Despite advances in therapy, patients with heart failure (HF) continue to experience unacceptably high rates of hospitalization and death, as well as poor quality of life. As a consequence, there is an urgent need for new treatments that can improve the clinical course of the growing worldwide population of HF patients. Serelaxin and ularatide, both based on naturally occurring peptides, have potent vasodilatory as well as other effects on the heart and kidneys. For both agents, phase 3 studies that are designed to determine whether they improve outcomes in patients with acute HF have completed enrollment. TRV027, a biased ligand for the type 1 angiotensin receptor with effects that extend beyond traditional angiotensin-receptor blockers is also being studied in the acute HF population. Omecamtiv mecarbil, an inotropic agent that improves myocardial contractility by a novel mechanism, and vericiguat, a drug that stimulates soluble guanylate cyclase, are both being developed to treat patients with chronic HF. Finally, despite the negative results of the CUPID study, gene transfer therapy continues to be explored as a means of improving the function of the failing heart. The basis for the use of these drugs and their current status in clinical trials are discussed. (Circ J 2016; 80: 1882–1891)

Background:The long-term prognosis of cardiac ryanodine receptor (RyR2) positive catecholaminergic polymorphic ventricular tachycardia (CPVT) patients after initiation of medical therapy has not been well investigated. This study aimed to assess the recurrence of fatal cardiac event after initiation of medical therapy inRyR2-positive CPVT patients.

Methods and Results:Thirty-fourRyR2-positive CPVT patients with a history of cardiac events were enrolled. All patients had medical treatment initiated after the first symptom or diagnosis. Exercise stress tests (ESTs) were performed to evaluate the efficacy of the medical therapy. Even after the initiation of medical therapy, high-risk ventricular arrhythmias (VAs), including premature ventricular contraction couplets, bigeminy, and ventricular tachycardia, were still induced in the majority of patients (80.6%). During 7.4 years of follow-up after the diagnosis, 7 of the 34 (20.6%) patients developed fatal cardiac events. Among those 7 patients, 6 (85.7%) were not compliant with either exercise restriction or medication therapy at the time of the events.

Conclusions:Even after initiation of medical treatment, high-risk VAs were induced during EST in mostRyR2-positive CPVT patients. Most fatal recurrent cardiac events occurred in patients who were noncompliant with exercise restriction and/or medical therapy. Medical management including strict exercise restriction should be emphasized to prevent recurrent cardiac event in mostRyR2-positive CPVT patients. (Circ J 2016; 80: 1907–1915)

Background:No previous study has reported a comprehensive comparison of the chronic angioscopic findings after bare metal stent (BMS), and 1st- and 2nd-generation drug-eluting stents (DES).

Methods and Results:The Multicenter Study on Intra-Coronary Angioscopy after Stent (MICASA) is a multicenter registry of coronary angioscopy. A total of 264 stents were observed by coronary angioscopy 1 year after PCI. There were 15 BMS, 90 1st-generation DES, and 159 2nd-generation DES. Neointimal coverage (NC) of the stent was classified into 4 grades from 0 (no coverage) to 3 (complete coverage). Yellow color (YC) of plaque at the stented segment was graded from 0 (white) to 3 (bright yellow). Minimum (Min-) and Maximum (Max-) NC grade were significantly lower with 1st- and 2nd-generation DES than with BMS. Although the Max-NC grade was similar, the Min-NC grade was significantly higher for 2nd-generation DES than for 1st-generation DES. Both the YC grade and the incidence of thrombus with 2nd-generation DES were lower than with the 1st-generation DES and were comparable to BMS. Multivariate analysis showed that low-density lipoprotein, 1st-generation DES, and acute coronary syndrome were independent factors for yellow plaque (YG2 or 3), and that hypertension and 1st-generation DES were independent factors for the incidence of thrombus.

Conclusions:Coronary angioscopy revealed more homogeneous coverage with white neointima and less thrombus after 2nd-generation DES as compared with 1st-generation DES. These findings may explain the favorable clinical outcomes observed for patients treated with 2nd-generation DES. (Circ J 2016; 80: 1916–1921)

Background:Percutaneous transluminal renal angioplasty (PTRA) improves patency in atherosclerotic renal artery stenosis (ARAS), but improvement in clinic blood pressure (BP) is seen in only 20–40% of patients who undergo PTRA. This study investigated the effects of PTRA on BP lowering, assessed on 24-h ambulatory BP monitoring (ABPM), and identified preoperative features predictive of satisfactory BP improvement after PTRA.

