Detection and Treatment of Vulnerable Patients

Current Intravascular Imaging for Detecting Vulnerable Plaque: IVUS and OCT

Hiroyuki Okura

Kawasaki Medical School, Kawasaki, Japan

Limitations with current imaging modalities have opened a search for newer, more accurate technologies and techniques. Coronary angiographic severity is unable to predict future acute myocardial infarction (AMI), with 70% of culprit lesions being identified as only a mild stenosis on the study prior to AMI. On IVUS, 50% of patients with unstable angina (UA) have positive remodeling (PR) and 50% have negative remodeling. Optical coherence tomography (OCT) is one modality studied by Okura and colleagues at Kawasaki Medical School.

In a study of 132 patients, Okura and colleagues identified the worst outcomes (death. MI, target lesion revascularization (TLR) and non-TLR survival) in the patients with both PR and plaque rupture of the culprit lesion—indicating vulnerable patients.

Multiple plaque rupture occurs in both acute coronary syndromes (ACS) and peripheral arterial disease. According to several single center observations, this occurs in 13-79% (30% overall ) of ACS patients. Okura et al showed in 120 patients in a multicenter 3-vessel ultrasound study, plaque rupture occurs in 47% of culprit lesions and 17% of nonculprit lesions.

Thin-cap fibroatheroma (TCFA) are characterized by a large lipid (necrotic core), thin fibrous cap (< 65 µm), inflammatory cell infiltration, and positive remodeling. Although IVUS studies have allowed characterization of the vulnerable plaque and plaque rupture, the key to improved outcomes is identifying the “unruptured” vulnerable plaque.

Virtual histology IVUS, using radiofrequency, has been used to overcome the limitations of gray-scale IVUS. More recently, OCT, with resolution nearly 10-fold greater than high-resolution IVUS, is being used. OCT can clearly differentiate the fibrous, calcified, and lipid aspects of the plaque component, e.g., the echolucent, diffuse border lipid segment, as validated by pathological examination.

Importantly, accurate measurement of the thin fibrous cap is possible with OCT, and was validated by Kume and Okura by comparison with pathological examination (Am Heart J 2006;152:755.el-755.el), particularly the very thin cap.

Okura et al performed a pathological study to determine the incidence and distribution of TCFA. A total of 38 autopsy cases (mean age 74, 24 men/14 women) were examined.

Of the 77 fibroatheroma, 30 were TCFA-positive (< 65 µm) and 47 were TCFA-negative. A representative histological image shows the large necrotic core with an overlying very thin fibrous cap and the OCT image also identifies the necrotic core, with a high sensitivity (90%) and specificity (84%). In this study population, 32% had multiple TCFA (19% had 2 and 13% had 3), while 50% had no TCFA and 19% had 1 TCFA. The majority of the TCFA were found within 30 mm of the coronary ostium.

Based on these study results, Okura et al are applying OCT in patients to diagnose TCFA. In one patient, at the 6 month follow-up, they found severe narrowing at the site of TCFA as identified OCT, showing its utility.

Impact of Multislice Computed Tomography on Diagnosing Vulnerable Plaques and Vulnerable Patients 

Nobusada Funabashi

Chiba University Graduate School of Medicine, Chiba, Japan

Multislice computed tomography (MSCT) is able to detect non-calcified plaques (NCP) in coronary arteries. Funabashi and colleagues pursued studies to further classify NCP, because they speculate that some NCPs may be similar to vulnerable plaques and thereby contribute to the incidence of acute coronary syndromes ACS), yet other NCPs may be early-stage soft plaques or intimal thickenings that are not vulnerable. Further, the thickness of the fibrous cap, which indicates the degree of vulnerability of coronary plaques, cannot be evaluated by MSCT.    

Significance of focal coronary calcification adjoining non-calcified plaques

MSCT was used to evaluate NCP characteristics, including adjoining focal calcified plaques (FCP), and to determine their link with cardiac risk factors (CRFs).

ECG-gated enhanced 16-slice MSCT was performed in 422 consecutive subjects (244 males, 17-91 years old, median age 67 years) and then categorized by presence or absence of NCP into four groups: 

• Group1: with mixed NCP with adjoined FCP
• Group2: with exclusive NCP, without mixed NCP
• Group3: with only calcified plaque (CP), without any NCP
• Group4: neither NCP nor CP

Group 1, compared to Group 4, had a higher incidence of hypertension (66% vs 36%), diabetes (32% vs 10%), and hyperlipidemia (56% vs 24%). The incidence of smoking was highest in Group 1 (66%) and was 53%, 41% and 27% in Groups 2, 3, and 4, respectively. OMI incidence was also highest in Group 1 (29%) and was 15%, 16%, and 1% in Groups 2, 3, and 4, respectively. No difference in the incidence in obesity (range 29%-39%) was seen.

A comparison of the two groups with NCP (Group 1 and 2) showed that the patients in Group 1 were older, more were men, and more had risk factors. Further, Group 1 had a higher incidence of hyperlipidemia (56% vs 38% Group 2) and smoking (66% vs 53% Group 2).

Age, male sex, hypertension, diabetes, and hyperlipidemia were associated with an increased incidence of calcified plaques of the coronary arteries on logistic regression analysis, controlled for presence of mixed NCP .

Based on these results, the presence of NCP can be classified as either mixed NCP with adjoining FCP or exclusive NCP. Further, persons with mixed NCP have more risk factors, and mixed NCP with adjoined FCP may indicate advanced arteriosclerosis.

