Observation of plaque behavior and tissue characterization of coronary plaque using speckle tracking intravascular ultrasound (ST-IVUS) and iMap imaging system.

Tissue characterization plays an important role in the development of acute coronary syndromes. iMap is an intravascular ultrasound (IVUS) tissue characterization system that provides useful information by reconstructing color-coded maps. Mechanical properties due to dynamic mechanical stress during a cardiac cycle may also trigger vulnerable plaque. Speckle tracking IVUS (ST-IVUS) has been introduced to observe plaque behavior in relation to mechanical properties. We report the case of an 84-year-old woman with stable coronary artery disease who underwent percutaneous coronary intervention, at which time IVUS demonstrated mainly three low echoic areas like lipid pools with thick fibrous caps. Pathological evaluation with iMap revealed that one low echoic area was occupied with necrotic tissue and that the other two areas occupied fibrotic. Although those tissue characterizations were different, they showed similar stretching behavior at systole by ST-IVUS which depicted plaque behavior from IVUS images using a color mapping. The mechanical properties of individual coronary plaques may differ depending on the tissue disposition. It is necessary to consider mechanical properties using ST-IVUS as well as to evaluate tissue characterization in plaque risk stratification.

Relationship between tissue characteristics and mechanical properties of coronary plaques: a comparison between integrated backscatter intravascular ultrasound (IVUS) and speckle-tracking IVUS.

High-risk coronary plaques have certain morphological characteristics. Thus, comprehensive assessment is needed for the risk stratification of plaques in patients with coronary artery disease. Integrated backscatter intravascular ultrasound (IB-IVUS) has been used successfully used to evaluate the tissue characteristics of coronary plaques; however, the mechanical properties of plaques have been rarely assessed. Therefore, we developed Speckle-tracking IVUS (ST-IVUS) to evaluate the mechanical properties of coronary plaque. This study aimed to evaluate the relation between the tissue characteristics of coronary plaques using IB-IVUS and their mechanical properties using ST-IVUS. We evaluated 95 non-targeted plaques in 95 patients undergoing elective percutaneous coronary intervention to the left anterior descending artery. We set regions of interest (ROIs) in the cross-sectional images of coronary plaques where we divided 120 degree plaques into four quadrants (every 30 degrees), with the center at the area of maximum atheroma thickness. We measured relative calcification area (%CA, relative fibrous area (%FI) and relative lipid pool area (%LP) in a total of 380 ROIs. In ST-IVUS analysis, we measured strain in the circumferential direction of the lumen area (LA strain: %), the external elastic membrane area strain (EEM strain: %), and strain in the radial direction (radial strain: %). On global cross-sectional area IB-IVUS analysis, the %CA was 1.2 ± 1.2%; the %FI was 49.0 ± 15.9%, and the %LP was 49.7 ± 16.5%. In ST-IVUS analysis, the LA strain was 0.67 ± 0.43%; the EEM strain was 0.49 ± 0.33%, and the radial strain was 2.02 ± 1.66%. On regional analysis, the %LP was not associated with the LA strain (r = - 0.002 p = 0.97), the EEM strain (r = - 0.05 p = 0.35), or with the radial strain (r = - 0.04 p = 0.45). These trends were seen between the %FI and the LA strain (r = 0.02 p = 0.74), the %FI and the EEM strain (r = 0.05 p = 0.35), and the %FI and the radial strain (r = 0.04 p = 0.50). A significant correlation was only observed between the %CA and the LA strain (r = - 0.15 p = 0.0038). Our findings indicate that the associations between mechanical properties and tissue characteristics lacked statistical significance, more often than not, and that it is necessary to evaluate the mechanical properties as well as plaque characteristics for risk stratification of coronary plaques.

Assessment of visit-to-visit variability in systolic blood pressure over 5 years and phasic left atrial function by two-dimensional speckle-tracking echocardiography.

