Ischemic heart disease is the single leading cause of death and a significant cause of morbidity among women in industrialized countries. Current guidelines recommend antiplatelet therapy as the main cornerstone for the prevention and treatment of cardiovascular disease. Unfortunately, evidence is emerging that the response to antiplatelet drugs differs according to sex, although the biological basis for this gender disparity is unknown. In order to explain the epidemiological data showing a more severe clinical expression of cardiovascular disease in addition to adverse outcomes despite optimal pharmacological and interventional approaches in women compared to men, differences in platelet reactivity related to sex and gender are currently under investigation. In this report, we review available data from clinical trials of antiplatelet drugs administered for primary and secondary prevention, focusing on the underenrollment of female subjects in interventional randomized studies and weak community awareness of the impact of cardiovascular disease on life expectancy in women. Based on our findings, the development of real gender-oriented evidence-based guidelines for antiplatelet use in the setting of cardiovascular disease is urgently required.

View full abstract

Aim: To investigate the usefulness of the plasma big endothelin-1 (big ET-1) level in predicting the severity of new-onset stable angiography-proven coronary artery disease (CAD).
Methods: A total of 963 consecutive stable CAD patients with more than 50% stenosis in at least one main vessel were enrolled. The patients were classified into the three groups according to the tertile of the Gensini score (GS, low GS ＜20, n=300; intermediate GS 20-40, n=356 and high GS ＞40, n=307), and the relationship between the big ET-1 level and GS was evaluated.
Results: The plasma levels of big ET-1 increased significantly in association with increases in the GS tertile (p=0.007). A multivariate analysis suggested that the plasma big ET-1 level was an independent predictor for a high GS (OR=2.26, 95%CI: 1.23-4.15, p=0.009), and there was a positive correlation between the big ET-1 level and the GS (r=0.20, p=0.000). The area under the receiver operating characteristic curve (AUC) for the big ET-1 level in predicting a high GS was 0.64 (95% CI 0.60-0.68, p=0.000), and the optimal cutoff value for the plasma big ET-1 level for predicting a high GS was 0.34 fmol/mL, with a sensitivity of 62.6% and specificity of 60.3%. In the high-big ET-1 level group (≥0.34 fmol/mL), there were significantly increased rates of three-vessel disease (43.6% vs. 35.4%, p=0.017) and a high GS [31 (17-54) vs. 24 (16-44), p=0.001] compared with that observed in the low-big ET-1 level group.
Conclusions: The present findings indicate that the plasma big ET-1 level is a useful predictor of the severity of new-onset stable CAD associated with significant stenosis.

View full abstract

Aim: Recent studies have suggested that the serum osteocalcin level is associated with various cardiovascular risk factors. The aim of this study was to determine whether the serum total osteocalcin level is associated with the development of cardiovascular disease (CVD).
Methods: A total of 1,290 men 40-78 years of age were enrolled. The subjects were followed regularly at the Health Promotion Center on an outpatient basis and during hospitalization for a mean of 8.7 years, and the incidence of CVD (coronary heart disease [CHD] and stroke) was determined.
Results: At baseline, the body mass index, body fat percentage, fasting glucose, homeostasis model assessment-insulin resistance, triglyceride and non-high density lipoprotein (HDL) cholesterol levels were inversely and the HDL cholesterol levels were positively associated with the serum osteocalcin levels. In addition, the prevalence of diabetes or metabolic syndrome decreased as the osteocalcin tertile increased. However, no differences were observed in the prevalence of hypertension across the osteocalcin tertiles. Incident CVD occurred in 74 (5.7%) of the study subjects (29 patients with CHD and 47 patients with stroke). According to the Cox proportional hazards models, however, there were no statistical differences in the development of stroke, CHD or CVD across the osteocalcin tertiles after adjusting for other risk factors for CVD, including age, body mass index, current smoking, low-density lipoprotein cholesterol, diabetes, hypertension and the serum creatinine level.
Conclusion: In conclusion, the serum total osteocalcin level was not associated with the development of CVD after adjusting for other risk factors for CVD in this cohort.

View full abstract

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.

