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Funding Acknowledgements Type of funding sources: None. Background With an aging cardiovascular disease population, frailty is become an important prognostic factor in patients, which is associated with poor quality of life outcomes, such as fatigue, and decreased physical activity. However, the relationship between frailty and health-related quality of life (HRQOL) in elderly patients undergoing cardiac rehabilitation (CR) remains unclear. Methods In this study, 217 patients (mean age: 74.6 ± 5.8 years; male: 67%) were recruited who participated in early phase II CR at a university hospital between November 2015 and December 2016. As part of the CR processed, patients were asked to complete the Kihon Checklist (KCL) and 36-Item Short Form Survey (SF-36). We divided patients into three groups according to their KCL results: the frailty group (n = 81; 37%), the pre-frailty group (n = 71; 32%), and the non-frailty group (n = 65; 29%). The three groups were compared based on their basic characteristics and SF-36 scores. Results Among the three groups, sex, body mass index, 6-minute walking distance (6MWD), hemoglobin level, and low-density lipoprotein cholesterol level varied significantly (p Conclusions HRQOL as well as physical and mental domains declined in frail elderly patients undergoing CR, which suggests that an intervention program considering social life and daily roles is necessary.

Objectives The aim of this AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial subgroup analysis was to examine rivaroxaban monotherapy benefits and their relation to the time between stenting and enrollment among patients after coronary stenting. Background Of 2,215 patients with atrial fibrillation and stable coronary artery disease in the AFIRE trial, rivaroxaban monotherapy was noninferior to rivaroxaban plus antiplatelet therapy (combination therapy) in terms of efficacy and superior for safety endpoints. However, thrombotic risk after antiplatelet therapy cessation remained a concern among 1,444 patients who had undergone coronary stenting >1 year before enrollment. Methods The benefits of rivaroxaban monotherapy in coronary stenting subgroups were assessed for efficacy (a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death of any cause), safety (major bleeding defined according to International Society on Thrombosis and Haemostasis criteria), ischemic endpoints, net adverse clinical event, and time between stenting and enrollment. Results Efficacy and safety endpoints for monotherapy were superior to combination therapy, with HRs of 0.70 for efficacy (95% CI: 0.50-0.98; P = 0.036) and 0.55 for safety (95% CI: 0.33-0.92; P = 0.019). For ischemic endpoints, the HR was 0.82 (95% CI: 0.58-1.15; P = 0.240). The HR became smaller with longer time between stenting and enrollment (efficacy, P for interaction = 0.158; safety, P = 0.097). Conclusions In patients with atrial fibrillation after coronary stenting, the benefits of rivaroxaban monotherapy for efficacy and safety endpoints were consistent with those in the whole AFIRE trial population. The benefits became apparent with longer time between stenting and enrollment. (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study [AFIRE]; UMIN000016612 , NCT02642419 )

Objectives As heart failure with concomitant sarcopenia has a poor prognosis, simple methods for evaluating the appendicular skeletal muscle mass index (ASMI) are required. Recently, a model incorporating anthropometric data and the sarcopenia index, that is, the ratio of serum creatinine to cystatin C (Cre/CysC), was developed to estimate the appendicular skeletal muscle mass. We hypothesized that this model would be superior to the previous model, which uses only anthropometric data to predict the prognosis. This study aimed to compare the prognostic value of low ASMI as defined by the biomarker and anthropometric models in patients with heart failure. Methods Among 847 patients, we estimated ASMI using an anthropometric model consisting of age, body weight, and height in 791 patients and a biomarker model that incorporates age, body weight, hemoglobin, and Cre/CysC in 562 patients. Patients were divided into low and non-low ASMI groups according to the ASMI estimated by each model, using the cut-off proposed by the Asian Working Group for Sarcopenia. The primary outcome was all-cause mortality. Results Overall, 53.4% and 39.1% of patients were diagnosed with low ASMI by anthropometric and biomarker models, respectively. The agreement of the diagnosis of low ASMI between the two models was poor, with a kappa coefficient of 0.56 (95% confidence interval: 0.49–0.63). Kaplan-Meier curves showed that a low ASMI was significantly associated with all-cause death in both models. However, this association was retained after adjustment for other covariates in the biomarker model (hazard ratio: 2.60, p=0.003), but not in the anthropometric model (hazard ratio: 0.70, p=0.257). Conclusions and implications Among patients hospitalized with heart failure, a low ASMI estimated using the biomarker model, but not the anthropometric model, was significantly associated with all-cause mortality. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Japan Agency for Medical Research and Development

Background Although risk stratification is important in patients with acute heart failure (AHF) to predict patient prognosis, pre-existing risk models have not often been used due to its complexity. Recently, machine learning methods have been presented as an alternative approach to analyzing the predictive probability of large clinical datasets. Purpose The aim of this study is to develop a user-friendly risk score developed by one of machine learning methods and compare the performance of the new risk score to the existing conventional risk models. Methods A machine-learning-based risk model was developed using least absolute shrinkage and selection operator (LASSO) regression by identifying predictors of in-hospital mortality in the derivation cohort (REALITY-AHF) and externally validating and comparing its performance with two pre-existing risk models: the Get With The Guidelines risk score incorporating brain natriuretic peptide and hypochloremia (GWTG-BNP-Cl-RS) and the acute decompensated heart failure national registry (ADHERE) risk model. Results In-hospital deaths in the derivation and validation (NARA-HF) cohorts were 76 (5.1%) and 61 (4.9%), respectively. The risk score comprised four variables (systolic blood pressure, blood urea nitrogen, serum chloride, and C-reactive protein) and was developed according to the results of the LASSO regression weighting the coefficient for selected variables using a logistic regression model (4V-RS). Even though 4V-RS comprised fewer variables, In the validation cohort, it showed a higher area under the receiver operating characteristic curve (AUC) than the ADHERE risk model (AUC, 0.783 vs. 0.740; P=0.059) and a significant improvement in net reclassification (0.359; 95% CI, 0.10–0.67; p=0.006). 4V-RS performed similarly to GWTG-BNP-Cl-RS in terms of discrimination (AUC, 0.783 vs. 0.759; p=0.426) and net reclassification (0.176; 95% CI, −0.08–0.43; p=0.178). Conclusions The 4V-RS model comprising only four readily available data points at the time of admission performed similarly to the more complex pre-existing risk model in patients with AHF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Cardiovascular Research Fund