Visit-to-visit variability in systolic blood pressure (VVV-SBP) has been associated with increased cardiac events. Hence, volume analysis by two-dimensional speckle-tracking echocardiography (2-DSTE) allows physicians to easily measure phasic left atrial (LA) function. However, the relationship of VVV-SBP and functional deformation of the left atrium with patients' clinical outcome is unclear. The aim of the study was to investigate the relationship between phasic LA function and VVV-SBP. The subjects were 70 male participants in whom 2-DSTE was performed to measure blood pressure at health check-ups every year for 5 years. The standard deviation of systolic blood pressure (SBP) was calculated to assess VVV-SBP. The average SBP (Ave-SBP) was also assessed. Total emptying function (EF) (reservoir function), passive EF (conduit function), and active EF (booster pump function) of the left atrium were calculated to evaluate phasic LA function by 2-DSTE. The Pearson correlation, simple regression analysis, and multivariate logistic regression analysis were used in data analysis. Participants' mean age was 50 ± 10 years, and 16 participants had hypertension. VVV-SBP correlated with total EF (r = - 0.30, p = 0.014) and active EF (r = - 0.35, p = 0.003). There was no correlation between the standard deviation of SBP and passive EF (r = - 0.10, p = 0.39). Ave-SBP had no significant relationship with total EF (r = - 0.06, p = 0.62), passive EF (r = - 0.08, p = 0.50), or active EF (r = - 0.03, p = 0.78). Active EF was also associated with VVV-SBP in multiple regression analysis. The active EF was significantly decreased in the highest quartile of VVV-SBP. Despite the small sample size of our study, the VVV-SBP showed a relationship with the phasic LA function. Our findings suggest that high VVV-SBP is noted to be associated with cardiovascular risk including a deterioration of LA function in clinical practice.

Relationships among pulmonary capillary wedge pressure, dry weight and natriuretic peptide in patients undergoing hemodialysis: a three-dimensional speckle tracking echocardiography study.

BACKGROUND: Although the evaluation of fluid status in hemodialysis (HD) patients is useful, relationship among pulmonary capillary wedge pressure (PCWP), dry body weight (DW) and natriuretic peptide has not been elucidated. In addition, there has been no objective marker for instantaneously monitoring hemodynamic improvement in response to HD. We previously reported that PCWP and time constant of left ventricular pressure decline (Tau) can be noninvasively estimated (ePCWP and eTau) by speckle tracking echocardiography (STE). The aim of this study was to elucidate the relationship among ePCWP, eTau, DW and natriuretic peptide in patients undergoing HD. METHODS: We measured ePCWP and body weight (BW) by STE in 81 patients and ANP and BNP by blood examination in 31 patients just before and after HD during sinus rhythm. RESULTS: The ePCWP decreased after HD, and this was associated with reductions in ln ANP, eTau and BW (r = 0.523, 0.271 and 0.814, respectively, p < 0.05). The % change in ePCWP was not correlated with the % change in ln BNP (p = 0.47). The change in ePCWP had a stronger correlation with the % change in BW than the change in any other parameters. CONCLUSIONS: The ePCWP is more sensitive to estimate the change in BW during HD than any other parameters such as ANP and BNP. These results indicated that a substantial amount of excess fluid can be assessed real-time by STE using ePCWP.

Relationship between electrical conduction and phasic left atrial function: P-wave signal-averaged electrocardiography and time-left atrial volume curve assessments using two-dimensional speckle-tracking echocardiography.

P-wave signal-averaged electrocardiography (P-SAECG) can detect imperceptible conduction abnormalities, and volume analysis using two-dimensional speckle-tracking echocardiography (2-DSTE) allows us to easily measure the phasic function of the left atrium (LA). Both conduction abnormalities and functional deformation of the LA may be linked to the clinical outcome; however, the exact relationship is unclear. The aim of this study was to investigate the relationship between the phasic function of the LA and electrical conduction using P-SAECG and 2-DSTE. The subjects were 112 male volunteers (age 46.9 ± 13.2 years) with normal cardiac function who underwent P-SAECG and 2-DSTE. The filtered p-wave duration (FPD) and the root-mean-square voltage for the last 20 ms (RMS20) on P-SAECG wave were measured in ms and µV, respectively. Total emptying function (EF) (reservoir function), passive EF (conduit function), and active EF (booster pump function) of the LA were calculated as percentages to evaluate phasic LA function using 2DSTE. The mean FPD was 134.3 ± 11.7 ms and the mean RMS20 was 4.59 ± 2.39 µV. The mean total EF was 60.5 ± 13.1%, mean passive EF was 39.4 ± 13.9%, and mean active EF was 35.1 ± 13.9%. FPD had a negative correlation with passive EF (r = - 0.20, p = 0.039). FPD showed no significant relationship with total EF (r = - 0.03, p = 0.78) or active EF (r = 0.13, p = 0.18). There was a significant association between RMS20 and passive EF (r = 0.19, p = 0.048); however, no there was no correlation between RMS20 and total EF (r = 0.12, p = 0.23), or between RMS20 and passive EF (r = - 0.02, p = 0.86). In multivariate regression analysis, passive EF was an independent factor that influenced FPD duration. This study indicated that FPD was associated with conduit function, which includes phasic LA function. Therefore, electrical conduction of the LA and left ventricular diastolic function are closely related. In the clinical setting, when conduction abnormalities are detected, lifestyle measures or interventions can be applied to reduce cardiovascular risk.

