Impact of Remodeling on Cardiac Events in Patients with
Angiographically Mild Left Main Coronary Artery Disease

Arterial remodeling is the geometric alteration of the arterial wall in response to atherogenesis. During the development and progression of atherosclerosis, the external elastic membrane cross-sectional area (EEM CSA) may increase (termed “positive,” “outward” or “expansive” remodeling) to accommodate an increasing plaque burden, especially during early stages of plaque accumulation.¹ Conversely, the EEM CSA may decrease (termed “negative,” “inward” or “constrictive” remodeling) to contribute to the development of significant stenoses.^2–4 Studies correlating intravascular ultrasound (IVUS) and clinical findings have suggested that positive remodeling (PR) in culprit lesions is more associated with acute coronary syndromes and events post intervention, while negative remodeling (NR) tends to be biologically inert or associated with stable symptoms.^5–7
Left main coronary artery (LMCA) atherosclerosis is a high-risk disease, but its occurrence is often underestimated by coronary angiography.^8–10 IVUS permits detailed, highquality, cross-sectional imaging of the coronary arteries and is an accurate method to determine vessel dimensions, wall characteristics and arterial remodeling. Numerous studies have shown that IVUS is helpful in assessing angiographically ambiguous LMCA disease.^11–14 In general, these studies have identified LMCA lumen dimensions as the strongest predictors of clinical events during the subsequent 12 months.^12–14
It was our hypothesis that LMCA lesion remodeling would also be an important predictor of clinical events in these patients because of the relationship between PR and clinical events in non-LMCA lesions. Therefore, the purpose of this study was to evaluate the impact of coronary arterial remodeling on cardiac events in patients with angiographically mild LMCA disease.

