Mitsumasa Sudo

Development of Human‐Like Advanced Coronary Plaques in Low‐Density Lipoprotein Receptor Knockout Pigs and Justification for Statin Treatment Before Formation of Atherosclerotic Plaques

Background Although clinical trials have proved that statin can be used prophylactically against cardiovascular events, the direct effects of statin on plaque development are not well understood. We generated low‐density lipoprotein receptor knockout (LDLR −/−) pigs to study the effects of early statin administration on development of atherosclerotic plaques, especially advanced plaques. Methods and Results LDLR −/− pigs were generated by targeted deletion of exon 4 of the LDLR gene. Given a standard chow diet, LDLR −/− pigs showed atherosclerotic lesions starting at 6 months of age. When 3‐month‐old LDLR −/− pigs were fed a high‐cholesterol, high‐fat (HCHF) diet for 4 months (HCHF group), human‐like advanced coronary plaques developed. We also fed 3‐month‐old LDLR −/− pigs an HCHF diet with pitavastatin for 4 months (Statin Prophylaxis Group). Although serum cholesterol concentrations did not differ significantly between the 2 groups, intravascular ultrasound revealed 52% reduced plaque volume in statin‐treated pigs. Pathological examination revealed most lesions (87%) in the statin prophylaxis group were early‐stage lesions, versus 45% in the HCHF diet group (P<0.01). Thin‐cap fibroatheroma characterized 40% of the plaques in the HCHF diet group versus 8% in the statin prophylaxis group (P<0.01), intraplaque hemorrhage characterized 11% versus 1% (P<0.01), and calcification characterized 22% versus 1% (P<0.01). Conclusions Results of our large animal experiment support statin prophylaxis before the occurrence of atherosclerosis. Early statin treatment appears to retard development of coronary artery atherosclerosis and ensure lesion stability. In addition, the LDLR −/− pigs we developed represent a large animal model of human‐like advanced coronary plaque suitable for translational research.

Stabilization of atherosclerotic plaque by pitavastatin in Watanabe heritable hyperlipidemic rabbits: A serial tissue-characterizing intravascular ultrasound study.

BACKGROUND To examine the effects of pitavastatin on atherosclerotic plaque in Watanabe heritable hyperlipidemic (WHHL) rabbits using serial in vivo tissue-characterizing intravascular ultrasound. METHODS A total of 11 WHHL rabbits of 10-12 weeks of age were divided into two groups, control and pitavastatin-administered groups. A total of 29 atherosclerotic plaque segments from control group and 43 plaque segments from the pitavastatin group were serially imaged by 40MHz intravascular ultrasound in vivo with a tissue characterization software (iMAP™, Boston Scientific, Natick, MA, USA) at the baseline and the follow-up (16th week). RESULTS The level of low-density lipoprotein cholesterol was significantly decreased in pitavastatin group. During the follow-up period, plaque area was significantly increased in the control group, whereas it was not significantly changed in the pitavastatin group. The fibrotic, necrotic, and necrotic plus lipidic areas were significantly increased in the control group, while no significant change was revealed for tissue profile in pitavastatin group. The change in the percent areas of fibrotic and lipidic plus necrotic tissues were significantly different between the two groups especially in the superficial half portion of plaque. CONCLUSIONS These data indicate that pitavastatin could attenuate atherosclerotic plaque formation and that it could stabilize the plaque in WHHL rabbits. Considering the fact that these were observed even with a high follow-up level of cholesterol, these data might come from the pleiotropic effects of pitavastatin.

Association between the epicardial adipose tissue thickness and the presence of multivessel disease in patients with acute myocardial infarction.

AIM Epicardial adipose tissue (EAT) is implicated in the development of coronary atherosclerosis.We sought to investigate the association between the EAT thickness and presence of multivessel disease (MV) in patients with acute myocardial infarction (AMI). METHODS We enrolled 45 consecutive patients with AMI who underwent primary percutaneous coronary intervention (PCI). The EAT thickness was measured on echocardiography. A follow-up study was performed using coronary angiography with coronary angioscopy two weeks after primary PCI. RESULTS Based on the angiographic findings, 21 patients had single-vessel disease (SV) and 24 patients had MV. The EAT thickness in the patients with SV was significantly smaller than that in the patients with MV (1.9±0.9 mm vs 2.8±1.3 mm, p=0.005, respectively). A multivariate logistic analysis demonstrated that the EAT thickness was the only independent predictor of MV (odds ratio=1.987, 95% confidence interval: 1.089-3.626, p=0.025). An EAT thickness of 2.3 mm was determined to be the optimal cut-off value for predicting MV, with a sensitivity of 70.8% and specificity of 71.4%. Between the thin EAT (＜2.3 mm) and the thick EAT (≥2.3 mm) groups, there were no difference in the number of intense yellow plaques in the non-infarct-related artery evaluated on angioscopy (2.0±2.2 vs 1.8±2.0, p=0.365, respectively). CONCLUSIONS The EAT thickness is closely associated with the presence of MV, but not vessel vulnerability in the non-infarct-related artery, in patients with AMI. Measuring the EAT provides important information for treating patients with AMI.