Left Ventricular Torsion in Hypertension and Hypertensive Heart Failure　- 3-Dimensional Speckle Tracking Echocardiography Assessment.

Background: Left ventricular (LV) torsion by contraction of inner and outer oblique muscles contributes to EF. Outer muscle plays a predominant role in torsion. We evaluated the impact of LV remodeling by hypertension (HTN) on torsion using 3-dimensional speckle tracking echocardiography (3D-STE). Methods and Results: LV strain, strain rate during systole (SR-S) and torsion at endocardium, mid-wall and epicardium were assessed on 3D-STE in 53 controls and 186 HTN patients. Torsion was defined as the difference between apical and basal rotation divided by long axis length. LVEF and strain, SR-S and torsion in all 3 layers in HTN without LV hypertrophy (LVH) were similar to those in controls. LV longitudinal strain at endocardium in HTN with LVH decreased, whereas LVEF was similar to that in controls and, which was associated with increased torsion at epicardium. Reduced LVEF in hypertensive HF was associated with reduced strain, SR-S and torsion in all layers and with LV dilation. On multivariate analysis, epicardial torsion was an independent determinant of LVEF. At epicardial torsion cut-off 0.41, the sensitivity and specificity for the identification of HFrEF were 88% and 68%. Conclusions: Torsion on 3D-STE may represent a compensatory mechanism to maintain LVEF despite reduced endocardial function, suggesting that the deterioration of torsion caused by insult to outer muscle and dilation may lead to HFrEF.

Non-Invasive Pulmonary Capillary Wedge Pressure Assessment on Speckle Tracking Echocardiography as a Predictor of New-Onset Non-Valvular Atrial Fibrillation　- Four-Year Prospective Study (NIPAF Study).

BACKGROUND: Although new-onset atrial fibrillation (AF) increases with ageing, the prediction of new-onset AF is complicated. We previously reported that pulmonary capillary wedge pressure (ePCWP) estimated by the combination of left atrial volume index (LAVI) and active left atrial emptying function (aLAEF) had a strong relationship with PCWP on catheterization (r=0.92): ePCWP=10.8-12.4×log (aLAEF/minimum LAVI). We sought to determine the usefulness of ePCWP to predict new-onset AF. Methods and Results: We measured LAVI, aLAEF and ePCWP on speckle tracking echocardiography (STE) in 566 consecutive elderly patients (72±6 years) without a history of AF. A total of 63 patients (73±6 years) developed electrocardiographically confirmed AF during a mean follow-up period of 50 months. Baseline aLAEF was significantly lower in patients with than without new-onset AF (17.9±6.5 vs. 28.2±7.5%), whereas ePCWP was significantly higher (14.8±3.7 vs. 10.3±3.1 mmHg). In multivariate logistic regression analysis, ePCWP and aLAEF were strong independent predictors of AF. Using ePCWP >13 mmHg or aLAEF ≤22% on univariate Cox regression analysis, the HR for new-onset AF were 3.53 (95% CI: 1.68-7.44, P<0.001) and 4.06 (95% CI: 1.90-8.65, P<0.001), respectively. By combining these 2 criteria (>13 mmHg and ≤22%), the HR increased to 11.84 (95% CI: 6.85-20.5, P<0.001). CONCLUSIONS: ePCWP and aLAEF measured on STE are useful predictors of new-onset AF. ePCWP provides added value for risk stratification of new-onset AF.

Association of genetic variants with atrial fibrillation.

Recent genome-wide association studies (GWASs) identified various genes and loci that confer susceptibility to coronary artery disease or myocardial infarction among Caucasian populations. As myocardial ischemia is an important risk factor for atrial fibrillation, we hypothesized that certain polymorphisms may contribute to the genetic susceptibility to atrial fibrillation through affecting the susceptibility to coronary artery disease. The aim of the present study was to examine the possible association of atrial fibrillation in Japanese individuals with 29 polymorphisms identified as susceptibility loci for coronary artery disease or myocardial infarction in the meta-analyses of GWASs in Caucasian populations. The study subjects comprised 5,470 Japanese individuals (305 subjects with atrial fibrillation and 5,165 controls). Genotypes for 29 polymorphisms were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons of the allele frequencies by the χ2 test revealed that rs599839 (G→A) of the proline/serine-rich coiled-coil 1 gene (PSRC1, P=0.0084) and rs11556924 (C→T, Arg363His) of the zinc finger, C3HC-type containing 1 gene (ZC3HC1, P=0.0076) were significantly (P<0.01) associated with atrial fibrillation. Multivariable logistic regression analysis with adjustment for age, gender, body mass index, estimated glomerular filtration rate, and the prevalence of smoking, hypertension, diabetes mellitus, and dyslipidemia revealed that rs599839 (P=0.0043; odds ratio, 1.56; dominant model) and rs11556924 (P=0.0043; odds ratio, 1.93; dominant model) were significantly associated with atrial fibrillation, with the minor G and T alleles, respectively, representing risk factors for this condition. PSRC1 and ZC3HC1 may thus be susceptibility loci for atrial fibrillation in Japanese individuals.

