Quantification of coronary atherosclerosis for cardiovascular risk assessment: the hole in the doughnut?

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atherosclerosis for cardiovascular risk assessment: the hole in the doughnut?

Paul Schoenhagen, Steven E. Nissen

Introduction

A tomographical section of a diseased coronary artery, which is characterized by the central lumen and the surrounding thickened vessel wall, roughly resembles a doughnut. Depending on the imaging modality used, this basic coronary anatomy is described from different perspectives.

Angiographical techniques described the size and characteristics of the lumen. In contrast, tomographical techniques, including intravascular ultrasound (IVUS), computed tomography (CT), and magnetic resonance imaging (MRI), describe the plaque and the vessel wall. If the overall diameter of the coronary arteries were fixed (as is the case in a pipe of a water faucet), changes in plaque size would always be reflected in luminal dimensions. However, it has become obvious that coronary pathophysiology is far more complex than reflected in the historical comparison of diseased arteries with “rusty pipes”. This has important implications for the quantitative assessment of coronary artery disease. The following selection of eight articles, reflecting 50 years of research, will provide a review of this changing understanding of coronary atherosclerosis and the emerging role of contemporary atherosclerosis imaging for cardiovascular risk assessment.

It is remarkable that two investigators, Crawford and Levene, already described the complexity of coronary pathology in 1953 (Paper no. 1). Based on the observations of pressure- distended and undistended aortic wall specimens, the authors stated that “ordinary atheromatous plaques do not project into the lumen but lie in a depression in the media, which may bulge outwards”. Not surprisingly, these post-mortem observations did not find widespread clinical atten- tion, because in vivo imaging of coronary arteries to confirm clinical significance, was not possible. A few years later, in the late 1950s, selective coronary angiography was the first imaging modality introduced to clinical cardiology. As described in the paper by Proudfit, Shirey, and Sones (Paper no. 2), the diagnosis of coronary disease in the pre-angiographical era relied solely on the elucidation of historical or clinical symptoms of ischaemia. The correlation of these ischaemic syndromes with angiographical findings naturally lead to the definition of disease by the severity of luminal stenosis. It therefore appeared logical to define changes of disease severity (progression/regression) by changes in luminal dimension. This became possible through quantitative coronary angiography, which allowed precise assessment of luminal dimensions in serial research protocols (Paper no. 3). Proudfit et al. had already described a correlation of disease severity and serum cholesterol levels in young patients (Paper no. 2), and subsequent serial studies using quantitative coronary angiography examined luminal changes during lipid-lowering treatment (Paper no. 4). These studies suggested less progression or greater propensity for regression in the treatment group and demonstrated the value of luminal dimensions in the assessment of disease severity. However, the changes in luminal size were surprisingly small in comparison to the observed large clinical benefit, demonstrated in a decreased event rate during follow-up. In order to explain this discrepancy, it has been suggested that changes in qualitative rather than quantitative plaque characteristics induce clinical disease stabilization.

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However, emerging tomographical imaging modalities demonstrated limitations of the angiographical description of coronary disease. IVUS, performed during cardiac catheterization, for the first time allowed in vivo assessment of the vessel wall (Paper no. 5). The initial observa- tions of atherosclerotic plaque characteristics coincided with a seminal post-mortem study of human coronary arteries reminiscent of Crawford and Levene’s observation. In this study, Dr Glagov, a pathologist at the University of Chicago, systematically described the relation between plaque size and luminal dimension, and suggested that early plaque accumulation was typically not reflected in luminal change because of an outward bulging or “remodelling” of the overall vessel size (Paper no. 6). In a clinical arena focused on luminal size and the paradigm that “big- ger is better”, outward or “positive” remodelling was understood as a compensatory mecha- nism intended to maintain luminal size. However, subsequent post-mortem and imaging studies challenged that view by consistently demonstrating an association between outward remodelling of coronary lesions and unstable clinical presentation (Paper no. 7). These results suggest that plaque progression is initially accommodated by an expansion of vessel diameter rather than luminal stenosis. It appears that these outward remodelled but mildly stenotic lesions (vulnerable or high-risk plaques) have a particular tendency to rupture, initiating acute coronary events.

It is an attractive hypothesis that changes of regression are also reflected mainly in plaque size rather than luminal dimension.