Aim To clarify the association between changes in the number of foundational medications for heart failure (FMHF) during hospitalization for worsening heart failure and post-discharge prognosis. Methods and results We retrospectively analyzed a combined dataset of three large-scale registries of hospitalized patients with heart failure in Japan (NARA-HF, WET-HF, and REALITY-AHF) and included patients already diagnosed with heart failure with reduced or mildly reduced left ventricular ejection fraction (HFr/mrEF) before admission. Patients were stratified by changes in the number of prescribed FMHF classes, namely angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta blockers, and mineralocorticoid receptor blockers, from admission to discharge. The primary endpoint was defined as the combined endpoint of heart failure rehospitalization and all-cause death within 1-year of discharge. The cohort consisted of 1,113 patients, and 482 combined endpoints were observed. In total, 413 (37.1%) patients were on increased FMHF (increased group), 607 (54.5%) remained unchanged (unchanged group), and 93 (8.4%) had a decreased number of FMHF (decreased group) at discharge compared to the time of admission. In multivariable analysis, the increased group was associated with a significantly lower incidence of the primary endpoint compared with the unchanged group (hazard ratio 0.56, 95% confidence interval 0.45–0.60; P Conclusion Increasing the number of FMHF cases during heart failure hospitalization is associated with a better prognosis in patients with HFr/mrEF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): REALITY registry was funded by the Cardiovascular Research Fund of Japan.WET-HF registry was supported by a Grant-in-Aid for Young Scientists (Y.S. JSPS KAKENHI, 18K15860).

Background and objective Percutaneous coronary intervention (PCI) with metallic coronary stent (bare-metal stents [BMS] and drug-eluting stents [DES]) implantation is most frequently performed therapeutic procedures for coronary artery disease. In-stent restenosis (ISR) is a critical drawback of metallic coronary stents. Incidence of ISR has been reported in up to 30% after BMS implantation. The use of DES has greatly reduced the proportion of restenosis compared with the BMS. However, ISR still remains the primary concern after PCI even in the contemporary DES era, and thought to be associated with worse clinical outcomes. However, comparative data on ISR and de novo lesions are rare. Purpose The aim of the present study was to compare the clinical outcomes after PCI for the de novo lesion and the ISR lesion. Methods We performed a retrospective analysis of patients who underwent PCI between 2013 and 2020. The incidences of major adverse cardiac and cerebrovascular events (MACCE) and all-cause death were evaluated. MACCE was defined as composite of cardiovascular death, non-fatal myocardial infarction, and stroke. Results In this study, 1538 patients were enrolled and divided into two groups: PCI for de novo lesion group (n=1258, 81.8%), and PCI for ISR lesion group (n=280, 18.2%). Patients in the ISR lesion group were significantly older and had higher prevalence of hypertension, diabetes mellitus, dyslipidemia and chronic kidney disease than patients in the de novo lesion group. During a median follow-up period of 1.9 years, Kaplan-Meier curves showed no significant differences in the incidences of MACCE (log-rank, p=0.86) and all-cause death (p=0.84) between two groups. After adjustment for other covariates, PCI for ISR lesion were not significantly associated with MACCE (hazard ratio [HR], 1.10; 95% confidential interval [CI], 0.61–1.97; p=0.76) and all-cause death (HR, 0.93; 95% CI, 0.56–1.56; p=0.79) Conclusion PCI for the ISR lesion was not associated with worse clinical outcomes compared with PCI for the de novo lesion. Funding Acknowledgement Type of funding sources: None.

Background Near-infrared spectroscopy (NIRS) and intravascular ultrasound (IVUS) are useful imaging modalities to identify lipid-rich plaque (LRP) which is associated with an increased risk of future cardiovascular events in individuals undergoing PCI. Pathological studies have raised concerns that treating LRP with stents may impair vascular healing. However, the impact of stent implantation to LRP lesions was less known. Moreover, little information is available about changes in the extent of LRP at before and after PCI. Purpose The aim of this study was to investigate changes in LRP by NIRS between pre- and post-stent implantation, and to evaluate an association among impact of LRP by NIRS at pre- and post-stenting and late lumen loss (LLL) by angiography. Methods We studied 175 lesions in 149 patients who underwent PCI under NIRS-IVUS guidance and follow-up angiography at 8-month later from 2017 to 2020. Plaque characteristics on IVUS, the extent of LRP [defined as a long segment with a 4-mm maximum lipid core burden index (maxLCBI4mm)] on NIRS, and quantitative coronary angiography measurements were analyzed. We evaluated a change of the extent of LRP between pre- and post-stenting at index PCI procedure, and association between the extent of LRP and a 8-month LLL at follow-up coronary angiography. A large LRP was defined as maxLCBI4mm>400 at pre-stenting. Results Mean age was 64.5 years old, and 123 (82%) patients were male. The prevalence of large LRP was 51% and median plaque burden at minimum lumen area was 81%. The extent of LRP at culprit lesion significantly decreased from pre- to post-stenting (median maxLCBI4mm [interquartile range (IQR)]: 407 [199, 580] to 133 [13, 319], p0.05). Median LLL at follow-up angiogram was 0.17 [0.07–0.35] mm. Both the extent of pre- and post-stenting LRP were not associated with LLL (r=0.018, p=0.80 and r=0.022, p=0.76, respectively) (Figure 2). In addition, there was no significant difference in LLL between the post-stenting large and non-large LRP (median [IQR] 0.18 [0.08–0.35] vs. 0.17 [0.07–0.35]; P=0.95). Conclusions This study showed coronary stent implantation significantly reduced the NIRS-derived LRP in patients undergoing PCI. Although the extent of pre-stenting LRP and IVUS plaque burden predicted the reduction of LRP, the extent of pre- and post-stenting LRP were not associated with LLL. These findings suggest that stent implantation for LRP, even in a large LRP, is safe and does not affect LLL. Funding Acknowledgement Type of funding sources: None. Figure 1. Scatter plotsFigure 2. CENTRAL Figure

