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Background An association between uric acid (UA) and cardiovascular diseases, including heart failure (HF), has been reported. However, whether UA is a causal risk factor for HF is controversial. In particular, the prognostic value of lowering UA in patients with HF with preserved ejection fraction (HFpEF) is unclear. Methods and Results We enrolled patients with HFpEF from the PURSUIT‐HFpEF (Prospective Multicenter Observational Study of Patients With Heart Failure With Preserved Ejection Fraction) registry. We investigated whether UA was correlated with the composite events, including all‐cause mortality and HF rehospitalization, in patients with hyperuricemia and HFpEF (UA >7.0 mg/dL). Additionally, we evaluated whether lowering UA for 1 year (≥1.0 mg/dL) in them reduced mortality or HF rehospitalization. We finally analyzed 464 patients with hyperuricemia. In multivariable Cox regression analysis, UA was an independent determinant of composite death and rehospitalization (hazard ratio [HR], 1.15 [95% CI, 1.03–1.27], P =0.015). We divided them into groups with severe and mild hyperuricemia according to median estimated value of serum UA (8.3 mg/dL). Cox proportional hazards models revealed the incidence of all‐cause mortality was significantly higher in the group with severe hyperuricemia than in the group with mild hyperuricemia (HR, 1.73 [95% CI, 1.19–2.25], P =0.004). The incidence of all‐cause mortality was significantly decreased in the group with lowering UA compared with the group with nonlowering UA (HR, 1.71 [95% CI, 1.02–2.86], P =0.041). The incidence of urate‐lowering therapy tended to be higher in the group with lowering UA than in the group with nonlowering UA (34.9% versus 24.6%, P =0.06). Conclusions UA is a predictor for the composite of all‐cause death and HF rehospitalization in patients with hyperuricemia and HFpEF. In these patients, lowering UA, including the use of urate‐lowering therapy, may improve prognosis.

Paroxysmal atrial fibrillation (PAF) is a common complication of patients with hypertrophic cardiomyopathy, often leading to acute or progressive heart failure and cerebral infarction. We assessed the echocardiographic data of 141 consecutive patients with hypertrophic cardiomyopathy, with and without PAF. In all, 31 patients (22%) had a history of PAF with spontaneous conversion to in sinus rhythm. Left atrial volume and left atrial volume indexed to body surface area were significantly increased for patients with PAF compared with those without PAF. Maximum left atrial volume was the most sensitive and specific parameter for the occurrence of PAF in patients with hypertrophic cardiomyopathy.

Background The measurement of flow velocity (FV) in coronary artery bypass grafts using a Doppler guidewire has provided useful clinical and physiologic information. The recently developed transcutaneous Doppler echocardiography is a noninvasive technique to measure FV and FV reserve (FVR) in the right gastroepiploic artery (GEA) graft. The purpose of this study was to evaluate whether transcutaneous Doppler echocardiography accurately measures FV and FVR in the right GEA graft in a clinical setting. Methods In 33 patients who underwent graft angiography for the assessment of the right GEA graft, FV in the right GEA graft was measured by transcutaneous Doppler echocardiography under the guidance of color flow Doppler imaging at the time of examination using a Doppler guidewire. FV in the midportion of the right GEA graft was measured at baseline and during hyperemic conditions using both transcutaneous Doppler echocardiography and a Doppler guidewire. Results There were excellent correlations between the value of FV obtained by transcutaneous Doppler echocardiography and those obtained with the Doppler guidewire (averaged peak velocity: y=0.95 x + 1.46, r = 0.98, standard error of the estimate [SEE] = 2.94 cm/s; averaged systolic peak velocity: y=0.94 x + 1.18, r = 0.97, SEE=3.15 cm/s; diastolic peak velocity: y=0.97 x + 1.62, r = 0.98, SEE=4.40 cm/s; averaged diastolic peak velocity: y=0.95 x + 1.75, r = 0.98, SEE=3.60 cm/s). The FVR as determined by transcutaneous Doppler echocardiography showed a good correlation with that determined using the Doppler guidewire method (y = 0.90 x + 0.21, r = 0.92, SEE=0.31). Conclusions Transcutaneous Doppler echocardiography proved to be an accurate noninvasive method to measure FV and FVR in the right GEA graft.