Methods and Results:Of 1,753 consecutive patients undergoing coronary angiography, 31 patients with angiographically significant ARAS and translesional pressure gradient (TLPG) >20 mmHg underwent PTRA. ABPM was performed before, at 1 month and at 1 year after PTRA; patients with average systolic ABPM-BP decrease >10 mmHg at 1 month from baseline were categorized as responders. There was no obvious relationship between clinic BP and ABPM-BP at baseline. ABPM-BP was significantly higher in responders at baseline (SBP: 148 vs. 126 mmHg, P<0.01) and was improved 1 month after PTRA. This difference persisted until 1 year after PTRA. Night-time BP improved more than daytime BP in responders. Patients with higher baseline ABPM-BP achieved a larger decrease in ABPM-BP, but the severity of stenosis reflected by TLPG; renal duplex findings; and neurohumoral parameters other than baseline renal function, did not differ between the groups.

Conclusions:Clinic BP does not represent daily hemodynamic status, whereas high ABPM-BP is a potent predictor of satisfactory BP response to PTRA. (Circ J 2016; 80: 1922–1930)

Background:The HeartMate II (HMII) continuous-flow LVAD was approved for Japanese health insurance coverage in April 2013 as a bridge to transplantation (BTT). We report on post-approval Japanese multicenter outcomes, and a comparison between patients with low and high body surface area (BSA).

Methods and Results:HMII LVAD was implanted in 104 consecutive patients at 15 Japanese centers between April 2013 and July 2014. Perioperative data were submitted to the Japanese Registry for Mechanically Assisted Circulatory Support. Patients were divided into 2 groups on the basis of BSA less or greater than 1.5 m². Survival outcomes, New York Heart Association functional class, and adverse event rates were compared between the 2 groups. Preoperative hemodynamics and INTERMACS profiles were similar between groups. There were more females and younger patients in the low BSA group. The respective 6-month and 1-year death- or pump exchange-free survival rates were excellent: 90% and 90% in the BSA <1.5 group vs. 90% and 85% in the BSA ≥1.5 group. In the BSA <1.5 group, occurrence of hemorrhagic stroke was 10% and occurrence of embolic stroke was 0%, vs. 12% and 8% in BSA ≥1.5 group. Driveline infection was encountered more frequently in the BSA <1.5 group.

Conclusions:Results for HMII LVAD as BTT in the post-approval era showed excellent survival and functional capacity improvement. Of particular interest to the Japanese patient population are the excellent results in patients with small BSA. (Circ J 2016; 80: 1931–1936)

Background:To determine the predictors of aggravated left ventricular diastolic dysfunction (LVDD) in patients undergoing off-pump coronary artery bypass grafting (OPCAB) and to compare late outcomes according to the aggravated LVDD.

Methods and Results:OPCAB was performed in 1,101 patients (2001–2013). LVDD was classified as normal, mild, moderate or severe. Patients were divided into 2 groups: non-aggravated LVDD (group I) and aggravated LVDD (group II). The primary endpoint was aggravation of LVDD. The secondary endpoint was late mortality and morbidity such as major adverse cardiac and cerebrovascular events (MACCE) related to LVDD aggravation postoperatively. There were 894 patients in group I and 207 in group II. Multivariate analysis revealed that preoperative peripheral artery obstructive disease (PAOD) (P=0.04), renal failure (P<0.01), and A′ velocity (P<0.01) anticipated aggravated LVDD. The Cox hazards model revealed that aggravated LVDD was a poor prognostic factor for MACCE (P<0.01) and overall survival (P<0.01). The Kaplan-Meier survival curve showed that aggravated LVDD was related to poor late outcomes (freedom from MACCE, P=0.01; overall survival, P<0.01).