Background Cardiac myosin–binding protein C (cMyC) is a cardiac-restricted protein that has more abundant, rapid release and clearance kinetics than cardiac troponin. The current ESC guideline suggests the cMyC may provide value as an alternative to cardiac troponin. The 99th percentile value is universally endorsed as the reference cut off to aid in the diagnosis of acute myocardial infarction (AMI), however, none of the report of healthy population of cMyC. Purpose The aim of this study was to evaluate the distribution of cMyC values in healthy subjects. Methods We used two cohorts in this retrospective study. 1) Healthy subjects; a total of 500 subjects (250 men and 250 women) who had annual health examinations in 2012 in the area of Kamigoto, a suburb of Nagasaki city in Southern Japan were enrolled. All participants showed none of abnormal findings including cell blood counts, chemical analysis, liver function tests, general urine tests, occult blood tests of stool, barium swallow, mammography for women, abdominal ultrasound sonography, and electrocardiogram. All blood samples were obtained in a fasting state in the morning. 2) Chest pain subjects; we collected samples from 250 subjects including 50 with non-ST elevation myocardial infarction visited admitted to a university hospital for measurement of high-sensitivity troponin T and coronary artery assessment by coronary angiography. We measured cMyC level in both cohorts by HISCL™-800 system (Sysmex corporation, Japan). The assay has a limit of detection of 0.5 ng/L and a lower limit of quantification of 1.3 ng/L. Result In healthy subjects, median age (IQR) was 44 (20, 82) in men and 50 (23, 91) in women. The 99th percentile of cMyC was 27.3 ng/L, which was around one-third lower than that in previous report (87 ng/L). In chest pain subjects, the concentrations of cMyC at presentation were significantly higher in those with versus without AMI (median, 66 ng/L versus 10 ng/L, P Conclusion We defined the normal range of cMyC in healthy Japanese subjects. The level of cMyC at presentation provides discriminatory power comparable to hs-cTnT in the diagnosis of AMI. To determine the physiological value of a biomarker may be necessary to evaluate enough information about their health status. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Scientific Research

Background Asians have a much lower incidence of adverse coronary events than Caucasians, and the characteristics of vulnerable plaque might be different among the ethnics. Purpose The aim of this study was to investigate the clinical characteristics of lipid-rich plaque (LRP) in the Asian population and we also aimed to distinguish the characteristics of an acute coronary syndrome (ACS) culprit lesion and a chronic coronary syndrome (CCS) culprit lesion. Furthermore, we evaluated the association between lipid core burden index (LCBI) and cardiovascular risk factors, lipid profiles, and inflammatory biomarkers, as determined in vivo by near infrared spectroscopy intravascular ultrasound (NIRS-IVUS) imaging in patients undergoing percutaneous coronary intervention (PCI). Methods We evaluated 207 patients (ACS, n=75; CCS, n=132) who underwent PCI under NIRS-IVUS. Plaque characteristics and the extent of LRP [defined as a long segment with a 4-mm maximum LCBI (maxLCBI4mm)] on NIRS in de-novo culprit and non-culprit segments were analyzed. Results The mean age was 65 years old and 82% of patients were male. The ACS culprit lesions had a significantly higher maxLCBI4mm (median [interquartile range (IQR)]: 533 [385–745] vs. 361 [174–527], p Conclusions We confirmed that NIRS-IVUS plaque assessment could be useful to differentiate ACS from CCS culprit lesions, and that a threshold maxLCBI4mm ≥400 was clinically suitable in Japanese patients. No systemic surrogate markers were found to be associated with the extent of LRP by NIRS in culprit and non-culprit segments. Consequently, we believe that direct intravascular evaluation of coronary plaque characteristics remains important for identification of high-risk LRP. Funding Acknowledgement Type of funding sources: None. Figure 1. The difference of maxLCBI4mmFigure 2. ROC curve

HTS cable demonstration project supported by Ministry of Economy, Trade and Industry (METI) and New Energy and Industrial Technology Development Organization (NEDO) has started in Japan. The target of this project is to operate a 66 kV, 200 MVA HTS cable in the live network of Tokyo Electric Power Company in order to demonstrate its reliability and stable operation. The design of the HTS cable with DI-BSCCO has been completed as well as those of a termination and a joint. A 30-meter HTS cable system with terminations, a joint and a cooling system was installed in SEI facility to confirm their design and performance. Various tests as voltage tests, nominal and over current tests, heat cycle tests, heat loss measurements and so on were conducted and it is verified that the cable has good performances as design. This paper describes the design and test results of a 30-meter HTS cable, and discusses required test items of HTS cables.

In the new national project, as wire and cable development, Sumitomo Electric Industries, Ltd. (SEI) is trying to develop a 66 kV/5 kArms high temperature superconducting (HTS) cable with its own REBa 2 Ca 3 O x (RE-123, RE = rare earth element) coated conductors. In an actual power grid, an inflow of current higher than the normal rated power (fault-current) can occur. The maximum fault-current condition is set at 31.5 kArms for 2 s for 66 kV-class transmission system in this project. Therefore, one of the technical targets in this project is to design the wires and cables to survive at this fault-current condition. As the first step, the prototype HTS cable was designed against the fault-current condition of 31.5 kArms for 2 s. The wires have copper plating as a stabilizer layer not to be damaged by over-currents. The designed HTS cable has a copper former and copper shield layers in parallel with the HTS conducting layers and HTS shield layers, respectively, to control the temperature rises in the cable core at fault-current conditions. As the second step, a sample HTS cable core was fabricated and fault-current tests were conducted to check its soundness. The temperature rises in the cable core were measured under various fault-current conditions. The critical current of the cable core was measured before and after the fault-current tests, and no deterioration in the critical current characteristics was observed. However, there was slight degradation of the n value. The investigation will be conducted, and the results will be fed back to designs of the RE-123 wires and cables.

