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Additional file 3: Table S3. Assessment for the deviation from time-constant assumption for hazard ratios. Asterisks exhibit correlation between the Schoenfeld residuals and rank-transformed time at events. Daggers mean that P value is based on Chi-square test for time-constant hazard ratio.

Additional file 4: Figure S1. The cumulative martingale residuals (blue, thick line) plotted against 10-mg/dl LDL-C levels above the threshold value set by each model to check the linearity assumption in the Cox models, accompanied by 1000 resampled zero-mean random Gaussian processes (black, thin lines). If the relationship between LDL-C above the threshold and event hazards is actually linear in the Cox model (i.e., the linearity assumption holds), the cumulative sum of martingale residuals will approximately follow the zero-mean Gaussian process and fluctuate randomly. The supremum of the cumulative martingale residuals along the LDL-C levels can be tested against the suprema from randomly sampled zero-mean Gaussian processes. A small p-value from this resampling-based test would provide evidence against the linearity assumption.

Additional file 1: Table S1. LDL-C category-specific event rates (pitavastatin 4 mg/day group). Data are adjusted for gender, age (

Additional file 2: Table S2. LDL-C category-specific event rates (pitavastatin 1 mg/day group). Data are adjusted for gender, age (

Aim: Diabetic patients with coronary artery disease have a high incidence of cardiovascular events, which was associated with increased coronary plaque volume. Low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) play pivotal roles in the progression of coronary plaque. Several trials have shown that intervention for a single risk factor reduced the development of coronary plaque progression. However, it remained uncertain whether total risk management for LDL-C, BP, and glycosylated Hb (HbA1c) has a beneficial effect on coronary plaque volume in diabetic patients. Methods: This study was a sub-study of the JAPAN-ACS that was a prospective, randomized, open-label trial that evaluated the impact of intensive lipid-lowering therapy on coronary plaque volume in patients with acute coronary syndrome (ACS). Among a total of 252 patients, 73 diabetic patients were analyzed. We examined the impact of total risk management (LDL-C ＜80 mg/dL, systolic BP ＜130 mmHg, and HbA1c ＜6.5%) on changes in coronary plaque volume. The patients were divided into four groups according to the number of risk factors that achieved the target value. Results: Baseline characteristics were similar among the groups. The degree of coronary plaque regression was greater in patients who achieved total risk management. The number of risk factors that achieved the target level was associated with the extent of the coronary plaque volume reduction in a dose-dependent manner. Conclusion: Total risk management that focused on LDL-C, BP, and HbA1c had a beneficial impact on the coronary plaque regression in diabetic patients with ACS., 出版者照会後に全文公開

Background: Improving the survival of transplanted cells is a critical is- sue in the use of stem cell transplantation therapy for cardiovascular disease. Many transplanted cells are lost through apoptosis or necrosis triggered by hypoxia or superoxide. Methods and Results: Tongue muscle-derived Sca-1(+) cells were isolated from the mouse and cultured for 2 weeks and then exposed to hydrogen peroxide (H_2O_2

Stem cell therapy for cardiac regeneration is hindered by poor homing to infarcted legion because of poor expression of homing factor, CXCR4, on the stem cell surface. A strategy for enhancing CXCR4 is promising to acceler- ate stem cell homing to infarcted lesion. Methods and Results: Heart muscle-derived Sca-1(+) cells (HDSCs) were isolated from normal mouse heart using surface antigen Sca-1. The expression of CXCR4 was determined by the fluorescence-activated cell sorting by labeling the cells with CXCR4 antibody with fluorescence. The expression of CXCR4 was enhanced by stimulation of hydrogen peroxide (0.1, 0.33, 1μM) for 24h. The Western blotting showed no significant increase in the protein level of CXCR4. The enhancement of CXCR4 can be attributed to translocation of CXCR4 from the cytosolic fraction to cell surface. H_2O_2 stimulation enhanced ASK1 p966 phosphory- lation. Conclusions: The expression of CXCR4 on HDSCs was augmented by H_2O_2 through the translocation from cytosolic to membrane surface through ASK1 phos-phorylation

