thereby, relieve angina. However, the plaque in the reference segment must also be addressed by appropriate lipid-lowering therapy, because it is the stability of this plaque that will determine the patient’s prognosis.
This finding raises the question: At what age does the disease begin? As the following slide shows, significant lesions can be present in young, otherwise healthy individuals.

11. Prevalence of atherosclerosis by donor age
Content Points:
Since 1992, all cardiac transplants at the Cleveland Clinic are routinely examined by IVUS shortly after transplantation. Thus, any lesions found are atherosclerotic disease that occurred prior to transplantation and not due to transplant vasculopathy.
All donor candidates died from noncardiovascular causes. They were required to be free from known heart disease or diabetes and be otherwise healthy. Thus, they were expected to be free from CAD. The angiograms of these patients were normal, with minor luminal irregularities evident in only approximately 3% of cases.
The slide summarizes preliminary data from a study of transplanted hearts. Overall, 25% of heart transplant donors under the age of 25 showed clear evidence of atherosclerotic disease, as indicated by IVUS.
These data suggest that CAD is highly prevalent and that even relatively young individuals may have a substantial plaque burden that will require aggressive intervention.

12. Coronary stenosis severity prior to MI
Content Points:
In a review of coronary plaque disruption, Falk, Shah, and Fuster12 collated data from studies by Ambrose et al,13 Little et al,14 Nobuyoshi et al,15 and Giroud et al.16
The slide summarizes the number of patients with myocardial infarction caused by rupture of plaques causing either > 70%, 50%-70%, or < 50% stenosis. In 68% of cases, the coronary event was caused by plaques causing < 50% stenosis.
This finding provides further support for the hypothesis that luminal narrowing may not identify vulnerable plaque. An example is given in the next slide.

13. Plaque rupture proximal to a severely stenotic lesion
Content Points:
This images on this slide were obtained from a patient who presented with an acute coronary syndrome. The patient was admitted to the CCU and received aspirin, heparin, nitroglycerin, and a glycoprotein IIb/IIIa antagonist.
After the patient stabilized, angiography and IVUS were carried out. Site B on the angiogram shows the lesion that was identified by the interventional cardiologist as the probable culprit lesion. However, IVUS showed that this lesion had a fibrous plaque with no evidence of rupture and thrombosis. A side branch can be clearly seen at the top of the image.
In fact, thrombosis occurred at site C. The rupture occurred in the dark area at the lower left of the IVUS image.
Site B was the source of the patient’s chronic stable angina. But the source of the acute syndrome was site C.

14. Atheroma rupture: Ultrasound features
Content Points:
This slide shows an enlargement of the IVUS image taken at site C in the previous slide. The lipid core is indicated by the arrow on the left, the point of rupture by the arrow on the right.
Note that the rupture occurred at the shoulder (edge) of the fibrous cap. This is a common finding.

15. AVERT: Ischemic events at 18 months
Content Points:
We have seen in the previous slides that a stenotic lesion is simply the tip of the iceberg—that the bulk of atherosclerotic plaque is located in the vessel wall and is undetectable by angiography. This provides insight into the results of the AVERT (Atorvastatin VErsus Revascularization Treatments) study, which evaluated the effects of aggressive lipid-lowering therapy (atorvastatin 80 mg/day) or angioplasty in patients with significant CAD.17
As shown on the slide, a total of 22 patients (13.4%) in the atorvastatin group and 37 (20.9%) in the intervention group had any ischemic event, a 36% difference (P = .048).
Because 2 interim analyses were carried out, the significance level for the final analysis was adjusted from 5% to 4.5%. Consequently, the difference between the groups for any ischemic event narrowly missed the level of significance as adjusted for interim analysis.
Because CAD is a systemic not a focal disease, the patients in the atrovastatin group experienced a reduction in events because their soft, lipid-laden plaques distal from their stenotic lesions were being treated.

16. Anatomy of atherosclerotic plaque
Content Points:
What characterizes plaques that are more likely to rupture in response to mechanical stress or other trigger? We know from the work of Libby and colleagues that vulnerable plaque have a relatively large lipid core and a thin fibrous cap.18
By IVUS, morphological characteristics of vulnerable and unstable plaques are emerging.