Conclusions:Aggravated LVDD significantly affects late clinical outcomes after OPCAB and preoperative PAOD, renal failure, and A′ velocity might be predictors. (Circ J 2016; 80: 1937–1945)

Background:Transcatheter aortic valve implantation (TAVI) has become an alternative procedure for treating aortic stenosis (AS) in patients with advanced age and severe comorbidities. Ischemic heart disease (IHD) is present with AS in 40–50% of patients with typical angina. Considering the high operative mortality and morbidity rates in these patients, hybrid TAVI and off-pump CABG (OPCAB) have become realistic treatment options.

Methods and Results:Between August 2014 and November 2015, 12 patients were evaluated for simultaneous TAVI and OPCAB. Because of their advanced age and comorbidities these patients were not considered suitable for standard open heart surgery. PCI was also considered unsuitable, because of left anterior descending artery (LAD) proximal lesions and/or high SYNTAX score. TAVI was conducted through a median sternotomy after left internal thoracic artery (LITA) to LAD anastomosis. In 11 cases OPCAB with LITA and composite RA graft was performed using an aorta no-touch technique. Mean age at operation was 81±6.3 years. Average number of distal anastomoses was 2.6. Perivalvular leakage was mild in 3 patients, trivial in 8, and none in 1. There was no conversion to on-pump procedure and no hospital deaths.

Conclusions:Simultaneous transaortic TAVI and OPCAB in high-risk patients with severe AS and IHD is a reasonable option. This method could be an alternative to surgical aortic valve replacement and CABG. (Circ J 2016; 80: 1946–1950)

Background:Obesity has been found to be associated with future development of diastolic heart failure. Other evidence has indicated that the effect of obesity on left ventricular (LV) mass varies among ethnicities. However, there are few data on the relationship between body mass index (BMI) and LV diastolic dysfunction in the Japanese population.

Methods and Results:We performed echocardiography in 788 subjects without valvular disease or LV systolic dysfunction. They were divided into 3 groups by BMI: normal weight, overweight, and obese. We used multivariable linear regression analysis to assess the clinical variables associated with diastolic parameters, including BMI. We also assessed the risk of diastolic dysfunction associated with BMI using multivariable logistic models. Overweight and obese subjects had significantly worse LV diastolic function and greater LV mass than normal weight subjects. In the multivariable analysis, BMI was independently associated with diastolic parameters. Furthermore, after adjusting for clinical factors, the increased risks of diastolic dysfunction in overweight subjects (adjusted odds ratio: 2.02, 95% confidence interval 1.21–3.36) and obese subjects (4.85, 3.36–16.27) were greater than those previously observed in Western populations.

Conclusions:The Japanese population might be more susceptible than Western subjects to the effect of BMI on LV diastolic function. Differences between ethnicities should be taken into consideration in strategies for the prevention of diastolic heart failure. (Circ J 2016; 80: 1951–1956)

Background:Diabetic nephropathy is independently associated with longitudinal systolic dysfunction of the left ventricle (LV) in asymptomatic diabetes mellitus (DM) patients with preserved LV ejection fraction (LVEF). However, the effect of diabetic nephropathy on left atrial (LA) function remains unknown.

Methods and Results:We studied 198 asymptomatic DM patients (LVEF ≥50%). Diabetic nephropathy was defined as a protein level higher than for micro-albuminuria. LV global longitudinal strain (GLS) and LA strain were analyzed by 2D speckle-tracking; 69 age-, sex-, and LVEF-matched controls were also studied. GLS and LA strain in systole (LAS-s) decreased significantly from normal controls to DM patients without (n=137) and with nephropathy (n=61), in that order. Furthermore, GLS, LAS-s, and LA strain in late diastole (LAS-a) were significantly lower in DM patients with macro-albuminuria (n=19) than in those with micro-albuminuria (n=42). Although 1 multivariate regression analysis identified albuminuria as an independent determinative factor of LAS-s among other relevant clinical background factors (β=−0.16, P=0.002), another multivariate regression model for LAS-s+GLS (β=0.40, P<0.001) showed that albuminuria was not a significant factor (β=−0.02, P=0.68). Similarly, another multivariate regression model including GLS (β=0.32, P<0.001) demonstrated that clinical features relevant for LAS-a, except for age, were not independent determinants of LAS-a.