Impact of gender and healthy aging on pulmonary capillary wedge pressure estimated by the kinetics-tracking index using two-dimensional speckle tracking echocardiography.

Risk stratification in heart failure (HF) among patients and healthy subjects using pulmonary capillary wedge pressure (PCWP) is important for understanding when and why HF develops. The aim of the present study was to evaluate the impact of gender and healthy aging on estimated PCWP using a kinetics-tracking index in patients and in healthy subjects without hypertension. The study population consisted of 198 healthy subjects without cardiovascular or other systemic diseases and who were not taking any medications. Echocardiographic studies were performed using an ACUSON Sequoia 512 ultrasound system. Active left atrial (LA) emptying function (EF) was defined as (pre-atrial contraction LA volume-minimum LA volume)/pre-atrial contraction LA volume × 100%. With an increase in age, the E/A and E/e' ratios (markers of left ventricular (LV) diastolic dysfunction (DD)) showed a similar decrease in males and females. PCWP was maintained at 8.3±1.8 mm Hg in males and 8.2±2.3 mm Hg in females because of compensation by an increase in active LA EF. In contrast, the compensation for LV DD with an increase in active LA EF in females tended to be more gradual (slope=0.11) than in males (slope=0.18, P=0.060 vs. female). The parameters that indicated LV DD deteriorated with advancing age. PCWP might be maintained because of compensation, namely an increase in active LA EF in both males and females. The compensation in female septuagenarians and octogenarians was weaker than in male septuagenarians and octogenarians. This difference in compensation may explain why HF with preserved LV ejection fraction occurs more frequently in females than in males.

Association of FURIN and ZPR1 polymorphisms with metabolic syndrome.

Although genome-wide association studies (GWASs) have identified various genes and loci in predisposition to metabolic syndrome (MetS) or each component of this condition, the genetic basis of MetS in individuals remains to be identified definitively. The aim of the present study was to examine the possible association of MetS in individuals with 29 polymorphisms that were previously identified as susceptibility loci for coronary artery disease or myocardial infarction by meta-analyses of GWASs. The study population comprised 1,822 subjects with MetS and 1,096 controls. Subjects with MetS had ≥3 of the 5 components of the diagnostic criteria for MetS, whereas control individuals had 0-1 of the 5 components. The genotypes for the 29 polymorphisms were determined by the multiplex bead-based Luminex assay. Comparisons of allele frequencies by the χ2 test revealed that rs17514846 (A→C) of the furin (paired basic amino acid-cleaving enzyme) gene (FURIN; P=0.0006), rs964184 (C→G) of the ZPR1 zinc finger gene (ZPR1; P=0.0078) and rs599839 (G→A) of the proline/serine-rich coiled-coil 1 gene (P=0.0486) were significantly (P<0.05) associated with the prevalence of MetS. Multivariable logistic regression analysis with adjustment for age, gender and smoking status revealed that rs17514846 of FURIN (P=0.0016; odds ratio, 0.76; dominant model) and rs964184 of ZPR1 (P=0.0164; odds ratio, 1.21; dominant model) were significantly associated with MetS. The minor A allele of rs17514846 of FURIN was significantly associated with a decrease in the serum concentration of triglycerides (P=0.0293) and to an increase in the serum concentration of high-density lipoprotein (HDL) cholesterol (P=0.0460). The minor G allele of rs964184 of ZPR1 was significantly associated with increases in the serum concentration of triglycerides (P=6.2×10-9) and fasting plasma glucose level (P=0.0028) and to a decrease in the serum concentration of HDL cholesterol (P=0.0105). FURIN and ZPR1 may thus be susceptibility loci for MetS.

Association of genetic variants with dyslipidemia.