These data provided the rational of using tomographical imaging for the quantitative assessment of disease progression and regression. Several invasive and non-invasive imaging modalities are used to assess disease burden in different areas of the vascular tree. In the last few years, IVUS has been developed into a reliable quantitative modality, allowing serial observation of coronary plaque volume during pharmacological treatment. A series of such studies are currently examining changes in plaque volume in non-intervened vessels of patients enrolled at the time of coronary intervention. The recently published results from the Apo A-I Milano Trial (Paper no. 8), demonstrate for the first time that disease regression in patients presenting with acute coronary syndromes can be induced by aggressive modification of high-density lipoprotein (HDL) levels. The response in the first weeks after the event emphasizes the highly dynamic nature of coronary artery disease.

These serial studies will eventually allow to compare plaque burden, plaque characteristics, systemic markers of inflammation, and clinical outcome. These results will be important for disease prevention in primary setting but also for secondary prevention following the interventional treatment of symptomatic patients.

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Medial thinning in atheroma

Author

Crawford T, Levene CI

Reference

J Pathol Bacteriol 1953; 66: 19–23

Abstract

The amount of medial thinning at atheromatous areas was measured from aortas and iliac arteries fixed in the usual way and in the distended state at arterial pressure. All but one of 134 plaques from undistended vessels and all 76 plaques from vessels fixed in distension showed definite medial thinning.

In the distended vessels the ordinary atheromatous plaques do not project into the lumen but lie in a depression in the media which may bulge outwards. Only advanced plaques with recent thrombotic accretions project noticeably into the lumen. The familiar intimal bulge is in fact a post-mortem artifact.

Physical considerations rule out pressure as the cause of the medial thinning, and the occur- rence of outward bulging of the media indicates that something more than a disuse atrophy is concerned. The early and constant appearance of the medial thinning supports the contention that it is not a secondary result of the atheromatous process but an essential part of it, and the lesion as a whole is comparable to a shallow aneurysm partially or completely filled by the plaque of intimal thickening.

Summary

This paper from 1953 already described the complexity of coronary pathology. Based on observations of pressure-distended or undistended aortic wall specimens, the authors demonstrate that atherosclerotic plaque progression may occur without changes in luminal dimension, as

“ordinary atheromatous plaques do not project into the lumen but lie in a depression in the media, which may bulge outwards”.

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Related References

1. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990’s. Nature 1993;

362: 801–809.

2. Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001; 104: 365–372.

3. Moreno PR, Purushothaman KR, Fuster V, O’Connor WN. Intimomedial interface damage and adventitial inflammation is increased beneath disrupted atherosclerosis in the aorta:

implications for plaque vulnerability. Circulation 2002; 105: 2504–2511.

4. Zarins CK, Xu C, Glagov S. Atherosclerotic enlargement of the human abdominal aorta.

Atherosclerosis 2001; 155: 157–164.

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5. Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med 1984; 310: 1137–1140.

Key message

The shape of the lumen of the distended vessels is of further interest in that it implies that the familiar centrally bulging plaques which are such a feature of the aorta in the autopsy room are in fact a post-mortem artefact produced by abnormal shortening of the medial fibres when the blood pressure falls at death. Our observations have been limited to the aorta and iliac arteries, but that the same holds for the coronary arteries is suggested by the work of Stewart, Birchwood and Wells (1935), and of Harrison and Wood (1949).

Why it’s important

This paper challenges the role of luminal dimension as the sole predictor of disease significance at a time when coronary angiography was just emerging.

Strengths

It is remarkable that Crawford and Levene made these observations based on a simple but ori- ginal experiment in 1953, before the availability of in vivo imaging.

Weaknesses

The lack of in vivo imaging did not allow confirmation in clinical studies.

Relevance

This study emphasized that plaque development may be dissociated from luminal dimensions, a concept reappearing in later studies. However, it is not surprising that these post-mortem observations did not find widespread clinical attention, because in vivo imaging of coronary arteries was not possible.

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Selective cine coronary arteriography: correlation with clinical findings in 1000 patients

Author

Proudfit WL, Shirey EK, Sones Jr FM

Reference

Circulation 1966; 33: 901–910

Abstract

Symptoms of coronary arterial disease generally occur in association with obstruction of the coronary arteries in the absence of valvular defects. Until recent years accurate information relative to obstructive lesions in the coronary arteries could not be obtained from the living patient.