Conclusions:The cross-linked association of LA strain with GLS and albuminuria may be important for better understanding the development of diabetic cardiomyopathy. (Circ J 2016; 80: 1957–1964)

Background:The monitoring of tissue hypoperfusion and the subsequent neurohumoral activation (ie, arterial underfilling) during decongestion is important for the management of acute decompensated heart failure (ADHF). The transtubular potassium concentration gradient (TTKG) has been reported to be a marker of renal aldosterone bioactivity. This study tested the hypothesis that TTKG can be a surrogate of arterial underfilling in patients with ADHF.

Methods and Results:We measured TTKG at discharge in 100 ADHF patients. The primary outcome measure was the occurrence of tissue hypoperfusion events (defined according to the “Cold Modified 2014” definition criteria) within 1 month after discharge. The secondary outcome measure was the occurrence of cardiac death or ADHF readmission within 3 months after discharge. On receiver operating characteristic curve analysis, TTKG predicted tissue hypoperfusion events with high accuracy (C-statistic, 0.889) for a cut-off of 6.0. Multivariate Cox regression analyses demonstrated independent relationships between TTKG and both the primary and secondary outcomes.

Conclusions:TTKG has utility as a surrogate of arterial underfilling, and spot TTKG at discharge may be a prognostic marker in ADHF patients. (Circ J 2016; 80: 1965–1970)

Background:Inflammatory responses, especially by CD4⁺T cells activated by dendritic cells, are known to be important in the pathophysiology of cardiac repair after myocardial infarction (MI). Although co-stimulatory signals through B7 (CD80/86) and CD28 are necessary for CD4⁺T cell activation and survival, the roles of these signals in cardiac repair after MI are still unclear.

Methods and Results:C57BL/6 (Control) mice and CD28 knockout (CD28KO) mice were subjected to left coronary artery permanent ligation. The ratio of death by cardiac rupture within 5 days after MI was significantly higher in CD28KO mice compared with Control mice. Although there were no significant differences in the infarct size between the 2 groups, left ventricular end-diastolic and end-systolic diameters were significantly increased, and fractional shortening was significantly decreased in CD28KO mice compared with Control mice. Electron microscopic observation revealed that the extent of extracellular collagen fiber was significantly decreased in CD28KO mice compared with Control mice. The number of α-smooth muscle actin-positive myofibroblasts was significantly decreased, and matrix metalloproteinase-9 activity and the mRNA expression of interleukin-1β were significantly increased in CD28KO mice compared with Control mice.

Conclusions:Deletion of CD28 co-stimulatory signals exacerbates left ventricular remodeling and increases cardiac rupture after MI through prolongation of the inflammatory period and reduction of collagen fiber in the infarct scars. (Circ J 2016; 80: 1971–1979)

Background:The ODYSSEY Japan study was designed to demonstrate the reduction in low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on to existing lipid-lowering therapy in Japanese patients with heterozygous familial hypercholesterolemia (heFH) or non-FH at high cardiovascular risk who require additional pharmacological management to achieve their LDL-C treatment goal (<2.6 or <3.1 mmol/L, depending on risk category).

Methods and Results:This randomized, double-blind, parallel-group, 52-week study was conducted in Japan. Patients (n=216) with heFH, non-FH at high cardiovascular risk with coronary disease, or classified as category III were enrolled. The prespecified safety analysis was done after the last patient completed 52 weeks. Patients were randomized (2:1, alirocumab:placebo) with stratification for heFH to s.c. alirocumab (75 mg every 2 weeks [Q2 W] with increase to 150 mg if week 8 LDL-C ≥2.6/3.1 mmol/L) or placebo for 52 weeks plus stable statin therapy. At week 24, mean±SE change in LDL-C from baseline was –62.5±1.3% in the alirocumab group and 1.6±1.8% in the placebo group (difference, –64.1±2.2%; P<0.0001); the reduction was sustained to week 52 (alirocumab, –62.5±1.4%; placebo, –3.6±1.9%). No patterns were evident between treatment groups for adverse events at 52 weeks.

