对急性冠脉综合征患者二级预防的强降脂治疗：

用血管内超声法作体积和回声分析

第68届科学会报告

Tadateru Takayama. 日本大学医学部

A组服用阿托伐他汀，每天10mg； P组服用普罗布考，每天500mg； A+P组服用阿托伐他汀和普罗布考。结果：6个月，总胆固醇：A组从228 mg/dl降至147.1 mg/dl；P组从207 mg/dl 降至 158 mg/dl；A+P 组从 233 mg/dl 降至 140.4 mg/dl；每组均 p< 0.05。LDL-C： A组从 149.4 mg/dl 降至 88.8 mg/dl； P组从138 mg/dl 降至 99 mg/dl； A+P组从160.7 mg/dl 降至82.3 mg/dl；每组均 p< 0.05。血管内超声(IVUS)表明，A+P组明显降低斑块体积，约65%，p<0.05；A组降低约15%；P组降低约20%。A+P组明显增加腔体积，约80%，p<0.05； A和P组均增加约40%。P组和A+P组的斑块回声均明显增加，A+P组(约90%)大于P组(约30%), 这两组均p<0.05。A+P组的冠脉血管造影未见变化。治疗后，A+P组的脂质池消失，一67岁男患者的斑块灰值从52增至65.3。普罗布考和阿托伐他汀联合用药可消除并稳定动脉粥样硬化斑块。

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.