Shigemasa Tani

Smoking Increases Tissue Factor Expression in Atherosclerotic Plaques Implications for Plaque Thrombogenicity

BACKGROUND Smoking increases the risk of atherothrombotic events. To determine whether smoking influences plaque thrombogenicity, we examined the effect of cigarette smoking and aspirin use on tissue factor (TF) expression in atherosclerotic plaques. METHODS AND RESULTS A total of 23 apoE-/- mice were exposed to cigarette smoke with (n=9) or without (n=14) aspirin treatment. Eleven mice who were exposed to filtered room air served as controls. Aortic root plaques of mice exposed to smoke had higher immunoreactivity for TF (14+/-4% versus 6.4+/-3%; P=0.0005), vascular cell adhesion molecule-1 (15+/-4% versus 5+/-2%; P=0.002), and macrophages (16+/-5% versus 6+/-2%; P=0.002) compared with nonsmoking controls. Aspirin treatment attenuated smoking-induced changes in plaque composition. In human plaques obtained by carotid endarterectomy, TF immunoreactivity (8+/-5% versus 2+/-2%; P=0.0002) and activity (P=0. 03) were higher in the plaques from smokers (n=28) than those from nonsmokers (n=28). Aspirin use was associated with reduced TF expression in smokers (9+/-8% versus 3+/-4%; P=0.0017). CONCLUSIONS Our results suggest increased plaque TF expression and thrombogenicity as a novel mechanism for the increased risk of atherothrombotic events in smokers. Treatment with aspirin may reduce TF expression.

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.

Significance of imbalance in the ratio of serum n-3 to n-6 polyunsaturated fatty acids in patients with acute coronary syndrome.

This study aimed to assess the balance of serum n-3 to n-6 polyunsaturated fatty acids (PUFAs) in patients with acute coronary syndrome (ACS). We enrolled 1,119 patients who were treated and in whom serum PUFA level was evaluated in 5 divisions of cardiology in a metropolitan area in Japan. Serum levels of PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA), were compared between patients with and without ACS. We also evaluated the balance of serum n-3 to n-6 PUFAs, including EPA/AA and DHA/AA ratios. EPA/AA values were 0.46 ± 0.32 and 0.50 ± 0.32 in the ACS and non-ACS groups, respectively. DHA/AA values were 0.95 ± 0.37 and 0.96 ± 0.41 in the ACS and non-ACS groups, respectively. Next, we divided the patients into 3 groups based on the tertiles of EPA/AA or tertiles of DHA/AA to determine the independent risk factors for ACS. According to multivariate logistic regression analysis, the group with the lowest EPA/AA (≤0.33) had a greater probability of ACS (odds ratio 3.14, 95% confidence interval 1.16 to 8.49), but this was not true for DHA/AA. In conclusion, an imbalance in the ratio of serum EPA to AA, but not in the ratio of DHA to AA, was significantly associated with ACS.

Diagnosis of anomalous origin of the right coronary artery using multislice computed tomography: evaluation of possible causes of myocardial ischemia.

Anomalous origin of the right coronary artery (RCA) is a rare condition, but may cause myocardial ischemia and sudden death. Multislice computed tomography, which allows three-dimensional visualization of the coronary artery with high spatial resolution, may be the most promising imaging modality for diagnosing this anomaly. We describe a patient with anomalous origin of the RCA arising from the left sinus of Valsalva. Volume rendering, and axial and curved multiplanar images showed stenosis in the proximal portion of the RCA that coursed between the aorta and the pulmonary artery, and an acute angled take-off of the RCA from the aorta. Three-dimensional virtual angioscopic images showed a hypoplastic RCA orifice and luminal narrowing in the proximal portion of the RCA. Multislice computed tomography was thought to be useful for detecting anomalous origin of the RCA and for evaluating possible causes of myocardial ischemia.

Effect of Pravastatin on Coronary Plaque Volume

A volumetric analysis by 3-dimensional intravascular ultrasound revealed that lipid-lowering therapy with pravastatin significantly reduced coronary plaque volume. The changes in plaque volume were inversely correlated with the changes in plasma levels of high-density lipoprotein cholesterol but not with changes in levels of total cholesterol or low-density lipoprotein cholesterol.