In the absence of definite electrocardiographic diagnosis of myocardial infarction, clinical diagnosis of coronary disease has been dependent principally on the elicitation and proper evaluation of the history, and therefore, the accuracy has varied with the care, ability, and experience of the physician. In other fields of medicine in which clinical diagnosis can be compared with those based on objective criteria, it is evident that errors in clinical diagnoses are common. The development of selective cine coronary arteriography has made possible the correlation of clinical syndromes and evidence of arterial obstruction during life. If this method of study is valid, there should be a close relationship between the typical clinical syndromes (angina pectoris and myocardial infarction) and the presence of significant arteriographic abnormality.

Summary

Before the introduction of coronary angiography the diagnosis of coronary disease relied on elu- cidating historical or clinical symptoms of ischaemia. This and other papers correlated these ischaemic syndromes with angiographical findings based on the severity of luminal stenosis.

These findings would subsequently revolutionize the field of cardiovascular medicine.

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Related References

1. Forssmann W. Die Sondierung des rechten Herzens. Klin Wochenschr 1929; 8: 2085.

2. Seldinger SI. Catheter replacement of the needle in percutaneous arteriography: a new tech- nique. Acta Radiol 1953; 39: 368.

3. Judkins MP. Selective coronary arteriography: a percutaneous transfemoral technique.

Radiology 1967; 89: 815.

4. Proudfit WL, Shirey EK, Sones Jr FM. Distribution of arterial lesions demonstrated by selective cinecoronary arteriography. Circulation 1967; 36: 54–62.

Key message

One of the difficulties encountered in the correlation of clinical and arteriographical findings is the necessarily arbitrary separation of degrees of estimated arterial obstruction. It is apparent

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that mild degrees of obstruction rarely cause angina pectoris or myocardial infarction. Arterio- graphical evidence of obstruction is almost always severe in symptomatic patients. Therefore, precise classification of relatively minor degrees of obstruction does not seem to be so important as it was considered to be during early progress of the study.

Why it’s important

The correlation of ischaemic syndromes with angiographical findings defined the role of high- grade luminal stenosis in clinical coronary syndromes.

Strengths

1. Systematic correlation of clinical syndromes with angiographical findings.

2. Observation of role of risk factors (hypercholesterolemia) for angiographical disease manifestation.

Weaknesses

Based on the understanding of coronary artery disease at the time, the role of mildly stenotic lesions for the initiation of acute coronary syndromes was underestimated.

Relevance

The correlation of clinical, ischaemic syndromes with angiographical findings led to the definition of disease by the severity of luminal stenosis. This paradigm has been the basis for the enormous success of coronary revascularization of symptomatic patients.

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Quantitative coronary arteriography: estimation of

dimensions, hemodynamic resistance, and atheroma mass of coronary artery lesions using the arteriogram and digital computation

Author

Brown BG, Bolson E, Frimer M, Dodge HT

Reference

Circulation 1977; 55: 329–337

Abstract

More accurate characterization of coronary artery lesions is needed for evaluation of short- and long-term interventions in coronary disease. A method of segmental artery analysis has been developed to maximize the information obtained from coronary arteriograms.

Coronary lesions are traced from two projected, perpendicular, 35 mm cineangiographic views and transmitted, in digital form, to a PDP 11/45 computer. Magnification and distortion of the image are compensated for in order to determine the actual vessel profiles, using the catheter and its location as a scaling device. The two views are matched; a spatial repre- sentation of the vessel centerline is constructed mathematically; and orthogonal vessel diame- ters are computed at increments along this centerline. Assuming an elliptical lumen, the absolute and percentage reduction in diameter and cross-sectional area in the stenosis are computed. More complex functions (integrated atheroma mass, Poiseuille resistance, and orifice resistance) are then calculated. The accuracy and variability of the different steps involved in lesion analysis have been determined. Dimensional accuracies of150 microns (SD) are fea- sible. Examples are given of patients with Prinzmetal’s angina and with progressive coronary disease.

Summary

The authors describe a quantitative method of describing disease severity applicable in clinical and research studies.

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Related References

1. Reiber JH, Serruys PW, Kooijman CJ, et al. Assessment of short-, medium-, and long-term variations in arterial dimensions from computer-assisted quantitation of coronary cineangio- grams. Circulation 1985; 71: 280–288.

2. Keane D, Haase J, Slager CJ, et al. Comparative validation of quantitative coronary angio- graphy systems. Results and implications from a multicenter study using a standardized approach.

Circulation 1995; 91: 2174–2183.

