Shinji Kishimoto

Digital Subtraction High-Frame-Rate Echocardiography in Detecting Delayed Onset of Regional Left Ventricular Relaxation in Ischemic Heart Disease

BACKGROUND Because left ventricular (LV) diastolic function is impaired before systolic function in patients with ischemic heart disease and because ischemic heart disease is constituted of regional rather than global abnormalities of the left ventricle, measures of LV regional diastolic dysfunction, if possible, should provide the most sensitive assessment of the coronary involved region. The objectives of this study are to clarify whether high-frame-rate two-dimensional echocardiography, combined with digital subtraction image processing, may be used to visualize regional LV relaxation abnormalities in patients with ischemic heart disease and to clarify whether this technique provides a measure for the noninvasive assessment of the coronary involved region. METHOD AND RESULTS In 30 normal subjects and 59 patients with ischemic heart disease, two-dimensional echocardiograms obtained at a rate of 60 frames per second were provided on line for digital subtraction analysis, with which digitized images were continuously subtracted on a frame-by-frame basis. The subtracted images were analyzed to determine the onset of the segmental outward motion of the LV wall in early diastole in each of 16 segments per subject. Regional relaxation index, defined as the interval from the second heart sound to the onset of outward wall motion, was significantly prolonged in the coronary involved segments compared with the normal segments (36.3 +/- 18.0 versus 101.2 +/- 34.0 ms, P < .01). The prolongation in the regional relaxation index was observed even in the coronary involved segments without reduction in systolic wall motion. When a cutoff level of 50.0 ms was used, coronary involved segments could be distinguished from normal or border segments with a sensitivity of 92% and a specificity of 81%. CONCLUSIONS Digital subtraction high-frame-rate echocardiography may be used to visualize regional LV relaxation abnormalities in patients with ischemic heart disease. The time interval from the second heart sound to the onset of the segmental outward motion of the LV wall (regional relaxation index) obtained with this technique provides a noninvasive and accurate measure for assessing coronary involved regions.

Longitudinal extent of lipid pool assessed by optical coherence tomography predicts microvascular no-reflow after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction

BACKGROUND Distal embolization during percutaneous coronary intervention (PCI) may deteriorate microvascular reperfusion in patients with ST-elevation myocardial infarction (STEMI). Reperfusion at the coronary microvascular level is important for STEMI and culprit plaque is associated with distal embolization and microvascular reperfusion. ST-segment resolution (ST-R) in the electrocardiogram reflects microvascular reperfusion after primary PCI. Longitudinal extent of lipid pool assessed by optical coherence tomography (OCT) may predict the risk of failure of microvascular reperfusion after primary PCI. METHODS AND RESULTS This study consisted of 39 patients with STEMI who underwent primary PCI within 24h after the onset of chest pain. Immediately after thrombectomy, OCT was performed and length of lipid pool was measured. Microvascular reperfusion after primary PCI was assessed by ST-R, which was defined as >50% decrease in ST elevation at 1h after primary PCI. There were 23 patients with ST-R and 16 patients without ST-R, with no significant difference in baseline clinical and angiographical variables between the 2 groups. Final thrombolysis in myocardial infarction 3 flow was obtained in all of the patients. Peak creatine kinase was significantly higher in the ST-R (-) group than in the ST-R (+) group (p=0.01). Length of lipid pool was 10.1 ± 2.8mm in the ST-R (-) group and 7.8 ± 3.2mm in the ST-R (+) group (p=0.02). In receiver operating characteristics curve assessing the ability of length of lipid pool to predict ST-R, area under the curve was 0.74 (p=0.02). Length of lipid pool >9.0mm best predicted the absence of ST-R with sensitivity 88% and specificity 78%. CONCLUSIONS These findings suggest that length of lipid pool estimated by OCT may predict microvascular no-reflow after primary PCI.