Methods
Study population. From December 19, 2002 to January 1, 2005, a total of 236 patients with a mild LMCA stenosis on coronary angiography underwent IVUS imaging. These patients had ischemic symptoms before diagnostic coronary angiography and were referred because the angiographic assessment of LMCA lesion severity was inconclusive. All met the following criteria: (1) an analyzable length of LMCA ≥ 4 mm; (2) no evidence of critical LMCA disease (angiographic lumen diameter stenosis < 50% by “worst-view” visual assessment); and (3) lack of calcifications that would limit quantitative assessment of EEM CSA.
The study involved 125 males and 111 females with a mean patient age of 62 ± 11 years. Hospital records of all the patients were reviewed to obtain information on clinical demographics and medical history. Follow-up information was obtained through review of hospital charts and telephone interviews, as part of the interventional database of the Washington Hospital Center.Patients were included only if follow-up information was available for at least 1 year after the date of IVUS examination. Major adverse cardiac events (MACE) included cardiac death, target lesion revascularization or myocardial infarction. All deaths were considered to be of cardiac origin unless a noncardiac origin was established clinically or at autopsy. Target lesion revascularization was defined as any intervention (surgical or percutaneous) to treat a stenosis within the LMCA or within 5 mm distal to the ostia of the left anterior descending and left circumflex artery. Target lesion revascularization was further characterized as “ischemia-driven” if signs or symptoms of ischemia were present. A myocardial infarction was defined as ischemic symptoms associated with cardiac enzyme elevation ≥ 3 times the upper limit of the normal value. These definitions have been used and reported previously.^15–17
At the time of IVUS imaging, a total of 206 patients underwent intervention of a non-LMCA epicardial artery lesion; 150 had one-vessel intervention, 45 had two-vessel intervention, and 11 had three-vessel intervention with no difference between patients who subsequently had LMCA-related events versus patients who did not have LMCA events (p = 0.414). The non-LMCA culprit artery was the left anterior descending artery in 128 patients, the left circumflex artery in 48 patients and the right coronary artery in 50 patients.
Quantitative coronary angiography (QCA) analysis. Quantitative analysis (CAAS II, Pie Medical, The Netherlands) was performed using standard protocols.¹⁸ With the outer diameter of the contrast-filled catheter as the calibration standard, the minimal lumen diameter, reference diameter and lesion length were measured in diastolic frames from orthogonal projections. Target lesion location was designated as ostial, proximal, middle or distal. Ostial lesions were those lesions that began within 3 mm of the LMCA ostium.
IVUS imaging protocol. All IVUS examinations were performed before any intervention after intracoronary administration of 200 μg nitroglycerin using a commercially available IVUS system (Boston Scientific Corp., Natick, Massachusetts). The IVUS catheter was advanced distal to the target lesion, and imaging was performed using retrograde pullback to the aorto-ostial junction at an automatic pullback speed of 0.5 mm/second. The guiding catheter was typically disengaged to allow visualization of the proximal LMCA. The distal end of the LMCA was the first image slice in which the contralateral vessel (i.e., the left circumflex, if the IVUS catheter was positioned in the left anterior descending artery) was no longer seen. The proximal end of the LMCA was the last image slice in which the entire circumference of the LMCA was seen just before entering the aorta.
IVUS analysis. Qualitative analysis was performed according to criteria of the American College of Cardiology clinical expert consensus document on IVUS.¹⁹ Using planimetry software (TapeMeasure, INDEC Systems Inc., Capitola, California), we measured EEM and lumen CSA. Plaque plus media (P&M) CSA was calculated as EEM CSA minus lumen CSA, and plaque burden was calculated as P&M CSA divided by EEM CSA. The EEM CSA was measured by tracing the leading edge of the adventitia; this has been shown to be a reproducible measure of total arterial CSA. P&M CSA was used as a measure of atherosclerotic plaque. The lesion was the site with the smallest lumen CSA; if there were multiple image slices with the same minimum lumen CSA, then the slice with the largest EEM and P&M was measured.
Calcium was brighter than the adventitia with acoustic shadowing; the arc of calcium within the LMCA was measured with a protractor centered on the lumen. Soft plaque was defined as the plaque less bright compared with the reference adventitia. Fibrotic plaque was defined as the plaque that was as bright as or brighter than the reference adventitia without acoustic shadowing. Calcific plaque was defined as a lesion containing > 90^° of calcium (bright echoes within the plaque along with acoustic shadowing). When there was no dominant plaque composition, the plaque was considered mixed.
Arterial remodeling was assessed by comparing the lesion site EEM to the proximal and distal reference EEM CSA. Remodeling index (RI) was defined as the lesion EEM CSA divided by the average of the proximal and distal reference EEM CSA. PR was defined as a RI > 1.05, intermediate remodeling (IR) as a RI between 0.95 and 1.05, and NR as a RI < 0.95.²⁰
Statistical analysis. Statistical analysis was performed using SAS, version 9.1 (SAS Institute, Cary, North Carolina). Continuous variables were presented as the mean value ± 1SD; comparisons were conducted by the Student’s t-test or the nonparametric Wilcoxon test if the normality assumption was violated. Discrete variables are presented as percentages and relative frequencies; comparisons were conducted by the chi-square test or Fisher’s exact test as appropriate. Logistic regression analysis was used to identify the independent predictors of MACE. Survival curves were constructed by the Kaplan-Meier method. A p-value < 0.05 was considered statistically significant.

Results

Baseline characteristics. NR was observed in 156 patients (66%), and IR/PR was observed in 80 patients (34%) with mild LMCA disease. There was female predominance in the NR group. Other baseline parameters were almost the same between the NR and IR/PR groups (Table 1).
Coronary angiographic findings. The minimal lumen diameter was 3.10 ± 0.63 mm, and the diameter stenosis was 21 ± 12%. LMCA lesion location was more proximal and the diameter stenosis was smaller in the NR group. The minimal lumen diameter and lesion length did not differ between the NR and IR/PR groups (Table 2).
IVUS findings. Lesion length and minimum lumen CSA were similar between the two groups; however, the EEM CSA, P&M CSA and plaque burden were significantly smaller in the NR group. Soft plaque was more frequently observed in the IR/PR group (Table 3).

