Nozomu Oda

Assessment of outcomes and differences between in- and out-of-hospital cardiac arrest patients treated with cardiopulmonary resuscitation using extracorporeal life support☆

AIM Cardiopulmonary resuscitation (CPR) using extracorporeal life support (ECLS) for in-hospital cardiac arrest (IHCA) patients has been assigned a low-grade recommendation in current resuscitation guidelines. This study compared the outcomes of IHCA and out-of-hospital cardiac arrest (OHCA) patients treated with ECLS. METHODS A total of 77 patients were treated with ECLS. Baselines characteristics and outcomes were compared for 38 IHCA and 39 OCHA patients. RESULTS The time interval between collapse and starting ECLS was significantly shorter after IHCA than after OHCA (25 (21-43)min versus 59 (45-65)min, p<0.001). The weaning rate from ECLS (61% versus 36%, p=0.03) and 30-day survival (34% versus 13%, p=0.03) were higher for IHCA compared with OHCA patients. IHCA patients had a higher rate of favourable neurological outcome compared to OHCA patients, but the difference was not statistically significant (26% versus 10%, p=0.07). Kaplan-Meier analysis showed improved 30-day and 1-year survival for IHCA patients treated with ECLS compared to OHCA patients who had ECLS. However, multivariate stepwise Cox regression model analysis indicated no difference in 30-day (odds ratio 0.94 (95% confidence interval 0.68-1.27), p=0.67) and 1-year survival (0.99 (0.73-1.33), p=0.95). CONCLUSION CPR with ECLS led to more favourable patient outcomes after IHCA compared with OHCA in our patient group. The difference in outcomes for ECLS after IHCA and OHCA disappeared after adjusting for patient factors and the time delay in starting ECLS.

Ratio of Serum Levels of AGEs to Soluble Form of RAGE Is A Predictor of Endothelial Function

OBJECTIVE Advanced glycation end products (AGEs) and their specific receptor, the receptor for AGEs (RAGE), play an important role in atherosclerosis. Recently, a soluble form of RAGE (sRAGE) has been identified in human serum. However, the role of sRAGE in cardiovascular disease is still controversial. There is no information on the association between simultaneous measurements of AGEs and sRAGE and vascular function. In this study, we evaluated the associations between serum levels of AGEs and sRAGE, ratio of AGEs to sRAGE, and vascular function. RESEARCH DESIGN AND METHODS We measured serum levels of AGEs and sRAGE and assessed vascular function by measurement of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in 110 subjects who underwent health examinations. Multivariate regression analyses were performed to identify factors associated with vascular function. RESULTS Univariate regression analysis revealed that FMD correlated with age, BMI, systolic blood pressure, diastolic blood pressure, heart rate, triglycerides, HDL cholesterol, glucose, smoking pack-years, nitroglycerine-induced vasodilation, serum levels of AGEs and sRAGE, and ratio of AGEs to sRAGE. Multivariate analysis revealed that the ratio of AGEs to sRAGE remained an independent predictor of FMD, while serum level of AGEs alone or sRAGE alone was not associated with FMD. CONCLUSIONS These findings suggest that sRAGE may have a counterregulatory mechanism that is activated to counteract the vasotoxic effect of the AGE–RAGE axis. The ratio of AGEs to sRAGE may be a new chemical biomarker of endothelial function.

Who benefits most from mild therapeutic hypothermia in coronary intervention era? A retrospective and propensity-matched study

IntroductionThe aim of the present study was to investigate the impact of the time interval from collapse to return of spontaneous circulation (CPA-ROSC) in cardiac arrest patients and the types of patients who will benefit from therapeutic hypothermia.MethodsFour hundred witnessed adult comatose survivors of out-of-hospital cardiac arrest of cardiac etiology were enrolled in the study. The favorable neurological outcome was defined as category 1 or 2 on the five-point Pittsburgh cerebral performance scale at the time of hospital discharge. A matching process based on the propensity score was performed to equalize potential prognostic factors in the hypothermia and normothermia groups, and to formulate a balanced 1:1 matched cohort study.ResultsThe rate of favorable neurological outcome was higher (P < 0.05) in the hypothermia group (n = 110) than in the normothermia group in patients with CPA-ROSC of 15 to 20 minutes (64% vs. 17%), 20 to 25 minutes (70% vs. 8%), 25 to 30 minutes (50% vs. 7%), 35 to 40 minutes (27% vs. 0%) and 40 to 45 minutes (29% vs. 2%). A similar association was observed in a propensity-matched cohort, but the differences were not significant. There was no significant difference in the rate of favorable neurological outcome between the hypothermia-matched group and the normothermia-matched group. In the patients whose CPA-ROSC was greater than 15 minutes, however, the rate of favorable neurological outcome was higher in the hypothermia-matched group than in the normothermia-matched group (27% vs. 4%, P < 0.001). In multivariate analysis, the CPA-ROSC was an independent predictor of favorable neurological outcome (every 1 minute: odds ratio = 0.89, 95% confidence interval = 0.85 to 0.92, P < 0.001).ConclusionsThe CPA-ROSC is an independent predictor of neurological outcome. Therapeutic hypothermia is more beneficial in comatose survivors of cardiac arrest with CPA-ROSC greater than 15 minutes.

