Different role of macrophages and vascular smooth muscle cells in atherosclerotic lesions of Watanabe heritable hyperlipidemic (WHHL) rabbit between aorta and coronary artery.

The WHHL rabbit is often used to investigate the pathogenesis of atherosclerosis. Here we elucidate differences in the pathogenesis of atherosclerosis in coronary arteries (CA) and aorta (AO) by comparing dynamic changes in the distribution of vascular smooth muscle cells (VSMCs), macrophages, collagen and extracellular deposit during atherosclerosis in WHHL rabbits. Sections of CA and AO were obtained at the early, transitional and advanced stages of atherosclerosis and stained with hematoxilin-eosin, elastica van Gieson, antibodies specific to the above components, antibody against proliferated cell nuclear antigen (PCNA) and TUNEL. The relative areas of VSMCs, macrophages, collagen fibers and lipid deposits were calculated. In the early-stage atherosclerosis, VSMCs were predominant in CA lesions, while macrophages were predominant in AO lesions. PCNA-positive VSMCs and macrophages were noted in early-stage atherosclerosis in CA and AO. Collagen type I, III-V fibers were present in early-stage lesions of the AO, while type VI increased in the deep layer during the progression of atherosclerosis. The proportion of apoptotic cells increased in CA and AO lesions with the progression in atherosclerosis. Our results showed differences in the distribution patterns of VSMCs and macrophages at various stages of atherosclerosis in CA and AO of WHHL rabbits.

Successive, rapid recurrences of in-stent restenoses in a woman with angina pectoris.

A 62-year-old woman was admitted because of chest pain. Coronary angiography demonstrated stenosis of the left anterior descending coronary artery, where two bare metal stents had been implanted. Over 5 months in-stent restenosis occurred four times, and was treated at first with angioplasty but finally with two sirolimus-eluting stent insertions. Six months after the second insertion, angiography showed restenosis within one stent. The mechanism underlying this succession of rapid restenoses is unknown, but sirolimus-eluting stents appeared to show relative resistance.

Biphasic effect of HMG-CoA reductase inhibitor, pitavastatin, on vascular endothelial cells and angiogenesis.

BACKGROUND: HMG-CoA reductase inhibitors (statins) have pleiotropic effects beyond their cholesterol-lowering effect. However, consensus on the effect of statins on endothelial cells and angiogenesis has not yet been reached. METHODS AND RESULTS: The effects of pitavastatin on the migration, proliferation and viability of human epidermal microvessel endothelial cells (HMVECs) were examined using scratch assay, chemotaxis chamber, bromodeoxyuridine incorporation, trypan blue dye exclusion test, and nuclear DNA staining. Pitavastatin enhanced the migration, proliferation and viability of HMVECs at a low concentration (0.01 micromol/L) but inhibited them at high concentration (1 micromol/L). The inhibitory effect on cell viability by high concentration of pitavastatin was recovered by geranylgeranyl pyrophosphate, but the effect on migration and proliferation was not. The cell activating effect of a low concentration of pitavastatin was reversed by both farnesyl pyrophosphate and geranylgeranyl pyrophosphate. A quail chorioallantoic membrane assay showed that high concentration (1 micromol/L) of pitavastatin reduced fibroblast growth factor-2-induced angiogenesis, whereas low concentration (0.3 micromol/L) tended to increase angiogenesis. CONCLUSION: Pitavastatin has a biphasic effect on HMVECs and on angiogenesis through at least 2 different pathways that include the mevalonate pathway.

Improvement of atrial signal-averaged electrocardiographic abnormalities after radiofrequency catheter ablation in persistent atrial flutter.

It has been reported that abnormalities of atrial conduction are present in patients with atrial flutter (AFL). We analyzed the P wave signal-averaged ECG (PSE) in patients after cardioversion of chronic AFL by radiofrequency catheter ablation (RFCA) to determine whether abnormalities of atrial conduction exist in patients with AFL and whether they recover. We studied 11 patients undergoing ablation of persistent AFL (AFL group), 11 patients with paroxysmal AFL (PAFL group), and 14 patients without any evidence of arrhythmias (control group). The PSEs were recorded 1 day, 7 days, and 1 month after RFCA. The filtered P wave duration (FPD) was calculated from the PSE recording. The FPD correlated with interatrial conduction time (r = 0.644) and left atrial dimension (r = 0.675) in combined assessment of the AFL and PAFL groups. The FPD was longer in the AFL group 1 day (165 +/- 14 ms, P < 0.001) and 1 month (150 +/- 18 ms, P < 0.05) after RFCA than in the control group (134 +/- 10 ms). Our findings suggest that atrial conduction abnormalities detected by PSE are present in patients with persistent AFL and improve 1 month after cardioversion.

Diagnostic evaluation of acute pancreatitis in two patients with hypertriglyceridemia.

We present two diagnostically challenging cases of acute pancreatitis with hypertriglyceridemia accompanied with chylomicronemia caused with a deficiency of lipoprotein lipase and with the presence of type V hyperlipidemia. Both cases suffered from acute abdomen following the ingestion of fatty food and revealed the increase in parameters of inflammation without significant elevation of serum amylase levels. The imaging examination of ultrasonography could not detect significant findings of acute pancreatitis and a computer tomography scan eventually confirmed the findings of acute pancreatitis. Both cases responded to a low fat diet and administration of a cholecystokinin receptor antagonist, exhibiting a relief of abdominal symptoms. As in the present cases with acute abdomen following the ingestion of fatty food, the identification of serum hypertriglyceridemia and an abdominal computer tomography scan might be useful in establishing the diagnosis of acute pancreatitis and in developing the therapeutic regimen, when hypertriglyceridemia interferes with the evaluation of pancreatic enzyme activities and ultrasound examination provides poor pancreatic visualization.