MACE. Follow-up clinical data were available in all patients; the mean follow-up time was 12.8 months. At 1-year follow up, LMCA-relate d MACE occurred in 15 patients (6.4%). There were 3 cardiac deaths (at 38, 92 and 229 days after their IVUS study); 2 patients underwent stenting of the LMCA (at 129 and 172 days after IVUS study); 7 patients underwent bypass surgery (at 124, 193, 223, 230, 259, 260 and 358 days after their IVUS study); and 3 patients had a myocardial infarction (at 33, 134 and 150 days after their IVUS study). Three patients had sudden cardiac death. Follow-up angiography was performed in 139 patients. By follow-up angiography, LMCA disease was aggravated in the body of the LMCA in 2 patients, and in the distal LMCA bifurcation in 10 patients. Two patients underwent stenting of the LMCA because their LMCA disease was aggravated in the body of the LMCA at follow up. Seven patients underwent bypass surgery because their LMCA disease was aggravated in the distal LMCA bifurcation accompanied by aggravation of lesions in the ostial left anterior descending artery and ostial left circumflex artery. Three patients had myocardial infarction during follow up due to aggravation of 2 left anterior descending artery lesions and 1 left circumflex artery lesion accompanied by aggravation of LMCA disease in the distal LMCA bifurcation. NR was less frequently associated with LMCA-related cardiac events than IR/PR [6/156 (3.8%) vs. 9/80 (11.3%); p = 0.027] (Table 4, Figure 1).

At 1-year follow up, 30 non-LMCA-related events occurred (9 myocardial infarctions and 21 percutaneous coronary interventions in other vessels). In the NR group, 13 patients underwent stenting for other vessels (6 left anterior descending artery, 4 left circumflex artery and 3 right coronary artery); and 8 patients (10.0%) in the IR/PR group underwent stenting for other vessels (5 left anterior descending artery and 3 left circumflex artery; p = 0.670). Five patients had myocardial infarctions in the NR group, and 4 patients had myocardial infarctions in the IR/PR group (p = 0.496).
Clinical, angiographic and IVUS findings according to presence or absence of LMCA-related events. Angiographic minimal lumen diameter was smaller and lesion length was longer in the LMCA-related cardiac event group (Table 5).

Lesion site lumen CSA and lesion site IVUS minimal lumen diameter were significantly smaller, and RI was significantly greater in the LMCA-related cardiac event group. Soft plaque was more frequently observed and NR was less frequently observed in the LMCA-related cardiac event group (Table 6).
Independent predictors of LMCA related MACE. Variables tested included diabetes mellitus, angiographic reference diameter, minimal lumen diameter and lesion length, IVUS reference EEM CSA and lumen CSA, and IVUS lesion site EEM CSA, minimum lumen area, minimal lumen diameter, plaque burden, the presence of soft plaque and remodeling pattern. Univariate predictors of LMC Arelated MACE were non-negative remodeling, diabetes mellitus and soft plaque morphology. In the multivariate analysis, only non-NR was found to be the independent predictor of LMCA-related MACE (hazard ratio 4.095; 95% CI, 1.275–13.149; p = 0.018) (Table 7).

