EDITORIAL COMMENT
Diabetic Coronary Artery DiseaseHow Little We Know and How Little Intravascular Ultrasound Has Taught Us*
Gary S. Mintz, MD, FACC*
Cardiovascular Research Foundation, New York, New York.
* Reprint requests and correspondence: Dr. Gary S. Mintz, 611 Pennsylvania Avenue SE, #386, Washington, DC 20003. (Email: gsm18439{at}aol.com).
Key Words: intravascular ultrasound • diabetes mellitus • atherosclerosis
Coronary arteries in diabetic patients are typically described as small, diffusely atherosclerotic with more distal involvement and more prone to acute coronary events. What does the intravascular ultrasound (IVUS) study by Nicholls et al. (1) in this issue of the Journal add to our understanding of these issues?
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Coronary Arteries in Diabetic Patients Are Described as Small
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Nicholls et al. (1) reported that IVUS lumen volumes were smaller in diabetic patients compared with those in nondiabetic patients. While it may be assumed that the corresponding angiograms would also show small lumen dimensions, IVUS versus angiographic lumen diameter comparisons consistently show poor correlations.
There are at least 3 potential mechanisms for angiographically small coronary arteries: 1) anatomically small arteries that are nondominant, distal in location, supply limited amounts of myocardium, or occur in women; 2) arteries that have a large atherosclerotic burden; and 3) arteries with negative remodeling or impaired adaptive remodeling.
The authors showed that diabetic patients had more atherosclerosis whether assessed by the absolute volume of atherosclerotic plaque or the percent of external elastic membrane (EEM) occupied by plaque (percent atheroma volume calculated as [EEM – lumen]/EEM). However, the authors also presented inferential data that remodeling was different in diabetic patients compared with that in nondiabetic subjects.
What is remodeling? Remodeling is the change in arterial (or EEM) dimensions, typically in response to atherosclerotic plaque accumulation (2). It has been exhaustively studied using pathology and IVUS; however, the literature continues to be confusing because of the many definitions and methodologies used.
First, remodeling can be defined by comparing the lesion EEM to the reference (3–5): positive remodeling is a lesion EEM greater than the reference, intermediate remodeling is a lesion EEM roughly equivalent to the reference, and negative remodeling is a lesion EEM smaller than the reference. Although this is the most commonly used approach, there are limitations including reference site selection, the fact that reference segments have also undergone remodeling, the impact of branch points, vessel tapering, and (as in the current study) the lack of well-defined lesions or lesions with modest plaque burden (2).
Second, remodeling can be defined in terms of dynamic changes in arterial dimensions. An increase in EEM would indicate positive remodeling with an increase in EEM exactly matching the increase in plaque indicating "perfect" positive remodeling, an increase in EEM greater than the increase in plaque indicating excessive positive remodeling, and an increase in EEM less than the increase in plaque indicating inadequate positive remodeling. No change in EEM would indicate an absence of remodeling. A decrease in EEM would indicate negative remodeling. Considering that the authors had serial IVUS data available for analysis, this would seem to be the ideal approach. However, previous serial IVUS studies have shown that baseline remodeling (comparing the lesion EEM to the reference) does not necessarily predict serial IVUS findings (6,7). In the current study, both diabetic subjects and nondiabetic subjects had identical decreases in EEM volume suggesting negative remodeling in both groups. Decreases in EEM volumes can be "primary" or can occur secondary to decreases in plaque as was the case in both diabetic and nondiabetic groups. While arterial responses to plaque increase have been extensively studied, arterial responses to plaque decrease are not well known (8).
Third, remodeling can be inferred from "expected" baseline or serial IVUS measurements. The argument goes something like this. If EEM volumes are similar when comparing 2 groups, then the group with more plaque had less adaptive positive remodeling because more plaque should have been associated with a larger EEM. Thus, because diabetic subjects had a greater plaque volume at baseline, a smaller decrease in plaque volume at follow-up, and similar baseline and serial measurements of EEM volume compared with nondiabetic subjects, Nicholls et al. (1) concluded that compensatory positive remodeling was impaired (or negative remodeling was present) in diabetic subjects.