Background The inhibition of sarcolemmal Na + ,K + -ATPase activity is closely related to ischemic myocardial cell injury. However, the involvement of this enzyme in preconditioning has not been determined. Methods and Results We assessed the effect of ischemia on sarcolemmal Na + ,K + -ATPase activity. Control and preconditioned rabbits were subjected to 0, 10, 20, 30, and 60 minutes of coronary occlusion. Ten to 60 minutes of ischemia reduced Na + ,K + -ATPase activity, whereas preconditioning preserved the activity of this enzyme only during the first 20 minutes of ischemia. To determine whether the preservation of Na + ,K + -ATPase activity in the early phase of ischemia contributed to limiting the infarct size, additional rabbits underwent 30 minutes of occlusion followed by 3 hours of reperfusion with or without pretreatment with digoxin, an inhibitor of Na + ,K + -ATPase. Infarct size in animals pretreated with digoxin in the absence of preconditioning did not differ from that in controls. It was markedly reduced by preconditioning, whereas digoxin reduced the infarct size–limiting effect. Moreover, preconditioning increased sarcolemmal Na + -Ca 2+ exchange activity in rabbits subjected to 20 minutes of ischemia, whereas digoxin diminished this increase. Conclusions Preconditioning preserves the ischemia-induced reduction in sarcolemmal Na + ,K + -ATPase activity in the early phase of ischemia in rabbit hearts. Inhibition of Na + ,K + -ATPase activity reduces the infarct size–limiting effect of preconditioning with a loss of increased Na + -Ca 2+ exchange activity, implying that this preservation is responsible for the cardioprotective effect of preconditioning.

著者らは合理的な列車ダイヤの選定方法として, (1) 列車ダイヤの客観的評価方法の確立 (2) 望ましい列車ダイヤの概要を把握 (3) 実線区における列車ダイヤの客観的評価というステップワイズな手法を開発してきた. 今回その第三段階として, 東急田園都市・新玉川線を対象に実際にダイヤ案を様々な角度から比較評価し望ましいダイヤを選定した.

This paper provides the “Speedup Model on Intercity Railway in Japan”, in which velocity on each railway line is calculated with social benefit, railway operator's profit and cost under the condition that OD flow and service levels of all modes are given. By applying this model to both the present network and the 2000-year network in Japan, the speedup-level and the technical option are calculated both when the railway operator's profit is maximised and when the social benefit is maximised.

BACKGROUND The effects of chronic exercise training on myocardial contractility and beta-adrenergic signal transduction in hearts with left ventricular dysfunction have not been determined. METHODS AND RESULTS Fourteen-week-old cardiomyopathic BIO 53.58 and normal F1B Syrian hamsters underwent 10 weeks of treadmill training and were compared with 24-week-old BIO 53.58 and F1B untrained controls. Left ventricular isovolumic maximum positive dP/dt and peak developed pressure were significantly lower in BIO 53.58 than in F1B controls. Exercise training improved left ventricular contractile indices in BIO 53.58 but not F1B hamsters. The left ventricular beta-adrenergic receptor number (Bmax) was similar in BIO 53.58 and F1B controls. Basal adenylate cyclase activity (ACA) and ACAs stimulated by isoproterenol, 5'-guanylylimidodiphosphate (GppNHp), sodium fluoride, and forskolin were significantly lower in BIO 53.58 than in F1B controls. The functional activity of stimulatory guanine nucleotide-binding protein (Gs), as determined by reconstitution with S49 lymphoma cyc- cell membranes, was significantly lower in BIO 53.58 controls. After 10 weeks of exercise training, Bmax and basal and isoproterenol-stimulated ACAs were unchanged in either BIO 53.58 or F1B hamsters compared with controls. However, in F1B hamsters, training decreased ACAs stimulated by GppNHp, sodium fluoride, and forskolin, with a reduced functional activity of Gs. In contrast, these ACAs increased significantly in association with an enhanced Gs activity in cardiomyopathic BIO 53.58 hamsters after training. CONCLUSIONS Chronic exercise training does not change receptor-mediated beta-adrenergic responsiveness in either F1B or BIO 53.58 hamsters. However, exercise training reduces Gs activity in normal F1B hamsters and improves the functional abnormality of Gs in cardiomyopathic BIO 53.58 hamsters. This improvement may potentially contribute to augmented left ventricular contractility in BIO 53.58 after training.

