Pathogenetic Perceptions of Acute Coronary Syndrome: Insights into Plaque Rupture, Plaque Erosion and Coronary Thrombosis in Japanese

Hiroyuki Hao
National Cardiovascular Center, Osaka, Japan

Rupture of unstable plaque is a major cause of acute coronary syndromes (ACS). However, in 2000, Virmani and colleagues proposed a modified classification of coronary atherosclerotic lesions, based on their observations of more than 200 cases of sudden cardiac death (SCD). Based on their observation of the lack of a relationship between SCD and the classic AHA classification, their modified classification focuses on the intermediate or advanced lesion, and indicates seven different categories of lesions. Lesions with thrombus, which causes ACS, including SCD, exhibited 3 distinct processes: rupture, erosion, calcified node. Regarding erosion, they noted a cycle that can be continuous. Intimal thickening progressed to pathologic intimal thickening and to erosion, which can lead to thrombosis and SCD or to thrombosis, and then healing and formation of a fibrocalcific plaque, which can be followed by a new erosion; this cycle can then continue.

Rupture of the fibrous cap is often seen in the shoulder of the lesion, followed by focal foam cell infiltration. Erosion is identified when serial sectioning of thrombosed coronary artery fails to reveal plaque rupture. Surprisingly, the eroded lesion shows minimal inflammation. In the US, about 40% of SCD is associated with lesion erosion. It is more common in men and women below 50 years of age and is associated with smoking, especially in women.

Virmani and colleagues examined the accumulation of extracellular matrix at the erosion site of the culprit lesion to understand the mechanisms of erosion. Staining showed strong presence of versican and bHABR, but biglycan and decorin were weak. The fibrous cap of stable plaque showed strong bigylcan and weak bHABR staining.

Further investigation by Gabbiani, Bochaton-Piallat and Virmani focused on cell density and smooth muscle (SM) cell differentiation in the erosion. They examined the expression of alpha-SM actin, smooth muscle myosin heavy chain (SMMHC), and smoothelin, which are all well accepted SM cell differentiation markers. In the intima, a high density of alpha-SM actin positive cells was found, weak expression of SMMHC, and no staining of smoothelin by histochemistry. In the intima, the degree of differentiation of SM cells was significantly lower than in stable plaque—suggesting that plaque erosion may have a close connection with the phenotype of the intimal SM cells, as myofibroblastic phenotype.

Erosion in lesions in Japanese AMI patients

In 159 carotid lesions in Japanese patients with an AMI analyzed by Hao and colleagues, plaque rupture was the cause of death in 86%,  and erosion in 14% of patients (Figure 1). Notably, the mean age of the patients with erosion as the cause of death was 71 years, significantly older than the US patients with SCD due to erosion.

Based on histological features, they classified the erosions into 4 different categories: fibrocalcific lesions and fresh thrombus in 12 cases, eroded cellular intima in 6, complex lesion in 2, and thin fibrous cap in 2 cases.

In the fibrocalcific lesions, extracellular matrix, which was very often calcification, was accumulated. In eroded fibrous atheroma, mature extracellular matrix was present, and alpha-SM actin in media and especially intima thickening on immunohistochemistry.

The broad density of alpha-SM actin positive cells in the intima was quite different in the Japanese AMI patients compared to SCD in the US.

In the 6 Japanese cases of eroded cellular intima, there was diffuse intimal thickening with occlusive thrombus formation in the right coronary artery; the intima contained no lipid (Figure 2). The medial SM cells had a minimal reaction with alpha-SM actin, indicating these cells are less differentiated compared to the normal media or media in advanced lesions. In the cellular intima, alpha-SM actin positive cells were seen, which is similar to erosion in SCD in the US.

Closing

Coronary thrombosis is not a simple process. Complex lesions show multiple complications of the plaque rupture and erosion, such as healed rupture where an old rupture is followed by thrombus formation; the thrombus is organized and the fresh thrombus is superimposed and the fresh thrombus occludes the coronary tree (Figure 3).
 