High temperature superconducting (HTS) cables are expected as a large capacity cable with lower transmission loss. Numerous HTS cable demonstration projects using Bi-2223 superconducting wires are being promoted around the world for practical utility usage. RE-123 coated conductors, which are still at the research and development stage, will also be applied to several demonstration projects in coming years in addition to Sumitomo Electric's world first 30-m HTS cable project using RE-123 conductors which was successfully energized in early 2008. As wire and cable manufacturer, Sumitomo Electric has also been developing it's own RE-123 conductors, and has succeeded in fabricating a 200-m-class conductor. One of the important challenges associated with the use of RE-123 conductors in power cables is to ensure stability against over-current. In order to evaluate over-current characteristics, a 10-meter ldquo3-in-Onerdquo RE-123 superconducting cable was manufactured and over-current tests were performed. No Ic degradation was observed after exposure to over-currents with a maximum current of 31.5 kArms for 2 s (120 cycles), which meets the requirements for 66-77 kV class power cables in Japan. It was confirmed that RE-123 conductors have satisfactory over-current characteristics for use as superconducting cable wires.

This study was undertaken to test whether a brief period of ischemia affects the coronary pressure-flow relationship during reduction of coronary perfusion pressure (CPP). The left anterior descending coronary artery was cannulated and perfused with blood from the left carotid artery in 40 open-chest dogs. Coronary blood flow (CBF) was measured during intracoronary administrations of papaverine and adenosine. The coronary pressure-flow relationship was assessed during transient reduction of CPP from 100 to 30 mmHg. Coronary hyperemic flow due to adenosine and papaverine was attenuated 30 min after transient 10- and 15-min periods of ischemia. In the group of transient 10-min ischemia, both fractional shortening (FS) and CBF returned to the preischemic values at 30 and 60 min of reperfusion; however, marked decreases in CBF (35 ± 5 vs. 56 ± 4 ml.100 g -1 .min -1 at CPP = 60 mmHg, P < 0.01) during graded reductions in CPP were observed. The endomyocardial blood flow was reduced relative to the control condition. Furthermore, both FS (6 ± 1 vs. 14 ± 1% at CPP = 60 mmHg, P < 0.01) and lactate extraction ratio (-41 ± 15 vs. 1 ± 6% at CPP = 60 mmHg, P < 0.05) were decreased. The downward shift of the CPP-CBF relationship and the deterioration of myocardial contractile and metabolic function during reduction of CPP were restored 60 min after the onset of reperfusion. In contrast, in the group of transient 15-min ischemia, although both baseline FS and coronary hyperemic flow due to adenosine and papaverine remained reduced 30 and 60 min after the onset of reperfusion, the CPP-CBF relationship was not shifted. These results indicate that a transient brief period of ischemia can reversibly affect the coronary pressure-flow relationship due to the reduced capability of vascular relaxation however, the downward shift of the coronary pressure-flow relationship can be blunted when the myocardial contractile dysfunction due to transient ischemia becomes apparent.

In this paper we consider autonomous control of a snake-like robot using reinforcement learning. Conventional methods of reinforcement learning have significant problems in practical use. That is curse of dimensionally and lack of generality. To solve these problems, we focus on design of the mechanical body of the snake-like robot, and abstract necessary small state-action space from complex environments by utilizing the function of the body. To discuss the function of the body, experiments have been conducted and transition probability has been identified. As the result, we confirmed that by the function of the body, learning machine can observe different complex environments as similar simple environments.

The ATPase FliI of the Salmonella type III flagellar protein export apparatus is a 456 amino acid residue cytoplasmic protein consisting of two regions, an N-terminal flagellum-specific region and a C-terminal ATPase region. It forms a complex with a regulatory protein FliH in the cytoplasm. Multi-angle light-scattering studies indicate that FliH forms a homodimer, (FliH)2, and that FliH and FliI together form a heterotrimer, (FliH)2FliI. Mobility upon gel-filtration chromatography gives much higher apparent molecular masses for both species, whereas the mobility of FliI is normal. Sedimentation velocity measurements indicate that both (FliH)2 and the FliH/FliI complex are quite elongated. We have analyzed FliH, FliI and the FliH/FliI complex for proteolytic sensitivity. FliI was degraded by clostripain into two stable fragments, one of 48 kDa (FliI(CL48), missing the first seven amino acid residues) and the other of 46 kDa (FliI(CL46), missing the first 26 residues). Small amounts of two closely spaced 38 kDa fragments (FliI(CL38), missing the first 93 and 97 residues, respectively) were also detected. The FliH homodimer was insensitive to clostripain proteolysis and provided protection to FliI within the FliH/FliI complex. Neither FliI(CL48) nor FliI(CL46) could form a complex with FliH, demonstrating that the N terminus of FliI is essential for the interaction. ATP, AMP-PNP, and ADP bound forms of FliI within the FliH/FliI complex regained sensitivity to clostripain cleavage. Also, the sensitivity of the two FliI(CL38) cleavage sites was much greater in the ATP and AMP-PNP bound forms than in either the ADP bound form or nucleotide-free FliI. The ATPase domain itself was insensitive to clostripain cleavage. We suggest that the N-terminal flagellum-specific region of FliI is flexible and changes its conformation during the ATP hydrolysis cycle.

Chronic inhibition of nitric oxide (NO) synthesis is reported to induce the thickening of coronary artery walls and cardiac hypertrophy in vivo via angiotensin II receptors. Increased protein synthesis is the main feature of these structural changes. Activation of 70 kD S6 kinase (p70S6K) phosphorylates the 40S ribosomal protein S6 that regulates protein synthesis. We examined the role of p70S6K in the vascular and myocardial structural changes induced by the chronic inhibition of NO synthesis. The following 5 groups were studied: untreated Wister-Kyoto rats, those treated with an inhibitor of NO synthase, Nomega-nitro-L-arginine methyl ester (L-NAME), those treated with L-NAME and an angiotensin I converting enzyme inhibitor (imidapril), those treated with L-NAME and hydralazine, and those treated with L-NAME and an inhibitor of p70S6K (rapamycin). After 8 weeks, wall-to-lumen ratio in myocardium and cardiomyocyte cross-sectional areas were quantified. L-NAME increased systolic blood pressure, wall-to-lumen ratio, and cardiomyocyte cross-sectional area compared with control animals. Imidapril or rapamycin, but not hydralazine, markedly reduced these structural changes. L-NAME increased p70S6K activity in myocardium compared with control rats. Imidapril or rapamycin prevented the activation of p70S6K activity in myocardium induced by L-NAME. These results suggest that activation of p70S6K plays an important role in coronary vascular remodeling and cardiac hypertrophy induced by the chronic inhibition of nitric oxide synthesis in vivo.

