Rabbit plaque models closely resembling lesions in human coronary artery disease.

BACKGROUND: A suitable animal model is required to investigate plaque biology. Here, we examined 6 rabbit models of plaque generated by balloon injury and sequential combinations of normal and high-cholesterol diets. METHODS AND RESULTS: Fifty-eight male Japanese White rabbits were used. Lipid-rich macrophages accumulated in the center of the intima, and smooth muscle cells were located on the luminal side of the intima (similar to stable plaques in human coronary arteries) of a model in which balloon injury was followed by a normal diet for 4 weeks and then by a high-cholesterol diet for 4 weeks. Extending the high-cholesterol diet for a further 4 weeks increased accumulation of lipid-rich macrophages, diminished the amounts of elastic fibers and smooth muscle cells in the intima and caused the expression of matrix metalloproteinase-9 and tissue factor. All of these features are characteristic of unstable plaques. Moreover, quantitative analysis revealed that matrix metalloproteinase-9 expression and elastic-fiber content inversely correlated with statistical significance (R(2) = 0.52, p = 0.0003). CONCLUSION: A high-cholesterol diet for 0 to 8 weeks after a normal diet for the first 4 weeks following balloon injury induced various arterial lesions resembling the diffuse intimal thickening, as well as stable and unstable plaques that accumulate in human coronary arteries. The present models might be useful for plaque studies.

Switching to aggressive statin improves vascular endothelial function in patients with stable coronary artery disease.

AIM: The clinical relevance of the suggested pleiotropic effects of hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) is controversial. Aggressive statins effectively reduce lipid levels, but whether their other effects are more powerful than those of regular statins is unknown. METHODS: We enrolled 32 patients (mean age, 65 y; male, 23) who had undergone coronary revascularization over 6 months previously and whose serum LDL cholesterol levels persisted at >100 mg/dL, regardless of pravastatin (10 mg/day). Before and 1 and 6 months after switching to atorvastatin (10 mg/day), we evaluated lipid profiles, including RLP-C (remnant-like particle cholesterol), high sensitive CRP (hsCRP), soluble CD40 ligand (sCD40L), TBARS (thiobarbituric acid reactive substances), and endothelial function determined from flow-mediated dilation (FMD) of the brachial artery. RESULTS: One month on atorvastatin lowered LDL cholesterol by 24% (131 to 100 mg/dL, p<0.001). In addition, RLP-C, sCD40L and hsCRP significantly decreased, whereas FMD did not change. After 6 months of this therapy, FMD significantly improved compared to baseline values (5.1 vs 3.6%, p=0.04). Changes in FMD and in total and RLP cholesterol significantly correlated. Moreover, FMD was remarkably improved in patients who achieved target LDL levels (<100 mg/dL). CONCLUSIONS: Switching from a regular to an aggressive statin can improve endothelial function at 6 months in patients with previous coronary artery disease. This effect is suggested to be mainly due to the lipid-lowering effect. Achievement and maintenance of the target LDL level by switching statins is beneficial in the clinical setting.

Adrenal androgen dehydroepiandrosterone sulfate inhibits vascular remodeling following arterial injury.

Recent epidemiologic studies have suggested that serum dehydroepiandrosterone sulfate (DHEAS) levels have a significant inverse correlation with the incidence of cardiovascular diseases. However, direct evidence for the association with DHEAS and vascular disorders has not yet been explored. DHEAS significantly reduced neointima formation 28 days after surgery without altering other serum metabolite levels in a rabbit carotid balloon injury model. Immunohistochemical analyses revealed the reduction of proliferating cell nuclear antigen (PCNA) index and increase of TdT-mediated dUTP-biotin Nick End Labeling (TUNEL) index, expressing differentiated vascular smooth muscle cell (VSMC) markers in the media 7 days after surgery. In vitro, DHEAS exhibited inhibitory effects on VSMC proliferation and migration activities, inducing G1 cell cycle arrest with upregulation of one of the cyclin dependent kinase (CDK) inhibitors p16(INK4a) and apoptosis with activating peroxisome proliferator-activated receptor (PPAR)-alpha in VSMCs. DHEAS inhibits vascular remodeling reducing neointima formation after vascular injury via its effects on VSMC phenotypic modulation, functions and apoptosis upregulating p16(INK4a)/activating PPARalpha. DHEAS may play a pathophysiological role for vascular remodeling in cardiovascular disease.

Vascular Behçet's disease with coronary artery aneurysm.

A 33-year-old man with a 4-year history of Behçet's disease was hospitalized with acute myocardial infarction. Percutaneous coronary intervention (PCI) treated 99% stenosis of the right coronary artery but follow-up coronary arteriography clearly revealed a coronary artery aneurysm (CAA) at the lesion proximal to the PCI site and intravascular ultrasound confirmed that it was a true aneurysm. We speculated that Behçet's disease might be involved in coronary lesion, especially in CAA formation. We decided to increase the dose of prednisolone and to add warfarin. The size of the CAA was not altered after 6 months.

Re-entry circuit in ventricular tachycardia due to focal fatty-fibrosis in a patient with myotonic dystrophy.

A 69-year-old man with a recurrent ventricular tachycardia (VT) was admitted. The patient was diagnosed as myotonic dystrophy type 1 (DM1) and DNA analysis revealed 1,800 CTG-repeat expansion in the myotonic dystrophy protein kinase (DMPK) gene. Ultrasonic cardiogram (UCG), left ventriculogram (LVG) and magnetic resonance imaging (MRI) did not show any abnormal sign including fatty infiltration. But, endomyocardial biopsy obtained from ventricular outflow tract revealed severe fatty infiltration and interstitial fibrosis. Radiofrequency catheter ablation at the biopsy site could eliminate VT, so it was strongly suggested that the re-entry circuit was formed by focal fatty-fibrosis. Careful observation should be continued for a long period.