Combination of Flow-Mediated Vasodilation and Nitroglycerine-Induced Vasodilation Is More Effective for Prediction of Cardiovascular Events

Measurement of nitroglycerine-induced vasodilation has been performed to differentiate endothelium-dependent vasodilation from endothelium-independent vasodilation as a control test for flow-mediated vasodilation (FMD). Recently, nitroglycerine-induced vasodilation per se has been reported to be a useful marker of the grade of atherosclerosis. The present study aimed to evaluate the prognostic value of FMD combined with nitroglycerine-induced vasodilation for future cardiovascular events. We measured FMD and nitroglycerine-induced vasodilation in 402 subjects, including patients with cardiovascular diseases. During a median follow-up period of 32.3 months, 38 first major cardiovascular events (death from cardiovascular causes, acute myocardial infarction, stroke, and coronary revascularization) occurred. Receiver-operator characteristic curve analysis revealed that FMD alone and nitroglycerine-induced vasodilation alone can predict cardiovascular events with areas under the curve of 0.671 (cutoff 3.3%) and 0.692 (cutoff 11.6%), respectively. FMD combined with nitroglycerine-induced vasodilation predicts cardiovascular events with an area under the curve of 0.701. After adjustment for age, sex, and cardiovascular risk factors, above cutoff FMD (≥3.3%) and below cutoff nitroglycerine-induced vasodilation (<11.6%; hazard ratio, 5.55; 95% confidence interval, 1.61–25.46; P=0.006) and below cutoff FMD (<3.3%) and below cutoff nitroglycerine-induced vasodilation (<11.6%; hazard ratio, 7.20; 95% confidence interval, 2.37–31.36; P<0.001) remained strong independent indicator of cardiovascular events. These findings suggest that the combination of FMD and nitroglycerine-induced vasodilation measurements can more accurately predict cardiovascular events compared with FMD alone. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: UMIN000001167.

Coronary angioscopic findings 9 months after everolimus-eluting stent implantation compared with sirolimus-eluting stents

OBJECTIVES We assessed angioscopic findings after everolimus-eluting stents (EES) implantation, compared with sirolimus-eluting stents (SES). BACKGROUND Coronary angioscopy (CAS) provides an opportunity to assess neointimal coverage over stent struts, thrombus, and plaque color by direct visualization. CAS is a useful tool for evaluating stent struts after drug-eluting stent implantation. Angioscopic findings after EES implantation have not been reported before. METHODS We performed CAS in 23 patients who were treated with EES and 41 patients with SES. CAS was performed 8.5 months after stent implantation. We assessed neointimal coverage, thrombus, and plaque color. We classified neointimal coverage in 4 grades: grade 0=struts were completely exposed; grade 1=struts were visible with dull light reflexion; grade 2=there was no light reflexion from slightly visible struts; grade 3=struts were completely covered. RESULTS There was no significant difference in minimum, maximum, dominant grade of neointimal coverage, and heterogeneity index between EES and SES. Thrombus was less frequently observed in EES than SES (4% vs 29%, p=0.02). When we divided study patients into acute coronary syndrome (ACS) or stable angina pectoris (SAP), there was a tendency toward less thrombus in EES than SES, in both ACS and SAP. Maximum color grade of the plaques was less advanced in EES than SES (p<0.01). Yellow plaques of grade 2 or 3 were less frequent in EES than SES (35% vs 76%, p<0.01). CONCLUSIONS This study suggested that EES were associated with lower risk of thrombus formation than SES.

Comparison of gender-specific mortality in patients < 70 years versus ≥ 70 years old with acute myocardial infarction.

The aim of the present study was to investigate the gender-specific mortality after acute myocardial infarction in those aged < 70 years versus ≥ 70 years. The present study consisted of 2,677 consecutive patients with acute myocardial infarction who had undergone coronary angiography within 24 hours after the onset of symptoms. The patients were divided into 2 groups: 1,810 patients < 70 years old and 867 patients ≥ 70 years old. Women were older and had a greater incidence of hypertension and diabetes mellitus and a lower incidence of current smoking and previous myocardial infarction in both groups. The in-hospital mortality rate was significantly greater in women ≥ 70 years old age than in men ≥ 70 years old (16.2% vs 9.3%, respectively; p = 0.003) but was comparable between women and men in patients < 70 years old (5.7% vs 4.9%, respectively; p = 0.59). On multivariate analysis, the association between female gender and in-hospital mortality in patients ≥ 70 years old remained significant (odds ratio 1.78, 95% confidential interval 1.05 to 3.00), but the gender difference was not observed in patients < 70 years old (odds ratio 1.09, 95% confidence interval 0.53 to 2.24). In conclusion, female gender was associated with in-hospital mortality after acute myocardial infarction in patients ≥ 70 years old but not in patients < 70 years old.