View full abstract

Aims: Cilostazol may have a positive chronotropic or pro-arrhythmic effect. However, there have been no randomized trials to confirm these effects.
Methods: This randomized prospective trial compared dual (DAT, aspirin and clopidogrel, n=114) versus triple antiplatelet therapy (TAT, DAT plus cilostazol, n=113) at baseline and after six months in patients receiving intracoronary drug-eluting stents (DES). The primary endpoint was the 24-hour heart rate (24h-HR) at six months determined using 24h-Holter ECG monitoring. The secondary endpoints were the 24h-HR ≥70 bpm, 24h-HR increase ≥5 bpm and the counts or presence of arrhythmias.
Results: At six months after DES implantation, the 24h-HR (73 [68-83] vs. 68 [62-75] bpm, p＜0.001), presence of a 24h-HR ≥70 bpm (71.4 vs. 47.1%, p＜0.001) and presence of a 24h-HR increase ≥5 bpm (44.8 vs. 24.5%, p=0.002) were significantly higher for the TAT group than for the DAT group. A multivariate analysis showed that the use of cilostazol (OR: 3.10, p=0.035) and a baseline 24h-HR ＜70 bpm (OR: 4.60, p＜0.001) were strong predictors of a 24h-HR increase ≥5 bpm. However, there were no significant intergroup differences in arrhythmias.
Conclusions: Cilostazol appears to result in an increase in the 24h-HR after DES implantation. Therefore, some caution should be exercised regarding the use of cilostazol in patients with tachycardia, when planning DES implantation.

View full abstract

Aim: Silent mating type information regulator 2 homolog 1 (SIRT1) functions as an atheroprotective factor in vascular biology, and genetic variations in SIRT1 are associated with coronary artery calcification and type 2 diabetes in several populations. In this study, we investigated the relationship between the mRNA expression levels of the SIRT1 gene and single nucleotide polymorphisms (SNPs) in the context of acute coronary syndrome (ACS).
Methods: Whole-genome expression microarray and real-time PCR techniques were used to detect the gene expression levels, and Western blotting was performed to determine the protein expression level. The four selected SNPs were genotyped in a Taqman genotyping platform.
Results: Compared with that observed in the controls, the mRNA expression levels of the SIRT1 gene in the microarray study were significantly lower in the acute myocardial infarction (AMI), unstable angina (UA) and overall ACS patients. These results were replicated in another independent cohort with respect to the mRNA (AMI, p＜0.001; UA, p＜0.001; ACS, p＜0.001) and protein (p＜0.05) levels. Furthermore, the relationship between the SIRT1 mRNA expression and the genotypes of four possible functional SNPs (rs12778366, rs3758391, rs2273773 and rs4746720) was tested, the results of which showed significant differences in the SIRT1 mRNA expression among the allelic genes of rs3758391 (p＜0.01) in the healthy participants.
Conclusions: The present results confirm that the SIRT1 gene plays a protective role against ACS and that the rs3758391 SNP affects the mRNA expression in healthy participants, providing new insight into the processes regulating the genetic control of the SIRT1 gene with respect to the pathogenesis of ACS.

View full abstract

Aim: Intracranial atherosclerotic major artery stenosis (IMAS) is associated with a high risk of ischemic stroke. Carotid ultrasound (US) has been widely used to evaluate an individual’s atherosclerotic burden, but no information is available on whether the carotid US findings are associated with IMAS progression. The aim of the present study was to identify the associations among traditional risk factors, the duplex carotid US findings and IMAS progression in patients with varying degrees of carotid atherosclerosis.
Methods: All patients who underwent a set of imaging studies (MRI, MRA and carotid US) in our outpatient clinic were screened. A total of 101 patients with a mean age of 75.0±10.6 years, who received the same imaging studies with a mean interval of two years, were studied. In each patient, the extent of stenosis of three arteries (both middle cerebral arteries [MCAs] and the basilar artery [BA]) was classified into five grades. The total score of the three arteries was calculated as the global stenosis score (GSS). The progression of IMAS was defined as worsening of stenosis by ≥1 grade on final MRA. The maximum IMT (maxIMT), plaque findings and carotid stenosis were measured by carotid US. A multivariate stepwise logistic regression analysis was used to identify independent predictors of IMAS progression.
Results: Follow-up MRA revealed IMAS progression in 12 patients (11.9%). The logistic regression analysis demonstrated that the baseline GSS (p=0.008) and carotid stenosis ≥70% on the baseline carotid US (p=0.023) were significantly associated with IMAS progression.
Conclusions: The baseline severity of intracranial and extracranial atherosclerosis was significantly associated with the progression of IMAS.