Conclusions:In high-risk Japanese patients with hypercholesterolemia on stable statin therapy, alirocumab markedly reduced LDL-C vs. placebo and was well tolerated over 52 weeks. (Circ J 2016; 80: 1980–1987)

Background:Activation of glucose-dependent insulinotropic polypeptide receptor (GIPR) has been shown to be protective against atherosclerosis. However, effects of GIP on the heart have remained unclear. To address this question, in vitro and in vivo experiments were conducted.

Methods and Results:In isolated mouse cardiomyocytes, GIPR mRNA was detected by reverse transcription-polymerase chain reaction, and GIP stimulation increased adenosine 3′,5′-cyclic monophosphate production. In apolipoprotein E-knockout mice, infusion of angiotensin II (AngII; 2,000 ng·kg^–1·min^–1) significantly increased the heart weights, and co-administration of GIP (25 nmol·kg^–1·day^–1) reversed this increase (both P<0.01). In the left ventricular walls, GIP suppressed AngII-induced cardiomyocyte hypertrophy by 34%, apoptosis by 77%, and interstitial fibrosis by 79% (all P<0.01). Furthermore, GIP reduced AngII-induced expression of transforming growth factor-β1 (TGF-β1) and hypoxia inducible factor-1α. In wild-type mice, cardiac hypertrophy was induced by AngII to a lesser extent, and prevented by GIP. In contrast, GIP did not show any cardioprotective effect against AngII-induced cardiac hypertrophy in GIPR-knockout mice. In an in vitro experiment using mouse cardiomyocytes, GIP suppressed AngII-induced mRNA expression of B-type natriuretic peptide and TGF-β1.

Conclusions:It was demonstrated that cardiomyocytes represent a direct target of GIP action in vitro, and that GIP ameliorated AngII-induced cardiac hypertrophy via suppression of cardiomyocyte enlargement, apoptosis, and fibrosis in vivo. (Circ J 2016; 80: 1988–1997)

Background:Management of cardiac amyloidosis (CA) is related to amyloid deposition. Our aim was to assess the effect of amyloid deposition on myocardial function.

Methods and Results:Twenty-eight patients with transthyretin mutation and a group of 14 controls underwent echocardiography to quantify left ventricular (LV) dimensions, function, and global (G) longitudinal (L), radial (R) and circumferential (C) strain (S). ^99mTc-3,3-diphosphono-1,2-propanodicarboxylic-acid-scintigraphy (^99mTc-DPD) was used to quantify CA. ^99mTc-DPD revealed accumulation in 14/28 patients (CA group) and no accumulation (no-CA group) in 14. Cardiac accumulation was lower-than-bone uptake in 5 (mild-CA group) and higher-than-bone uptake in 9 (severe-CA group). Ejection fraction was similar among groups. GLS was lower (P<0.001) in the severe-CA group (−12.2±4.5) with respect to the no-CA group (−19.3±3.0) and to the control group (−20.9±2.5). Conversely, GCS and GRS were lower (P<0.05) in the mild-CA group (−10.8±4.1 and 9.5±5.7, respectively) with respect to the severe-CA group (−18.9±5.1 and 23.9±6.3 respectively), no-CA group (−19.2±4.1 and 28.4±10.2, respectively) and the control group (−23.9±4.4 and 29.9±8.7, respectively). A correlation was found between the scintigraphic heart retention index (HRI) and LV septal thickness (ρ=0.72), E/E’ (ρ=0.46) and GLS (ρ=−0.40).

Conclusions:Myocardial deformation is impaired in a different stage of CA. The ^99mTc-DPD HRI correlated well with morphologic, diastolic and strain abnormalities. (Circ J 2016; 80: 1998–2003)

Background:The temporal change in ankle-brachial index (ABI) in the general population, especially in those aged <40 years, remains unclear.

Methods and Results:ABIs of 23,673 individuals were measured in 1-day health checkups between 2003 and 2010. Among them, 1,117 participants aged 28–76 years (mean 53±9 years) whose ABI was measured at least twice within an interval of ≥4 years (mean: 4.9 years) were selected for this study. Baseline ABI was the lowest at age <40 years and increased with age. ABI significantly increased in participants aged <40 and 40–49 years, but not in participants aged 50–59 and ≥60 years. ABI increased in participants with borderline-low baseline ABI (0.9<ABI<1.0, 0.09; P<0.001) and normal baseline ABI (1.0≤ABI<1.2, 0.006; P=0.017). ABI decreased in participants with high-normal baseline ABI (1.2≤ABI<1.4, −0.04; P<0.001). Stepwise multivariate analysis revealed that ABI change was independently associated with baseline ABI (β=−0.566), height (β=0.162), body mass index (β=0.093), and sex (women, β=−0.08).