FK506, an immunosuppressant, modulates phosphorylation of nitric oxide (NO) synthase, and induces cardiac hypertrophy in clinical settings. Having recently reported that chronic treatment with an inhibitor of NO synthase induces cardiac hypertrophy associated with the activation of 70-kD S6 kinase (p70S6K), which plays an important role in cardiac hypertrophy by regulating protein synthesis, we investigated the effects of chronic administration of FK506 on NO synthase and p70S6K activities in hearts. Twenty rabbits were divided into four groups: untreated rabbits, those treated with low-dose FK506 (0.10 mg/kg), those treated with medium-dose FK506 (0.20 mg/kg), and those treated with high-dose FK506 (0.40 mg/kg). FK506 was administered intravenously twice a day. After 4 weeks of treatment with FK506, calcium-dependent NO synthase activity in myocardium in the high-dose FK506 group was lower (P0.05) than in the untreated group. p70S6K activity in myocardium in the high-dose group was higher (P0.05) than in the untreated group. There was a significant (P0.05) inverse correlation between NO synthase and p70S6K activities in myocardium. However, the endothelial-dependent vasodilation of aortic rings or plasma levels of NO metabolites during experimental protocols did not differ among the groups studied. These findings suggest that chronic treatment of FK506 activates p70S6K and reduces NO synthase activity in rabbit hearts. Reduced NO synthase and/or activated p70S6K activities in hearts might contribute to the cardiac hypertrophy observed in some patients receiving FK506.

ATP generates nitric oxide (NO) via activation of P2y receptors, and is degraded to adenosine. This study was undertaken to examine whether ATP causes coronary hyperemic flow via purinoceptors-, NO- and adenosine-dependent mechanisms, and attenuates the severity of contractile and metabolic dysfunction in the ischemic myocardium. In the non-ischemic canine hearts, the infusions of ATP into the coronary artery dose-dependently increased coronary blood flow. The levels of adenosine and end-product of NO in coronary venous blood over the arterial blood also increased. This hyperemic flow was partially attenuated by either 8-sulfophenyltheophylline (8SPT) or L(omega)-nitro arginine methyl ester (L-NAME), and completely blocked by the treatment with 8SPT, L-NAME and suramin (SRM). During myocardial ischemia, exogenous ATP increased coronary blood flow, and attenuated myocardial metabolic and contractile dysfunction, which was completely blunted by the treatment with 8SPT, L-NAME and SRM. We conclude that exogenous ATP increases coronary blood flow in the non-ischemic and ischemic myocardium mainly via either NO- or adenosine-dependent mechanisms.

We examined whether nisoldipine, a calcium (Ca) channel blocker, increases coronary blood flow (CBF) without decreasing aortic blood pressure (AoP) with ischemic and nonischemic hearts, and whether the presence of cellular acidosis in ischemic myocardium contributes to the augmentation of coronary vasodilation due to nisoldipine. In 42 dogs, coronary perfusion pressure (CPP) was reduced so that CBF decreased to 60% of the baseline, and CPP was maintained constant thereafter. First, we administered nisoldipine into a systemic vein in the ischemic and nonischemic hearts. Second, nisoldipine was administered into the canine coronary artery of the ischemic myocardium, with and without administration of either sodium bicarbonate (NaHCO3), sodium hydroxide (NaOH), or amiloride. Nisoldipine (0.25-4.0 mg/kg, i.v.) increased CBF by 59% in the ischemic myocardium more than the nonischemic myocardium (by 34%) without reducing AoP. The infusion of nisoldipine (40 ng/kg/min, IC) increased CBF markedly by about 55% in the ischemic myocardium with increases in fractional shortening (FS; 11 +/- 2% to 21 +/- 2%) and lactate extraction ratio (LER; -19 +/- 4% to 15 +/- 2%). Increases in CBF, FS, and LER were markedly attenuated during administration of nisoldipine with concomitant administration of either NaHCO3 or NaOH. Furthermore, the extent of increases in CBF (54 +/- 2 mL/100 g/min), FS (13 +/- 2%), and LER (-17 +/- 4%) were also markedly attenuated due to the concomitant treatment with amiloride. We conclude that myocardial cellular acidosis plays an important role in mediating coronary vasodilation affected by nisoldipine in the ischemic myocardium. H+ may modulate the property of voltage-dependent Ca channels via Na(+)-H+ exchange.

Adenosine is known to be an endogenous cardioprotective substance. Since we have reported that adenosine levels increase in patients with chronic heart failure, we tested whether further elevation of the adenosine levels due to dipyridamole or dilazep for 6 months modulates the pathophysiology of chronic heart failure. In patients with chronic heart failure, either dipyridamole (300 mg/d n = 17) or dilazep (300 mg/d n = 5) were administered for 6 months. Twenty-two patients (mean +/- SE age 58 +/- 4 years old) attending a specialized chronic heart failure (CHF) clinic over 6 months and judged as in New York Heart Association (NYHA) function class II or III were examined. The other drugs used for the treatment of CHF were not altered during the study. There were 5 patients with CHF caused by ischemic heart diseases, and 17 patients with either valvular heart diseases or dilated cardiomyopathy. We found that increases in the plasma adenosine levels (202 +/- 34 and 372 +/- 74) nmol/L before and after dipyridamole administration, P0.005 ameliorate the severity of CHF (NYHA: 2.1 +/- 0.5 to 1.7 +/- 0.2). Both ejection fraction and maximal oxygen consumption increased. These improvements in the severity of chronic heart failure returned to baseline levels 6 months after discontinuation of dipyridamole. Comparable results were obtained in the dilazep protocol. We suggest that the elevation of plasma adenosine levels improves the pathophysiology of CHF.

