Clinical research plays a central role in the development of medical therapeutics, but the current system is estimated to take 10–15 years from initial discovery to regulatory approval, at a cost of approximately US$1 billion. Contrast the paths by which 2 anticoagulant options for atrial fibrillation were discovered and ultimately established as treatment options in clinical medicine. Warfarin was discovered by serendipity and compared with placebo in relatively small trials; this was associated with a low cost of development. The new oral anticoagulants were synthesized to provide highly specific, targeted inhibition of critical steps in the coagulation system. They were compared with warfarin for prevention of stroke and systemic embolic events in large, phase 3 trials; this resulted in very expensive development programs. Neither of these paths is desirable for future development of therapeutics. We need to focus on innovative approaches at the preclinical level (systems approach, greater use of inducible pluripotent stem cells, use of novel bioengineering platforms) and clinical trial level (adaptive design, greater use of new and emerging technology). Focusing on disruptive innovations for development of medical therapeutics has the potential to bring us closer to the goal of precision medicine where safer, more effective treatments are discovered in a more efficient system. (Circ J 2014; 78: 1267–1271)

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The sinoatrial node (SAN) is the normal pacemaker of the heart. During a human lifetime it must initiate approximately 2 billion heartbeats and coordinate the cardiovascular response to our physiological and emotional demands. Disease of the SAN is common, and one of the leading indications for electronic pacemaker implantation. Advances in understanding the genetics and molecular mechanisms determining normal SAN function, and of the pathways controlling remodeling are revealing SAN disease to be heterogeneous. We review the contemporary concepts of SAN function, heart rate adaptation and SAN disease from the molecular level to clinical application. (Circ J 2014; 78: 1272–1282)

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In the heart, mechanical load is a crucial regulator of myocardial structure and function; however, mechanical overload is a pathogenesis or comorbidity existing in a variety of heart diseases, such as hypertension, aortic regurgitation and myocardial infarction. Mechanical overload can be generally differentiated into 2 types, pressure overload (PO) and volume overload (VO), causing concentric and eccentric cardiac hypertrophy, respectively. The angiotensin II (AngII) type 1 receptor (AT1-R) is a 7 transmembrane G protein-coupled receptor that plays a critical role in load-induced cardiac hypertrophy. Early studies revealed the involvement of autocrine/paracrine mechanisms through stretch-induced release of AngII. Recent conceptually inspiring studies unraveled that the AT1-R could be also directly activated by mechanical stress. The activated AT1-R initiates intricate intracellular signaling pathways through G protein-dependent and G protein-independent mechanisms. AT1-R blocker (ARB) antagonizes the activation of AT1-R to regress cardiac remodeling. Some ARBs show properties of inverse agonism and arrestin-biased agonism at the AT1-R, which are potential therapeutic targets for the treatment of load-induced cardiac hypertrophy. This review summarizes the progress in the understanding of ligand- and mechanical stress-dependent activation of AT1-R, highlights recent data that investigate the role of AT1-R in the differentiation of PO- and VO-induced cardiac hypertrophy, and discusses the clinical relevance of inverse agonism and biased agonism of AT1-R ligands.  (Circ J 2014; 78: 1283–1289)

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Speckle tracking echocardiography (STE) was popularized in the first decade of this century. Analysis of cardiac mechanics has been the focus of ultrasonics, and the breakthrough came with STE. Beyond analysis solely of left ventricular ejection fraction, STE allows the assessment of various pathophysiologies, including myocardial layer-specific myocardial function, twist and rotation, and dyssynchrony. Recent developments in the technology have resulted in commercially available 3-dimensional (D)-STE systems. Through experimental studies and clinical investigations, the reliability and feasibility of 3D-STE-derived data have been validated, and the advantages of 3D-STE over 2D-STE have been revealed. In addition, because of the 3D nature of the technology, 3D-STE provides novel deformation parameters (ie, 3D-strain and area change ratio) that have the potential for more accurate assessment of overall and regional myocardial function. Recently, various preliminary studies using 3D-STE have reported on myocardial characteristics, novel mechanics in the left ventricle, prediction of therapeutic effects, observations of cardiac function through interventions, and challenges for left atrial and right ventricular functions. In this review, we focus on the features of the methodology, validation, and clinical application of 3D-ST.  (Circ J 2014; 78: 1290–1301)