Discussion

The findings in the current study of angiographically mild LMCA disease showed that the LMCA lesion was associated with NR in two-thirds of the patients. One-year LMCArelated cardiac events (cardiac death, myocardial infarction or need for LMCA revascularization) occurred in 6.4% of these patients, but NR was less frequently associated with LMCArelated cardiac events than was IR/PR (3.8% vs. 11.3%). The only independent predictor of LMCA-related cardiac events in this population was non-NR as assessed by IVUS.
LMCA remodeling can vary from negative to positive and may affect the whole LMCA, even in the early stages of atherosclerosis.^1,21 In mild coronary stenosis, Rodes-Cabau et al reported that the RI of the lesions studied was 0.90 ± 0.14, and NR, IR and PR were observed in 62%, 13% and 25% of cases, respectively.²² In the study by Abizaid et al,¹² the mean RI was 0.94 in patients with mild LMCA disease. In the present study, the RI was 0.90 ± 0.11 in patients with mild LMCA disease. The present study demonstrated that in patients who have mild LMCA disease, IR/PR is present in only 34% of lesions, with NR being present in most lesions. These data also agree with some previous reports, suggesting that in the presence of stable mild atherosclerotic disease, there is not only a lack of compensatory enlargement of the EEM during plaque development, but also a predominant constriction response at sites of maximal stenosis.^20,23,24
PR has been shown to be a predictor of recurrent ischemia within 1 month after thrombolysis for acute myocardial infarction,⁵ inhospital complications and MACE in patients with stable angina undergoing single-vessel intervention,⁶ MACE in patients with unstable angina undergoing revascularization,⁷ target vessel revascularization in patients undergoing bare-metal stent implantation²⁵ and intimal hyperplasia in patients undergoing drug-eluting stent implantation.²⁶ The current study expands our knowledge to non-lumen compromising, non-culprit LMCA lesions to show that the remodeling pattern may also influence subsequent clinical events.
Abizaid et al¹² reported that the presence of diabetes mellitus, the presence of an untreated vessel and IVUS minimal lumen diameter were independent predictors of cardiac events at follow up in patients with noncritical LMCA lesions. Fassa et al¹³ suggest ed that pat ients with an LMCA minimum lumen area < 7.5 mm² undergo revascularization, while those with a minimum lumen area ≥ 7.5 mm² be treated medically; age, smoking status and the number of diseased non-LMCA vessels were predictors of MACE. Jasti et al¹⁴ reported that an IVUS minimum lumen diameter of 2.8 mm or minimum lumen area of 5.9 mm² strongly predicted physiological significance (measured using fractional flow reserve) in patients with an ambiguous LMCA lesion. In the present study, the only independent predictor of cardiac events in patients with mi ld LMCA dise ase — disease that would not be treated using any of these various study criteria — was non-NR pattern by IVUS; IVUS lumen dimensions were not predictors of events. The reason for the discrepancy between the current study and previous studies is unclear, but is probably related to the differences in LMCA EEM and lumen dimensions. Of note: (1) most of the patients in the current studies had lumen dimensions that were larger than the threshold for predicting events in the previous studies; and (2) these published studies did not test remodeling as a predictor of events. Specifically, in the present study, only 20 pati ents had a minimum lumen area < 7.5 mm² (the criterion suggested by Fassa et al¹³), and only 6 patients had a minimum lumen area < 5.9 mm² (the criterion suggested by Jasti et al¹⁴). The current study, therefore, suggests that remodeling should be factored into clinical decision making, especially when lumen dimensions are borderline or larger than the threshold for revascularization. While we only tested this concept in LMCA lesions, it may also extend to non-LMCA lesions.
In the current study, diabetes mellitus trended toward a predictor of events. Similarly, in the study by Abizaid et al,¹² 25% of the diabetic patients versus 11% of the nondiabetics had an event, and for every given LMCA lumen diameter, diabetic patients had more events — and had a higher lumen diameter threshold for events — than patients without diabetes.
Study limitations. There are several limitations to be mentioned. Firstly, this analysis is retrospective and is therefore subject to all the limitations inherent in this type of clinical investigation. The results of this study should be verified by further prospective investigation. Secondly, IVUS imaging and clinical decisions were made at the discretion of the individual operators, potentially introducing bias. Thirdly, this study only included patients with mild lumen compromise by IVUS. At our institution, IVUS is routinely used to assess ambiguous LMCA lesions, and those with significant lumen compromise (lumen CSA < 6.0 mm²) are routinely treated. Finally, the marginal significance of diabetes mellitus is likely due to the limited number of LMCA-related events and short follow-up period. In patients with modest degrees of LMCA disease, studies of larger populations for long-term follow-up periods are probably needed.

Conclusions
Most mild LMCA lesions had NR characteristics. However, among LMCA lesions with adequate lumen dimensions, non-NR patterns had an important impact on clinical outcomes in patients with mild LMCA disease.

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