Hyperhomocysteinemia has been identified as a possible risk factor for coronary artery disease. The association of the alanine/valine (A/V) polymorphism of 5, 10-methylenetetrahydrofolate reductase (MTHFR), one of the key enzymes catalyzing re-methylation of homocysteine, with coronary artery disease was examined in 362 Japanese males with a diagnosis of coronary artery disease confirmed with coronary angiography. The A/V polymorphism was analyzed with PCR followed by Hinf I digestion. The screening of 778 male volunteer controls revealed that the frequency of V allele in Japanese was 0.33, comparable to that in the French Canadian population. The VV genotype, which correlates with increased plasma homocysteine levels due to reduced activity and increased thermolability of this enzyme, was significantly more frequent in patients with coronary artery disease (15.7%, n = 362) than in controls (10.2%, n = 778; p = 0.0067). The association of the VV genotype with coronary artery disease was further increased in patients withor = 99% stenotic lesion (p = 0.0010). In these patients, the frequency of the VV genotype was significantly higher in patients with triple-vessel disease (26%) than in patients with single- or double-vessel disease (15% and 14%, respectively). The fasting plasma homocysteine levels in VV subjects were higher than those in AV or AA subjects. The VV genotype of MTHFR associated with increased plasma homocysteine levels may represent an important genetic risk factor for coronary artery disease, especially with the occurrence of myocardial infarction.

This prospective, randomized, double-blind multicenter trial evaluated the efficacy and safety of a single bolus injection of the novel modified tissue-type plasminogen activator (t-PA) E6010 in the treatment of acute myocardial infarction compared with that of native t-PA.E6010 is a novel modified t-PA with a prolonged half-life (t1/2 alphaor = 23 min) compared with native t-PA (t1/2 alpha = 4 min). E6010 can be administered in patients as a single intravenous bolus injection, and early recanalization can be expected.The efficacy of E6010 was compared with that of native t-PA in 199 patients with acute myocardial infarction who were treated within 6 h of onset in a prospective, randomized, double-blind multicenter trial. Patients were given either 0.22 mg/kg body weight of E6010 intravenously over 2 min or native t-PA (tisokinase) 28.8 mg or 14.4 million IU (10% of the total dose over 1 to 2 min, the remainder infused over 60 min).The primary end point was the recanalization rate of the infarct-related coronary artery at 60 min after the start of treatment. Time to reperfusion was shorter in the E6010 group than in the native t-PA group. Thrombolysis in Myocardial Infarction flow grade 2 or 3 recanalization at 15, 30, 45 and 60 min after administration was observed in 37%, 62%, 74% and 79% (95% confidence interval [CI] 70% to 87%) of the E6010-treated patients and in 14%, 32%, 50% and 65% (95% CI 55% to 74%) of native t-PA-treated patients, respectively (p = 0.032 at 60 min).The present study indicates that, compared with native t-PA, a single bolus injection of E6010 over 2 min produces a higher rate of early recanalization of the infarct-related coronary artery without fatal bleeding complications.

A 17-year-old motorcyclist was killed in a traffic accident. The urine sample collected at autopsy was screened by the Toxi-Lab system; it showed a possible presence of either methamphetamine (MA) or ephedrine (Eph). Gas chromatography-mass spectrometry (GC-MS) was carried out for a trifluoroacetyl (TFA)-derivatized sample after extraction with an Extrelut column. A peak was detected at the same retention time as that of the authentic Eph by GC-MS with a DB-17 wide-bore column; the mass spectrum of the peak was, however, very similar to that of MA. The presence of Eph and absence of MA were proved by GC-MS using a DB-1 column. The Eph in the urine was further confirmed by high performance liquid chromatography (HPLC)-MS using an ODS column. By the REMEDi HS system, Eph and methylephedrine were determined in the urine, and their concentrations (hydrochloride salt) were 0.752 and 2.13 micrograms/ml, respectively. Ethanol was detected as well in the blood (1.55 mg/ml) and urine (2.01 mg/ml) by a pulse heating method. Nicotine, caffeine and dihydrocodeine were also qualitatively detected in the urine by Toxi-Lab, HPLC-MS and REMEDi HS systems. The present case warned that urinary Eph can be misidentified as MA by GC-MS with an intermediately polar column after TFA derivatization.

v-Rel is a transforming protein of the reticuloendotheliosis virus, and is a transcription factor regulating various cellular genes. We found that v-Rel activates the promoter of the proto-oncogene c-jun in a transient transfection assay system. Moreover, the expression of endogenous c-jun was augmented in cells expressing exogenous v-Rel, but not c-Rel. The transcriptional activities of v-Rel to the tested promoters containing the kB-site are lower than that of c-Rel, but that to the c-jun promoter was much higher than that of c-Rel. The N-terminal DNA binding domain of v-Rel, which is responsible for its high transforming activity of v-Rel was also responsible for the high transcriptional activity to the c-jun promoter. Thus, the activity of v-Rel upon the c-jun promoter correlates well with its transforming ability. Since c-Jun plays pivotal roles on cell proliferation in various types of cells, the activation of c-jun expression by v-Rel may be an essential step for the oncogenic transformation caused by v-Rel.

Histological findings in the acute phase of myocarditis were evaluated as a prediction of hemodynamic state in the chronic phase in 20 patients with clinical and pathological diagnoses of myocarditis who were followed up with echocardiography for at least 1 year. Endomyocardial biopsy samples were obtained from the left ventricle within 1 year of the onset of symptoms. Azan-Mallory staining was performed on the myocytes, which were categorized as either well stained or poorly stained. The point counting method was used to determine the fraction of each type. The improvement in ejection fraction within 1 year correlated significantly with the fraction of poorly stained myocytes (r = 0.46, p0.05). The ejection fraction at biopsy was negatively correlated with the volume fraction of well stained myocytes (r = -0.64, p0.01). The staining condition of myocytes may be useful in predicting the hemodynamic recovery of patients with myocarditis.

ABO genotyping was carried out using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method on the dried remains of nine human mummies which had been discovered at Taklamakan desert in 1912. In all the nine mummies, ABO genotype could be determined as BO type, and ABO phenotype of the eight mummies with hair specimen could be revealed as B type using absorption-elution method. These results mean that ABO phenotype estimated from its genotype by PCR-RFLP was consistent with that by absorption-elution method in all of the eight cases examined. And in the other one child mummy, ABO phenotype could not be examined because of no hair specimen. Although it is impossible to assess the allele frequency of ABO blood group system in the populations having lived in Gao Chang at that time, the present study shows a possibility of ABO genotyping from ancient human remains.