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Key message

Estimates of minimum cross-sectional area appear to provide a sensitive means of determining progression of an atherosclerotic lesion. The computed Poiseuille resistance represents an integrated average of a function of lumen constriction, weighted by the nature of the function towards the most severely constricted portion of the lesion; it appears to provide an even more sensitive index of disease progression than diameter or area estimations alone. Resistance is also (in theory) a more relevant index of the physiological severity of the arterial stenosis.

Why it’s important

Based on the definition of coronary disease by the severity of luminal stenosis it appeared logical to define changes of disease severity (progression/regression) by changes in luminal dimension as well. This became possible through quantitative coronary angiography.

Strengths

Quantitative coronary angiography allowed precise assessment of luminal dimensions in serial research protocols.

Weaknesses

The authors acknowledge the limitations of the angiographical description of coronary disease, which is based on a planar projection of the luminal silhouette.

Relevance

These studies introduced the concept of imaging as endpoint in clinical and research studies.

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Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of

apolipoprotein B

Author

Brown G, Albers JJ, Fisher LD, et al.

Reference

N Engl J Med 1990; 323: 1289–1298

Abstract

BACKGROUND AND METHODS: The effect of intensive lipid-lowering therapy on coronary atherosclerosis among men at high risk for cardiovascular events was assessed by quantitative arteriography. Of 146 men no more than 62 years of age who had apolipoprotein B levels greater than or equal to 125 mg per deciliter, documented coronary artery disease, and a family history of vascular disease, 120 completed the 2.5-year double-blind study, which included arteriography at base line and after treatment. Patients were given dietary counseling and were randomly assigned to one of three treatments: lovastatin (20 mg twice a day) and colestipol (10 g three times a day); niacin (1 g four times a day) and colestipol (10 g three times a day); or conventional therapy with placebo (or colestipol if the low-density lipoprotein [LDL] cholesterol level was elevated). RESULTS: The levels of LDL and high-density lipoprotein (HDL) cholesterol changed only slightly in the conventional-therapy group (mean changes,7 and 5 percent, respectively), but more substantially among patients treated with lovastatin and colestipol (46 and 15 percent) or niacin and colestipol (32 and 43 percent). In the conventional- therapy group, 46 percent of the patients had definite lesion progression (and no regression) in at least one of nine proximal coronary segments; regression was the only change in 11 percent.

By comparison, progression (as the only change) was less frequent among patients who received lovastatin and colestipol (21 percent) and those who received niacin and colestipol (25 percent), and regression was more frequent (lovastatin and colestipol, 32 percent; niacin and colestipol, 39 percent; p less than 0.005). Multivariate analysis indicated that a reduction in the level of apolipoprotein B (or LDL cholesterol) and in systolic blood pressure, and an increase in HDL cholesterol correlated independently with regression of coronary lesions. Clinical events (death, myocardial infarction, or revascularization for worsening symptoms) occurred in 10 of 52 patients assigned to conventional therapy, as compared with 3 of 46 assigned to receive lovastatin and colestipol and 2 of 48 assigned to receive niacin and colestipol (relative risk of an event during intensive treatment, 0.27; 95 percent confidence interval, 0.10 to 0.77). CONCLUSIONS: In men with coronary artery disease who were at high risk for cardiovascular events, intensive lipid- lowering therapy reduced the frequency of progression of coronary lesions, increased the frequency of regression, and reduced the incidence of cardiovascular events.

Summary

This study describes the change of angiographical lesion severity during lipid-lowering treatment concordant with clinical benefit.

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Related References

1. Jukema JW, Bruschke AV, van Boven AJ, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to mod- erately elevated serum cholesterol levels. The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995; 91: 2528–2540.

2. Blankenhorn DH, Azen SP, Kramsch DM, et al. Coronary angiographic Changes with Lovastatin Therapy. The Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med 1993; 119:

969–976.

3. Pitt B, Mancini GB, Ellis SG, Rosman HS, Park J-S, McGovern ME. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. J Am Coll Cardiol 1995; 26: 1133–1139.

4. MAAS Investigators. Effect of Simvastatin on coronary atheroma: the Multicentre Anti- Atheroma Study (MAAS). Lancet 1994; 344: 633–638.

5. Waters D, Higginson L, Gladstone P, et al. Effects of monotherapy with an HMG-CoA reduc- tase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography. The Canadian Coronary Atherosclerosis Intervention Trial. Circulation 1994; 89:

959–968.

Key message

Our results show that quantitative arteriography is an effective method of assessing interventions against the atherosclerotic process. Although it answers different questions from those answered by clinical trials, arteriography permits a direct assessment of the vascular processes underlying clinical disorders, and it is currently the only reliable way to study the regression of lesions.