17. Plaque morphology: Vulnerable vs stable
Content Points:
The slide shows 2 plaques of similar size and with lumens of similar size. The IVUS image on the left shows a plaque with a thick fibrous cap (shown as a bright, sonogenic crescent).
The image on the right shows a thin fibrous cap. Note that the lipid core is larger (the sonolucent or darker area between the cap and the EEM). It is now believed that lipid lowering encourages fibrosis, and the conversion to a plaque similar to that on the left.
It has also been shown that these plaques exhibit different types of remodeling.

18. Remodeling: Stable and unstable lesions
Content Points:
Schoenhagen et al studied culprit lesions in 85 patients with unstable and 46 patients with stable coronary syndromes.19 All patients had a single culprit lesion.
Positive remodeling (with the EEM adapting outwardly to accommodate large plaques) was observed in 51.8% of unstable and 19.6% of stable lesions. Negative remodeling (with local shrinkage of the vessel) was observed in 31.8% of unstable and 56.5% of stable lesions (P = .001 for both comparisons) (Figure 3).
Unstable lesions were more likely to contain sonolucent plaque than stable lesions (19% versus 4%, P = .02).
Because the lumen remains relatively unchanged during positive remodeling, the patient may not experience any symptoms of chronic stable angina and the angiogram appears normal. The first indication of any disease is an acute MI or sudden cardiac death. That is, preserving luminal size does not reduce the risk of an MI.
The next sequence of slides show cases illustrating positive and negative remodeling.

19. Rupture in bulky, remodeled atheroma: Angiographic findings
Content Points:
The slide shows an angiogram of the right coronary artery of a patient 5 days after an inferior wall MI. Only a hazy luminal contour, indicating a subtle intraluminal filling defect, was noted.

20. Rupture in bulky, remodeled atheroma: IVUS findings
Content Points:
On IVUS, a very different clinical profile emerged. Note the atheroma in the reference segment, suggesting that the patient had widespread CAD.
The IVUS image of the culprit lesion shows where the plaque ruptured, with subsequent loss of the lipid core into the bloodstream.

21. Rupture in bulky, remodeled atheroma
Content Points:
This slide shows the measurements of the EEM and lumen areas at the reference site and culprit lesion.
Note that the lumen areas are similar at both sites. However, the EEM area in the culprit lesion is 4.1 mm2 larger than that of the reference segment, indicating positive remodeling of the culprit lesion.
The phenomenon of positive remodeling explains the angiographic findings that myocardial infarctions occur most frequently at sites of < 50% luminal narrowing The IVUS data show that vulnerable plaques are not “small” as was originally proposed; they are, in fact, large.

22. Stable angina with negative remodeling
Content Points:
This IVUS image shown on the slide was taken from a patient who presented with stable angina caused by a tight stenosis.19 The EEM area at the lesion is 7.5 mm2, which is 3 mm2 smaller than the EEM area at a reference segment proximal to the lesion.

23. Potential role of MMP 3 in positive remodeling
Content Points:
Matrix metalloproteinases (MMPs) are proteolytic enzymes implicated in angiogenesis and other processes involving degradation of the extracellular matrix. They are also expressed by macrophages in atherosclerotic plaque and data suggest that they may be involved in degradation of a plaque’s fibrous cap, thereby rendering the plaque more prone to rupture.20
Schoenhagen et al conducted a study in 25 patients undergoing directional atherectomy.21 Using IVUS, the remodeling characteristics of a lesion were determined prior to directional atherectomy being performed on that lesion. Samples of the lesion were obtained and evaluated for the presence of MMP 1, 2, 3, and 9 by immunostaining. MMP levels were classified according to whether staining was absent, mild, or moderate-to-heavy.
All samples tested negative for MMP 2 and MMP 9.
Moderate-to-heavy staining for MMP 3 was more common in lesions exhibiting positive remodeling than in those exhibiting negative remodeling, 58% versus 17%, respectively (P = .035).
Moderate-to-heavy staining for MMP 1 was observed in 30% and 41% of positively remodeled and negatively remodeled lesions, respectively, a nonsignificant difference (P = .57).
This finding implicates MMP 3 in the positive remodeling process.