In another study by this group, emergent 64-slice-CT acquisition before coronary angiography in 11 stable subjects (angina, atypical ECG finding) was shown to accurately image occluded coronary arteries in AMI.  Also, characteristics of low-CT-areas in the coronary arteries in AMI may be obtained, which may help to differentiate thrombi due to plaque rupture from stable NCP and predict plaque rupture.

Study of atorvastatin on NCP using MSCT

Node and colleagues assessed the effect of atorvastatin on NCP in the coronary arteries using MSCT, and compared these finding to the effect on LDL-cholesterol (LDL-C) levels.  A total of 21 asymptomatic persons (16 men, 35-79 years, average age 65 years) with NCP by MSCT were enrolled. After measuring LDL-C, atorvastatin 10 mg was given for 1 year, and then MSCT and LDL-C measurements were repeated. One remarkable NCP was selected in each subject and evaluated as the optimal representative effect of atorvastatin. The area and CT values of NCP, excluding calcified portions, were manually measured.

A high incidence of CRFs was found: hypertension in 71%, hyperlipidemia in 81%, and smoking history in 71%.

A significant decrease in mean LDL-C was seen at 1 year (to 96 mg/ml from 122 mg/dl at baseline). No significant difference in the mean area of the NCP was found (11.8 mm² at baseline, 12.6 mm² at 1 year). The averages of mean CT values were 55 HU at baseline and 62 HU at 1 year. After 1 year of atorvastatin treatment, significantly higher mean CT values of NCPs were found. The standard deviation of the CT values of NCP were significantly higher after 1 year of atorvastatin treatment (P<0.01).

A significant positive correlation between LDL levels and the annual change in NCP area after 1 year of atorvastatin treatment (P<0.05) was found.

Dr. Funabashi concluded that atorvastatin may decrease the area of NCP if LDL-C levels are sufficiently decreased. Also, atorvastatin may  increase CT values, which could suggest a change in NCP components. LDL-C levels may be an important factor in decreasing the area of NCP. These results indicate that MSCT may evaluate changes in NCP and vulnerabilities of NCP in coronary arteries.

Management of Vulnerable Plaque and Vulnerable Patients 

Koichi Node

Saga University Faculty of Medicine, Saga, Japan

Pentraxin 3 (PTX3) of the pentraxin superfamily, a biomarker more specific to vascular inflammation than C-reactive protein (CRP) is the focus of studies by Node and colleagues to reach the clinical goal of treating both the vulnerable plaque and vulnerable patient. The measurement of inflammatory markers is useful to detect the pathophysiology of acute coronary syndromes (ACS).

The other two members of the pentraxin superfamily are CRP and serum amyloid P component (SAP). CRP and SAP are the classic members of the short pentraxins, while PTX3 is the prototypic member of the long-pentraxin family. PTX3 is produced at the inflammatory site by monocytes/ macrophages, endothelial cells, vascular smooth muscle cells, fibroblasts, and cardiomyocytes in response to primary inflammatory stimuli. The alteration of serum PTX3 level in patients with coronary artery disease after PCI has not been established.    

PTX3 was cloned as an IL-1 inducible gene in endothelial cells, which is produced locally at the sites of inflammation under the control of proinflammatory signals.   

In vasculitis, PTX3 levels correlate with disease activity independently from CRP.  PTX3 was called ‘vessel-related pentraxin. Percutaneous coronary intervention (PCI) produces inflammatory reaction in the injured vessel wall that leads to the development of neointimal thickening and restenosis. Activation and up-regulation of integrin Mac-1 (CD11b/CD18) on the surface of neutrophils and local production of CRP at the site of the atherosclerosis were induced by PCI, which is also associated with restenosis.

Study of PTX3 and stent implantation

In 20 patients with isolated atherosclerotic coronary artery disease who underwent initial elective coronary stent implantation and follow-up coronary angiography, coronary sinus and peripheral blood were taken before PCI,  15 minutes after coronary stenting, and 24 hours and 48 hours after PCI. Plasma concentrations of PTX3 were measured using a sandwich enzyme-linked immunosorbent assay (ELISA).  

Key results showed an increase in plasma PTX3 levels, activated Mac-1, and plasma CRP levels after coronary stenting. A positive correlation was found between late lumen loss and the percent of increase in plasma PTX3 levels at 24 and 48 hours after PCI and between the percent of increase in activated Mac-1 and plasma CRP levels at 48 hours. The most powerful predictor of the late lumen loss was the percent of increase in plasma PTX3 level at 24 hours after PCI.

SAMIT study with atorvastatin

Coronary stenting was shown to enhance plasma PTX3 levels in association with an inflammatory response. Thus, PTX3 may be a useful marker for evaluation of stent-induced Mac-1-mediated inflammatory reaction and of vulnerable patients. 

Node and colleagues conducted the open-label, multicenter Statin Acute Myocardial Infarction Trial (SAMIT). One dose of atorvastatin 40 mg was given in the emergency room and PCI performed, and atorvastatin 10 mg daily began one month later. The primary endpoint was levels of inflammatory markers (high-sensitivity CRP, platelet-derived microparticles, GPI-80, MCP-1, RANTES, RANKL, and OPG. The secondary endpoint was the 2-year prognosis (death, MACE).

A tight correlation between PDMP and Mac-1 was found. Plasma PDMP was higher in AMI than stable angina patients. PDMP levels were increased at 12 hours after admission. 

Node concluded that unstable plaque, infarct myocardium, and vascular injury caused by PCI might accelerate PDMPs, and that statin treatment attenuated the serial activation of PDMP in patients with AMI. PDMP may be a biomarker of vascular inflammation that is more specific for leukocytes and neutrophils.