In the early morning of late December, a 63-year-old man was found dead in front of his apartment house. At medico-legal autopsy, subcutaneous hemorrhages of the occipital region and linear fractures of the occipital bone was observed, but there was no cerebral contusion leading him to death. Many white tumors, ranging from 0.5 to 2.0 cm in diameter, were observed in the liver. On sections of the liver, hepatic parenchyma was found entirely occupied by the tumors, which were histopathologically diagnosed as moderately- or well-differentiated hepatocellular carcinoma. Alcohol concentrations of the mixed intracardiac blood and the urine were determined to be 1.9 and 3.6 mg/ml, respectively. Through the police investigation, it became clarified that the male had been sleeping in front of his apartment house about at 10:30 p.m. on the day before he was found dead. The cause of his death was, therefore, considered due to cold, and the authors gave a bibliographic consideration on blood and urine alcohol concentrations and alcohol metabolism of a patient with liver dysfunction due to hepatocellular carcinoma.

The transcription factor v-Rel is a transforming protein of the reticuloendotheliosis virus. We found that v-Rel activates the promoter of the proto-oncogene c-jun. Two elements in the c-jun promoter were required for the activation by v-Rel. One was a kB-site (v-Rel binding site), and the other was a c-jun promoter region between -52 and +148 (c-jun promoter (-52/+148)). Two promoters with the kB-site(s), those of human immunodeficiency virus (HIV) and SV40, were not activated by v-Rel, but their kB-sites were activated when introduced upstream of the c-jun promoter (-52/+148). Thus, the c-jun promoter (-52/+148) had information for the selective activation of the c-jun promoter by v-Rel. v-Rel bound to the c-jun kB-site with the higher affinity than c-Rel, thereby activating the c-jun promoter more efficiently than c-Rel. Moreover, the activity of v-Rel mutants upon the c-jun promoter correlates with their transforming activity. Thus, the c-jun promoter activation by v-Rel may play a role in the transformation caused by v-Rel.

Characteristics of multiple-drug resistance of rat ascites hepatoma AH66, a cell line induced by dimethylaminoazobenzene and established as a transplantable tumor, were compared with those of AH66F, a drug sensitive line obtained from AH66. The AH66 cell line was resistant to vinblastine, adriamycin, SN-38 an active form of camptothesine, etoposide, and clorambucil by 10-fold or more than the AH66F cell line. The resistance of AH66 cells to vinblastine, adriamycin, and SN-38 was closely related to P-glycoprotein overexpression in the plasma membrane, because the resistance was significantly inhibited by verapamil. AH66 cells contained much glutahione and had a high activity of glutathione S-transferase P-form (GST-P), compared with AH66F cells, and resistance to clorambucil was decreased by treatment with buthionine sulfoximine, an inhibitor of glutathione synthesis. AH66 cells have a similar topoisomerase I activity, but about 6 times lower topoisomerase II activity than AH66F cells. Therefore, the resistance to etoposide and a part of the resistance to adriamycin of AH66 cells seems to depend upon this low topoisomerase II activity. These results, show that the AH66 cell line has high multiple-drug resistance compared with the AH66F cell line, by several mechanisms. Consequently, the AH66 and AH66F cell lines are useful to study naturally acquired multiple-drug resistance of hepatomas.

A 22-year-old male, who could not escape from a residential fire, was found dead at the scene, although the other three persons who had been in the same room escaped safely. At the medico-legal autopsy, the burned body presented the second degree level of body destruction (T. Nagano. Jpn J Legal Med., 1982) and the pugilistic attitude caused by fire. Soot was observed not only in the trachea but also in the bronchi or even the alveoli. Forensic toxicological analyses were performed using the intratracheal gas, left and right ventricular blood, urine, stomach contents, cerebrum, cerebellum, left and right lungs, liver, spleen, kidney, skeletal muscle and adipose tissue. The carboxyhemoglobin concentration was 61.4% in the left ventricular blood and 59.5% in the right ventricular blood. Ethanol and toluene were qualitatively detected in the intratracheal gas by gas chromatography-mass spectrometry. The ethanol and toluene concentration was 0.48 mg/g and 20.4 microgram/g, respectively, in the blood, and 0.40 mg/g and 28.7 microgram/g, respectively, in the cerebrum. Moreover, the urinary hippuric acid concentration was 1.76 mg/ml. The ethanol concentrations were not at the toxic level, while the toluene concentrations in the blood and cerebrum were almost at the lethal level. However, since the preservation of the capacity for vital reactions was apparent at the autopsy in the form of soot in the air passages and the formation of CO-Hb in the blood, it was surmised that the victim was still alive when the fire broke out, but subject to severe disturbance of the central nervous system function. The cause of death in the present case was diagnosed as death due to fire.

Tax of human T-cell leukemia virus type I (HTLV-I) activates transcription at a CArG box of various immediate early genes such as the proto-oncogene c-fos. To do this, Tax does not directly bind to the CArG box, but instead binds to the CArG binding factor SRF. In this study, we investigated the domain of SRF required for the activation by Tax and studied the role of this domain on transcriptional regulation at the CArG box. Using a fusion protein of SRF with a yeast transcription factor GAL4, the 14 amino acid (aa) portion (aa 422-435) of SRF was identified as the domain required for Tax activation [Tax-responsive region of SRF (TRRS)]. By means of a two hybrid system, we showed that TRRS was essential for the interaction of SRF with Tax in vivo. The over-expression of SRF with a deletion of TRRS inhibited the Tax activation at the CArG box. Thus, TRRS is the domain of SRF that is essential for Tax activation at the CArG box. Unlike to Tax activation, TRRS was not required for TPA (12-o-tetradecanoylphobol-13-acetate) induction at the CArG box, but a TRRS deletion enhanced the basal activity at the CArG box both under serum-starved and TPA-stimulated conditions. These results suggest that TRRS negatively regulates the transcriptional activation function of SRF, and consequently contributes to the low basal activity at the CArG box before TPA induction.