View full abstract

Aim: Our objective was to evaluate the incidence of cardiovascular complications before and after unilateral adrenalectomy in patients with and without KCNJ5 gene mutations harboring aldosterone-producing adenoma (APA).
Methods: A total of 108 APA patients were evaluated in the present study. We compared the clinical characteristics and laboratory findings according to the cardiovascular complications in the patients with or without KCNJ5 gene mutations harboring APA after excluding five APA patients with ATPase or CACNA1D gene mutations.
Results: There were 75 and 28 APA patients with somatic mutations of KCNJ5 (p.G151R, p.L168R, p.E145Q, p.T158A or 157del) and no mutations, respectively. There were no double mutations in any of the subjects. The KCNJ5-mutated and wild type groups demonstrated similar advances in left ventricular hypertrophy prior to surgery, although the mutated group was significantly younger, with higher plasma and urine aldosterone levels, than the wild type group (48.2 vs. 55.8 (years old); p＜0.001, 436.0 vs. 247 (pg/mL); p＜0.001, 22.2 vs. 12.6 (μg/day); p=0.008). Both groups displayed postoperative improvements in hyperaldosteronism and hypertension. Moreover, the LV mass index (LVMI) significantly improved after surgery in the mutated group (p＜0.001), but not in the wild type group (p=0.256). A multiple linear regression analysis showed that an improvement in the LVMI was independently associated with KCNJ5 mutations and the plasma aldosterone level in that order (p=0.034, 0.050, respectively).
Conclusion: The present findings clearly demonstrated that KCNJ5 mutations are common among Japanese APA patients (frequency: 69.4%). In this study, the KCNJ5-mutated group demonstrated significant postoperative improvements in LVMI, possibly due to strong autonomous aldosterone production. Hence, it is necessary to precisely diagnose younger APA patients possessing a strong capacity for aldosterone production due to KCNJ5 gene mutations, as such cases may be easily complicated by cardiovascular events.

View full abstract

Aim: Computer simulation is a new method for understanding biological phenomena. In this report, we developed a simple platelet simulator representing platelet adhesion under blood flow conditions.
Methods: We generated virtual platelets based on the functions of three key adhesive proteins: glycoprotein (GP) Ibα, GPIIb/IIIa and collagen receptors. The adhesive force between GPIbα and von Willebrand factor (VWF) was set to increase in association with increments in the fluid shear stress. GPIIb/IIIa acquires an adhesive force to bind with ligands only when platelets are activated following multiple GPIbα stimulation by VWF or collagen receptors.
Results: Upon perfusion over the area of virtual endothelial injury, the virtual platelets adhered and became activated to form platelet thrombi. A total of 286/mm² of activated platelets was found to have accumulated downstream of the flow obstacle within 30 seconds, with 59/mm² platelets adhering upstream. The results obtained with the virtual model were consistent with those for real platelets in human blood in the presence of similarly shaped flow obstacles.
Conclusions: Our computer platelet simulator, which employs the functions of three key platelet membrane proteins, shows similar findings for adhesion in the presence and absence of blood flow obstacles.

View full abstract

Aim: A noninvasive approach to assess atherosclerosis in young people is of great concern. The cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI) reflect the arterial conditions, although the CAVI has not fully been studied in Russian populations. This study aimed to determine the CAVI and ABI in young Russians, to compare these findings with those in their Japanese peers and to investigate the lifestyle correlates and genetic associations with the CAVI and ABI in the Russians.
Methods: In addition to several atherosclerotic parameters and self-reported lifestyle factors, the CAVI and ABI levels were measured in 114 Russians (mean 21 years). Four gene polymorphisms, including cholesteryl ester transfer protein (CETP) Taq1B polymorphism, were typed in some of the subjects.
Results: The Russians exhibited significantly higher CAVI levels compared to their Japanese counterparts (5.87 vs. 5.36; p＜0.05), while the ABI levels were similar between the two populations. In the Russians, the ABI was significantly correlated with the mean blood pressure (r=−0.26) and heart rate (r=−0.43), while the CAVI did not show such correlations. No significant associations existed between lifestyle-related factors and the CAVI or ABI levels. A lower ABI level was found in carriers with the T-allele of CETP Taq1B in the Russians.
Conclusions: The reference CAVI value can be specified for individual ethnic populations. Our findings suggest that Russians may develop atherosclerosis-related conditions at a younger age compared to Japanese subjects, although this must be verified in additional studies. The possible association between CETP polymorphisms and the ABI deserves further investigation.

View full abstract

In the recent issue of the Journal of Atherosclerosis and Thrombosis, Wang et al. assessed the relationship between the red cell distribution width (RDW) and acute myocardial infarction (AMI). However, assessing all parameters affecting the RDW, determining the optimum RDW cut-off value for predicting the prognosis of coronary artery disease (CAD), excluding metabolic comorbidities affecting the RDW values and identifying the specific range for the WBC count within the exclusion criteria would provide more reliable results and improve the credibility of the entire article in this study population.

View full abstract