BACKGROUND It has been reported that the A1-adenosine receptor mediates the cardioprotective effect of ischemic preconditioning. This receptor couples inhibitory guanine nucleotide-binding protein (Gi) and inhibits adenylate cyclase activity. However, the role of adenylate cyclase in preconditioning is unknown. METHODS AND RESULTS We compared the effects of ischemia on the sarcolemmal beta-adrenergic receptor density (Bmax), the stimulatory guanine nucleotide-binding protein (Gs) activity as determined by reconstitution with S49 lymphoma cyc- membranes, and baseline and maximally stimulated adenylate cyclase activities (ACAs) in control and preconditioned rabbit hearts. The control population (n = 28) received 0, 10, 20, and 60 minutes of coronary occlusion (n = 6 to 8 per stage), and preconditioned rabbits (n = 24) received two cycles of alternating 5-minute occlusion and reperfusion before sustained ischemia (n = 6 per stage). In control hearts, occlusion induced rapid and progressive reductions in the Bmax, Gs, and ACAs after 10 to 60 minutes of ischemia. Preconditioning did not affect the reduction in Bmax, but it preserved reductions in Gs activity and ACAs after 10 to 20 but not 60 minutes of sustained ischemia. In another study, 18 rabbits were treated with pertussis toxin 48 hours before surgery to block Gi. During treatment, no significant difference was observed in the ischemia-induced reduction in ACAs in the ischemic region between control (n = 8) and preconditioned (n = 10) animals after 20 minutes of ischemia. CONCLUSIONS Preconditioning delays ischemia-induced reductions in beta-adrenergic signal transduction. Inhibition of ACA is not the target effect of the A1-adenosine receptor-Gi pathway responsible for the cardioprotective role of preconditioning.

Train scheduling is nowadays regarded as one of the effective ways to improve user's benefit on commuter railways with heavy congestion in highly populated metropolitan region. In this study, many model cases varing either demand pattern and its level or train schedule pattern are analized to find the feature of the desirable train schedule, using user equilibrium theory in network assignment. Then some practical formulas to evaluate user's benefit are derived from the upper mentioned analysis, and their adaptability is verified in the situation of real railway lines. Finaly, the formulas are practically applied to the existing lines to compare train schedule at present with several proposed alternatives.

Background: The development of congestive heart failure (CHF) is associated with left ventricular (LV) remodeling. However, fundamental mechanisms that contribute to this remodeling process remain unclear. The matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have been demonstrated to play a significant role in tissue remodeling through a number of pathological processes. Objectives: The purpose of this study was to investigate whether MMPs and TIMPs represent autocrine/paracrine factors and are accumulated in pericardial fluid. We previously reported that active MMP-2 levels in pericardial fluid served as more sensitive and accurate indicators of LV remodeling than did active MMP-2 levels in plasma. Methods: We measured the concentrations of the enzyme (active MMP-9) in both plasma and pericardial fluid in 20 patients during coronary artery bypass graft surgery. Results: The active MMP-9 level was significantly higher in pericardial fluid than in plasma (4.68 ± 1.17 vs. 2.58 ± 0.29 ng/ml, p Conclusions: Active MMP-9 levels in pericardial fluid serve as more sensitive and accurate indicators of LV remodeling than did active MMP-9 levels in plasma. Thus, active form of MMP-9 may be also secreted from the heart into the pericardial space with the progression of CHF, and it may have a pathophysiologic role in LV remodeling process as an autocrine/paracrine factor.

Background— Although animal studies showed that annular remodeling may be related to the pathogenesis of chronic ischemic mitral regurgitation (CIMR), little was known in humans. A better understanding of the precise 3D geometry of the mitral valvular-ventricular complex in CIMR is needed to devise a better surgical technique. The purpose of the study was to elucidate mitral annular geometry in patients with CIMR using cardiac MRI. Methods and Results— Thirty-eight patients with previous inferior or posterior myocardial infarction were studied. With the 3D reconstruction of the mitral annulus and subvalvular apparatus from a series of longitudinal cine MRIs, end-systolic mitral annulus dimensions and 3D geometry were calculated. Patients were grouped by mitral regurgitation grade using echocardiography (≥2+, n=15 versus ≤1+, n=23). Both septal-lateral and commissure-commissure mitral annular diameters were significantly greater in CIMR(+) patients (35±5 versus 30±4 mm, P =0.005; 46±6 versus 39±4 mm, P P P =0.002), and the annular height to commissural width ratio was significantly lower in CIMR(+) patients (12±3 versus 21±5%; P Conclusions— Patients with CIMR had greater septal-lateral and commissure-commissure mitral annular dimension, larger intertrigonal distance, and flattened saddle shape of mitral annulus. These associated geometric alterations may be important in the pathogenesis of CIMR.