Endothelial dysfunction and abnormal vascular structure are simultaneously present in patients with heart failure with preserved ejection fraction

BACKGROUND Endothelial dysfunction and abnormal vascular structure may be involved in the pathogenesis of chronic heart failure (HF). The purpose of this study was to evaluate simultaneously vascular function and vascular structure in patients with heart failure with preserved ejection fraction (HFpEF). METHODS We measured flow-mediated vasodilatation (FMD) and nitroglycerine-induced vasodilation as indices of vascular function and intima-media thickness (IMT) as an index of vascular structure of the brachial artery in 41 patients with HFpEF (23 men and 18 women; mean age, 66±12yr) and 165 patients without HF (95 men and 70 women; mean age, 54±16yr). RESULTS FMD was significantly smaller in patients with HFpEF than in patients without HF (2.9±2.1% versus 4.6±2.7%, P=0.0002). Nitroglycerine-induced vasodilation was significantly smaller in patients with HFpEF than in patients without HF (9.3±4.1% versus 12.9±4.9%, P<0.0001). Brachial artery IMT was significantly larger in patients with HFpEF than in patients without HF (0.35±0.06mm versus 0.31±0.07mm, P=0.0002). After adjustment for age, sex, hypertension, dyslipidemia, and diabetes mellitus, the associations remained significant between HFpEF and FMD (odds ratio, 0.79; 95% confidence interval, 0.66-0.92; P=0.0032), nitroglycerine-induced vasodilation (odds ratio, 0.88; 95% confidence interval, 0.80-0.96; P=0.0039), and brachial artery IMT (odds ratio, 1.08; 95% confidence interval, 1.01-1.17; P=0.033). CONCLUSIONS These findings suggest that both endothelial dysfunction and abnormal vascular structure may contribute to the pathogenesis and maintenance of HFpEF. Endothelial function and vascular structure may be potential therapeutic targets for HFpEF.

Circulating level of pigment epithelium-derived factor is associated with vascular function and structure: A cross-sectional study

BACKGROUND Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors. It is thought that PEDF plays a protective role against atherosclerosis. Clinical studies have shown that serum levels of PEDF are increased in subjects with cardiovascular risk factors. The role of PEDF in cardiovascular disease is still controversial. The purpose of this study was to evaluate the associations between serum levels of PEDF and vascular function and structure. METHODS We measured serum levels of PEDF, assessed vascular function by measurements of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in the brachial artery, and measured brachial artery intima-media thickness (IMT) in 150 subjects who underwent health examinations. RESULTS AND CONCLUSIONS Univariate regression analysis revealed that serum level of PEDF was significantly correlated with body mass index, high-density lipoprotein cholesterol, glucose, FMD, nitroglycerine-induced vasodilation, and brachial artery IMT. Multivariate analysis revealed that serum levels of PEDF remained an independent predictor of nitroglycerine-induced vasodilation (β=-0.20, P=0.02) and brachial artery IMT (β=0.14, P=0.03) after adjustment of cardiovascular risk factors, while serum level of PEDF was not associated with FMD (β=-0.02, P=0.79). These findings suggest that PEDF may be a factor directly associated with atherosclerosis. The serum level of PEDF may be a new biochemical marker of atherosclerosis.

Common Variant Near HEY2 Has a Protective Effect on Ventricular Fibrillation Occurrence in Brugada Syndrome by Regulating the Repolarization Current