We previously reported that Tax1 of human T-cell leukemia virus type I interacts directly with serum response factor (SRF) and that Tax1 activates the transcription of several cellular immediate-early genes through the SRF binding site (CArG box). This activation required the transcriptional activation function of Tax1, identified as an activity of GALTax (a chimeric Tax1 with the yeast transcription factor GAL4) at the GAL4-binding site. In this study, we examined whether SRF plays a role in the transcriptional activation function of Tax1. Expression of Tax1 suppressed the GALTax activity at the GAL4 site as a result of squelching, and the suppressed activity was recovered by the overexpression of SRF, suggesting that SRF is a factor that is required for GALTax activity and that is inhibited by competition with Tax1. The expression of antisense SRF RNA specifically inhibited GALTax activity to less than 20%. Deletion of the Tax1 interaction domain of SRF at its C terminus converted SRF from an activator of GALTax to an inhibitor. These results suggest that SRF is an essential component of the transcriptional activation of Tax1 in addition to a mediator of CArG box binding.

To test the hypothesis that aggressive cholesterol lowering results in a rapid regression of coronary atherosclerosis, the effect of low-density lipoprotein (LDL)-apheresis for 1 year on coronary artery diameters was studied in patients with heterozygous familial hypercholesterolemia. LDL-apheresis was performed every 2 weeks in 13 patients with LDL-cholesterol levelsor = 200 mg/dL despite treatment with conventional dietary and drug therapies. Coronary arteriography was performed before and 1 year after the initiation of treatment. The LDL-cholesterol level was decreased by an average of 71% immediately after the initial LDL-apheresis and by 30% before the second apheresis. Such phasic changes were observed throughout the trial. Computer-assisted automated quantitative arteriograms analyzed 101 proximal coronary segments. The mean lumen diameter of angiographically normal sections of each segment was slightly but significantly increased from 2.93 +/- 0.89 mm at baseline to 3.05 +/- 0.93 mm at the follow-up arteriogram (P0.05); 54 of the 101 segments showed a lesion stenosed by 20% or more in diameter. The minimal diameter of individual lesions was also significantly increased from 2.17 +/- 0.67 mm to 2.36 +/- 0.76 mm (P0.05), and thus the diameter stenosis was significantly reduced from 32.3 +/- 10.5% to 28.2 +/- 12.1% (P0.05). It is concluded that 1 year of aggressive cholesterol lowering, using LDL-apheresis, can significantly reduce coronary atherosclerosis in patients with familial hypercholesterolemia.

We assessed the usefulness of ventricular late potentials (VLP) for detecting ventricular tachycardia (VT), and of the relationship between VLP and left ventricular dysfunction. The subjects consisted of 21 patients with dilated cardiomyopathy (DCM) not accompanied with ventricular conduction disturbances. Signal-averaged electrocardiograms were recorded by using VCM-3000. The signals of 200 or more beats were averaged through the 40-300 Hz band-pass filter until the noise level was reduced to less than one microvolt (microV). The duration (fQRSd) and the root mean square voltage (LP40) for the last 40 msec of the filtered QRS complex were calculated. The left ventricular diastolic dimension (LVDd), systolic dimension (LVDs) and the ejection fraction (EF) were obtained by echocardiography. Five of 21 patients had VT. fQRSd was significantly longer in patients with VT than in those without VT (158.8 +/- 8.6 vs 126.5 +/- 10.4 msec, p0.01). LP40 was significantly less in patients with VT than in those without VT (8.7 +/- 2.7 vs 24.1 +/- 12.3 microV, p0.01). If the presence of "fQRSdor = 120 msec" or "LP40or = 20 microV" was defined as VLP positive, as in patients with old myocardial infarction, the criteria sensitivity was 100% and their specificity was 25% for detecting VT. If the presence of both "fQRSdor = 135 msec" and "LP40or = 20 microV" was defined as VLP positive, the criteria sensitivity was 100%, and their specificity, 88%.(ABSTRACT TRUNCATED AT 250 WORDS)

Color flow imaging of the regurgitant areas has been used to quantitate the severity of valvular regurgitation, however, the exact relationship between color flow areas and regurgitant volumes or fraction has not been clarified. This study was designed to determine whether measurements of jet flow areas and distances using color flow imaging are closely related to the regurgitant volume (MRV:ml/beat) and fraction (MRF: %). Doppler examinations were performed in 29 patients with mitral regurgitation (MR). The MR jet was depicted as the largest clearly definable flow disturbance on the echo images, and the maximal jet area (cm2) and length (cm) were measured. The MRV and MRF were obtained from the Doppler measurements of the transmitral flow (TMF) and the aortic flow (AF) as follows: MRV = TMF-AF, MRF = MRV/TMF x 100. The maximal jet area showed significant correlations with the MRV and MRF (r = 0.75 and 0.75, p0.01), and the maximal jet length showed even better correlations with the MRV and MRF (r = 0.82 and 0.80, p0.01), irrespective of the etiology of MR. Thus, both the maximal jet area and length obtained from color flow imaging can be simple and useful measurement methods for predicting the MRV and MRF.

Clinical information on the regional myocardial blood flow in the post-ischemic myocardium has been limited. In the present study, we assessed the influence of early coronary reperfusion and coronary obstruction that remained after reperfusion on regional myocardial perfusion by myocardial contrast echocardiography. The study population consisted of 17 patients with acute myocardial infarction who underwent either successful PTCR or emergent PTCA within 6 hours after the onset of the symptom. Myocardial blood flow was visualized by selective injections of hand-agitated poly-gelin colloid solutions into the right and left coronary arteries before and after coronary reperfusion. Before coronary reperfusion, the area at risk for necrosis was defined as the area of contrast defects by the intracoronary injection of contrast medium. The size (severity) of this defect correlated with the anatomic distribution of the obstructed coronary artery. Immediately after emergent PTCA (mean residual stenosis = 25%), 2 of 10 patients still showed injected contrast medium, however, in the remaining 8 patients (80%), the contrast washout time in the risk area was 1.5 times (mean value) longer than that in the normal region. This indicated impairment of the microcirculation in the post-ischemic myocardium. Immediately after PTCR (mean residual stenosis = 89%, p0.01 vs PTCA), contrast enhancement was observed only in the peripheral region of the risk area; contrast defects at the center of this region were observed on contrast echocardiography after reperfusion for all patients. This showed that there was impairment of myocardial blood flow in the risk area, even after successful recanalization in patients undergoing PTCR.(ABSTRACT TRUNCATED AT 250 WORDS)