Matrix metalloproteinase-9 contributes to human atrial remodeling during atrial fibrillation.

OBJECTIVES: The purpose of this study was to determine the relationship between matrix metalloproteinases (MMPs)-1, -2, and -9, and tissue inhibitors of metalloproteinases (TIMP)-1 and the atrial structural remodeling during atrial fibrillation (AF). BACKGROUND: Matrix metalloproteinases, a family of proteolytic enzymes and TIMPs, regulate the extracellular matrix turnover in cardiac tissue. METHODS: Tissue samples were obtained from 25 patients without a history of AF (regular sinus rhythm [RSR]) and 13 patients with AF (paroxysmal AF: 6, chronic AF 7) undergoing cardiac operations. We performed a western blotting analysis of the MMP-1, -2, and -9, and quantitatively analyzed the expression of the MMP-9 and TIMP-1 by real time polymerase chain reaction and ELISA. The localization of the MMP-9 was investigated by in situ zymography and immunohistochemistry. RESULTS: The active form of the MMP-9 was significantly increased in the AF group in comparison to that in the RSR group (p < 0.05), but there were no differences between the groups in the protein level of the latent form of the MMP-9 and active and latent forms of the MMP-1 and MMP-2. We also demonstrated that the expression of the MMP-9 was significantly more increased in the atria of the AF group than in that of the RSR group for both the messenger ribonucleic acid (mRNA) (AF: RSR; 1: 1.5) and protein levels (AF: RSR; 3.9 +/- 1.3 : 1.5 +/- 0.4 ng/mg atrium). The expression level of the MMP-9 was also higher in the PAF group than in the RSR group, however, the diameter of the left atrium was similar in both groups. The gelatinase activity and left atrium diameter were positively correlated (p < 0.05, R = 0.766). The relative expression of the mRNA for the monocyte chemoattractant protein-1 was higher in the AF group than in the RSR group. Immunohistochemical analysis revealed that the MMP-9 was distributed within the perivascular area and under the epicardium of the atria. CONCLUSIONS: We clearly showed that the expression of the MMP-9 increased in fibrillating atrial tissue, which may have contributed to the atrial structural remodeling and atrial dilatation during AF.

Angiotensin-converting enzyme insertion/deletion genotype is associated with the activities of plasma coagulation factor VII and X independent of triglyceride metabolism.

BACKGROUND: The D allele of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and coagulation activity play important roles in cardiovascular events, however, the precise association between these two risk factors remains unclear. METHODS: We identified the ACE I/D genotype and measured the plasma coagulation factor VII and X (FVII and FX) activities and serum lipids in 172 patients (110 men and 62 women, mean age 56.7+/-13.3 years) undergoing coronary angiography. RESULTS: The frequency of the D allele was significantly higher in those with a history of myocardial infarction (MI) than in those with normal coronary arteries, but there was no significant association between FVII and FX activities and the stage of coronary disease. Plasma coagulation factor VII and FX activities were significantly lower in the DD genotype (n=42) than in the II genotype (n=67, P<0.001 and P<0.001, respectively) or the ID genotype (n=63, P<0.01 and P<0.05, respectively). The association of the ACE D allele with lower activities of FVII and FX was also seen in patients with coronary artery disease (CAD). There was a significant association between serum triglyceride levels with FVII and FX, but not with the ACE I/D genotype. CONCLUSION: We concluded that the ACE I/D polymorphism may contribute more to the onset of MI than the activities of FVII and FX and that the ACE D allele might be associated with lower plasma activities of FVII and FX. The potential link between ACE I/D polymorphism and the plasma activities of FVII and FX is probably independent of triglyceride metabolism.

Sweet elements of Siraitia grosvenori inhibit oxidative modification of low-density lipoprotein.

This study examined the ability of sweet elements extracted from Siraitia grosvenori (SG) to inhibit the oxidation of LDL. We monitored the formation of conjugated diene during copper-mediated LDL oxidation in the presence or absence of sweet elements of whole extract of SG (SG extract) or cucurbitane glycosides (CGs) purified from SG extract as sweet elements. CGs consist of Mogroside IV (Mog.IV), Mogroside V (Mog.V), 11-Oxo-mogroside V (11-Oxo-mog.V), and Siamenoside I (Sia.I). In addition, the effect of these elements on human umbilical vein endothelial cell (HUVEC)- mediated LDL oxidation was tested by measuring production of lipid peroxides. SG extract inhibited copper-mediated LDL oxidation in a dose-dependent fashion, but neither glucose nor erythritol suppressed the oxidation. Among CGs, 11-Oxo-mog.V significantly inhibited LDL oxidation, and prolongation of the lag time during LDL oxidation by 11-Oxo-mog.V was dose-dependent. The lag time (119.7 +/- 8.9 min) in the presence of 200 microM 11-Oxo-mog.V was significantly longer than that (76.8 +/- 5.5 min) of control (p < 0.01). In addition, SG extract and 11-Oxo-mog.V inhibited HUVEC-mediated LDL oxidation in a dose-dependent manner. These results demonstrate that SG extract can inhibit LDL oxidation and that 11-Oxo-mog.V, a sweet element of SG extract, provides the anti-oxidative property of SG which might reduce the atherogenic potential of LDL.