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Inflammation is a determinant of atherosclerotic plaque rupture, the event usually responsible for myocardial infarction and stroke. Possible causes of inflammatory cardiomyopathy include myocarditis, eosinophilic disease, and sarcoidosis. Although conventional imaging techniques can identify the site and severity of luminal stenosis, they do not provide information regarding inflammatory status. ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for imaging of inflammatory cardiovascular diseases has been rapidly evolving. Integrated PET/computed tomography (CT) is becoming the method of choice for quantification of arterial inflammation across multiple vessels. Moreover, PET/CT provides information about the activation status of inflammatory cells in the vessel wall, thus allowing early diagnosis and risk stratification of patients. The Japanese health insurance system approved reimbursement for FDG-PET use to detect inflammation sites in cardiac sarcoidosis as of April 2012. This approval has necessitated a more detailed assessment of the clinical value of FDG-PET. Standardized preparation, imaging, and image interpretation protocols should be established to sufficiently suppress physiological FDG uptake in the normal myocardium, and thereby facilitate detection of early-stage cardiac inflammatory lesions with more favorable specificity. This review summarizes the background, clinical utility, state-of-the-art advances, and potential future applications of FDG-PET for imaging inflammatory cardiovascular diseases including cardiac sarcoidosis, large-vessel arteritis, and atherosclerosis.  (Circ J 2014; 78: 1302–1310)

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The American College of Cardiology (ACC) Scientific Session was held at the Walter E. Washington Convention Center in Washington, DC from March 29–31, 2014. The ACC Scientific Session is one of 3 major scientific cardiology meetings in the world, with over 20,000 attendees from 109 countries. There were over 2,200 oral and poster abstracts, and 22 late-breaking clinical trials (LBCTs), which are the focus of this report. Interestingly, in the CoreValve trials, transcatheter aortic valve replacement with a self-expanding transcatheter aortic-valve bioprosthesis was associated with a higher survival rate at 1 year than surgical aortic valve replacement. Long-term results in a further study are needed. I hope the present report will encourage others to attend the ACC Scientific Session 2015 to be held in San Diego on March 14–16, 2015.  (Circ J 2014; 78: 1311–1316)

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Background: The incidence of intracranial bleeding during dabigatran treatment is lower than that during warfarin treatment. The characteristics of intracranial hemorrhage during dabigatran therapy, however, remain unclear. Methods and Results: The clinical data and treatment summaries of 9 intracranial bleeds that developed during dabigatran treatment in 8 patients with non-valvular atrial fibrillation were retrospectively reviewed. Five patients had small–moderate subdural hematomas, 2 had intracerebral hemorrhage and 1 had traumatic subarachnoid and parenchymal hemorrhage associated with cerebral contusion. Activated partial thromboplastin time upon admission ranged from 31.6 to 72.4s. After admission, systolic blood pressure in the 2 patients with intracerebral hemorrhage was maintained below 140mmHg, and the subdural hematomas in 4 patients were surgically treated. None of the hematomas became enlarged and outcome was good in most cases. Conclusions: Hematomas that arise due to acute intracranial bleeding during dabigatran treatment seem to remain small to moderate, hard to expand, and manageable.  (Circ J 2014; 78: 1335–1341)

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Background: Warfarin reduces the risk of stroke in patients with atrial fibrillation, but requires a moderate-to-high time in therapeutic range (TTR). We hypothesized that point-of-care (POC) testing for prothrombin time-internationalized normalized ratio (PT-INR) could improve the TTR in patients receiving warfarin. Methods and Results: Eight outpatient clinics that introduced POC testing for PT-INR participated in this study. We identified 148 consecutive patients who received warfarin for at least 12 months before and after the introduction of POC testing. We compared the TTR before and after the introduction of POC testing for each patient. TTR after the introduction of POC testing was significantly higher than that beforehand (51.9%±33.0% vs. 69.3%±26.3%; P<0.0001). The improvement in TTR was statistically significant in patients who had low TTR (<70%) before the introduction of POC testing. After the introduction of POC, the time spent above the target INR showed no significant change (3.7%±10.6% vs. 3.3%±6.3%, P=0.7322), while that spent below the target INR improved significantly (44.4%±34.4% vs. 27.4%±27.6%, P<0.0001). Conclusions: The introduction of POC testing was associated with an improvement in TTR, mainly through a reduction in the time spent below the target INR.  (Circ J 2014; 78: 1342–1348)

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Background: The J-ROCKET AF study found that rivaroxaban was non-inferior to warfarin with respect to the principal safety outcome in patients with atrial fibrillation (AF). The aim of this subgroup analysis was to assess the safety and efficacy of rivaroxaban and warfarin in relation to patient age. Methods and Results: A total of 39.0% were elderly (aged ≥75 years). In elderly patients, the principal safety outcome occurred at 25.05%/year with rivaroxaban vs. 16.95%/year on warfarin (hazard ratio [HR], 1.49; 95% confidence interval [CI]: 1.02–2.16), whereas the primary efficacy endpoint occurred at 2.18%/year vs. 4.25%/year (HR, 0.51; 95% CI: 0.20–1.27), respectively. There were significant interactions in the principal safety outcomes of rivaroxaban compared with warfarin between the elderly and non-elderly groups, but not in the primary efficacy endpoints (P=0.04 and 0.82 for both interactions, respectively). Furthermore, in elderly patients, in the rivaroxaban group there was a trend to increase the principal safety outcome regardless of renal function. In elderly patients with preserved renal function, however, patients on rivaroxaban had a marginally favorable trend in the primary efficacy endpoint incidence rate compared with patients on warfarin. Conclusions: There is a need to carefully consider the risks and benefits of therapy with rivaroxaban in elderly patients with non-valvular AF.  (Circ J 2014; 78: 1349–1356)