Background Myocardial contrast echocardiography and coronary flow velocity pattern with a rapid diastolic deceleration time after percutaneous coronary intervention has been reported to be useful in assessing microvascular damage in patients with acute myocardial infarction. Aim To evaluate myocardial contrast echocardiography with harmonic power Doppler imaging, coronary flow velocity reserve and coronary artery flow pattern in predicting functional recovery by using transthoracic echocardiography. Methods Thirty patients with anterior acute myocardial infarction underwent myocardial contrast echocardiography at rest and during hyperemia and were quantitatively analyzed by the peak color pixel intensity ratio of the risk area to the control area (PIR). Coronary flow pattern was measured using transthoracic echocardiography in the distal portion of left anterior descending artery within 24 hours after recanalization and we assessed deceleration time of diastolic flow velocity. Coronary flow velocity reserve was calculated two weeks after acute myocardial infarction. Left ventricular end-diastolic volumes and ejection fraction by angiography were computed. Results Pts were divided into 2 groups according to the deceleration time of coronary artery flow pattern (Group A; 20 pts with deceleration time ≧ 600 msec, Group B; 10 pts with deceleration time < 600 msec). In acute phase, there were no significant differences in left ventricular end-diastolic volume and ejection fraction (Left ventricular end-diastolic volume 112 ± 33 vs. 146 ± 38 ml, ejection fraction 50 ± 7 vs. 45 ± 9 %; group A vs. B). However, left ventricular end-diastolic volume in Group B was significantly larger than that in Group A (192 ± 39 vs. 114 ± 30 ml, p < 0.01), and ejection fraction in Group B was significantly lower than that in Group A (39 ± 9 vs. 52 ± 7%, p < 0.01) at 6 months. PIR and coronary flow velocity reserve of Group A were higher than Group B (PIR, at rest: 0.668 ± 0.178 vs. 0.248 ± 0.015, p < 0.0001: during hyperemia 0.725 ± 0.194 vs. 0.295 ± 0.107, p < 0.0001; coronary flow velocity reserve, 2.60 ± 0.80 vs. 1.31 ± 0.29, p = 0.0002, respectively). Conclusion The preserved microvasculature detecting by myocardial contrast echocardiography and coronary flow velocity reserve is related to functional recovery after acute myocardial infarction.

Background It has been reported that pioglitazone reduces neointimal hyperplasia after balloon-induced vascular injury in an experimental model. Methods To determine whether pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus, we studied 44 stented lesions in 44 patients with diabetes mellitus who underwent successful coronary stent implantation. Study patients were randomized into 2 groups: the pioglitazone group (23 patients with 23 lesions) and the control group (21 patients with 21 lesions). All patients underwent serial quantitative coronary angiography and serial intravascular ultrasound scanning studies. With a motorized pullback system, multiple image slices within the stent were obtained at every 1 mm. The stent area and lumen area were measured, and the neointimal area was calculated. Measurements were averaged over the number of selected image slices. The neointimal index was calculated as the averaged neointimal area divided by the averaged stent area multiplied by 100 (%). Results After 6 months of treatment, angiographic in-stent restenosis (17% vs 43%, respectively, P = .0994) and target lesion revascularization (13% vs 38%, respectively, P = .0835) were less frequent in the pioglitazone group than the control group; however, these differences did not reach significance. The intravascular ultrasound scanning study demonstrated that the neointimal index in the pioglitazone group was significantly smaller than that in the control group (28% ± 9% vs 48% ± 15%, respectively, P Conclusion A serial intravascular ultrasound scanning assessment demonstrated that pioglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus.

