Takeo Anazawa

Effect of Exposure to Cigarette Smoke on Carotid Artery Intimal Thickening: The Role of Inducible NO Synthase

Objective—We investigated the role of inducible NO synthase (iNOS) in intimal thickening with exposure to cigarette smoke (CS). Methods and Results—Intimal thickening in wild-type (WT) and iNOS-deficient (iNOS−/−) mice subjected to CS exposure was induced by placement of a cuff around the carotid artery. CS exposure in WT mice was associated with increased arterial iNOS expression, superoxide production, activator protein-1 (AP-1) activation, and serum NO. Intimal thickening 21 days after cuff placement was significantly greater in mice exposed to CS compared with air (0.023±0.013 mm2 versus 0.009±0.008 mm2; P<0.05). iNOS inhibitor mercaptoethylguanidine-treated WT mice exposed to CS had reduced iNOS activity and intimal thickening (0.006±0.005 mm2; P<0.05). Intimal thickening was significantly less in iNOS−/− mice compared with WT mice (0.006±0.005 mm2; P<0.01) and was not augmented with CS (0.002±0.002 mm2). The aryl hydrocarbon receptor (AhR) was detected in arteries in vivo and in smooth muscle cells (SMCs) in vitro. CS condensate treatment of SMCs increased AhR binding to the core xenobiotic-responsive element of the iNOS promoter and increased iNOS expression. Conclusions—Increased arterial expression of iNOS, mediated at least in part by AhR signaling, may be an important mechanism by which CS increases carotid intimal thickening. CS exposure in mice was associated with increased arterial iNOS expression, superoxide production, AP-1 activation, serum NO expression, and intimal thickening. Inhibition or deletion of iNOS abrogated the effects of CS.

Treatment of coronary spastic angina with a statin in addition to a calcium channel blocker: a pilot study.

Combined therapy with a statin and a calcium channel blocker, which can improve lipid metabolism and reduce oxidative stress, may attenuate coronary vasoconstriction in patients with coronary spastic angina (CSA). After 6 months of therapy with benidipine and pravastatin, an acetylcholine provocation test was performed a second time in 25 patients with CSA. The patients were divided into 2 groups according to whether the result of this second test was positive (n = 13) or negative (n = 12). The test was designated as positive when the intracoronary injection of acetylcholine induced angiographically demonstrable total or subtotal occlusion (positive-test group). In the negative-test group, significant decrease in the plasma levels of low-density lipoprotein (LDL) cholesterol (−20.7 ± 11.1%, P < 0.01 versus baseline) were observed along with a dramatic increase in the serum level of high-density lipoprotein (HDL) cholesterol (26.8 ± 13.2%, P < 0.01 versus baseline). Furthermore, a significant decrease of the malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, a marker of oxidative stress, was also observed (-22.6 ± 14.1%, P < 0.01 versus baseline) in this group. In the positive-test group, however, no significant changes were found in any of the aforementioned parameters. The results showed that improvement of lipid metabolism, especially an increase of HDL cholesterol level and a reduction of MDA-LDL, may inhibit vascular contractility.

Association of plasma level of malondialdehyde-modified low-density lipoprotein with coronary plaque morphology in patients with coronary spastic angina: implication of acute coronary events.

BACKGROUND Focal vasospasm is reportedly involved in a high incidence of acute coronary syndrome (ACS) as compared with diffuse vasospasm. No adequate studies have been conducted on the mechanism underlying the higher incidence of ACS involving focal vasospasm than of those involving diffuse vasospasm in patients with coronary spastic angina. METHODS AND RESULTS Blood samples were collected from the aortic root (Ao) and the coronary sinus (CS) before provoking left coronary vasospasm using intracoronary administration of acetylcholine. After relief of vasospasm, volumetric analyses of vasospastic lesions were evaluated with 3-dimensional intravascular ultrasound in 64 patients. The percent plaque volume was more prominent in focal (n=31) than in diffuse vasospasm (n=33) (40.9+/-9.4 vs. 23.3+/-9.2%, p<0.0001). The Cs-Ao difference of malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, as a marker of atherothrombosis, in focal vasospasm increased significantly as compared with diffuse vasospasm (6.9+/-6.7 vs. 1.2+/-5.7 U/L, p=0.001). In a multiple-logistic regression analysis with the traditional risk factors, the Cs-Ao difference of MDA-LDL level was a variable differing independently between the 2 types of vasospasm. CONCLUSIONS Higher MDA-LDL levels were observed in the coronary circulation in patients with focal vasospasm than in those with diffuse vasospasm. Under these conditions, the dramatically increased percent plaque volume in cases with focal vasoconstriction may play an important role in the development of acute coronary events.