Why it’s important

This and other studies demonstrated less progression or greater propensity for regression in the treatment group and demonstrated the value of luminal dimensions in the assessment of disease severity as a clinical endpoint.

Strengths

Applies coronary angiography to the quantitative assessment of atherosclerosis progression and regression in clinical research.

Weaknesses

The authors describe that other pathological processes including arterial remodelling, vaso- motor tone, and endothelial function initiate changes of arterial architecture independent of changes in luminal dimension.

Relevance

These studies demonstrate the dynamic nature of coronary artery disease (CAD) and the value of luminal dimensions in the assessment of disease severity.

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Application of a new phased-array ultrasound imaging catheter in the assessment of vascular dimensions:

in vivo comparison to cineangiography

Author

Nissen SE, Grines CL, Gurley JC, et al.

Reference

Circulation 1990; 81: 660–666

Abstract

Tomographic imaging techniques such as ultrasound can provide important information in the evaluation of vascular anatomy. Recent technical advances have permitted fabrication of a small (1.83 mm), phased-array, intravascular ultrasonic imaging catheter capable of continuous real- time, cross-sectional imaging of blood vessels. We used this imaging catheter to compare intra- luminal ultrasound with cineangiography in the measurement of vascular dimensions in animals and to assess the intraobserver and interobserver variability of the technique. Segmental deformation of vessel anatomy was produced by stenoses created with a tissue ligature or by balloon dilation. The mean value for measurements of vessel diameter was 5.6 mm by cineangiography and 5.7 mm by intravascular ultrasound. The correlation between cineangiography and ultrasound was close (r 0.98). Mean cross-sectional area by angiography was 28.8 mm² and 29.6 mm²(r 0.96) by ultrasound. Percent diameter reduction produced by the stenoses averaged 48.4% by cineangiography and 40.1% by ultrasound, and the two methods cor- related closely (r 0.89). Correlation between cineangiography and ultrasound for vessel diam- eter and area before balloon dilation was closer (r 0.92 and 0.88) than after balloon dilation (r 0.86 and 0.81). This difference reflected an increase in measured vessel eccentricity following balloon dilation. These data demonstrate that intravascular ultrasound is an accurate and reproducible method for measurement of vascular diameter and cross-sectional area in vivo. Intravascular ultrasound is capable of accurately identifying and quantifying segmental deformation of vascular dimensions produced by either stenoses or balloon dilation.

Summary

This paper describes the development of intravascular ultrasound (IVUS) technology in an initial in vitro model.

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Related References

1. St Goar FG, Pinto FJ, Alderman EL, Fitzgerald PJ, Stadius ML, Popp RL. Intravascular ultra- sound imaging of angiographically normal coronary arteries: an in vivo comparison with quanti- tative angiography. J Am Coll Cardiol 1991; 18: 952–958.

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2. Yock PG, Linker DT, Angelsen BA. Two-dimensional intravascular ultrasound: technical developments and initial clinical experience. J Am Soc Echocardiogr 1989; 2: 296–304.

3. McPherson DD, Hiratzka LF, Lamberth WC, et al. Delineation of the extent of coronary atherosclerosis by high-frequency epicardial echocardiography. N Engl J Med 1987; 316:

304–309.

4. Ge J, Liu F, Gorge G, Haude M, Baumgart D, Erbel R. Angiographically “silent” plaque in the left main coronary artery detected by intravascular ultrasound. Coron Artery Dis 1995; 6: 805–810.

5. Schoenhagen P, Nissen S. Understanding coronary artery disease: tomographic imaging with intravascular ultrasound. Heart 2002; 88: 91–96 [Review].

Key message

IVUS has the potential to be the most sensitive technique by which to define the progression or regression of atherosclerosis, and to study the response of intravascular size to pharmacological agents. The use of ultrasonic catheters also holds the enormous potential for anatomic definition of the vessel wall, and the possible assessment of the extent and composition of atherosclerotic plaque.

Why it’s important

This and other early studies validated IVUS for subsequent in vivo assessment of the vessel wall.

Strengths

Despite the initial limitation on comparison of luminal measurements between IVUS and angiography, these studies already realized the importance for vessel wall imaging.

Weaknesses

These early in vitro studies were limited by many technical deficiencies of the IVUS technology, which were subsequently resolved allowing routine clinical imaging.

Relevance

Intravascular ultrasound allowed for the first time in vivo assessment of the atherosclerotic plaque and directed the clinical interest to the vessel wall.