Takotsubo-shaped cardiomyopathy with type I CD36 deficiency

A transient left ventricular apical ballooning (so-called “ampulla” or “Takotsubo-shaped” cardiomyopathy) with type I CD36 deficiency is described in a 71-year-old woman. The patient was referred because of chest pain and worsening of dyspnea. Electrocardiogram showed T-wave inversions on the precordal leads, and acute coronary syndrome was suspected. Left ventricular apical ballooning was observed by echocardiogram and left ventriculography, and coronary arteriography did not reveal any significant stenosis. Left ventricular motion normalized at the follow-up period and there were no increases in specific markers for myocardial damage, such as myocardial band fraction of creatine kinase and troponin T, through out the admission. 123I-metaiodobengylguanidine myocardial single photon emission computed tomography (SPECT) revealed decreased accumulation areas at the apex, while 201Tl SPECT showed normal accumulation. An abnormal metabolism of cardiac free fatty acid was suggested by lack of accumulation of 123I beta-methyliodophenyl pentadecanoic acid (BMIPP) SPECT. No CD36 expression in either platelets or monocytes/macrophages was shown using flow cytometer analysis and type I CD36 deficiency was diagnosed. DNA sequencing showed that the patient had compound heterozygosity of the CD36 gene (a nucleotide change in C478T and an adenine insertion at nucleotide 1159 in exon 10). Although CD36 deficiency is thought to be involved with many cardiovascular disease and metabolic abnormalities, Takotsubo-shaped cardiomyopathy with CD36 deficiency had not been reported. Further studies of Takotsubo-shaped cardiomyopathy and CD36 deficiency may reveal an association between this cardiomyopathy and specific genetic profiles.

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 triglyceride-rich lipoproteins-related markers and low-density lipoprotein heterogeneity with cardiovascular risk: Effectiveness of polyacrylamide-gel electrophoresis as a method of determining low-density lipoprotein particle size

BACKGROUND Despite well-controlled low-density lipoprotein cholesterol (LDL-C), hypertriglyceridemia is an independent predictor of coronary events. We investigated the risk of atherosclerotic cardiovascular disease through examining the relation between triglyceride (TG) metabolism and LDL-heterogeneity as assessed by polyacrylamide-gel electrophoresis (PAGE). METHODS AND RESULTS Estimated LDL-particle size [relative LDL migration (LDL-Rm value)] measured by PAGE with the LipoPhor system (Joko, Tokyo, Japan) was evaluated in 645 consecutive patients with one additional risk factor for atherosclerotic cardiovascular disease.Multivariate regression analysis after adjustments for traditional risk factors revealed an elevated triglyceride-rich lipoproteins (TRLs)-related markers [TG, remnant-like particle cholesterol (RLP-C), very LDL (VLDL) fraction, apolipoprotein (apo) C-II, and apo C-III] level to be an independent predictor of smaller-size LDL-particle size, both in the overall population, and in a subset of patients with serum LDL-C <100 mg/dL. Even among the patients with LDL-C levels <100 mg/dL, the serum levels of atherogenic lipid markers in those with a LDL-Rm value ≥0.40, suggesting the presence of large amounts of small-dense LDL and upper limit (mean+2 standard deviation) in this population, were significantly higher than in those with a LDL-Rm value <0.40. Moreover, the serum levels of TRLs-related markers showed high accurate area under the receiver-operating characteristic curve (TG, 0.896; RLP-C, 0.875; VLDL fraction, 0.803; apo C-II, 0.778; and apo C-III, 0.804, respectively) in terms of evaluation of the indicators of LDL-Rm value ≥0.40. CONCLUSION To further reduce the risk of atherosclerotic cardiovascular disease, it may be of particular importance to pay attention not only to the quantitative change in the serum LDL-C, but also TG-metabolism associated with LDL-heterogeneity. Combined evaluation of TRLs-related markers and LDL-Rm value may be useful for assessing the risk of atherosclerotic cardiovascular disease.

Association of Fish Consumption-Derived Ratio of Serum n-3 to n-6 Polyunsaturated Fatty Acids and Cardiovascular Risk With the Prevalence of Coronary Artery Disease.

We investigated the relationships between the ratio of serum n-3 polyunsaturated fatty acids (n-3PUFAs: eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) to n-6PUFA (arachidonic acid [AA]) and the prevalence of coronary artery disease (CAD), and assessed the association of the ratio of serum n-3 to n-6 PUFAs with atherosclerosis-related markers.This study was designed as a hospital-based cross-sectional study of 649 consecutive outpatients who had undergone regular examinations between April 2009 and October 2009. We divided the patients into 5 groups based on the quintiles of the EPA/AA ratio or quintiles of the DHA/AA ratio to determine independent factors for the prevalence of CAD.In multivariate logistic regression analyses after adjustment for coronary risk factors and serum n-3PUFAs levels to minimize confounding factors to the extent possible because the serum levels of EPA and DHA showed a strong correlation (r = 0.812, P < 0.0001), the group with the highest EPA/AA ratio had a lower probability of CAD prevalence (odds ratio: 0.328, 95% confidence interval: 0.113 to 0.956, P = 0.041), but this was not true for the DHA/AA ratio. Multivariate analysis showed an increase in the EPA/AA ratio, but not in the DHA/AA ratio, was associated with effects on atherosclerosis-related markers, especially triglyceride-rich lipoproteins, high-density lipoprotein cholesterol (HDL-C) containing apolipoprotein A-1, and leukocyte count in an anti-atherogenic direction.The results suggest a higher EPA/AA ratio, but not a higher DHA/AA ratio, might be associated with a lower prevalence of CAD and improvements of triglyceride metabolism and HDL metabolism, and systemic inflammation.

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.