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.

Effect of aldosterone-producing adenoma on endothelial function and Rho-associated kinase activity in patients with primary aldosteronism.

The purpose of this study was to evaluate vascular function and activity of Rho-associated kinases (ROCKs) in patients with primary aldosteronism. Vascular function, including flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation, and ROCK activity in peripheral leukocytes were evaluated in 21 patients with aldosterone-producing adenoma (APA), 23 patients with idiopathic hyperaldosteronism (IHA), and 40 age-, sex-, and blood pressure–matched patients with essential hypertension (EHT). FMD was significantly lower in the APA group than in the IHA and EHT groups (3.2±2.0% versus 4.6±2.3% and 4.4±2.2%; P<0.05, respectively), whereas there was no significant difference in FMD between the IHA and EHT groups. There was no significant difference in nitroglycerine-induced vasodilation in the 3 groups. ROCK activity was higher in the APA group than in the IHA and EHT groups (1.29±0.57 versus 1.00±0.46 and 0.81±0.36l; P<0.05, respectively), whereas there was no significant difference in ROCK activity between the IHA and EHT groups. FMD correlated with age (r=−0.31; P<0.01), plasma aldosterone concentration (r=−0.35; P<0.01), and aldosterone:renin ratio (r=−0.34; P<0.01). ROCK activity correlated with age (r=−0.24; P=0.04), plasma aldosterone concentration (r=0.33; P<0.01), and aldosterone:renin ratio (r=0.46; P<0.01). After adrenalectomy, FMD and ROCK activity were restored in patients with APA. APA was associated with both endothelial dysfunction and increased ROCK activity compared with those in IHA and EHT. APA may have a higher risk of future cardiovascular events.

Critical Role of Exogenous Nitric Oxide in ROCK Activity in Vascular Smooth Muscle Cells

Objective Rho-associated kinase (ROCK) signaling pathway has been shown to mediate various cellular functions including cell proliferation, migration, adhesion, apoptosis, and contraction, all of which may be involved in pathogenesis of atherosclerosis. Endogenous nitric oxide (NO) is well known to have an anti-atherosclerotic effect, whereas the exogenous NO-mediated cardiovascular effect still remains controversial. The purpose of this study was to evaluate the effect of exogenous NO on ROCK activity in vascular smooth muscle cells (VSMCs) in vitro and in vivo. Methods VSMCs migration was evaluated using a modified Boyden chamber assay. ROCK activities were measured by Western blot analysis in murine and human VSMCs and aorta of mice treated with or without angiotensin II (Ang II) and/or sodium nitroprusside (SNP), an NO donor. Results Co-treatment with SNP inhibited the Ang II-induced cell migration and increases in ROCK activity in murine and human VSMCs. Similarly, the increased ROCK activity 2 weeks after Ang II infusion in the mouse aorta was substantially inhibited by subcutaneous injection of SNP. Conclusions These findings suggest that administration of exogenous NO can inhibit ROCK activity in VSMCs in vitro and in vivo.

Relationship between nitroglycerine-induced vasodilation and clinical severity of peripheral artery disease.

OBJECTIVE Nitroglycerine-induced vasodilation is usually used as a control test for flow-mediated vasodilation (FMD). However, nitroglycerine-induced vasodilation per se has also been reported to be impaired in patients with atherosclerosis. The purpose of this study was to determine the relationship between nitroglycerine-induced vasodilation and the clinical severity of peripheral artery disease (PAD). METHODS AND RESULTS We measured nitroglycerine-induced vasodilation and FMD in 144 subjects (mean age: 63.8 ± 15.1 years), including 32 PAD patients with critical limb ischemia (CLI group), 28 PAD patients without CLI (non-CLI group), 60 age- and sex-matched patients without established cardiovascular disease (at-risk group), and 24 healthy subjects (healthy group). Nitroglycerine-induced vasodilation was significantly impaired in the CLI group compared to that in the other three groups (healthy group, 16.0 ± 5.3%; at-risk group, 12.9 ± 3.8%; non-CLI group, 10.3 ± 5.1%; CLI group, 6.7 ± 3.9%; P < 0.05, respectively). Even after multivariate adjustment, the differences remained significant. On the other hand, FMD was significantly impaired in the at-risk, non-CLI, and CLI group compared with that in the healthy group (healthy group, 7.1 ± 2.9%; at-risk group, 3.4 ± 2.3%; non-CLI group, 3.5 ± 2.7%; CLI group, 3.0 ± 2.8%; P < 0.001, respectively), but the differences among the at-risk, non-CLI, and CLI groups were not significant. Multivariate analysis revealed that nitroglycerine-induced vasodilation (odds ratio: 0.77, 95% confidence interval [CI]: 0.61-0.97) and diabetes mellitus (odds ratio: 8.75, 95% CI: 1.74-44.2) were independent variables for CLI in PAD patients. CONCLUSIONS There was no significant difference in FMD between PAD patients with and those without CLI, but nitroglycerine-induced vasodilation was significantly smaller in PAD patients with CLI compared with those without CLI.

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.