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Compensatory enlargement of human atherosclerotic coronary arteries

Author

Glagov S, Weisenberg E, Zarins CK, et al.

Reference

N Engl J Med 1987; 316: 1371–1375

Abstract

Whether human coronary arteries undergo compensatory enlargement in the presence of coronary disease has not been clarified. We studied histological sections of the left main coronary artery in 136 hearts obtained at autopsy to determine whether atherosclerotic human coronary arteries enlarge in relation to plaque (lesion) area and to assess whether such enlargement pre- serves the cross-sectional area of the lumen. The area circumscribed by the internal elastic lamina (internal elastic lamina area) was taken as a measure of the area of the arterial lumen if no plaque had been present. The internal elastic lamina area correlated directly with the area of the lesion (r 0.44, p less than 0.001), suggesting that coronary arteries enlarge as lesion area increases. Regression analysis yielded the following equation: Internal elastic lamina area 9.26 0.88 (lesion area) 0.026 (age) 0.005 (heart weight). The correlation coeffi- cient for the lesion area was significant (p less than 0.001), whereas the correlation coefficients for age and heart weight were not. The lumen area did not decrease in relation to the percentage of stenosis (lesion area/internal elastic lamina area 100) for values between zero and 40% but did diminish markedly and in close relation to the percentage of stenosis for values above 40% (r 0.73, p less than 0.001). We conclude that human coronary arteries enlarge in relation to plaque area and that functionally important lumen stenosis may be delayed until the lesion occupies 40% of the internal elastic lamina area. The preservation of a nearly normal lumen cross-sectional area despite the presence of a large plaque should be taken into account in evaluating atherosclerotic disease with use of coronary angiography.

Summary

In this seminal post-mortem study of human coronary arteries, Dr Glagov et al. systematically described the relation between plaque size and luminal dimension, and suggested that early plaque accumulation was frequently not reflected in luminal change because of an outward bulging or “remodelling” of the overall vessel size. The results are reminiscent of Crawford and Levene’s observation (Paper no. 1).

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Related References

1. McPherson DD, Sirna SJ, Hiratzka LF, et al. Coronary arterial remodeling studies by high- frequency epicardial echocardiography. J Am Coll Cardiol 1991; 17: 79–86.

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2. Hermiller JB, Tenaglia AN, Kisslo KB, et al. In vivo validation of compensatory enlargement of atherosclerotic coronary arteries. Am J Cardiol 1993; 71: 665–668.

3. Armstrong ML, Heistad DD, Marcus ML, Megan MB, Piegors DJ. Structural and hemodynamic responses of peripheral arteries of macaque monkeys to atherogenic diet. Arteriosclerosis 1985; 5: 336–346.

4. Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability. Circulation 2002; 105: 939–943.

5. Burke AP, Kolodgie FD, Farb A, Weber D, Virmani R. Morphological predictors of arterial remodeling in coronary atherosclerosis. Circulation 2002; 105: 297–303.

Key message

Our findings do indicate that many persons have an adequate, if not normal, lumen cross- sectional area in the presence of advanced atherosclerosis and that such a possibility should be taken into account in evaluating the extent and severity of disease with angiography. The arrest of progression and the stabilization of a plaque before cross-sectional stenosis exceeds 40%

could be consistent with preservation of an adequate, if not normal lumen area in such patients.

Identification of the clinical, functional and anatomical factors that influence plaque stabilization could have important clinical consequences, even if the disease is not reversible and regression is not achieved.

Why it’s important

This and subsequent papers explained why plaque accumulation was not always associated with luminal stenosis.

Strengths

1. Systematic observation of early atherosclerotic lesions in human post-mortem arteries.

2. The authors suggest an explanation for the dissociation between plaque and lumen size, which subsequently will have significant influence on our current understanding of coronary artery disease (CAD).

Weaknesses

Owing to the cross-sectional design of post-mortem studies, the findings regarding plaque development needed confirmation in serial studies.

Relevance

The simultaneous description of the compensatory changes of vessel size during plaque development in post-mortem and imaging studies provided the rational for tomographical imaging of coronary atherosclerosis.

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Relation of arterial geometry to luminal narrowing and histological markers for plaque vulnerability:

the remodeling paradox

Author

Pasterkamp G, Schoneveld AH, van der Wal AC, et al.