Angioscopic differences of coronary intima between diffuse and focal coronary vasospasm: Comparison of optical coherence tomography findings

BACKGROUND Coronary artery vasospasm (CS) can be identified as either a diffuse type or focal type; however, the difference in endothelial characteristics between these spasm types remains unclear. The features of coronary intima associated with diffuse spasm and focal spasm using coronary angioscopy (CAS) were evaluated and the optical coherence tomography (OCT) findings were compared. METHODS CAS and/or OCT observational analysis was performed in 55 patients (mean age: 61.4 years, 31 men) who had acetylcholine-provoked CS (diffuse CS, 31 patients; focal CS, 24 patients). The yellowness of the intima, presence of thrombus in CAS, and intimal characteristics based on the OCT results were evaluated. RESULTS CAS showed more atherosclerotic yellow plaques at the focal spasm segment than at the diffuse spasm segment (p=0.032). Moreover, there were more thrombi at the focal spasm segment (p=0.039). In addition, OCT results revealed that the intima area, maximum intima thickness, and lipid content in the focal CS group were larger than the diffuse CS group (4.22±1.67mm2 vs. 3.45±2.36mm2; 0.71±0.29mm vs. 0.53±0.30mm; 55.9% vs. 32.0%, p<0.001, respectively). CONCLUSIONS These results indicate that the presence of atherosclerotic plaques at the spasm site is likely to be related to the occurrence of a focal vasospasm. This may support the difference of features between focal CS and diffuse CS and contribute to precise treatment for each spasm type.

The Spatial Distribution of Plaque Vulnerabilities in Patients with Acute Myocardial Infarction

Objective Although the plaque characteristics have been recognized in patients with acute myocardial infarction (AMI), the plaque spatial distribution is not well clarified. Using color-mapping intravascular ultrasound (iMAP-IVUS), we examined culprit lesions to clarify plaque morphology, composition and spatial distribution of the sites of potential vulnerability. Methods Sixty-eight culprit lesions in 64 consecutive AMI patients who underwent angiography and IVUS examinations before intervention were analyzed. Plaque morphology and composition were quantified with iMAP-IVUS. The spatial distribution of the sites of potential vulnerability was assessed with longitudinal reconstruction of the consecutive IVUS images. The plaque characteristics were also compared between ruptured and non-ruptured lesions, and between totally occlusive (TO) and non-TO lesions. Results The sites with maximum necrotic area (maxNA), maximum plaque burden (maxPB) and most severely narrowed (minimal luminal area, MLA) were recognized vulnerability. In the majority of cases, maxNA sites were proximal to the maxPB sites, and MLA sites were distal to the maxNA and maxPB sites. Ruptures usually occurred close to maxNA sites and proximal to maxPB and MLA sites. The average distance from the site of rupture to the maxNA site was 0.33 ± 4.04 mm. Ruptured lesions showed significant vessel remodeling, greater plaque volume, and greater lipidic volume compared to those of non-ruptured lesions. Both the length and plaque burden (PB) of TO lesions were greater than those of non-TO lesions. Conclusions Instead of overlapping on maxPB sites, most maxNA sites are proximal to the maxPB sites and are the sites most likely to rupture. Plaque morphology and composition play critical roles in plaque rupture and coronary occlusion.

Multimodality visualization with 3-dimensional reconstruction of neointimal plaque rupture after bare-metal stent implantation.

After bare-metal stent implantation, very late stent thrombosis (VLST) is considered to be rare. The most frequent cause of VLST is neointimal plaque rupture [(1)][1]. Some previous reports with using a single imaging device have revealed that it is based on atheromatous changes of the neointima [(2