Background: It has been suggested that intensive lipid-lowering therapy using statins significantly decreases atheromatous plaque volume. The effect of rosuvastatin on plaque volume in patients with stable coronary artery disease (CAD), including those receiving prior lipid-lowering therapy, was examined in the present study. Methods and Results: A 76-week open-label trial was performed at 37 centers in Japan. Eligible patients began treatment with rosuvastatin 2.5 mg/day, which could be increased at 4-week intervals to ≤20 mg/day. A total of 214 patients underwent intravascular ultrasound (IVUS) at baseline; 126 patients had analyzable IVUS images at the end of the study. The change in the serum low-density lipoprotein-cholesterol level from baseline to end of follow-up was -38.6 ±16.9%, whereas that of high-density lipoprotein-cholesterol was +19.8 ±22.9% (both P, 出版者照会後に全文公開

Abnormal regulation of intracellular Ca2- by sarcoplasmic reticulum plays a part in the mechanism underlying contractile and relaxation dysfunction in heart failure (HF). The protein-kinase-A-mediated hyperphosphorylation of ryanodine receptors in the sarcoplasmic reticulum has been shown to cause the dissociation of FKBP12.6 (also known as calstabin-2) from ryanodien receptors in HF. In addition, several disease-linked mutations in the ryanodine receptors have been reported in patients with catecholaminergic polymorphic ventricular tachycardia or arrhythmogenic right ventricular cardiomyopathy type2. The unique distribution of these mutation sites has led to the concept that the interaction among the putative regulatory domains within the ryanodine receptors has a key role in regulating channel opening. The knowledge gained from various studies of ryanodine receptors under pathologic conditions might lead to the development of new pharmacological or genetic strategies for the treatment of HF or cardiac arrhythmia. In this review, we focus on the role of the Ca2--release channel, the ryanodine receptor, in the pathogenesis of HF and fatal arrhythmia, and the possibility of developing new therapeutic strategies by targeting this receptor.

金沢大学医薬保健研究域医学系, Background: Many trials have shown that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce the incidence of cardiovascular events and mortality. One method of decreasing the incidence of cardiovascular events could be to reduce the progression of coronary atherosclerosis, and a recent study found that atorvastatin can cause coronary plaque to regress. To generalize this finding, using conventional HMG-CoA reductase inhibitors at many Japanese centers, randomized trials of pitavastatin and atorvastatin will be conducted with patients with acute coronary syndrome (ACS). Methods and Results: Patients with ACS who have undergone successful percutaneous coronary intervention under intravascular ultrasound guidance will be studied. They will be randomly allocated to pitavastatin or atorvastatin groups and followed up for 8-12 months. The primary endpoint will be the percent change in coronary plaque volume, and secondary endpoints will include absolute changes in coronary plaque volume, serum lipid levels and inflammatory markers. The safety profile will also be evaluated. Conclusions: This study will examine the ability of HMG-CoA reductase inhibitors to regress coronary plaque in Japanese patients with ACS and the findings should help to improve the prognosis of such patients and clarify the involved mechanisms., 出版者照会後に全文公開