In the setting of AMI in Japanese patients, former observations indicated that intimal thickening could progress to fatal thrombotic occlusion. Vasospasm may contribute to this process. However, based on the analysis by Hao and colleagues, fibrocalcific plaque, which might be stable, could progress to erosion and cause SCD. Hao ended his presentation, therefore, with this provocative question: Is “stable plaque” always calm? 

A Role for Coronary Angioscopy for the Prevention and Treatment of Acute Coronary Syndrome

Yasunori Ueda
Osaka Police Hospital, Osaka, Japan

Angioscopy is useful for the diagnosis, classification, risk stratification, and as a treatment guide for acute coronary syndromes (ACS), and for the evaluation of drug effects to prevent ACS events.

Diagnosis and classification using angioscopy

Angioscopy is a useful device to detect the ACS lesion, usually characterized by yellow plaque and thrombus. Angioscopy can be used to classify rupture, erosion, or vasospasm in ACS. Angioscopic classification of plaque rupture is a large disruption with visible protrusion, and plaque erosion a small disruption without visible protrusion of the lipid core. Vasospasm is characterized angioscopically by the lack of yellow plaque and only smooth white normal coronary artery, normal coronary vessel wall, and no adherent thrombus.

In the setting of ruptured plaque, much thrombus and lipid material is washed away into the distal circulation system, which may cause microembolization. Distal protection devices can collect this microembolization material.

Plaque rupture is also associated with a higher amount of thrombus, demonstrated by the higher concentration of TAT in the coronary artery distal from the culprit lesion. The type of plaque disruption is associated with infarct size, evaluated by peak-CK, TI-SPECT, left ventricular ejection fraction (LVEF), and ST resolution. In the rupture type, the infarct size is larger and has a higher restenosis rate.

Risk stratification by angioscopy

Risk stratification of plaque and the patient can be performed used angioscopy. As plaque progresses from stable to vulnerable, it progresses from white to intensely yellow, with the greater intensity in the yellow color associated with an increasingly larger lipid core and thinner fibrous cap. Ueda and colleagues classified the color of the plaque into 4 grades, Grade 0 being white and Grades 1, 2, and 3 being progressively more intensely yellow. The higher the grade the more thrombus is present. The presence of thrombus means plaque disruption, so the higher grade is associated with higher plaque vulnerability. The higher yellow color intensity of the plaque is associated with a higher prevalence of positive remodeling; Grade 1 was associated with 10% prevalence, Grade 2 with 30%, and Grade 3 with 70% remodeling, in their experience. Therefore, they believe the plaque becomes more and more yellow, and finally disrupts and causes thrombosis. However, not all thrombosed plaques cause ACS. Most thrombosis disruption occurs silently. In 140 patients, the mean number of yellow plaques was 2.9, and the average maximum color grade was 2.4 (Figure 1). However, 18 patients suffered a second ACS event, 3 of whom had undergone angioscopy observation of the culprit lesion before the second event. Using angioscopy, determining which plaque may cause a future ACS event is difficult.

However, an MI patient is a vulnerable patient, meaning they have many vulnerable plaques. Although which plaque may cause a future ACS can not be identified, the presence of many plaques with higher yellow intensity may be associated with a higher probability of a future ACS event. Therefore, they tried to validate the extent of atherosclerosis by angioscopy using these parameters: number of yellow plaques, maximum color grade, sum of color grade, and plaque index (number of plaque multiplied by the maximum color grade).

These parameters were higher in the patients with a history of MI, compared with patients without a history of MI, and were also higher in patients with AMI compared to patients with unstable angina.

They hypothesized the progression of coronary atherosclerosis as: Yellow plaques develop in the left coronary artery (LCA), left circumflex (LCx), and left anterior descending (LAD), some of which cause disruption and thrombosis and is asymptomatic. The organization of the thrombus may cause the progression of stenosis, which may lead to stable angina. However, the disruption of the plaque in more advanced stages may cause unstable angina. In more advanced stages, the disruption of the plaque will cause AMI.

