Frequency and Evolution of Thin-Capped Fibroatheromas in Left Main Coronary Artery as Assessed by Serial Virtual Histology Intravascular Ultrasound Analysis

Abstract: Background. The objective of the current study was to assess thin-capped fibroatheroma (TCFA) of the left main coronary artery (LMCA) and its changes after statin therapy. Methods. We assessed the frequency and distribution of virtual histology intravascular ultrasound (VH-IVUS) thin-capped fibroatheroma (VH-TCFA) in the LMCA in 500 patients. Serial VH-IVUS examinations were available in 50 patients at 12-month follow-up. Results. The incidence of LM-TCFA was 8.8% (44/500). IVUS LMCA length was longer in patients with VH-TCFA vs without VH-TCFA. Reference external elastic membrane (EEM) area was similar, but reference lumen area and minimal lumen area were smaller in LMCA with VH-TCFA vs without VH-TCFA (P<.001). LMCA with VH-TCFA had a higher plaque burden (P<.001), a larger necrotic core area (P<.001), and more dense calcium (P<.001) at the maximum necrotic core (NC) site vs LMCA without VH-TCFA. In patients with an LMCA length greater than the median, 62% were located in the distal half of the LMCA. After 12 months of statin therapy, only 44.4% (4/9) of VH-TCFA had evolved to a non-VH-TCFA phenotype and 3 new VH-TCFA had appeared. Conclusion. VH-TCFAs are clustered in the distal half of the LMCA with infrequent positive remodeling. It might persist despite the usual dose of statin therapy. Further study should confirm the changes in large vessels like the LMCA. 

J INVASIVE CARDIOL 2014;26(4):175-179

Key words: left main coronary artery disease, vulnerable plaque, virtual histology intravascular ultrasound 

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Occlusion of the left main coronary artery (LMCA) following plaque rupture can be disastrous because it’s the major source of blood supply to the myocardium.^1-10 The importance of intravascular ultrasound (IVUS) examination in assessing LMCA disease has been reported in numerous studies.^4,11-13 These studies showed that LMCA atherosclerosis and its progression are often underestimated by coronary angiography.^3,14

Thin-capped fibroatheroma (TCFA) is the most common type of vulnerable plaque, the precursor of plaque rupture and thrombosis.^15-17 In one study of stable patients, new virtual histology (VH)-TCFAs developed and most existing VH-TCFAs healed during 12-month follow-up;¹⁸ however, this study did not include LMCA lesions. Thus, because the characteristics and natural history of LMCA TCFAs have not been well studied, the objective of the current study was to use VH-IVUS to assess LMCA TCFAs and their changes after statin therapy.

Methods

Study population. We used VH-IVUS to assess mild to moderate LMCA disease (angiographic diameter stenosis, 20%-60%) in 500 consecutive patients and identified 44 patients with VH-TCFA. Serial VH-IVUS examinations were available in 50/500 patients (10%) at 12 months of follow-up. Of the 50 patients, 39 were statin naïve and all were subsequently treated with the usual dose of statins during follow-up: pitavastatin 2 mg (Kowa Pharmaceuticals) in 28 patients who were part of LAMIS (Livalo Acute Myocardial Infarction Study) trial,¹⁹ atorvastatin 10 mg (Pfizer) in 14 patients, and simvastatin 10 mg (Merck) in 8 patients.

We excluded patients with a large LMCA that exceeded the diameter of the IVUS image (10 mm; n = 32), patients with a short LMCA (<3 mm; n = 48), and patients without adequate grayscale or VH-IVUS data (n = 28). The protocol was approved by the Institutional Review Board, and written informed consent was obtained from all patients. 

Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of an antihypertensive drug. Patients with diabetes mellitus had a confirmed diagnosis or were using antidiabetic medications. A lipid disorder was defined as total cholesterol level ≥240 mg/dL, low-density lipoprotein cholesterol ≥100 mg/dL, triglycerides ≥150 mg/dL, or medication use. Current smoking was defined as tobacco use within past 12 months. A family history of coronary artery disease was defined as myocardial infarction of a first-degree relative <60 years of age.