Relation of change in apolipoprotein B/apolipoprotein A-I ratio to coronary plaque regression after Pravastatin treatment in patients with coronary artery disease.

Some investigations have looked into the ability of measurements of apolipoprotein B/apolipoprotein A-I (apoB/apoA-I) ratio to predict cardiovascular events. We hypothesized that a decrease in the apoB/apoA-1 ratio by statin therapy would act on suppression of coronary plaque progression. A 6-month prospective study was conducted of 64 patients with coronary artery disease treated with pravastatin. The plaque volume, assessed by volumetric intravascular ultrasonography, had decreased significantly by 12.6% (p <0.0001 vs baseline). Although a significant decrease of 6.4% and 14.6% was found in the serum level of apoB and the apoB/apoA-1 ratio (p = 0.0001 and p <0.0001, respectively, vs baseline), a significant increase of 14.0% of and 12.0% in the level of apoA-I and apoA-II (both p <0.0001 vs baseline). No significant changes were found in the level of apoC-II or apoE. A stepwise regression analysis revealed that the change in the apoB/apoA-1 ratio was an independent predictor of the change in coronary plaque volume (beta coefficient 0.386; p = 0.0023). In conclusion, our results have indicated that the decrease in the apoB/apoA-I ratio is a simple predictor for coronary atherosclerotic regression: the lower the apoB/apoA-I ratio, the lower the risk of coronary atherosclerosis.

Efficacy of Calcium Channel Blocker in the Secondary Prevention of Myocardial Infarction

BACKGROUND Calcium channel blockers (CCBs) may have a positive influence on the long-term prognosis of Japanese patients with ischemic heart disease. METHODS AND RESULTS The effect of nifedipine-retard (NR) (n=202) compared with that of non-CCB treatment (n=92) on the secondary prevention of myocardial infarction (MI) was retrospectively investigated in patients who had survived acute MI between 1987 and 1996. The primary endpoint was the occurrence of cardiac death or non-fatal MI. The median follow-up was 6.3+/-2.4 years. The incidence of cardiac events was 8.9% in the NR group and 14.1% in the non-CCBs group (p=0.14, odds ratio (OR): 0.584, 95% confidence interval (CI): 0.286-1,193). However, subanalysis revealed that NR significantly reduced the incidence of cardiac events in patients aged less than 55 years (4.2 vs 18.2%, p=0.016, OR: 0.180, 95%CI: 0.045-0.721) and those who did not smoke (8.6 vs 16.4%, p=0.048, OR: 0.462, 95%CI: 0.203-0.999). CONCLUSION Although this was a retrospective analysis, it showed that NR did not cause an increase in the incidence of cardiac events in post-MI patients; it even prevented cardiac events, especially in those who were less than 55 years of age and in non-smokers, suggesting the potential usefulness of CCBs in the secondary prevention of MI in Japan.

iNOS is a mediator of increased arterial intimal thickening induced by passive cigarette smoke exposure in mice

vasodilatation (P8.03) and resulted in higher plasma t-PA antigen and activity concentrations during bradykinin Infusion (11.3+0.8 vs 6.6~0.5 ng/mL and 16.5t3.9 vs 6.6k2.0 IU/mL at peak bradykinin dose: PcO.002) and a doubling of estimated net t-PA release (PcO.05). Conclusion: Intra-arterial TNF-a causes an acute local vascular inflammation associated with a substantial and sustained increase in local t-PA and IL-6 release. TNFa also impairs endothelium-dependent vasomotion and augments acute endothelial t-PA release. These findings indicate that TNF-a has potentially adverse and beneficial effects on endothelial and vascular function.