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Coronary Arteries in Diabetic Patients Are Described as Diffusely Atherosclerotic With More Distal Involvement
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The authors did not report the location of the analyzed segments; it would have been useful to have compared distal segments in diabetic subjects versus nondiabetic subjects. However, the authors did state: "Diabetic subjects did not demonstrate more diffuse disease, as evidenced by a similar percentage of images containing plaque . . . as observed in nondiabetic subjects" (1). It is hard to interpret this finding without knowing whether a similar percentage of images were excluded in diabetic subjects compared with nondiabetic subjects for reasons such as calcification, side branch involvement, and imaging artifacts.
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Coronary Arteries in Diabetic Patients Are More Prone to Acute Coronary Events
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The current study implies that atherosclerosis progression is one explanation for more events in diabetic subjects compared with nondiabetic subjects. Proponents of the use of IVUS measures of progression/regression as surrogate end points have assumed that greater plaque progression must be associated with more events. However, this may not be correct.
First, serial IVUS studies have shown only minimal changes in overall plaque volume or plaque burden. In the current analysis, the change in absolute or percent atheroma volume averaged only 1% to 2%. Similarly, the threshold for substantial progression or regression was only a 5% relative increase or decrease in percent atheroma volume (1).
Second, there may be significant heterogeneity among patients and arterial segments. In the current study, 50% of all patients were substantial progressors while 35% were substantial regressors.
Third, the arterial segment analyzed may not be representative of segments containing lesions that cause events. Most acute events are caused by minimally stenotic lesions that progress rapidly, but comparing 2 or more lesions, lesions with the greatest lumen compromise most likely cause events (9–11). As stated by Kern and Meier (11), "Because the aggregate risk of rupture associated with many nonsignificant lesions (each with an admittedly lower individual potential) exceeds that of the fewer significant lesions, a myocardial infarction will more likely originate from a nonsignificant lesion." At the other end of the spectrum, pathologic studies have shown relatively few thin-capped fibroatheromas (TCFAs), vulnerable plaques most likely to cause events (12,13), making it unlikely that a "blindly" selected >30-mm long coronary arterial segment would contain even 1 vulnerable plaque. The TCFAs accounted for only 1.6% of the length of the coronary tree in patients dying of cardiovascular causes (13).
Fourth, pathologic studies have shown that necrotic core size and fibrotic cap thickness and macrophage infiltration are among the factors that contribute to lesion stability/instability (12,14). Quantitative changes in atherosclerotic plaque mass may not reflect changes in plaque stability or composition—even if the analyzed segment fortuitously contains a TCFA. In addition, one consistent predictor of lesion instability is positive remodeling (5); yet in the current analysis, diabetic subjects had less positive remodeling.
Fifth, some antiatherosclerotic drugs can have paradoxic, adverse clinical effects and cause an increase in events. Therefore, recent studies such as the ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by Cholesteryl Ester Transfer Protein Inhibition and High-Density Lipoprotein Elevation) trial and the ILLUMINATE (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) trial suggest that clinical trials may be inevitable and not obviated by surrogate end point studies (15,16).
Finally, the primary end point used in most grayscale IVUS end point trials—the absolute change in percent atheroma volume—may be too sensitive. Percent atheroma volume can be as affected by remodeling as by progression and regression. Negative remodeling alone can increase percent atheroma volume whereas positive remodeling alone can decrease percent atheroma volume. In the current study, percent atheroma volume increased whereas absolute atheroma volume decreased in both diabetic subjects and nondiabetic subjects.
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How Little We Still Know
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Nicholls et al. (1) are to be congratulated for having published the largest, most completely analyzed study of diabetic subjects with coronary artery disease—2,237 patients studied using serial volumetric IVUS. The amount of work involved is staggering. Nevertheless, in comparison with the profound clinical differences between diabetic patients and nondiabetic subjects (and among subpopulations of diabetic patients), the IVUS findings in the current study are modest, somewhat internally inconsistent, and partially at odds with pathologic data (17). Thus, if anything, the analysis by Nicholls et al. (1) highlights the limitations of grayscale IVUS. Perhaps, after almost 2 decades of work and thousands of publications, the revelations of IVUS have reached a plateau.