Conclusions:ABI was lowest at age <40 years and increased with age. In participants aged <50 years, ABI significantly increased over the mean observation period of 4.9 years. (Circ J 2016; 80: 2004–2009)

Background:In patients with proximal pulmonary artery (PA) thromboembolism, an increased PA resistance contributes to abnormal right ventricular (RV) afterload. However, the effects of proximal thromboembolism on the dynamic properties of RV afterload, which is determined by PA impedance, have not been analyzed quantitatively. The present study aimed to identify changes in PA impedance after the pulmonary perfusion volume was greatly reduced by unilateral proximal PA occlusion.

Methods and Results:Ten male Sprague-Dawley rats were used. PA flow and pressure waveforms were recorded during irregular pacing, before and 10 min after left PA occlusion. PA impedance was parameterized by using a three-element Windkessel model consisting of peripheral resistance (R_P), arterial compliance (C_P) and characteristic impedance (Z_C). After proximal PA occlusion, PA impedance modulus increased over a frequency range of interest.Z_Cincreased significantly (after PA occlusion vs. baseline: 0.128±0.016 vs. 0.074±0.010 mmHg·min/ml, P<0.001), whereasC_PandR_Pdid not change significantly.

Conclusions:Proximal PA occlusion increasedZ_Cwith the attenuation ofR_Pincrease andC_Pdecrease predicted from the decreased pulmonary perfusion volume. The insignificant changes inR_PandC_Pindicate that a recruitment phenomenon may result in this attenuation. The existence of compensation by a recruitment mechanism suggests the relative importance of increasedZ_Cin defining abnormal RV afterload in patients with proximal PA thromboembolism. (Circ J 2016; 80: 2010–2018)

Background:Echocardiography (ECHO) plays a key role in both the diagnosis and prognosis of pulmonary hypertension (PH). Many equations have been published to assess right heart hemodynamics using ECHO. The objective of this study was to test the accuracy and precision of different echocardiographic equations in comparison with the right heart catheterization.

Methods and Results:Complete right heart hemodynamic assessments were prospectively obtained from 115 individuals (mean age 66±1 years; 57 males) who had known or suspected PH. Several equations were tested for the estimation of right atrial pressure, mean and systolic pulmonary artery pressure (MPAP), cardiac output, pulmonary capillary wedge pressure (PCWP), and pulmonary vascular resistance (PVR). The accuracy of ECHO was good, with a mean difference <2 mmHg for all of the pressure calculations and ±0.6 L/min for cardiac output. However, the PVR estimation was weak using any one of the formulae. For all the parameters, the precision of ECHO was moderate. The MPAP calculation detected PH with a sensibility of 97% and specificity of 83%. However, ECHO underdiagnosed post-capillary PH.

Conclusions:ECHO is a good method for the diagnosis of PH, with an adequate calculation of right pressures, but cannot accurately calculate PCWP and PVR. (Circ J 2016; 80: 2019–2025)

Background:Cardiac dysfunction (CD) associated with brain hemorrhage is similar to that with takotsubo cardiomyopathy but still not well understood. We aimed to investigate the clinical and echocardiographic findings of acute CD (ACD) related to brain hemorrhage.

Methods and Results:Between 2013 and 2014, consecutive patients diagnosed with spontaneous and traumatic brain hemorrhage were prospectively enrolled. Electrocardiography, cardiac enzymes, and echocardiography were performed. Left ventricular (LV) systolic dysfunction on echocardiography was defined as ACD related to brain hemorrhage when all the following conditions were satisfied: abnormal ECG and cardiac troponin level, LV wall motion abnormality or decreased LV systolic function on echocardiography, and no previous history of cardiac disease. Otherwise, LV dysfunction was considered to be other CD unrelated to brain hemorrhage. In a total of 208 patients, 15 (7.2%) showed ACD. Of them, 8 patients were men and 8 showed apex-sparing LV hypokinesia and 9 died in hospital. Other cardiac abnormalities observed in the study patients were NT-proBNP elevation (n=123), QT interval prolongation (n=95), LV hypertrophy (n=89), and troponin I elevation (n=47). There were 36 in-hospital deaths (17.3%). Glasgow coma score and ACD were independently associated with in-hospital death.