Quantitative coronary angiography analysis. Coronary angiography was performed after 200 µg of intracoronary nitroglycerin. All angiograms were analyzed independently with an automated edge-detection algorithm (AI-1000 Century; GE Medical Systems) using standard protocols. For each LMCA lesion, lesion length, minimal luminal diameter, reference vessel diameter, and percent diameter stenosis were measured using end-diastolic frames.

IVUS imaging and analysis. A commercially available VH-IVUS system (Volcano Therapeutics) and 20 MHz transducers were used for all IVUS examinations. All IVUS studies were performed after intracoronary administration of 200 µg nitroglycerin using an automatic pullback device (R-100; Volcano Therapeutics). The distal end of the LMCA was the first image slice in which the contralateral vessel was no longer seen (ie, the left circumflex [LCX] if the IVUS catheter was positioned in the left anterior descending [LAD] artery). 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. Studies were recorded onto electronic media for off-line analysis. Two experienced analysts (SWK and WSL) reviewed the VH-IVUS pullbacks to assess lesion phenotype and make precise measurements by defining the two standard IVUS regions of interest: the inner border (lumen, excluding IVUS-detectable thrombus) and outer border (EEM). Qualitative analysis was performed according to criteria of the American College of Cardiology clinical expert consensus document on IVUS to include external elastic membrane (EEM), lumen, and plaque and media (EEM minus lumen) areas.²⁰ Volumes were calculated using Simpson’s rule. VH-IVUS analyses were reported in absolute amounts and as percentages (relative amounts) of plaque area. LMCA lesion phenotype was classified as pathologic intimal thickening (PIT), VH-TCFA, thick-capped fibroatheroma (ThCFA), and fibrotic or fibrocalcific plaque as defined before.²¹Positive remodeling was defined as remodeling index (lesion/reference EEM area) greater than 1.05. Subjects were divided into two groups depending on median LMCA length: less than or greater than the median. LMCAs greater than the median were divided into three segments: ostial (3 mm distal to the LMCA ostium), mid-body, and distal bifurcation (3 mm proximal to the polygon of confluence). 

Statistical analysis. Statistical analysis was performed with SAS version 9.2 (SAS Institute, Inc). Continuous variables are presented as mean ± 1 standard deviation and compared using student’s t-test. Chi-Square test was used to assess the categorical variable. A P-value <.05 was considered statistically significant.

Results

Patient characteristics and angiographic findings. Baseline clinical characteristics and procedural details are shown in Table 1. The angiographic length of the LMCA was longer (P<.01); however, the angiographic minimal lumen diameter and reference vessel diameter were smaller in LMCA with VH-TCFA vs LMCA without VH-TCFA (P<.001 and P=.01, respectively). 

IVUS and VH-IVUS findings. The incidence of LMCA VH-TCFAs was 8.8% (44/500). IVUS LMCA length was longer in patients with VH-TCFA vs without VH-TCFA. Reference EEM area was similar, but reference lumen area and minimal lumen area were smaller in LMCA with VH-TCFA vs without VH-TCFA (P<.001). LMCA with VH-TCFA had a greater plaque burden (P<.001), a larger necrotic core area (P<.001), and more dense calcium (P<.001) at the maximum NC site compared to LMCA without VH-TCFA (Table 2). 

Comparing LMCAs that were longer than the median vs LMCAs that were shorter than the median length, longer LMCAs had a larger EEM CSA (P<.001), a smaller minimum lumen area (P=.01), and a larger plaque burden (P=.01); however, plaque composition was similar, as was the frequency of positive remodeling (data not shown). In LMCAs longer than the median in length, 63.6% of VH-TCFAs were located in the mid-body and the rest at the distal bifurcation; however, 62% were located in the distal half of the LMCA (Figure 1). 

Serial IVUS and VH-IVUS LMCA changes. In the 50 patients with serial VH-IVUS examinations at baseline and 12-month follow-up, LDL levels decreased from 121 ± 42 mg/dL to 89 ± 18 mg/dL (P<.001). After 12 months of statin therapy, the lumen area at the maximum NC site decreased (P=.01) while the plaque burden increased (P=.03) (Table 3). 