心筋細胞間のギャップ結合の発現・分布はコネキシン蛋白の半減期が短いことにより様々な病態において直ちに変化しうる.高頻度電気刺激(RES)によるギャップ結合リモデリングへの効果はいまだ明らかにされていない.培養5日目のラット心室筋細胞に120分間3HzのRESを負荷した.RESによりCx43蛋白質および遺伝子発現量は60分後には有意に増加した.免疫染色においても同様の結果であった.心筋細胞中のangiotensin II (AngII)は15分後に約2倍に上昇した.MAPK系のリン酸化型ERKは2峰性に5分と60分で, またリン酸化型JNKも15分と60分で著明に活性化された.リン酸化型p38 MAPKは5分後に1峰性に活性化された.細胞外電位記録法により心筋細胞の興奮伝播特性の変化を解析したところ, RESにより伝導速度は有意に増加した.これらの変化はlosartanにより抑制された.RESによるCx43の発現増加はまたERK, p38の特異的阻害剤にても抑制された.RESは, 早期より心筋細胞内のAng II産生を増加し, MAPK系を活性化することによりCx43発現量を増加させた.その結果, 細胞間の刺激伝播異常を引き起こし, 不整脈基質の一つとなる可能性が示された., BACKGROUND The expression and distribution of gap junctions in cardiac muscle can be changed readily under a variety of pathological conditions because of dynamic turnover of connexins. The effects of rapid electrical stimulation (RES) of contraction on the gap junction remodeling are not well-understood. METHODS Neonatal rat ventricular myocytes cultured for 5 days were subjected to RES at 3.0 Hz for up to 120 min. RESULTS RES resulted in a significant upregulation of Cx43. Angiotensin II content was increased significantly by RES>15 min. Phosphorylated forms of extracellular signal-regulated protein kinase (ERK), c-Jun NH_2-terminal kinases (JNK) and p38 mitogen-activated protein kinases (p38 MAPKs) were all increased dramatically by RES with peaks at 5～60 min. Propagation of excitation was visualized by extracellular potential mapping by using a multiple electrode array system. Conduction velocity was increased significantly by RES for 60 to 90 min. Treatment of myocytes with losartan prevented most of these effects of RES. RES-induced upregulation of Cx43 was also prevented by specific inhibitors for ERK and p38 MAPKs. CONCLUSIONS A short-term RES causes upregulation of Cx43 in cardiomyocytes and a concomitant increase of conduction velocity mainly through an autocrine action of Angiotensin II to activate ERK and p38 MAPKs., (小西賞受賞者)(Konishi Prize)

金沢大学大学院医学系研究科, The Japan Lipid Intervention Trial (J-LIT) study, a nationwide cohort study utilizing the clinical practice of general physicians, was designed to clarify the relationship between the incidence of coronary heart disease and serum lipid concentrations during simvastatin therapy, as well as the safety of the therapy, in a large number of Japanese hypercholesterolemic patients. All the enrolled patients were treated with simvastatin. The current study analyzed the lipid lowering effect and safety of the low-dose simvastatin therapy used in the J-LIT study. Open-labeled simvastatin was given to 51,321 patients at an initial dose of mostly 5 mg/day. After 6 months of the treatment, the average serum total cholesterol (TC) and low density lipoprotein-cholesterol concentrations in all the patients followed up were reduced by 18.3% and 26.0%, respectively, and that of high density lipoprotein-cholesterol increased 2.3% on average. These concentrations were well maintained throughout the 6-year treatment period. A minority of patients (1.4%) unexpectedly had a remarkable reduction in TC concentration by more than 40%. Hyper-responders, even to low-dose statin, were found for the first time in this large-scale and long-term investigation. Overall adverse drug reactions occurred in 3.3% of subjects during the 6-year treatment, the major events being hepatic and musculoskeletal disorders, of which the incidence was less than 1%. Low-dose simvastatin therapy of 5 mg/day effectively controlled the serum TC concentration by reducing it by approximately 20% on average in hypercholesterolemic Japanese patients, a reduction that corresponds to the effect of simvastatin 20 mg/day in Western studies. In addition, the low incidence of drug-related adverse events in this study may. be also related to the low dosage of simvastatin.

A 36-year-old women (height 157cm, weight 114kg, body mass index 46.2kg/㎡) with intolerable sleepiness and cyanosis was diagnosed with respiratory failure caused by Pickwickian syndrome. Echocardiography showed normal left ventricular systolic function and moderate pulmonary hypertension. Pulmonary artery systolic pressure was estimated at 50mmHg with doppler echocardiography. Oxygen inhalation and diuretics were started. Althouth the patient was treated with nasal continuous positive airway pressure ventilation, her hypoxemia and hypercapnia did not improve. Bilevel positive airway pressure ventilation with inspiratory pressure 10cmH2O and expiratory pressure 2cmH2O was quite effective in improving hypoxemia and hypercapnia, and pulmonary hypertension had disappeared at the discharge.