They followed 81 patients who suffered their first MI for about 5 years, 8 of whom suffered a second ACS event (Figure 2). The baseline plaque index of these 8 patients was divided into 2 groups. The patients with a higher plaque index (>10) had a higher incidence of an ACS event compared to a lower plaque index (“10) [28.6% vs 4.3%, p=0.02; Figure 3]. Therefore, they believe it is possible to evaluate the risk of a second ACS event by counting the number of yellow plaques or evaluating the yellow color intensity of the plaques, on angioscopy.

Evaluation of plaque stabilization

It is possible to evaluate the plaque stabilization by counting the number of yellow plaques or evaluating the yellow color intensity, which can show the drug effect. This group evaluated the effect of probucol (500 mg/day) and found that the drug regresses the yellow plaque and the lesion becomes white after 1-year of administration. They are now evaluating this with statins.         

Evaluation of PCI devices

PCI devices, such as drug-eluting stents, can be evaluated by angioscopy. For example, at 3 months after implantation of a bare metal stent, neointima can be seen covering the stent and the yellow plaques. It is possible that the neointima reduces the possibility of a second ACS event at that site. In the natural course of neointima formation, the neointima becomes thinner over time, as shown by angioscopy at 3 years.

This group will use angioscopy to study DES and evaluate the natural course for neointimal coverage and how long thrombosis will continue. This data will help to determine the length of time the antiplatelet drugs should be continued after implantation.

Distal protection devices are used to prevent microembolization and reduce slow flow and infarct size. Stent thrombosis is another important problem when treating ACS. Ueda and colleagues believe this is actually a highly thrombogenic culprit lesion. To prevent re-thrombosis of the lesion, it is thought that removal of the disrupted plaque is needed. Although the frequency is low, re-thrombosis of the culprit lesion can be fatal. Angioscopy-guided PCI would be beneficial for removal of the debris.     

Aggressive Lipid-Lowering Therapy for Secondary Prevention in Patients with Acute Coronary Syndrome: Volumetric and Echogenicity Analysis Using Intravascular Ultrasound

Tadateru Takayama
Nihon University School of Medicine, Tokyo, Japan

Intensive lipid-lowering therapy for the secondary prevention of cardiac events is based on data from several studies, including the findings that plaque rupture occurs in patients with stable angina or no symptoms, not just patients with MI or unstable angina, multiple plaque ruptures may occur in a patient, and ruptured plaques are eccentric with positive remodeling. In acute coronary syndrome (ACS), Asakura and colleagues have shown that a potentially vulnerable plaque was observed with equal frequency in the infarct-related and non-infarct-related artery. In other data, multiple ruptures were observed in 15% of patients.

Vulnerable plaques are frequently observed by intravascular ultrasound (IVUS) both in the area adjacent to the culprit lesion and in the non-culprit vessel in patients with acute coronary syndrome. On IVUS, the vulnerable plaque is characterized by eccentric, low echogenic plaque with lipid pool and thin fibrous cap, and positive remodeling. Typical findings on angioscopy are yellow plaque, thrombus, and ulceration or erosion.

Randomized clinical trials have demonstrated effective lipid lowering with a statin in patients with ACS, and the reduction of primary coronary events, and reduction of events in patients with stable coronary artery disease (CAD).

Study design

To study the effect of aggressive LDL-cholesterol (LDL-C) lowering on changes in plaque volume and echogenicity on IVUS, Takayama and colleagues conducted a study comparing therapy with atorvastatin with or without anti-oxidant therapy with probucol.  Group A was given atorvastatin 10mg/day, Group P probucol 500mg/day, and Group A+P atorvastatin and probucol.

Inclusion criteria were patients with ACS and non-culprit lesions, and mild to moderate lesions (< 50% on QCA). The targets for LDL-C were defined as: LDL-C ³ 140 mg/dl in Group A, < 140 mg/dl in Group P, and ³ 140 mg/dl in Group A+P.

Baseline and follow-up studies (> 6 months) were performed with coronary angiogram (CAG) and IVUS (volumetric and densitometric analysis).