Although genetic variants, which regulate lipid metabolism, have been extensively investigated in Caucasian populations, the genes, which confer susceptibility to dyslipidemia in Japanese individuals, remain to be elucidated. The aim of the present study was to examine a possible association among hypertriglyceridemia, hypo­high density lipoprotein (HDL)­cholesterolemia or hyper­low density lipoprotein (LDL)­cholesterolemia in Japanese individuals with 29 polymorphisms observed to confer susceptibility for coronary heart disease. This was performed through meta­analyses of genome­wide association studies in Caucasian populations. The study population comprised 2,354 individuals with dyslipidemia (hypertriglyceridemia, hypo­HDL­cholesterolemia or hyper­LDL­cholesterolemia) and 3,106 control individuals. To compensate for multiple comparisons of genotypes, a false discovery rate (FDR) of <0.05 was adopted to determine the statistical significance of the associations. Comparisons of allele frequencies using the χ2 test revealed that rs964184 of zinc finger gene (ZPR1; FDR=2.1x10­7), rs4845625 of interleukin 6 receptor (IL6R; FDR=0.032), rs46522 of ubiquitin­conjugating enzyme E2Z gene (UBE2Z; FDR=0.032) and rs17514846 of furin (FDR=0.041) were significantly associated with hypertriglyceridemia. The χ2 test revealed that rs599839 of proline/serine­rich coiled­coil 1 (PSRC1; FDR=0.004) and rs2075650 of translocase of outer mitochondrial membrane 40 homolog (TOMM40; FDR=0.004) were significantly associated with hyper­LDL­cholesterolemia. Multivariate logistic regression analysis with adjustment for age, gender and body mass index revealed that rs964184 of ZPR1 (P=5.1x10­7; odds ratio, 1.37; dominant model), rs4845625 of IL6R (P=0.0019, odds ratio, 1.25; dominant model) and rs46522 of UBE2Z (P=0.0039, odds ratio, 1.19; dominant model) were significantly associated with hypertriglyceridemia, and that rs599839 of PSRC1 (P=0.0004, odds ratio, 0.70; dominant model) and rs2075650 of TOMM40 (P=0.0004, odds ratio, 1.43; dominant model) were significantly associated with hyper­LDL­cholesterolemia. Therefore, ZPR1, IL6R, and UBE2Z may be susceptibility loci for hypertriglyceridemia, whereas PSRC1 and TOMM40 may be such loci for hyper-LDL-cholesterolemia in Japanese individuals.

Association of TOMM40 and SLC22A4 polymorphisms with ischemic stroke.

Recent genome-wide association studies (GWASs) and their meta-analyses have identified various genes and loci underlying the predisposition to ischemic stroke or coronary artery disease in Caucasian populations. Given that ischemic stroke and coronary artery disease may have a shared genetic architecture, certain polymorphisms may confer genetic susceptibility to these two diseases. The aim of the present study was to examine the possible association of ischemic stroke with 29 single-nucleotide polymorphisms (SNPs) previously identified by the meta-analyses of GWASs as susceptibility loci for coronary artery disease. The study population comprised 3,187 Japanese individuals, including 894 subjects with ischemic stroke and 2,293 controls. The genotypes for the 29 SNPs of the 28 genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons of the allele frequencies by the χ2 test between subjects with ischemic stroke and controls revealed that rs9319428 (G→A) of the fms-related tyrosine kinase 1 gene (P=0.0471), rs2075650 (G→A) of the translocase of outer mitochondrial membrane 40 homolog gene (TOMM40, P=0.0102) and rs273909 (T→C) of the solute carrier family 22, member 4 gene (SLC22A4, P=0.0097) were significantly (P<0.05) associated with the prevalence of ischemic stroke. Multivariable logistic regression analysis with adjustment for age, gender, body mass index, smoking status and the prevalence of hypertension, diabetes mellitus and dyslipidemia revealed that rs2075650 of TOMM40 (P=0.0443; recessive model; odds ratio=0.50) and rs273909 of SLC22A4 (P=0.0123; dominant model; odds ratio=0.45) were significantly associated with ischemic stroke with the minor G and C allele, respectively, being protective against this condition. TOMM40 and SLC22A4 may thus be susceptibility loci for ischemic stroke in Japanese individuals.

Anti-inflammatory and morphologic effects of pitavastatin on carotid arteries and thoracic aorta evaluated by integrated backscatter trans-esophageal ultrasound and PET/CT: a prospective randomized comparative study with pravastatin (EPICENTRE study).