The contribution of ATP sensitive potassium (K(ATP)) channels to the infarct-size limiting effect of preconditioning is considered to be anaesthetic-dependent in the rabbit heart. It has previously been reported that ischaemic preconditioning prevents ischaemia-induced reductions in activities of sarcolemmal adenylate cyclase (AC) and Na+, K(+)-ATPase. Anaesthetic dependency of the role of K(ATP) channels in the preservation of these enzyme activities, induced by ischaemic preconditioning, as well as that induced by activation of A1-adenosine receptors, was examined in rabbits anaesthetized with either pentobarbital or ketamine-xylazine and subjected to 20 min of regional ischaemia. Adenylate cyclase and Na+, K(+)-ATPase activities were lower in the ischaemic than in the non-ischaemic region of the hearts in control rabbits, but not in animals subjected to ischaemic preconditioning, or those pretreated with the A1-adenosine receptor agonist R(-)-N6-(2-phenylisopropyl) adenosine. The protective effects of both ischaemic preconditioning and A1-adenosine receptor activation were prevented by 6 mg/kg, but not 3 mg/kg, of the K(ATP) channel blocker, glibenclamide, in rabbits anaesthetized with pentobarbital, while these effects were prevented by 3 mg/kg of the blocker in rabbits anaesthetized with ketamine-xylazine. Moreover, K(ATP) channel opener, cromakalim, prevented the ischaemia-induced decreases in enzymatic activities in rabbits subjected to either type of anaesthesia. Thus, although the antagonistic effect of glibenclamide is blunted under pentobarbital, compared to ketamine-xylazine anaesthesia, K(ATP) channels contribute to preservative actions independent of the type of anaesthesia in the rabbit heart.

Whereas mobilization of intracellular Ca2+ stimulates neuronal adenylyl cyclase via Ca2+/calmodulin, mobilized Ca2+ directly inhibits adenylyl cyclase in other tissues. To determine the physiologic role of the Ca(2+)-dependent interaction between Na+/Ca2+ exchange and beta-adrenergic signal transduction in the intact heart, digoxin (0.3 mg/kg) was administered intravenously in rabbits. 30 min after the administration, digoxin impaired the peak left ventricular dP/dt response to dobutamine infusions by up to 38% as compared with control rabbits. This impairment was not caused by changes in either beta-adrenergic receptor number or in the functional activity of stimulatory guanine nucleotide-binding protein. It was associated with 33-36% reductions in basal and stimulated adenylyl cyclase activities. Animals treated with calcium gluconate (20 mg/kg/min for 30 min) also demonstrated similar reductions in adenylyl cyclase activities. In addition, increasing the free Ca2+ concentration progressively inhibited adenylyl cyclase activity in the control, digoxin-treated, and calcium gluconate-treated sarcolemma preparations in vitro. Moreover, digoxin and calcium gluconate pretreatment blunted the increase in cAMP in myocardial tissue after dobutamine infusion in vivo. Thus, digoxin rapidly reduces beta-adrenergic contractile response in rabbit hearts. This reduction may reflect an inhibition of adenylyl cyclase by Ca2+ mobilized via Na+/Ca2+ exchange.

Single beat estimation of the slope of the end-systolic pressure-volume relation assumes symmetric left ventricular pressure increase and decay and requires extrapolation of peak isovolumic developed pressure (Pmax) from the left ventricular pressure curve of an ejection contraction. To test the sensitivity of this slope to positive inotropic stimuli, biplane cineangiocardiography and simultaneous high-fidelity left ventricular pressure measurements were performed in 50 patients with heart disease. The end-systolic pressure-volume relations were assessed under baseline conditions and during norepinephrine infusion (n = 19) or after postextrasystolic potentiation (n = 24), or both (n = 7). Norepinephrine did not change left ventricular end-systolic volume despite significant elevations of end-systolic pressure. Postextrasystolic potentiation significantly decreased end-systolic volume in association with an unaltered left ventricular end-systolic pressure. The potentiation significantly decreased the pressure half-time of contraction, an index of the speed of the left ventricular pressure increase, while it increased the pressure half-time of relaxation, an index of the speed of the pressure decline, indicating asymmetric pressure increase and decay. The slope of the end-systolic pressure-volume relation increased from 3.3 to 4.4 mm Hg/ml/m2 (p < 0.001) during norepinephrine infusion. In contrast, despite an augmented contractility, the slope decreased significantly from 3.2 to 2.4 mm Hg/ml/m2 (p < 0.0001) after the potentiation. The slope showed a high correlation with Pmax (r = 0.86, p < 0.0001, n = 107). Thus, the slope of the end-systolic pressure-volume relation derived from single beat analysis is not always sensitive to inotropic interventions. Its sensitivity is highly dependent on the accuracy of extrapolation of Pmax, and this assessment of the contractile state is limited especially when isovolumic contraction and relaxation are dissociated.

We describe two cases in which echocardiographic image enhancement with an intravenous contrast agent using harmonic power Doppler (HPD) imaging established the diagnosis of abnormal structures in the left ventricle (LV).