Yoshiaki Tsukamoto

Elevated Levels of Oxidized Low Density Lipoprotein Show a Positive Relationship With the Severity of Acute Coronary Syndromes

BackgroundThere is accumulating data that acute coronary syndromes relate to recent onset activation of inflammation affecting atherosclerotic plaques. Increased blood levels of oxidized low density lipoprotein (ox-LDL) could play a role in these circumstances. Methods and ResultsOx-LDL levels were measured in 135 patients with acute myocardial infarction (AMI; n=45), unstable angina pectoris (UAP; n=45), and stable angina pectoris (SAP; n=45) and in 46 control subjects using a sandwich ELISA method. In addition, 33 atherectomy specimens obtained from a different cohort of patients with SAP (n=10) and UAP (n=23) were studied immunohistochemically for ox-LDL. In AMI patients, ox-LDL levels were significantly higher than in patients with UAP (P <0.0005) or SAP (P <0.0001) or in controls (P <0.0001) (AMI, 1.95±1.42 ng/5 &mgr;g LDL protein; UAP, 1.19±0.74 ng/5 &mgr;g LDL protein; SAP, 0.89±0.48 ng/5 &mgr;g LDL protein; control, 0.58±0.23 ng/5 &mgr;g LDL protein). Serum levels of total, HDL, and LDL cholesterol did not differ among these patient groups. In the atherectomy specimens, the surface area containing ox-LDL–positive macrophages was significantly higher in patients with UAP than in those with SAP (P <0.0001). ConclusionsThis study demonstrates that ox-LDL levels show a significant positive correlation with the severity of acute coronary syndromes and that the more severe lesions also contain a significantly higher percentage of ox-LDL–positive macrophages. These observations suggest that increased levels of ox-LDL relate to plaque instability in human coronary atherosclerotic lesions.

Lysosomal accumulation of oxidized phosphatidylcholine-apolipoprotein B complex in macrophages: intracellular fate of oxidized low density lipoprotein.

Oxidized phosphatidylcholine (OxPC) formed in oxidized low density lipoprotein (OxLDL) is thought to be involved in the development of atherosclerosis. OxPC has been found in foam cells in atherosclerotic lesions and suggested to be the epitope for OxLDL recognition by macrophages. OxPC is present as a complex with apolipoprotein B (apoB) in OxLDL, since some OxPC can bind with proteins. In the current study, the intracellular fate of OxPC-apoB complexes after internalization of OxLDL by macrophages was investigated. Murine macrophage cell line J774.1 was incubated with either OxLDL or acetylated LDL for 24 h, then the cells were further incubated for up to 24 h in new medium without lipoprotein. Modified apoB in the cells was quantitated by sandwich ELISA using monoclonal antibodies against OxPC and apoB. Intracellular OxLDL decreased rapidly for the first 4 h to approx. 20% of that before medium change, with the apparent metabolism of OxPC-apoB complex ceasing. OxPC-apoB complexes that remained in the cells after 24 h chasing increased as the period of OxLDL loading in macrophages prolongs. Acetylated LDL in the cells decreased quickly and disappeared after 4 h of chasing. Subcellular fractionation using sucrose density gradient ultracentrifugation of macrophages, which had already accumulated OxPC-apoB complexes by 24 h of incubation with OxLDL and further 24 h chasing, showed that the complex was co-localized with endosomal and lysosomal markers. Immunohistochemical double staining studies demonstrated that OxPC and apoB co-localize in foam cells in early atherosclerotic lesions obtained from human coronary artery. These results suggest that OxPC-apoB complexes originating from OxLDL accumulate in foam cells in human atherosclerotic lesions as well as in macrophages in vitro.

Regional diagnosis in patients with unstable and stable angina pectoris: Nicorandil stress myocardial contrast echocardiography and magnetic resonance imaging

Background: Regional diagnostic imaging in patients with unstable angina is a challenge for cardiologists. To determine whether or not nicorandil, a hybrid compound of KATP channel opener and nitrate, stress myocardial contrast echocardiography (MCE) and magnetic resonance imaging (MRI) are clinically useful in prediction of critical coronary arterial stenosis in angina pectoris (AP) including unstable AP, we conducted a prospective study. Methods: Consecutive 101 patients with AP including unstable AP (n=50) without a history of ST elevation, previous myocardial infarction and coronary bypass surgery were enrolled. All the patients underwent nicorandil stress MCE and MRI. MCE was performed with gray scale ultra-harmonic mode (1.3 MHz/3.6 MHz) under maximum mechanical index during intravenous drip infusion of Levovist during rest and nicorandil stress (0.1 mg/kg iv). End-systolic triggering images (triggering interval of 1, 2, 3 and 4 beats) were recorded. Gadolinium-enhanced MRI was acquired at late-systolic phase during rest and nicorandil stress. Each myocardial region (left anterior descending artery, left circumflex artery, right coronary artery) imaged by MCE and MRI was evaluated before coronary arteriography (CAG) by two independent reviewers who were blinded to the clinical data. All the patients underwent quantitative CAG within five days after MCE and MRI. Results: There was no adverse effects or angina during nicorandil stress MCE in any patients. Prediction rate by the nicorandil stress MCE (303 regions) and MRI of critical stenosis (70% in QCA) were 79% and 89% in sensitivity, 96% and 96% in specificity, and 91% and 93% in accuracy, respectively. In a subgroup of multivessel disease (n=26), sensitivity, specificity and accuracy by MCE were 86%, 94%, and 88%, respectively. Conclusion: Nicorandil stress MCE and MRI are safe, useful and economical noninvasive techniques to assess myocardial regional perfusion in patients with AP including unstable AP, especially associated with multivessel lesions.