The International Conference on Control, Automation and Systems (ICCAS2001), October 17-21, 2001, Cheju National University, Jeju, Korea.

Aldosterone-producing adenoma is a rare but surgically surable disease of primary aldosteronism. We experienced two cases of aldosterone-prosucing adenoma

Multiple myeloma with immune thrombocytopenia in an 81-year-old male is reported. He was admitted to our hospital because of paresis of lower extremities. Prednisolone therapy for autoimmune thrombocytopenia was followed by combination therapy (melphalan 8 mg/day + prednisolone 30 mg/day) against multiple myeloma. The platelet count increasedto within normal range and correlated well with a decrease in PAIgG. There was no significant change in total IgG. Intermittent chemotherapy suppressed the proliferation of myeloma cells and maintained the platelet count in the normal range.

We investigated the correlations of blood pressure with intra- or extracellular and bone calcium matabolisms in the elderly. We measured serum calcium (Ca), inorganic phosphorus (Pi), C-terminal parathyroid hormone fragment (PTH-C), and calcitonin. Intracellular free calcium ([Ca2+]I) in platelet and erythrocyte was measured by fura- 2/AM from dual excitation wavelength using a fluorescence spectrophotometer. We calculated bone mineral content (BMC) of lumbar vertebral body using a calibration phantom by computed tomography. Systolic blood pressure had significant positive correlation with platelet [Ca2+]I (r=0.691

The rerationship between adominalaortic calcification and osteoporosis in 224 elderly patients (82 men, 142 women, age ranged from 60 to 94 yrs [77.8 ± 7.6] ) was investigated by computed tomography. We calculated the aortic calcification index (ACI

We investigated the affects of long-term oral vitamin D treatment on aortic wall and vetebral bone in the elderly patients with osteoporosis by computed tomography. We calculated the aortic calcification index (ACI) of calcification volume to aortic volume wuthin 10 slices in the lower abdominal aorta, and measured the bone mineral content (BMC) of three lumbar vertebral bodies (the 2nd, 3rd, 4th) using a calibration phantom. We compared the ACIs and BMCs between 15 patients under no vitamin D therapy (10 men, 5 women, 79±7 yrs)(Group-Ⅰ) and 17 patients with osteoporosis under vitamin D therapy (4 men, 13 women, 75±6 yrs)(Group-Ⅱ). The patients in Group-Ⅱ received vitamin D everyday to sum up the duration into 849±333 days and the dosage into 604±323μg. ACI slightly increased from 9.2±7.2 to 11.0±8.5% in Group-Ⅰ(NS), and similarly increased from 9.3±10.6 to 12.2±12.9% in Group-Ⅱ(NS). Percent change of ACI was higher in Group-Ⅱ(58±73%) than in Group-Ⅰ(32±52%)(NS). BMC slightly decreased from 63.2±40.6 to 62.4±45.4mg/ｃ? in Group-Ⅰ(NS), but increased a little from 57.8±51.4 to 63.3±44.6mg/ｃ? in Group-Ⅱ(NS). These results suggest that there is a tendency to increase in both aortic calcification and bone mineral content under an event small dosage but long-term treatment of oral vitamin D.

The provocation of atrial fibrillation (Af) was studied in 23 patients by 10 single extrastimulations, and by rapid pacing over three minutes at the mid-lateral right atrium. The frequency spectrum of atrial electrogram on the high- lateral right atrium (HRA) was simultaneously computed with the fast-Fourier transform analysis. Result were shown as follows: 1) The single extrastimulation induced no Af in any patients, but rapid pacing induced Af in 20 patients with various heart diseases and the shorter interval of atrial effective refractory period (AERP). 2) All of the 5 patients with a history of transient Af had significantly shorter AERP of the right atrium than that in patients without a history of Af. 3) During both single extrastimulation and rapid pacing, both the higer- and lower-frequency components of atrial electrogram in patients with induction of Af were greater in amplitude than those in patients without induction of Af. The patients with induction of Af by pacing of may have the vulnerable electrophysiologic condition around the region of HRA, probably related to the higher sensitivity of right atrium to the pacing stimuli, regardless of the basal heart disease.