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Background: Few data exist on the results of transcatheter aortic valve implantation (TAVI) via the transfemoral approach in small slightly built Japanese patients with severe aortic stenosis who are ineligible or at high-risk for conventional surgical aortic valve replacement (SAVR). Therefore, the purpose was to investigate the early outcomes of TAVI using the transiliofemoral approach in Japan. Methods and Results: Between June 2010 and June 2013, 21 consecutive patients (mean age, 81.0 years; 81.0% female) underwent TAVI with Edwards SAPIEN XT valves using the transiliofemoral approach. The mean body surface area was 1.44±0.15m². The device success rate was 90.5%. Although 2 patients did not meet the echocardiographic criteria for device success, no failure to deliver and deploy a valve occurred. The mean effective aortic valve area increased from 0.54±0.12cm² at baseline to 1.46±0.29cm² after the procedure (P<0.001), and the mean aortic transvalvular pressure gradient decreased from 51.0±15.6 at baseline to 11.2±3.6 after the procedure (P<0.001). The 30-day mortality and combined safety endpoint rates were 0% and 4.8%, respectively. All patients achieved New York Heart Association functional class I or II at 30 days. Conclusions: Early outcome of TAVI with the Edwards-SAPIEN XT valve via the transiliofemoral approach at Kurashiki Central Hospital is satisfactory for patients who are ineligible or at high risk for SAVR.  (Circ J 2014; 78: 1357–1363)

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Background: The clinical benefit of concomitant atrial fibrillation (AF) ablation at the time of aortic valve replacement (AVR) is uncertain. Methods and Results: A total of 124 patients with AF who underwent AVR with (n=50) or without (n=74) a concomitant maze procedure, between 2000 and 2011, were evaluated. There were no significant differences in early postoperative outcomes. During a median clinical follow-up of 18.1 months (interquartile range: 6.9–47.8 months), 19 late deaths (15.3%) and 33 valve-related complications (26.6%) occurred, but the differences between groups were not statistically significant. Major event-free survival at 5 years was 60.9±9.9% vs. 57.0±10.3% (P=0.41). After adjustment, the maze group demonstrated similar risks for major adverse cardiac events (hazard ratio, 1.18; 95% confidence interval, 0.56–2.49; P=0.67). However, the rate of sinus rhythm restoration at 4 years was significantly higher in the maze group (80.6% vs. 3.6%, P<0.001). Left atrial dimension was smaller (46.9 vs. 50.4mm, P=0.017), and the ejection fraction was higher (60.6% vs. 58.0%, P=0.059) in the maze group. The rate of postoperative anticoagulation was also lower in the maze group (53.1% vs. 89.2%, P<0.001). Conclusions: Concomitant AF ablation in patients undergoing AVR resulted in increased sinus rhythm restoration, better echocardiographic results, and decreased anticoagulation requirement, without increasing surgical morbidity or mortality.  (Circ J 2014; 78: 1364–1371)

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Background: The Trifecta valve (St Jude Medical) is a novel supra-annular aortic bioprosthesis designed to improve hemodynamic performance. We hypothesized that the Trifecta may offer better hemodynamic performance in Japanese patients, in whom the annulus is smaller, compared with Western populations. We compared the early results of hemodynamic performance between the Trifecta and the Magna (Edwards Lifescience) valves at our institution. Methods and Results: The Trifecta was implanted in 33 patients and the Magna was implanted in 41 patients who had aortic valve disease. Postoperative echocardiography was performed just before discharge, and the mean pressure gradient (MPG), effective orifice area (EOA) index and energy loss coefficient (ELCo) index were compared between the 2 groups. The average prosthesis size was similar between the 2 groups (21.1 vs. 21.3mm). The Trifecta group had a significantly lower MPG (P=0.001) and larger EOA index and ELCo index than the Magna group (P<0.001 for both). On multivariate linear regression analysis, use of the Trifecta was the strongest independent determinant of postoperative MPG, EOA and ELCo index. Conclusions: The Trifecta valve provides excellent early postoperative hemodynamic performance in Japanese patients. Patients with a small annulus size relative to body size may benefit more from the Trifecta in terms of postoperative hemodynamic performance.  (Circ J 2014; 78: 1372–1378)