IVUS analysis was performed using 30 MHz Ultracross or 40MHz Atlantis (Boston Scientific Scimed Inc.), with an automatic motor drive unit and pull-back speed at 0.5mm/sec. Off-line volumetric IVUS analysis was performed to measure lumen volume, vessel volume, and plaque volume.

Plaque intensity was also determined using Texture Videodensitometric Analysis. Contrast time investigation analyzed the change of contrast (gray values) in a sequence of IVUS images. Gray scales (between black and white) were divided into 256 values, allowing regions of interest (ROI) to be defined. The gray value was measured in the  ROI in both plaque and adventitia.

Study Results

At 6 months, the total cholesterol level was reduced in Group A from 228 mg/dl to 147.1 mg/dl, in Group P from 207 mg/dl to 158 mg/dl, and in Group A+P from 233 mg/dl to 140.4 mg/dl; p< 0.05 for each group. LDL-C levels was reduced in Group A from 149.4 mg/dl to 88.8 mg/dl, in Group P from 138 mg/dl to 99 mg/dl, and in Group A+P from 160.7 mg/dl to 82.3 mg/dl; p< 0.05 for each group.

Only Group A+P had a significant decrease (about 65%) in atheroma volume on volumetric IVUS analysis from baseline to 6 months (p<0.05). The decrease in Group A was about 15% and about 20% in Group P. Lumen volume was significantly increased only in Group A+P, by about 80% (p<0.05), compared to about 40% in both Group A and Group P. Vessel volume was the same, at about 1.0, in each group.

Plaque echogenicity significantly increased in Group P and Group A+P. However, the increase was greater in Group A+P (about 90%) than in Group P (about 30%), each p<0.05 against baseline. On CAG, no significant change was seen at 6 months in Group A+P.

Before treatment IVUS revealed lipid pools with an eccentric soft plaque and positive remodeling. At 6 months, in Group A+P the LDL-C was significantly decreased from 146 mg/dl to 65.3mg/dl, and IVUS revealed that the plaque area decreased and the lipid pool disappeared. In a 67-year-old male patient, the mean gray value of the plaque increased from 52 to 65.3. In this patient, the 3D-IVUS measurements showed a reduction in plaque volume and increase in lumen volume, indicating plaque regression.
Combination therapy of atorvastatin and probucol regressed and stabilized the plaque.

In summary, a significant reduction in plaque volume with a concomitant increase in lumen volume was obtained in Group A+P. An increase in echogenicity on videodensitometric analysis was seen in each group but was greatest in Group A+P.

Conclusions

Plaque stabilization and plaque regression could be assessed as changes in plaque volume or echo-intensity by IVUS. Aggressive lipid-lowering therapy may lead to plaque regression and stabilization of minor lesions, which potentially could cause a second cardiac event. Improvements in tissue characterization on IVUS images are anticipated with improved equipment for analysis.

Long-Term Management of Japanese patients with Coronary Artery Disease in the Recent Coronary Revascularization Era for Prevention of ACS

Masatoshi Kawana
Tokyo Women¡s Medical University, Tokyo, Japan

The Heart Institute of Japan (HIJC) group was organized in 1998 by 17 cardiology centers across Japan, who agreed to share common diagnostic and therapeutic strategies with several independent committees, such as endpoint classification and data and safety monitoring.

Data from HIJC studies presented here showed that the long-term prognosis of Japanese patients after acute myocardial infarction (AMI) is better compared to that in patients in US and European trials. Diabetes and hypertension are independent risk factors for morbidity and mortality in Japanese patients. Serum CRP concentration is a strong and independent predictor of risk for morbidity and mortality. The incidence of combined cardiovascular (CV) events was lower in patients treated with aspirin and statins. However, patients treated with nitrates and beta-blockers showed a higher incidence of CV events. In patients without MI, treatment with a calcium channel blocker (CCB) resulted in a lower incidence of CV events

The JAMI study

The HIJC investigated in 3 clinical studies the long-term outcomes of coronary artery disease (CAD) in Japanese patients. The endpoints in these studies were CV events (CV death, non-fatal MI, unstable angina, heart failure, revascularization), total death, and CV death.