Of the 9 patients with a VH-TCFA at baseline, 4 evolved to a non-VH-TCFA phenotype during follow-up, while 3 new VH-TCFAs appeared from fibrotic plaque even though LDL levels decreased in all patients (9/9), with 7/9 having an LDL <100 mg/dL. The follow-up level of LDL was <90 mg/dL in 2/3 patients with a newly developed VH-TCFA (Table 4).

Discussion

The main findings of the present study are as follows: (1) VH-TCFAs are present in 9% of LMCAs with mild to moderate disease; (2) when present, VH-TCFAs are located more frequently in the distal half of the LMCA; and (3) VH-TCFAs in the LMCA can persist despite statin therapy and reduction of LDL cholesterol. In patients undergoing primary percutaneous coronary intervention, the culprit lesion is located in the LMCA in 0.8%-7.0%. These patients have high rates of mortality because of frequent cardiogenic shock and malignant tachyarrhythmias.^6-9 When present, ruptured plaques almost exclusively involve the distal part of the LMCA and/or its bifurcation and occur opposite the distal flow divider.^22,23 In the current study, 72.7% of VH-TCFAs occurred opposite the flow divider and in the mid-portion of the LMCA. In addition, only 3 of the 44 VH-TCFAs in this study also showed plaque rupture. 

Three previous studies have used VH-IVUS to assess LMCA disease. Valmigli et al compared the LMCA and its carina to six consecutive non-overlapping 6 mm segments in the LAD or LCX; the NC was minimal in the LMCA, peaked in the first 6-mm long coronary segment in the LAD or LCX, and then decreased more distally.²⁴ In a global VH registry, dense calcium and NC were less in the LMCA compared to the LAD, and the frequency of VH-TCFA was lower in the LMCA than in the LAD (0% vs 16.9%; P<.001).²⁵ Using data from PROSPECT, the LMCA had a smaller percentage of NC and dense calcium than the proximal segments of the other three epicardial arteries and only 1.8% of 496 LMCA segments contained a lesion that was classified as a VH-TCFA compared to 18.9% of the proximal 30-mm long segments of the LAD, LCX, and RCA.²⁶ The frequency of VH-TCFA is higher compared to previous studies; however, the current study was performed in a difference racial population compared to either the global VH registry or PROSPECT.²⁷ In one previous study of non-LMCA lesions, most VH-TCFAs healed during 12-month follow-up. However, proximal VH-TCFAs in larger vessels with more plaque appeared to heal less often,¹⁸ similar to the current study of LMCA lesions that are located in a large proximal artery with a low wall shear stress, which might be one of the factors to cause a different nature of the LMCA.²⁸ There might be cultural differences of LMCA lesions in the Asian population.²⁹ In one serial grayscale IVUS study, LDL values <75 mg/dL were not associated with plaque progression.³⁰ This is in distinct contrast to the current study. However, the frequency of LMCA-TCFA was infrequent and sample size was relatively small for the conclusion. 

Study limitations. First, this study was a small observational registry. Second, most of the patients had mild to moderate LMCA disease. The inclusion of severe LMCA stenosis was limited because the IVUS catheter could not cross the severe stenotic lesion of the LMCA, and IVUS follow-up was impossible after stent implantation. Third, large diameter or very short LMCAs were excluded because of the difficulty in taking IVUS measurements. Fourth, we did not analyze or compare the LMCA to non-LMCA locations. Fifth, an LDL level <70 mg/dL was achieved in only 9/50 patients (18%) in the current study. We still do not know the adequate doses of statin in this study population. Finally, although the pathophysiologic mechanism of TCFA is similar, there might be racial differences contributing to the primary finding. 

Conclusion

VH-TCFAs are clustered in the distal half of the LMCA with infrequent positive remodeling. It might persist through the usual dose of statin therapy and reduction of LDL cholesterol. Further studies should identify the additional factors causing persistent TCFA in the LMCA. 

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