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Background: Chronic mental stress has been reported to be directly or inversely proportional to blood pressure (BP). To explain this inconsistent relationship, we assumed effect-modification by body mass index (BMI). Methods and Results: We examined 1,673 Japanese male local government employees who were not taking antihypertensive drugs or had no history of cardiovascular disease. BP and BMI were recorded at yearly health checkups. Exposure to mental stress, smoking, drinking, exercising, and salty taste were checked by questionnaire in 1997 and 2002. The main effect and interaction of stress and BMI on the averages and changes of resting systolic and diastolic BPs over the 5 years were assessed by a general linear model by adjusting for confounders. Obesity (BMI ≥25kg/m²) was significantly related with higher average systolic and diastolic BPs (P<0.001, P<0.001, respectively), whereas mental stress was not, showing a significantly different relationship dependent on BMI (P for interaction =0.002, 0.004): a significant and directly proportional association with systolic and diastolic BPs (P=0.001, 0.001) in the obese, but borderline significant and inversely proportional association (P=0.07, 0.08) in the lean. Only BMI was significantly related to the degree of BP change. Conclusions: Whereas BMI was proportionally associated with BP, BMI was a modifier which, depending on its level, inverted the direction of the association between chronic mental stress and resting BP.  (Circ J 2014; 78: 1379–1386)

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Background: Long-term adaptive servoventilation (ASV) increases cardiac function more effectively than continuous positive airway pressure (CPAP), possibly via alleviation of sympathetic overactivation. The present study evaluated the effect of ASV and CPAP at comparable pressure on muscle sympathetic nerve activity (MSNA) in patients with heart failure (HF) and with or without periodic breathing (PB). Methods and Results: A total of 57 patients with HF (ejection fraction <0.45) were randomized to receive CPAP (n=28) or ASV (n=29). Respiratory profiles and MSNA were continuously monitored before and during CPAP and ASV (30min) at pressures of 6.5 and 6.6cmH₂O, respectively. The severity of respiratory instability was determined using the coefficient of variation of tidal volume (CV-TV). Although heart rate and blood pressure remained unchanged, only ASV improved CV-TV. MSNA decreased in the ASV (P<0.001), but not in the CPAP group. The change in CV-TV independently predicted changes in MSNA (P<0.001). Device type and PB significantly interacted with changes in MSNA (P<0.05) and ASV exerted sympathoinhibitory effects in patients with PB, whereas CPAP did not. A sympathoinhibitory effect in patients without PB was not evident in either treatment arm. Conclusions: ASV probably exerts its sympathoinhibitory effects in patients with HF and PB through pressure support.  (Circ J 2014; 78: 1387–1395)

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Background: Indication for mechanical circulatory support (MCS) has been a matter of debate in less sick status 2 patients. Methods and Results: Data were obtained from 183 consecutive patients assigned to stage D heart failure (HF) who were evaluated by the institutional review board of the University of Tokyo Hospital and then listed for heart transplantation as status 1 or 2 of the Japan Organ Transplant Network. Patients with status 2 (n=38) had a prognosis as poor as those dependent on inotropes (n=54) or MCS (n=91; P=0.615, log-rank test), and only 4 of them had eventual ventricular assist device (VAD) implantation (10.5%). Patients who eventually received VAD (n=92) had better 4-year survival than those without MCS among status 1 and 2 (P=0.030, log-rank test). On Cox regression analysis plasma B-type natriuretic peptide (BNP) >740pg/ml was the only significant predictor for 4-year survival among the status 2 group (P=0.014; hazard ratio, 8.267). Ten patients with status 2 died: 6 due to acute hemodynamic compromise and 4 due to ventricular fibrillation. Conclusions: Prognosis in status 2 patients was as poor as that of those dependent on inotrope infusion or VAD, mostly because of out-of-hospital sudden death without MCS. Status 2 patients with considerably high plasma BNP may be good candidates for continuous flow VAD therapy.  (Circ J 2014; 78: 1396–1404)

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Background: To identify a pharmacological agent that can selectively activate cardiac vagus nerve for potential use in vagal activation therapy against heart failure, the effects of medetomidine on autonomic nerve activities in both the heart and stomach were examined. Methods and Results: In anesthetized rabbits, microdialysis probes were implanted into both the right atrial and gastric walls. Dialysate acetylcholine (ACh) and norepinephrine (NE) concentrations were measured by high-performance liquid chromatography. First, the effects of 100μg/kg of intravenous medetomidine on vagal ACh and sympathetic NE releases were examined. Medetomidine significantly increased cardiac ACh release (4.7±1.1 to 7.8±0.9nmol/L, P<0.05), but suppressed gastric ACh release (8.0±2.6 to 3.5±1.5nmol/L, P<0.01). In contrast, medetomidine suppressed both cardiac and gastric NE releases. Second, the effects of medetomidine on ACh releases induced by electrical vagus nerve stimulation (VNS; 10Hz) were examined. Electrical VNS significantly increased both cardiac (6.7±1.2 to 14.8±1.8nmol/L, P<0.01) and gastric (3.8±0.8 to 181.3±65.6nmol/L, P<0.01) ACh releases. Medetomidine did not alter the VNS-induced increases in ACh release. Conclusions: Medetomidine suppresses both cardiac and gastric sympathetic nerve activities. In contrast, medetomidine activates cardiac vagus nerve but inhibits gastric vagal activity. Medetomidine might be one of the potential pharmacological agents for vagal activation therapy against heart failure without the risk of gastric adverse effects.  (Circ J 2014; 78: 1405–1413)