Conclusions:ACD was observed in patients with various brain hemorrhages. Unlike takotsubo cardiomyopathy, high proportions of male sex, apex-sparing LV dysfunction, and in-hospital death were observed for ACD associated with brain hemorrhage. (Circ J 2016; 80: 2026–2032)

Background:Few existing stroke registries allow for evaluation of stroke severity, stroke subtype and antithrombotic usage prior to stroke onset over a given time period. The present study aimed to elucidate temporal trends in initial presenting stroke severity, stroke subtype and prior antithrombotic use over a 12-year period in a Japanese multicenter stroke registry.

Methods and Results:We included 71,017 acute ischemic stroke patients (72±12 years old; 27,445 women) from the Japan Standard Stroke Registry Study (JSSRS) who were admitted to 94 hospitals between 2001 and 2012. The mean age of stroke onset increased gradually over time (P<0.001). Cardioembolic stroke patients (n=19,247) exhibited more severe NIHSS scores when compared with those with non-cardioembolic stroke (n=50,427). The proportion of cardioembolic stroke patients tended to increase over time, rising from 25.9% in 2001–2002 to 30.2% in 2011–2012 (P<0.001). Among the cardioembolic stroke patients, the frequency of prior anticoagulant use significantly increased from 15.6% in 2001–2002 to 24.8% in 2011–2012 (P<0.001). The frequency of prior antiplatelet use increased from 2001–2002 to 2007–2008 but decreased after 2007–2008. Among both cardioembolic and non-cardioembolic stroke patients, initial stroke severity at admission decreased over time, particularly after 2008.

Conclusions:In this Japanese study, the mean age of ischemic stroke onset increased, while the initial neurological severity at presentation decreased, over a 12-year period. (Circ J 2016; 80: 2033–2036)

Background:Substantial evidence indicates that molecular hydrogen (H₂) has beneficial vascular effects because of its antioxidant and/or anti-inflammatory effects. Thus, hydrogen-rich water may prove to be an effective anti-aging drink. This study examined the effects of H₂on endothelial senescence and clarified the mechanisms involved.

Methods and Results:Hydrogen-rich medium was produced by a high-purity hydrogen gas generator. Human umbilical vein endothelial cells (HUVECs) were incubated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for various time periods in normal or hydrogen-rich medium. The baseline H₂concentration in hydrogen-rich medium was 0.55±0.07 mmol/L. This concentration gradually decreased, and H₂was almost undetectable in medium after 12 h. At 24 h after TCDD exposure, HUVECs treated with TCDD exhibited increased 8OHdG and acetyl-p53 expression, decreased nicotinamide adenine dinucleotide (NAD⁺)/NADH ratio, impaired Sirt1 activity, and enhanced senescence-associated β-galactosidase. However, HUVECs incubated in hydrogen-rich medium did not exhibit these TCDD-induced changes accompanying Nrf2 activation, which was observed even after H₂was undetectable in the medium. Chrysin, an inhibitor of Nrf2, abolished the protective effects of H₂on HUVECs.

Conclusions:H₂has long-lasting antioxidant and anti-aging effects on vascular endothelial cells through the Nrf2 pathway, even after transient exposure to H₂. Hydrogen-rich water may thus be a functional drink that increases longevity. (Circ J 2016; 80: 2037–2046)

Background:This study compared the diagnostic efficacy of the common suspended diaphragm stethoscope (SDS) with a new extensible diaphragm stethoscope (EDS) for low-frequency heart sounds.

Methods and Results:The EDS was developed by using an ethylene propylene diene monomer diaphragm. The results showed that the EDS enhanced both the volume and quality of low-frequency heart sounds, and improved the ability of examiners to auscultate such heart sounds.

Conclusions:Based on the results of the sound analysis, the EDS is more efficient than the SDS. (Circ J 2016; 80: 2047–2049)