JAMI was a prospective cohort study to elucidate the clinical characteristics of AMI in Japanese patients. A total of 3,021 consecutive AMI patients randomized within 48 hours of onset in HIJC group hospitals were included from 1999. The mean age was 68 years, and 80% had ST elevation MI. In contrast to studies conducted in the US, 54% were smokers.

In contrast to the US and Europe, only 6.5% of the JAMI patients underwent thrombolysis, while 66% had primary PCI. Up to 77% of JAMI patients had coronary revascularization during hospitalization and hospital CV mortality was 7.9%.

The mean 2.4 years follow-up of 2,736 discharged patients showed that 57% of patients were on an ACE inhibitor and 89% on aspirin. The percentage of patients on a beta-blocker and nitrates, at 32% and 61% respectively, was higher in Japan compared to clinical trials conducted in the US and Europe. Patients in JAMI had better 1-year mortality, at 5.7%, than seen in US and European clinical trials, which ranged from 8.6% to 13.3%. 

The PROCES and CREATE studies

In the prospective cohort PROCES study, designed to elucidate the long-term prognosis of chronic CAD in Japanese patients, a total of 2,620 patients with angiographic evidence of coronary artery lesions were included in the study. Follow-up information was obtained from the HIJC registry, and demographic, clinical, and therapeutic variables were submitted for statistical analysis to determine the risk factors of adverse outcomes.

The ongoing CREATE study (Candesartan Randomized trial for the Evaluation in Coronary Artery Disease) is a prospective, randomized, open, blinded endpoint study conducted at HIJC centers. The goal of the study was to investigate whether the angiotensin receptor blocker candesartan provides a favorable impact on prognosis in patients with CAD associated with hypertension. After confirmation of CAD, including by coronary angiography, patients were randomized to either candesartan-based therapy or conventional therapy. The follow-up is 5 years. Patient randomization (n=2,050) was recently completed. The primary endpoint is CV events, including CV death, nonfatal MI, unstable angina, and heart failure requiring hospitalization.

Meta-analysis of JAMI and PROCES

Kawana and colleagues performed a meta-analysis of the combined cohort of JAMI and the mid-term analysis of PROCES. They analyzed the follow-up information of 5,317 patients with CAD in JAMI (n=2,736) and who were registered in PROCES. Demographic, clinical, angiographic, and therapeutic variables were submitted to statistical analysis to detect the risk factors of adverse outcomes.

Long-term survival rates at 48 months were significantly higher at just under 0.9 in patients who underwent coronary revascularization compared to just over 0.8 in those who did not have revascularization (p<0.0001).

Hypertension and diabetes were independent risk factors for CV events in the Japanese patients with CAD, in addition to age and number of diseased vessels (Figure 1). Hyperlipidemia was not an independent risk factor, probably because of the prevalence of statin treatment. Serum CRP was also an independent risk factor. Patients with CRP in the highest quartile had a 4-fold risk for total mortality and CV mortality, and a 2-fold risk for CV events, compared to those in the lowest quartile. The chronic CAD patients in the PROCES study in the highest CRP quartile had a 6-fold higher CV mortality. This is the first demonstration of the impact of CRP as a prognostic marker for stable CAD in this large number of patients in Japan. These patients may be candidates for aggressive statin therapy.

The impact of pharmacological interventions for CV morbidity and mortality was analyzed. The multivariate Cox model with propensity score adjustment analysis demonstrated that the incidence of combined CV events was lower in patients treated with aspirin and statins (Figure 2). However, patients treated with nitrates showed a higher incidence of CV events. Surprisingly, patients treated with beta-blockers also showed a higher incidence of CV events. Furthermore, in patients without MI, treatment with a CCB resulted in a lower incidence of CV events. The Kaplan-Meier curves in CAD patients without MI showed there was a 38% difference in CV events between patients treated with a CCB and those without a CCB. This difference was mainly due to the reduction of unstable angina requiring hospitalization.

The response to beta-blockers and CCBs seen in the Japanese patients is quite different from those in US and European trials. This suggests unique characteristics in Japanese patients, such as coronary spasm.