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Background: We examined which pathophysiological abnormalities of vascular function might be closely associated with abnormal baroreflex regulation in subjects with hypertension. Methods and Results: In the cross-sectional assessment, 280 subjects with hypertension were enrolled for measurement of brachial-ankle pulse wave velocity (baPWV), radial augmentation index (rAI), flow-mediated vasodilatation (FMD) of the brachial artery and baroreceptor sensitivity (BRS). These parameters were measured again as prospective assessment in some of these subjects. In the cross-sectional assessment, after adjustment for confounding variables including anti-hypertensive medication, the baPWV, but not the rAI or FMD, was found to have a significant independent relationship with BRS (standardization coefficient, –0.149, P<0.043). In the subjects who were newly started on anti-hypertensive medication (n=40), regression of baPWV before and 1 year after the start of medication was significantly associated with change in BRS during the same period. In subjects already on anti-hypertensive medication (n=92) also, the evolutional change of baPWV over a follow-up period >1.5 years was significantly associated with change in BRS during the same period. Conclusions: Increased stiffness of the large- to middle-sized arteries, rather than abnormal central hemodynamics or endothelial dysfunction, appears to contribute to abnormal baroreflex regulation in patients with hypertension.  (Circ J 2014; 78: 1414–1419)

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Background: The present study investigated whether cilostazol can eliminate adverse smoking outcome after percutaneous coronary intervention (PCI). Methods and Results: A total of 914 patients with successful drug-eluting stent (DES) implantation were randomly assigned to dual antiplatelet therapy (DAT; aspirin and clopidogrel, n=457) or to triple antiplatelet therapy (TAT; DAT with cilostazol, n=457). The effect of smoking on 2-year major adverse cardio/cerebrovascular events (MACCE) in both the TAT and DAT groups was evaluated. Total MACCE were not significantly different between the 2 anti-platelet regimens (9.8% in TAT vs. 11.4% in DAT groups, P=0.45), but the adverse effects of smoking on clinical outcome were different between DAT vs. TAT. Current smokers had a higher prevalence of MACCE than non-smokers in the DAT group (16.7% vs. 9.5%, P=0.04). In the TAT group, however, the adverse effect of smoking was abolished (9.2% vs. 10.1%, P=0.85). Regarding the effects of smoking on the antiplatelet effects of DAT or TAT, post-treatment platelet reactivity (in P2Y₁₂ reaction units; PRU) in current smokers was not significantly lower than that in non-smokers in the DAT group, whereas, in the TAT group, it was significantly lower than that of non-smokers (189±88 vs. 216±89 PRU, P=0.01). Conclusions: Adverse clinical effects of smoking may be eliminated by the addition of cilostazol to DAT after DES implantation. This may be due to the stimulation of cilostazol’s antiplatelet effects by smoking.  (Circ J 2014; 78: 1420–1427)

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Background: Atherosclerosis progression is thought to be one of the mechanisms of late stent failure. Atherosclerosis progression is detected as yellow plaque formation on angioscopy. Cypher sirolimus-eluting stent has been reported to accelerate atherosclerosis progression, but the influence of Endeavor zotarolimus-eluting stent (Endeavor-ZES) or Xience everolimus-eluting stent (Xience-EES) on atherosclerosis has not been clarified. Therefore, we examined the serial changes in extent of atherosclerosis after the implantation of Endeavor-ZES or Xience-EES. Methods and Results: Consecutive patients who received implantation of Endeavor-ZES (n=25) or Xience-EES (n=30) at de novo lesion of native coronary artery and who had successful angioscopy immediately after stent implantation (baseline) and at 1-year follow-up were included in the study. Change in the maximum yellow color grade (grade 0–3) of the stented segment from baseline to follow-up was examined and was compared between Endeavor-ZES and Xience-EES. The maximum yellow color grade decreased significantly from baseline to follow-up in Endeavor-ZES (1.6±1.1 vs. 0.4±0.8, P<0.001), but it did not change in Xience-EES (1.7±1.0 vs. 1.4±0.7, P=0.23). Although the maximum yellow color grade was not different between Endeavor-ZES and Xience-EES at baseline (P=0.72), it was significantly lower in Endeavor-ZES than in Xience-EES at follow-up (P<0.001). Conclusions: Atherosclerosis evaluated by yellow color of the plaque was significantly reduced at 1 year after Endeavor-ZES implantation, but was not changed after Xience-EES implantation.  (Circ J 2014; 78: 1428–1436)