Reference

J Am Coll Cardiol 1998; 32: 655–662

Abstract

OBJECTIVE: To relate local arterial geometry with markers that are thought to be related to plaque rupture. BACKGROUND: Plaque rupture often occurs at sites with minor luminal stenosis and has retrospectively been characterized by colocalization of inflammatory cells. Recent studies have demonstrated that luminal narrowing is related with the mode of atherosclerotic arterial remodeling. METHODS: We obtained 1521 cross section slices at regular intervals from 50 atherosclerotic femoral arteries. Per artery, the slices with the largest and smallest lumen area, vessel area and plaque area were selected for staining on the presence of macrophages (CD68), T-lymphocytes (CD45RO), smooth muscle cells (alpha-actin) and collagen. RESULTS:

Inflammation of the cap or shoulder of the plaque was observed in 33% of all cross sections.

Significantly more CD68 and CD45RO positive cells, more atheroma, less collagen and less alpha-actin positive staining was observed in cross sections with the largest plaque area and largest vessel area vs. cross sections with the smallest plaque area and smallest vessel area, respectively. No difference in the number of inflammatory cells was observed between cross sections with the largest and smallest lumen area. CONCLUSION: Intraindividually, pathohisto- logic markers previously reported to be related to plaque vulnerability were associated with a larger plaque area and vessel area. In addition, inflammation of the cap and shoulder of the plaque was a common finding in the atherosclerotic femoral artery.

Summary

This study describes an association between outward “positive” remodelling and lesion characteristics associated with unstable clinical presentation. It suggests that outward remodelled but mildly stenotic lesions appear to have a particular tendency to rupture initiating acute coronary events (vulnerable plaques).

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Related References

1. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direc- tion of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultra- sound study. Circulation 2000; 101: 598–603.

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2. Yamagishi M, Terashima M, Awano K, et al. Morphology of vulnerable coronary plaque:

insights from follow-up of patients examined by intravascular ultrasound before an acute coro- nary syndrome. J Am Coll Cardiol 2000; 35: 106–111.

3. Kotani J, Mintz GS, Castagna MT, et al. Intravascular ultrasound analysis of infarct-related and non-infarct-related arteries in patients who presented with an acute myocardial infarction.

Circulation 2003; 107: 2889–2893.

Key message

Both plaque and vessel area were geometrical determinants of the presence of markers related to plaque vulnerability. The type of arterial remodelling may have a dual impact on luminal narrowing. Compensatory enlargement will retard chronic luminal narrowing, but it might enhance the risk of plaque rupture and, hence, acute luminal narrowing or occlusion. Conversely, para- doxical shrinkage will accelerate chronic luminal narrowing, but it might reduce the risk of plaque rupture and, hence, acute luminal narrowing or occlusion. Future studies using intravascular ultrasound (IVUS) are needed to verify the inferred predictive value for unstable angina and acute myocardial infarction or compensatory enlarged lesions.

Why it’s important

Glagov’s observations demonstrate that plaque progression is initially accommodated by an expansion of vessel diameter rather than luminal stenosis (arterial remodelling). Based on the studies correlating remodelling with clinical presentation, it has become obvious that these outward remodelled but mildly stenotic lesions appear to have a particular tendency to rupture initiating acute coronary events (vulnerable plaques). It is an attractive hypothesis that changes of regression are also reflected in plaque size rather than luminal dimension.

Strengths

The careful comparison of lesion geometry with histological lesion characteristics allowed hypothesis about potential interactions between remodelling and plaque vulnerability/stability, which were later confirmed in clinical imaging studies.

Weaknesses

These results from femoral vessels may not apply to coronary vessels in particular in the setting of acute coronary syndromes. Therefore clinical confirmation was needed.

Relevance

This paper and subsequent post-mortem and IVUS studies of coronary arteries have modified the prevailing paradigm about high-risk lesions and focused attention to mildly stenotic but vulnerable plaques and overall plaque burden.

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Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized placebo controlled pilot study

Author

Nissen SE, Tsunoda T, Tuzcu EM, et al.

Reference

JAMA 2003; 290: 2292–2300

Abstract

CONTEXT: Although low levels of high-density lipoprotein cholesterol (HDL-C) increase risk for coronary disease, no data exist regarding potential benefits of administration of HDL-C or an HDL mimetic. ApoA-I Milano is a variant of apolipoprotein A-I identified in individuals in rural Italy who exhibit very low levels of HDL. Infusion of recombinant ApoA-I Milano/phospholipid complexes produces rapid regression of atherosclerosis in animal models. OBJECTIVE: We assessed the effect of intravenous recombinant ApoA-I Milano/phospholipid complexes (ETC-216) on atheroma burden in patients with acute coronary syndromes (ACS). DESIGN: The study was a double blind, randomized, placebo-controlled multicenter pilot study comparing the effects of ETC- 216 or placebo on coronary atheroma burden measured by intravascular ultrasound (IVUS).