BACKGROUND: We sought to evaluate the effects of a strong lipophilic statin (pitavastatin) on plaque components and morphology assessed by transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE), as well as plaque inflammation assessed by 18F-fluorodeoxyglucose (FDG) PET/CT in the thoracic aorta and the carotid artery. Furthermore, we compared the effects of pitavastatin with those of mild hydrophilic statin (pravastatin). METHODS: We examined atherosclerotic plaques in the thoracic aorta by TEE and those in the carotid artery by integrated backscatter (IBS)-TTE and PET/CT. We identified the target plaque, where there was macrophage infiltration and inflammation, by strong FDG uptake in the thoracic aorta and carotid arteries and measured maximum standard uptake values (max SUV) by PET/CT. We measured the intima-media thickness (IMT) and the corrected IBS (cIBS) values in the intima-media complex by TEE and TTE at the same site of FDG accumulation by PET/CT. RESULTS: Patients were randomly divided into two treatment groups: a pitavastatin group (PI group: n =10, 68.4 ± 5.1 years) and a pravastatin group (PR group: n =10, 63.9 ± 11.2 years). The same examinations were performed after six months at the same site in each patient. We used calculated target-to-background ratio (TBR) to measure max SUV of plaques and evaluated percent change of TBR. There was no significant difference in low density lipoprotein-cholesterol, TBR, IMT and cIBS values in plaques at baseline between the PI and PR groups. After treatment, there was greater improvement in TBR, cIBS values and IMT in the PI group than the PR group. CONCLUSIONS: The pravastatin treatment was less effective on plaque inflammation than pitavastatin treatment. This trend was the same in the carotid arteries and the thoracic aorta. Pitavastatin not only improved the atherosis as measured by IMT and cIBS values but also attenuated inflammation of plaques as measured by max SUV at the same site. The present study indicated that pitavastatin has stronger effects on the regression and stabilization of plaques in the thoracic aorta and carotid arteries compared with pravastatin.

Association of six genetic variants with myocardial infarction.

Although various genes that confer susceptibility to myocardial infarction (MI) have been identified for Caucasian populations in genome-wide association studies (GWAS), genetic variants related to this condition in Japanese individuals have not been identified definitively. The aim of the present study was to examine an association of MI in Japanese individuals with 29 polymorphisms identified as susceptibility loci for MI or coronary artery disease in Caucasian populations by meta-analyses of GWAS. The study subjects comprised 1,824 subjects with MI and 2,329 controls. Genotypes of the polymorphisms were determined by Luminex bead-based multiplex assay. To compensate for multiple comparisons, we adopted the criterion of a false discovery rate (FDR) of <0.05 for statistical significance for association. Comparisons of allele frequencies by the χ(2) test revealed that rs9369640 of the phosphatase and actin regulator 1 gene (PHACTR1, FDR=0.0007), rs4977574 of the CDKN2B antisense RNA 1 gene (CDKN2B-AS1, FDR=0.0038), rs264 of the lipoprotein lipase gene (LPL, FDR=0.0061), rs599839 of the proline/serine-rich coiled-coil 1 gene (PSRC1, FDR=0.0118), rs9319428 of the fms-related tyrosine kinase 1 gene (FLT1, FDR=0.0118) and rs12413409 of the cyclin and CBS domain divalent metal cation transport mediator 2 gene (CNNM2, FDR=0.0300) were significantly associated with MI. Multivariate logistic regression analysis with adjustment for covariates revealed that rs9369640 (P=0.0005; odds ratio, 0.89), rs4977574 (P=0.0001; odds ratio, 1.50), rs264 (P=0.0405; odds ratio, 0.85), rs599839 (P=0.0003; odds ratio, 0.68), rs9319428 (P=0.0155; odds ratio, 1.20) and rs12413409 (P=0.0076; odds ratio, 0.66) were significantly (P<0.05) associated with MI. PHACTR1, CDKN2B-AS1, LPL, PSRC1, FLT1 and CNNM2 may thus be susceptibility loci for MI in Japanese individuals.

Association of a genetic variant of the ZPR1 zinc finger gene with type 2 diabetes mellitus.

Various loci and genes that confer susceptibility to coronary heart disease (CHD) have been identified in Caucasian populations by genome-wide association studies (GWASs). As type 2 diabetes mellitus (DM) is an important risk factor for CHD, we hypothesized that certain polymorphisms may contribute to the genetic susceptibility to CHD through affecting the susceptibility to type 2 DM. The purpose of the present study was to examine a possible association of type 2 DM in Japanese individuals with 29 polymorphisms identified as susceptibility loci for CHD by meta-analyses of the GWASs. The study subjects comprised of 3,757 individuals (1,444 subjects with type 2 DM and 2,313 controls). The polymorphism genotypes were determined by the multiplex bead-based Luminex assay, which combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. To compensate for multiple comparisons of genotypes, the criterion of a false discovery rate (FDR) ≤0.05 was adopted for testing the statistical significance of the association. The comparisons of allele frequencies by the χ2 test revealed that the rs964184 (C→G) of the ZPR1 zinc finger gene (ZPR1) was significantly associated (P=0.0017; FDR=0.050) with type 2 DM. Multivariable logistic regression analysis with adjustment for age, gender and body mass index revealed that rs964184 of ZPR1 was significantly associated (P=0.0012; odds ratio, 1.25; dominant model) with type 2 DM with the minor G allele representing a risk factor for this condition. Fasting plasma glucose levels (P=0.0076) and blood glycosylated hemoglobin contents (P=0.0132) significantly differed among ZPR1 genotypes with the G allele associated with increases in these parameters. ZPR1 may thus be a susceptibility locus for type 2 DM in Japanese individuals.