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Background: Previous reports demonstrated mechanisms of cardiac toxicity in acute carbon monoxide (CO) poisoning. Still, none established CO-induced cardiomyopathy (CMP) as a clinical entity. The aim of this study is to investigate CO-induced CMP in patients with acute CO poisoning in terms of its epidemiology, clinical characteristics, and prognosis. Methods and Results: A retrospective study was conducted on consecutive patients who were diagnosed with acute CO poisoning at the emergency department of Ajou University Hospital during the period of 62 month. Six hundred and twenty-six patients were diagnosed with acute CO poisoning. During the initial echocardiography, 19 patients were abnormal: (1) global hypokinesia/akinesia (n=7), (2) regional wall hypokinesia/akinesia [n=12; takotsubo type (n=6), reverse takotsubo type (n=2), non-specific type (n=4)]. The ejection fraction (EF) was 36.3±13.5% (from 15% to 55%) and less than 45% for 14 patients. In the follow-up echocardiography performed within 12 days after the initial performance, most patients were found to have cardiac wall motion abnormalities, and their EF had returned to normal (ie, EF ≥50%). Conclusions: CO-induced CMP was identified in 3.04% (n=19) of all patients (n=626). It might not be too critical in acute clinical courses of acute CO poisoning because the prognosis seems favorable. Considering the common factors between CO-induced CMP and takotsubo CMP, myocardial stunning subject to a catecholamine surge most likely plays a central role in the development of CO-induced CMP.  (Circ J 2014; 78: 1437–1444)

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Background: Atherosclerosis is believed to be caused by oxidative stress. Endovascular therapy (EVT) is effective for claudication of patients with peripheral artery disease (PAD). However, its effect on oxidative stress in PAD patients is unknown. Here, the impact of EVT on oxidative stress in PAD patients is investigated. Methods and Results: Twenty-five PAD patients (Rutherford stage II or III) who underwent EVT were enrolled. The levels of diacron-reactive oxygen metabolite (d-ROM; an oxidative stress marker), ankle-brachial index (ABI), and maximum walking distance at baseline and at 3 months after EVT were measured. As compared with baseline values, the maximum walking distance and ABI improved significantly after EVT (109.9±104.2 vs. 313.7±271.8m, P<0.0001; 0.61±0.15 vs. 0.91±0.13m, P<0.0001, respectively). The improved exercise capacity and arterial flow induced a significant decrease in d-ROM levels (from 472.8±64.8 to 390.2±46.7U.CARR; P<0.0001). The decrease in d-ROM levels after EVT was more prominent in PAD patients with a high baseline d-ROM level. The increased ABI (r=0.524, P=0.0007) and maximum walking distance (r=–0.416, P=0.039) after EVT were significantly correlated with the decreased d-ROM levels. Conclusions: The improved exercise capacity and peripheral blood flow induced by EVT decreases oxidative stress in PAD patients.  (Circ J 2014; 78: 1445–1450)

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Background: Although previous intravascular ultrasound (IVUS) studies reported that the drug-eluting stent (DES) has successfully decreased in-stent restenosis (ISR) by inhibiting neointimal hyperplasia (NIH) in the coronary artery lesion, no IVUS data for vascular response after DES implantation in the superficial femoral artery (SFA) have been published. Methods and Results: We retrospectively analyzed 38 de novo SFA lesions from 32 patients who underwent endovascular therapy (EVT) with self-expanding bare-metal nitinol stent (25 lesions; BMS group) or self-expanding paclitaxel-eluting nitinol stents (13 lesions; PES group). At 6 months after EVT, follow-up IVUS was done to evaluate NIH. Serial IVUS volumetric analysis was done after stent deployment and at follow-up. Mean stent, lumen and neointimal areas were calculated as the volume divided by the stent length. The primary endpoint of this study was mean late lumen loss at 6-month follow-up. The mean follow-up period was 189±39 days. Mean neointimal area was smaller in the PES group compared to the BMS group (3.3±1.0mm² vs. 10.2±4.1mm², P<0.001). Mean late lumen loss was significantly lower in the PES group compared to the BMS group (−2.3±3.7mm² vs. 2.1±4.7mm², P<0.05). Conclusions: EVT with DES in SFA lesions might decrease NIH associated with ISR in short-term follow-up.  (Circ J 2014; 78: 1451–1458)

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Background: By combining the chick embryo model with incubation at high altitude (HA), the effects of chronic hypoxia on fetal growth, fetal cardiac and aortic wall remodeling and systemic arterial blood pressure at adulthood were reported. Using non-invasive functional echocardiography, here we investigated the in vivo effects of HA hypoxia on the pulmonary circulation at adulthood in male and female chickens. Methods and Results: Chick embryos were incubated, hatched and raised at sea level (SL) or at HA. At 6 months of age, functional echocardiography was performed and the body and heart weights were taken. Heart weight was heavier in males but not in female HA chickens compared to their same sex SL counterparts. Similarly, male but not female HA chickens had greater in vivo right ventricular wall thickness compared to their same sex SL counterparts. The tricuspid pressure gradient was greatly enhanced in HA male and HA female chickens. However, the increment in the tricuspid pressure gradient was greater in HA males than in HA females. The pulmonary artery diameter was also enhanced in HA males than in SL males. In contrast, HA did not affect this variable in female chickens. Conclusions: The data show that chronic hypoxia during development at HA is associated with echocardiocraphic indices of pulmonary hypertension at adulthood in a highly sex-dependent manner.  (Circ J 2014; 78: 1459–1464)