24. Clinical vs angiographic improvement
Content Points:
The data from many trials show a clear relationship between LDL-C reduction and clinical benefit.22 However, as illustrated on the slide, large reductions in clinical events were accompanied by very small changes in lumen size.23
Thus, angiographic data do not provide any insight into the mechanism of clinical benefit.

25. Regression of donor CAD
Content Points:
This slide provides an example of atheroma regression in a heart transplant recipient. This patient had required a transplant because of dilated cardiomyopathy and was at low risk for CAD.
In this case, the atheroma area shrank from 8.77 mm2 in the immediate post-transplant period to 6.75 mm2 at 1-year post-transplant. During that time, the EEM area shrank from mm2 to mm2, while the luminal area stayed virtually the same, 7.04 mm2 vs 7.08 mm2.

26. Glagov’s coronary remodeling hypothesis: Y2K
Content Points:
The emerging data suggest that the remodeling hypothesis postulated by Glagov may work in the opposite direction, with regression as well as progression occurring primarily in the vessel wall. This new hypotheis is being tested as described in the following slides.

27. Relationship between CHD events and LDL-C
Content Points:
Data from many studies show a clear relation between the degree of LDL-C lowering and the degree of clinical benefit.22

28. Comparison of LDL-C lowering by statins
Content Points:
The availability of the statins also affords clinicians and researchers with the ability to lower LDL-C by substantial amounts.24

29. REVERSAL: Study design
Content Points:
The REVERSAL (REVERSal of Atherosclerosis with Lipitor) study will take advantage of the lipid-lowering effects of the statins to test the hypothesis that regression is associated with shrinkage of the EEM not the lumen.
This is a prospective, randomized, double-blind, multicenter study.
Study subjects will be randomized to 1 of 2 arms differing in intensity of lipid-lowering therapy: atorvastatin 80 mg (potential 60% reduction in LDL-C) and pravastatin 40 mg (potential 34% reduction in LDL-C).
IVUS and quantitative coronary angiography (QCA) will be conducted at baseline and following 18 months of treatment. Qualifying patients must have a luminal irregularity as assessed by QCA of at least 20%. The primary end point will be the percent change in coronary atheroma volume.

30. REVERSAL: Atheroma measurements
Content Points:
For each site evaluated, the REVERSAL investigators will measure the EEM and lumen areas. Atheroma area will be defined as the difference between these values.

31. REVERSAL: Number of sites evaluated
Content Points:
The atheroma area will be assessed every 1 mm along a 50 mm segment of the coronary artery, using a motorized pullback of the IVUS transducer.
Values from each site will be summed to give the total atheroma volume for that patient.

32. ‘Minor’ luminal irregularity
Content Points:
The angiogram was obtained from a patient who qualified for the REVERSAL study. As shown, this patient exhibited only a minor luminal irregularity (arrow) and barely met the qualifying criteria.

33. ‘Minor’ luminal irregularity: IVUS findings
Content Points:
As shown by the IVUS image, the ‘minor’ luminal irregularity (right hand arrow) described in the previous slide was caused by a large atheroma.
In addition, another large atheroma can be seen at an angiographically normal site proximal to this lesion.
For its entire length, this vessel contained large amounts of atherosclerotic plaque in its wall.
REVERSAL will be the first trial to provide a true evaluation of the impact of lipid-lowering therapy on the total burden of atherosclerotic disease.

34. Clinical challenge
Content Points:
In summary, the IVUS data presented in this slide kit indicate that by the time a lesion is angiographically evident, it can be assumed that there is extensive disease involvement over much, if not all, of the coronary tree.
While PCI can effectively relieve the symptoms of chronic stable angina, aggressive lipid lowering (with statins in the majority of patients) is required if long-term morbidity and mortality are to be favorably affected.
However, as summarized on the slide, data from the National Health and Nutrition Examination Survey (NHANES) suggest that many patients who qualify for lipid-lowering therapy are not receiving it.25One explanation may be that the extent of the challenge posed by CAD has been underestimated.
It is to be hoped that the IVUS data presented here will help provide a clinical rationale for more aggressive lipid-lowering strategies, ensuring that all qualified patients are treated.