Association of a transcription factor 21 gene polymorphism with hypertension.

Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified mainly in Caucasian populations by genome-wide association studies (GWASs). As hypertension is a major risk factor for CAD, certain polymorphisms may contribute to the genetic susceptibility to CAD through affecting the predisposition to hypertension. The aim of the present study was to examine a possible association of hypertension with 29 single-nucleotide polymorphisms (SNPs) previously identified by meta-analyses of GWASs as susceptibility loci for CAD. Study subjects comprised of 5,460 individuals (3,348 subjects with hypertension and 2,112 controls). The genotypes of SNPs were determined by the multiplex bead-based Luminex assay. The χ2 test revealed that genotype distributions and allele frequencies for rs12190287 of the transcription factor 21 gene (TCF21) and rs1122608 of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 gene (SMARCA4) were significantly (P<0.05) associated with hypertension. Allele frequencies for rs9369640 of the phosphatase and actin regulator 1 gene (PHACTR1) and genotype distributions for rs599839 of the proline/serine-rich coiled-coil 1 gene (PSRC1) were also significantly associated with hypertension. Multivariable logistic regression analysis with adjustment for age, gender, body mass index and smoking status revealed that rs12190287 of TCF21 (P=0.0014; recessive model; odds ratio, 1.21) was significantly associated with hypertension, and the C allele represented a risk factor for this condition. Similar analyses revealed that rs1122608 of SMARCA4 (P=0.0305; dominant model; odds ratio, 0.86), rs9369640 of PHACTR1 (P=0.0119; dominant model; odds ratio, 0.82) and rs599839 of PSRC1 (P=0.0248; dominant model; odds ratio, 0.84) were also related to hypertension, with the minor T, C and G alleles, respectively, being protective against this condition. Thus, the present results indicate that rs12190287 (G→C) of TCF21 is a susceptibility locus for hypertension.

A novel ultrasound predictor of pulmonary capillary wedge pressure assessed by the combination of left atrial volume and function: A speckle tracking echocardiography study.

BACKGROUND: We hypothesized that a development of a novel index based on the combination of left atrial volume (LAV) and left atrial (LA) function evaluated by the time-LA volume curve using speckle tracking echocardiography (STE) would be accurate and useful to estimate pulmonary capillary wedge pressure (PCWP). Our goal was to develop a novel index of PCWP based on a combination of LAV and LA function using STE. METHODS: A cross-validation study was performed with the patients divided into a training study to define the novel index (n=50) and a testing study to validate the index (n=196). PCWP was measured by right heart catheterization, and phasic LAV and emptying function (EF) were measured by STE. RESULTS: Simple linear regression analysis in the training study revealed that the novel index that best estimated PCWP was the kinetics-tracking index [KT index=log10 (active LAEF/minimum LAV index)]. Multiple regression analysis revealed that the KT index was the most reliable predictor of PCWP. It had the strongest correlation with PCWP (r=-0.86, p<0.001) among all echocardiographic parameters. In the testing study, PCWP estimated by the KT index was also strongly correlated with measured PCWP (r=0.92, p<0.001). These correlations were also strong in the patients with reduced left ventricular ejection fraction (<50%), chronic heart failure, and chronic atrial fibrillation (r=0.92, r=0.91, r=0.79, p<0.001, respectively). CONCLUSIONS: A novel index (KT index) using a combination of LAV and LA function was a powerful and useful predictor of PCWP and may be valuable in routine clinical practice.

Association of a polymorphism of the interleukin 6 receptor gene with chronic kidney disease in Japanese individuals.