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Background: Pulmonary hypertension (PH) causes elevated right ventricular (RV) systolic pressure, RV remodeling and finally RV failure to death. However, the mechanisms of RV remodeling in PH remain to be fully elucidated. Methods and Results: RV autopsy samples from 6 PH patients with RV failure against 3 age- and sex-matched controls were first examined. Next, RV remodeling in 2 mouse models of chronic hypoxia-induced PH with endothelial nitric oxide synthase-deficient (eNOS^–/–) and collagenase-resistant knock-in (Col^R/R) mice were examined. In humans, RV failure was associated with RV hypertrophy, interstitial and perivascular fibrosis, decreased RV capillary density and increased macrophage recruitment. Furthermore, immunostaining showed that perivascular matrix metalloproteinase-2 was increased in PH patients with RV failure. In animals, both hypoxic eNOS^–/– and Col^R/R mice developed a greater extent of RV hypertrophy, perivascular remodeling and macrophage infiltration compared with wild-type mice. Capillary rarefaction was developed in hypoxic eNOS^–/– mice, while Col^R/R mice were able to increase their capillary density in the RV in response to chronic hypoxia. Both mouse models showed increased autophagy even under normoxic condition. Conclusions: These results indicate that RV remodeling occurs early during PH development through fibrosis, perivascular remodeling, capillary rarefaction and autophagy, in which the eNOS pathway and collagen metabolism might be involved.  (Circ J 2014; 78: 1465–1474)

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Background: Acute kidney injury (AKI) and acute hyperglycemia are associated with unfavorable outcomes. The impact of acute hyperglycemia on the development of AKI after acute myocardial infarction (AMI), however, remains unclear. This study was undertaken to assess the relationship between admission glucose and incidence of AKI after AMI. Methods and Results: This study consisted of 760 patients with AMI admitted to the National Cerebral and Cardiovascular Center within 48h after symptom onset. Blood sample was obtained on admission and repeated sampling was done at least every 1 or 2 days during the first week. AKI was diagnosed as increase in serum creatinine ≥0.3mg/dl or ≥50% within any 48h. Ninety-six patients (13%) had AKI during hospitalization for AMI, and these patients had higher in-hospital mortality than those without AKI (25% vs. 3%, P<0.001). Patients with AKI had higher plasma glucose (PG) on admission than those without (222±105mg/dl vs. 166±69mg/dl, P<0.001). The incidence of AKI increased as admission PG rose: 7% with PG <120mg/dl; 9% with PG 120–160mg/dl; 11% with PG 160–200mg/dl; and 28% with PG >200mg/dl (P<0.01). On multivariate analysis admission PG was an independent predictor of AKI (odds ratio, 1.10; 95% confidence interval: 1.03–1.18, P=0.02). Conclusions: Admission hyperglycemia might have contributed to the development of AKI in patients with AMI.  (Circ J 2014; 78: 1475–1480)

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Background: Recent reports have shown that CHADS₂ score can be applied to stroke risk in coronary artery disease (CAD) patients. This study evaluated the efficacy of CHADS₂, CHA₂DS₂-VASc and R₂CHADS₂ scores as prognostic tools for stroke subsequent to CAD. Methods and Results: We enrolled 159 consecutive patients with acute ischemic stroke who were (1) living independently before stroke; and (2) diagnosed with CAD before stroke. Comparisons were made between patients with poor and good 3-month functional outcome (modified Rankin scale ≥3 and <3, respectively) with regard to clinical characteristics and pre-stroke CHADS₂, CHA₂DS₂-VASc and R₂CHADS₂ scores. Multivariate analysis was used to assess the predictive value of each of the 3 scores for poor outcome. The patients with poor and good outcomes had significant differences in intracranial artery stenosis (31.4% vs. 14.9%; P=0.016), carotid artery stenosis (41.9% vs. 23.9%; P=0.019), atrial fibrillation (37.2% vs. 17.9%; P=0.008), NIHSS (11 vs. 5; P<0.001), CHADS₂ (3 vs. 2; P=0.004), CHA₂DS₂-VASc (5 vs. 4; P=0.003), and R₂CHADS₂ (3 vs. 3; P=0.005). Multivariate analysis showed that CHADS₂ >2 (OR, 1.65; 95% CI: 1.05–2.65; P=0.032), CHA₂DS₂-VASc >4 (OR, 1.60; 95% CI: 1.02–1.78; P=0.042), and R₂CHADS₂ >3 (OR, 1.57; 95% CI: 1.01–2.49; P=0.049) positively predicted poor outcome. Conclusions: CHADS₂, CHA₂DS₂-VASc and R₂CHADS₂ are useful in predicting functional status after stroke in CAD patients.  (Circ J 2014; 78: 1481–1485)