SETTING: Ten community and tertiary care hospitals in the United States. PATIENTS: Between November 2001 and March 2003, 123 patients consented, 57 were randomly assigned, and 47 completed the protocol. INTERVENTIONS: In a ratio of 1:2:2, patients received 5 weekly infu- sions of placebo or ETC-216 at 15 mg/kg or 45 mg/kg. Intravascular ultrasound was performed within 2 weeks following ACS and repeated after 5 weekly treatments. MAIN OUTCOME MEA- SURE: The primary efficacy parameter was the change in percent atheroma volume (follow-up minus baseline) in the combined ETC-216 cohort. Prespecified secondary efficacy meas- ures included the change in total atheroma volume and average maximal atheroma thickness.

RESULTS: The mean (SD) percent atheroma volume decreased by1.06% (3.17%) in the combined ETC-216 group (median,0.81%; 95% confidence interval [CI], 0.34% to 1.53%;

p 0.02 compared with baseline). In the placebo group, mean (SD) percent atheroma volume increased by 0.14% (3.09%) (median, 0.03%; p 0.97 compared with baseline). The absolute reduction in atheroma volume in the combined treatment groups was14.1 mm³or a 4.2%

decrease from baseline ( p 0.001). CONCLUSION: A recombinant ApoA-I Milano/phospholipid complex (ETC-216) administered intravenously for 5 doses at weekly intervals produced significant regression of coronary atherosclerosis as measured by IVUS. Although promising, these results require confirmation in larger clinical trials with morbidity and mortality end points.

Summary

This study describes the rapid regression of atherosclerotic plaque burden during treatment with an high-density lipoprotein (HDL) mimetic in patients with acute coronary syndromes.

Citation Count

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(18)

Related References

1. Takagi T, Yoshida K, Akasaka T, Hozumi T, Morioka S, Yoshikawa J. Intravascular ultrasound analysis of reduction in progression of coronary narrowing by treatment with pravastatin. Am J Cardiol 1997; 79: 1673–1676.

2. Matsuzaki M, Hiramori K, Imaizumi T, et al. Intravascular ultrasound evaluation of coronary plaque regression by low density lipoprotein-apheresis in familial hypercholesterolemia: the Low Density Lipoprotein-Apheresis Coronary Morphology and Reserve Trial (LACMART). J Am Coll Cardiol 2002; 40: 220–227.

3. Schartle M, Bocksch W, Koschyk DH, et al. Use of intravascular ultrasound to compare effects of different strategies of lipid-lowering therapy on plaque volume and composition in patients with coronary artery disease. Circulation 2001; 104: 387–392.

4. Serruys PWJC, de Feyter P, Macaya C, et al. Fluvastatin for prevention of cardiac events fol- lowing successful first percutaneous coronary intervention. JAMA 2002; 287: 3215–3222.

5. Schoenhagen P, Tuzcu EM, Stillman AE, et al. Non-invasive assessment of plaque morphol- ogy and remodeling in mildly stenotic coronary segments: comparison of 16-slice computed tomography and intravascular ultrasound. Coron Artery Dis 2003; 14: 459–462.

Key message

This initial trial of an exogenously produced HDL mimetic demonstrated significant evidence of rapid regression of atherosclerosis. The potential utility of the new approach must be fully explored in a larger patient population with longer follow-up, assessing a variety of clinical end points, including morbidity and mortality.

Why it’s important

These results demonstrate for the first time that disease regression in patients presenting with acute coronary syndromes can be induced by aggressive modification of HDL levels.

Strengths

First study showing regression of plaque burden after pharmacological treatment in acute coronary syndromes. The significant change in only 5 weeks is evidence of the highly dynamic nature of coronary artery disease (CAD).

Weaknesses

Eventually, these new imaging endpoints will need to the compared to clinical endpoints of morbidity and mortality.

Relevance

Serial imaging studies will eventually allow to compare plaque burden, plaque characteristics, systemic markers of inflammation, and clinical outcome. These results will be important for disease prevention in primary setting but also for secondary prevention following the interventional treatment of symptomatic patients.

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