AIM: Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified in Caucasian populations by genome-wide association studies (GWASs). The aim of the present study was to examine a possible association of chronic kidney disease (CKD) with 29 polymorphisms previously identified as susceptibility loci for CAD by meta-analyses of GWASs. METHODS: The study population comprised 2247 Japanese individuals, including 1588 subjects with CKD [estimated glomerular filtration rate (eGFR) of <60 mL min(-1) 1.73 m(-2) ] and 659 controls (eGFR of ≥90 mL min(-1) 1.73 m(-2) ). The genotypes for 29 polymorphisms of 28 candidate genes were determined. RESULTS: The χ(2) test revealed that rs4845625 (T→C) of IL6R, rs4773144 (A→G) of COL4A1, rs9319428 (G→A) of FLT1, and rs46522 (T→C) of UBE2Z were significantly (P < 0.05) related to CKD. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and dyslipidaemia revealed that rs4845625 of IL6R (P = 0.0008; dominant model; odds ratio, 1.49), rs4773144 of COL4A1 (P = 0.0252; dominant model; odds ratio, 1.28), and rs9319428 of FLT1 (P = 0.0260: additive model; odds ratio, 0.77) were significantly associated with CKD. The serum concentration of creatinine was significantly (P = 0.0065) greater and eGFR was significantly (P = 0.0009) lower in individuals with the TC or CC genotype of IL6R than in those with the TT genotype. CONCLUSION: The rs4845625 of IL6R may be a susceptibility locus for CKD in Japanese individuals.

Comparison between left atrial features in well-controlled hypertensive patients and normal subjects assessed by three-dimensional speckle tracking echocardiography.

BACKGROUND: Three-dimensional speckle tracking echocardiography (3D-STE) has a major advantage in the improvement of accuracy in the evaluation of cardiac chamber volume without any geometrical assumption. Thus, the aim of this study was to use 3D-STE to elucidate the features of left atrial (LA) volume and function that are altered by hypertension (HTN) by comparing well-controlled HTN patients with normal subjects. METHODS: Conventional echocardiographic parameters and LA phasic volume and function were measured from apical view by 3D-STE in 40 patients with well-controlled HTN [systolic blood pressure (BP) <140 and diastolic BP <90mmHg for more than one year] and 40 normotensive subjects. RESULTS: The passive LA emptying function (EF) in the patients with well-controlled HTN significantly decreased (16±7% vs. 22±8%, p=0.0013) and the active LAEF in patients with well-controlled HTN significantly increased (35±10% vs. 30±9%, p=0.029) compared with the values in normotensive subjects. Multivariate logistic regression analysis revealed that E/e' was an independent determinant of well-controlled HTN. The maximum LA volume index was correlated with elevated E/e' (r=0.30, p=0.0064), whereas the maximum LA volume index was not correlated with LV mass index or systolic BP. This change was independent of age. CONCLUSIONS: These results suggest that LV diastolic dysfunction occurs before structural changes of left atrium and left ventricle even in patients with well-controlled HTN.

Impact of tissue characteristics on luminal narrowing of mild angiographic coronary stenosis: assessment of integrated backscatter intravascular ultrasound.

Integrated backscatter intravascular ultrasound (IB-IVUS) is a useful method for analyzing coronary plaque tissue. We evaluated whether tissue composition determined using IB-IVUS is associated with the progression of stenosis in coronary angiography. Sixty-three nontarget coronary lesions in 63 patients with stable angina were evaluated using conventional IVUS and IB-IVUS. IB-IVUS images were analyzed at 1-mm intervals for a length of 10 mm. After calculating the relative areas of the tissue components using the IB-IVUS system, fibrous volume (FV) and lipid volume (LV) were calculated through integration of the slices, after which percentages of per-plaque volume (%FV/PV, %LV/PV) and per-vessel volume (%FV/VV, %LV/VV) were calculated. Progression of coronary stenosis was interpreted from the increase in percent diameter stenosis (%DS) from baseline to the follow-up period (6-9 months) using quantitative coronary angiography. %DS was 24.1 ± 12.8 % at baseline and 23.2 ± 13.7 % at follow-up. Using IB-IVUS, LV was 31.7 ± 10.5 mm(3), and %LV/PV and %LV/VV were 45.6 ± 10.3 % and 20.2 ± 6.0 %, respectively. FV, %FV/PV, and %FV/VV were 35.5 ± 12.1 mm(3), 52.1 ± 9.5 %, and 23.4 ± 7.1 %, respectively. The change in %DS was -0.88 ± 7.25 % and correlated closely with %LV/VV (r = 0.27, P = 0.03) on simple regression. Multivariate regression after adjustment for potentially confounding risk factors showed %LV/VV to be correlated independently with changes in %DS (r = 0.42, P = 0.02). Logistic regression analysis after adjusting for confounding coronary risk factors showed LV (odds ratio 1.08; 95 % confidence interval 1.01-1.16; P = 0.03) and %LV/VV (odds ratio 1.13; 95 % confidence interval 1.01-1.28; P = 0.03) to be independent predictors of the progression of angiographic coronary stenosis. Our findings suggest that angiographic luminal narrowing of the coronary artery is likely associated with tissue characteristics. IB-IVUS may provide information about the natural progression of luminal narrowing in coronary stenosis.