Background—Risk stratification of Brugada syndrome (BrS) remains controversial and the majority of patients with BrS have no genetic explanation. We investigated relationships between genotypes of 3 single-nucleotide polymorphisms reported in a recent genome-wide association study and BrS phenotypes. Methods and Results—SCN10A (rs10428132), SCN5A (rs11708996), and downstream from HEY2 (rs9388451) single-nucleotide polymorphisms were genotyped and compared between 95 Japanese patients with BrS and 1978 controls. Relationships between the single-nucleotide polymorphisms and clinical characteristics, 12-lead ECG findings, signal-averaged ECG findings, and electrophysiological parameters were also examined in patients with BrS. Both rs10428132 and rs9388451 were significantly associated with BrS (P=2.7×10−14; odds ratio, 3.0; P=9.2×10−4; odds ratio, 1.7, respectively). Interestingly, the HEY2 risk allele C was less frequent in BrS patients with ventricular fibrillation than in those without (59% versus 74%; P=4.1×10−2; odds ratio, 0.5). A significant linear correlation was found between HEY2 genotypes and QTc interval (CC: 422±27 ms; CT: 408±21 ms; and TT: 381±27 ms; P= 4.0×10−4). The HEY2 mRNA expression level in the right ventricular specimens from patients with BrS (n=20) was significantly lower in patients with CC genotype than the other genotypes (P=0.04). Additionally, during 63±28 months follow-up periods after implantable cardioverter defibrillator implantation (n=90), Kaplan–Meier event-free survival curves revealed that the cumulative rate of ventricular fibrillation events was significantly lower in cases with HEY2 CC genotype (P=0.04). Conclusions—Our findings suggest that HEY2 CC genotype may be a favorable prognostic marker for BrS, protectively acting to prevent ventricular fibrillation presumably by regulating the repolarization current.

Increasing Risk of Osteoporotic Fracture Is Associated With Vascular Dysfunction and Abnormal Vascular Structure in Both Men and Women

BACKGROUND Osteoporosis and cardiovascular disease are major public health problems. A number of clinical studies have shown a link between osteoporosis and cardiovascular disease, but there is no information on the associations of risk of osteoporotic fracture with vascular function and vascular structure.Methods and Results:The risk of major osteoporotic fracture was calculated using the World Health Organization fracture risk assessment tool (FRAX); vascular function was assessed using flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), and vascular structure was assessed on brachial artery intima-media thickness (IMT) in 414 subjects (241 men and 173 women) who underwent health examinations. On univariate regression, FRAX was negatively correlated with FMD (total, r=-0.16, P<0.001; men, r=-0.19, P=0.003; women, r=-0.25, P<0.001) and NID (total, r=-0.22, P<0.001; men, r=-0.19, P=0.003; women, r=-0.30, P<0.001) and was positively correlated with brachial artery IMT (total, r=0.12, P=0.02; men, r=0.22, P<0.001; women, r=0.33, P<0.001). On multivariate analysis FRAX remained an independent predictor of FMD, NID, and brachial artery IMT in both men and women. CONCLUSIONS Increase in the risk of osteoporotic fracture evaluated on FRAX is associated with vascular dysfunction and abnormal vascular structure in both men and women. Osteoporosis should be monitored in order to reduce the risk of cardiovascular events.

Endothelial Function Assessed by Automatic Measurement of Enclosed Zone Flow-Mediated Vasodilation Using an Oscillometric Method Is an Independent Predictor of Cardiovascular Events

Background A new device for automatic measurement of flow‐mediated vasodilation (FMD) using an oscillometric method has been developed to solve technical problems of conventional FMD measurement. This device measures enclosed zone FMD (ezFMD). The purpose of this study was to evaluate the prognostic value of endothelial function assessed by ezFMD for future cardiovascular events. Methods and Results We measured ezFMD in 272 participants who underwent health‐screening examinations. First, we investigated cross‐sectional associations between ezFMD and cardiovascular risk factors, and then we assessed the associations between ezFMD and first major cardiovascular events (death from cardiovascular causes, stroke, and coronary revascularization). Univariate regression analysis revealed that ezFMD was significantly correlated with age, triglycerides, glucose, smoking pack‐years, estimated glomerular filtration rate, high‐sensitivity C‐reactive protein, and Framingham risk score. During a median follow‐up period of 36.1 months (interquartile range 18.8–40.1 months), 12 participants died (6 from cardiovascular causes), 3 had stroke, 8 had coronary revascularization, and 10 were hospitalized for heart failure. There was no episode of acute coronary syndrome during the study period. Participants were divided into tertiles (low, intermediate, and high) based on ezFMD. Kaplan–Meier curves for first major cardiovascular events among the 3 groups were significantly different (P=0.004). After adjustment for cardiovascular risk factors, the low group was significantly associated with an increased risk of first major cardiovascular events compared with the high group (hazard ratio 6.47; 95% CI 1.09–125.55; P=0.038). Conclusions These findings suggest that endothelial function assessed by ezFMD may be useful as a surrogate marker of future cardiovascular events. Clinical Trial Registration URL: https://upload.umin.ac.jp. Unique identifier: UMIN000004902.