Just as IVUS was a step beyond angiography, it is now fashionable to point to new imaging modalities such as virtual histology or integrated backscatter IVUS, palpography, optical imaging, spectroscopy, and so on as technologies that are a step beyond IVUS. Although in their relative infancy, these techniques have the potential to assess changes in plaque composition and stability rather than just overall changes in atherosclerosis volume. It is the instability of the disease, not just the increase in plaque mass, that is different in high-risk patient subsets. However, these new techniques will yield significant information only with careful patient and coronary artery segment selection, the proper analysis, and correlation with clinical events.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Nicholls SJ, Tuzcu EM, Kalidindi S, et al. Effect of diabetes on progression of coronary atherosclerosis and arterial remodeling. a pooled analysis of 5 intravascular ultrasound trials. J Am Coll Cardiol 2008;52:255-262.[Abstract/Free Full Text]2. Schoenhagen P, Ziada KM, Vince DG, Nissen SE, Tuzcu EM. Arterial remodeling and coronary artery disease: the concept of "dilated" versus "obstructive" coronary atherosclerosis J Am Coll Cardiol 2001;38:297-306.[Abstract/Free Full Text] 3. Nishioka T, Luo H, Eigler NL, Berglund H, Kim CJ, Siegel RJ. Contribution of inadequate compensatory enlargement to development of human coronary artery stenosis: an in vivo intravascular ultrasound study J Am Coll Cardiol 1996;27:1571-1576.[Abstract] 4. Mintz GS, Kent KM, Pichard AD, Satler LF, Popma JJ, Leon MB. Contribution of inadequate arterial remodeling to the development of focal coronary artery stenoses. An intravascular ultrasound study. Circulation 1997;95:1791-1798.[Abstract/Free Full Text] 5. Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM. Extent and direction of arterial remodeling in stable versus unstable coronary syndromes: an intravascular ultrasound study Circulation 2000;101:598-603.[Abstract/Free Full Text] 6. von Birgelen C, Hartmann M, Mintz GS, et al. Remodeling index compared to actual vascular remodeling in atherosclerotic left main coronary arteries as assessed with long-term (> or =12 months) serial intravascular ultrasound J Am Coll Cardiol 2006;47:1363-1368.[Abstract/Free Full Text] 7. Von Birgelen C, Hartmann M, Mintz GS, et al. Spectrum of remodeling behavior observed with serial long-term ( 12 months) follow-up intravascular ultrasound studies in left main coronary arteries Am J Cardiol 2004;93:1107-1113.[CrossRef][Web of Science][Medline] 8. Schoenhagen P, Tuzcu EM, Apperson-Hansen C, et al. Determinants of arterial wall remodeling during lipid-lowering therapy: serial intravascular ultrasound observations from the Reversal of Atherosclerosis with Aggressive Lipid Lowering Therapy (REVERSAL) trial Circulation 2006;113:2826-2834.[Abstract/Free Full Text] 9. Ellis S, Alderman E, Cain K, Fisher L, Sanders W, Bourassa M. Prediction of risk of anterior myocardial infarction by lesion severity and measurement method of stenoses in the left anterior descending coronary distribution: a CASS registry study J Am Coll Cardiol 1988;11:908-916.[Abstract] 10. Abizaid AS, Mintz GS, Mehran R, et al. Long-term follow-up after percutaneous transluminal coronary angioplasty was not performed based on intravascular ultrasound findings: importance of lumen dimensions Circulation 1999;100:256-261.[Abstract/Free Full Text] 11. Kern MJ, Meier B. Evaluation of the culprit plaque and the physiological significance of coronary atherosclerotic narrowings Circulation 2001;103:3142-3149.[Free Full Text] 12. Burke AP, Virmani R, Galis Z, Haudenschild CC, Muller JE. Task force #2—what is the pathologic basis for new atherosclerosis imaging techniques? J Am Coll Cardiol 2003;41:1874-1886.[Free Full Text] 13. Cheruvu PK, Finn AV, Gardner C, et al. Frequency and distribution of fibroatheroma and ruptured plaque in human coronary arteries: a pathologic study J Am Coll Cardiol 2007;50:940-949.[Abstract/Free Full Text] 14. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque J Am Coll Cardiol 2006;47(Suppl):C13-C18.[Abstract/Free Full Text] 15. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis N Engl J Med 2007;356:1304-1316.[Abstract/Free Full Text] 16. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events N Engl J Med 2007;357:2109-2122.[Abstract/Free Full Text] 17. Virmani R, Burke AP, Kolodgie F. Morphological characteristics of coronary atherosclerosis in diabetes mellitus Can J Cardiol 2006;22:81B-84B.[Web of Science][Medline]
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