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Background: Increased sympathetic activity, commonly reported in mitral valve prolapse, indicates that the sympathetic nervous system might play an important role in regulating mitral interstitial cells. Hence, the aim of this study is to determine the level and pattern of adrenergic receptors expressed in human mitral valve leaflets and to investigate the effect of norepinephrine on physiologic behaviors of mitral interstitial cells. Methods and Results: Immunohistochemistry displayed significantly increased expressions of β1, β2, and α1 adrenergic receptors in mitral valve prolapse. Norepinephrine was found to activate the phenotype of interstitial cells with increased α-SMA expression (2.26 fold). In synthesis, norepinephrine downregulated levels of mRNA for type I to type III collagen in ratio, but increased the elastin gene transcription and glycosaminoglycan levels in valve interstitial cells greatly. In view of the extracellular matrix remodel, sympathetic effects presented catabolic metabolism displaying significantly increased expressions of total, secretory and active MMP-2 protein (matrix metalloproteinase-2), as well as MMP-9 protein. Diminished MMP inhibitor expression, TIMP2, also could reflect this effect in the norepinephrine medium. Conclusions: A novel role for the sympathetic effect in influencing physiologic behaviors in mitral interstitial cells was identified. It is indicated that sympathetic activity could promote myxomatous degeneration in mitral valve prolapse, propagating the disease severity, which might identify potential therapeutic targets.  (Circ J 2014; 78: 1486–1493)

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Background: Thyroid hormone is associated with arterial stiffness and left ventricular diastolic function in hypothyroid disease. The relationship of thyroid hormone level to cardio-ankle vascular index (CAVI) and left ventricular diastolic function, however, remains unclear in subjects with subclinical hypothyroidism. Methods and Results: We conducted a cross-sectional study of 83 patients with untreated subclinical hypothyroidism and compared them with 83 randomly selected controls from health check-ups. Log N-terminal prohormone of brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and arterial stiffness were measured. In addition, we measured early diastolic mitral annular velocity (E’) in 43 participants with subclinical hypothyroidism and in 40 controls. When compared with the control group, patients with subclinical hypothyroidism had higher logNT-proBNP (1.9±0.5 vs. 1.7±0.3pg/ml, P<0.05), CRP (0.22±0.04 vs. 0.09±0.06mg/dl, P<0.05), and CAVI (8.8±1.7 vs. 7.8±1.4, P<0.001) and lower E’ (5.8±1.7 vs. 7.5±2.1cm/s, P<0.001). CAVI was significantly associated with logNT-proBNP, CRP and E’ in the subclinical hypothyroidism group. Conclusions: High logNT-proBNP was associated with a raised CAVI in patients with subclinical hypothyroidism. Subclinical hypothyroidism may be a risk factor for cardiovascular events related to arterial stiffening and left ventricular diastolic dysfunction.  (Circ J 2014; 78: 1494–1500)

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Background: The blood flow capacity in subcutaneous adipose tissue in humans remains largely unknown, and therefore the aim of this study was to determine the physiological range of blood flow in this tissue. Methods and Results: The subcutaneous adipose tissue blood flow (ATBF) was measured in 9 healthy young men by positron emission tomography using radiowater tracer. Subcutaneous ATBF was determined in regions adjacent to knee extensors at rest and during dynamic knee extensor exercise, and with 2 physiological perturbations: while breathing moderate systemic hypoxic air (14% O₂) at rest and during exercise, and during intra-femoral artery infusion of high-dose adenosine infusion. ATBF was 1.3±0.6ml·100g^–1·min^–1 at rest and increased with exercise (8.0±3.0ml·100g^–1·min^–1, P<0.001) and adenosine infusion (10.5±4.9ml·100g^–1·min^–1, P=0.001), but not when breathing moderate systemic hypoxic air (1.5±0.4ml·100g^–1·min^–1). ATBF was similar during exercise and adenosine infusion, but vascular conductance was lower during adenosine infusion. Finally, ATBF during exercise in moderate systemic hypoxia was reduced (6.3±2.2ml·100g^–1·min^–1) compared to normoxic exercise (P=0.004). Conclusions: The vasodilatation capacity of human subcutaneous adipose blood flow appears to be comparable to, or even higher, than that induced by moderate intensity exercise. Furthermore, the reduced blood flow response in subcutaneous adipose tissue during systemic hypoxia is likely to contribute, in part, to the redistribution of blood flow to exercising muscle in a condition of reduced oxygen availability.  (Circ J 2014; 78: 1501–1506)

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