金沢大学医薬保健研究域医学系, Background: The Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome (JAPAN-ACS) trial demonstrated that early aggressive statin therapy in patients with ACS significantly reduces plaque volume (PV). Advanced glycation end products (AGEs) and the receptors of AGEs (RAGE) may lead to angiopathy in diabetes mellitus (DM) and may affect on the development of coronary PV. The present sub-study of JAPAN-ACS investigates the association between AGEs and RAGE, and PV.Methods: Intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) was undertaken, followed by the initiation of statin treatment (either 4 mg/day of pitavastatin or 20 mg/day of atorvastatin), in patients with ACS. In the 208 JAPAN-ACS subjects, PV using IVUS in non-culprit segment > 5 mm proximal or distal to the culprit lesion and, serum levels of AGEs and soluble RAGE (sRAGE) were measured at baseline and 8-12 months after PCI.Results: At baseline, no differences in the levels of either AGEs or sRAGE were found between patients with DM and those without DM. The levels of AGEs decreased significantly with statin therapy from 8.6 ± 2.2 to 8.0 ± 2.1 U/ml (p < 0.001), whereas the levels of sRAGE did not change. There were no significant correlations between changes in PV and the changes in levels of AGEs as well as sRAGE. However, high baseline AGEs levels were significantly associated with plaque progression (odds ratio, 1.21; 95% confidence interval, 1.01 - 1.48; p = 0.044) even after adjusting for DM in multivariate logistic regression models.Conclusions: High baseline AGEs levels were associated with plaque progression in the JAPAN-ACS trial. This relationship was independent of DM. These findings suggest AGEs may be related to long-term glucose control and other oxidative stresses in ACS.Trial registration: NCT00242944. © 2013 Fukushima et al.; licensee BioMed Central Ltd.

The expression of gap junctions in cardiac muscle can be changed readily under a variety of pathological conditions because of dynamic turnover of connexins (Cxs). We have previously reported that application of rapid electrical stumulation (RES) of contraction for 60-120 min to cultured ventricular myocytes increased Cx43 expression (by ∼1.5-fold in protein and by ∼1.9-fold in mRNA at 90 min), resulting in substantial increase of conduction velocity. This was associated with an increase of angiotensin II and upregulation of activated forms of ERK, JNK and p38 MAPKs in carddiomyocytes. To examine the relative contribution of different MAPKs, RES for 90 min was applied to cultured cardiomyocytes pretreated with specific inhibitors for each branches of the MAPKs. The baseline level of Cx43 protein was unaffected by either PD98059 (an inhibitor of ERK), SP600125 (an inhibitor of JNK) or SB203580 (an inhibitor of p38/JNK2). In the presence of PD98059, the RES-induced increase of Cx43 protein was almost abolished. Pretreatment with SP600125, in contrast, did not affect the RES-induced Cx43 upregulation. Pretreatment with SB203580 caused a partial prevention of the Cx43 upregulation. These results suggest that short-term RES-induced upregulation of Cx43 expression is mediated, at least in part, by activated ERK and p38 MAKPs in response to RES of contraction.

Differences in the distribution of gap junctions are considered to be an important factor in the origin of reentrant arrhythmias. We investigated the alterations in connexin (Cx)43 during development of heart failure in UM-X7.1 cardiomyopathic hamster (CM). We analyzed Cx43 expressions of the left ventricular (LV) myocardium at age of 6, 10, and 20w. Echocardiographic and ECG monitoring data were obtained. Results: In CM, LV hypertrophy had developed at 10w, and LV global hypokinesis at 20w. QRS interval was markedly prolonged compared with golden hamster (G), and polymorphic ventricular tachycardia was easily induced by burst pacing at 20w of CM. The interstitial fibrosis was significantly increased in CM (8.5 ± 2.6%) compared with G (1.9 ± 1.1%, p

Purpose: Mitochondrial membrane potential ([mP]) and intracellular calcium concentration ([Ca2+]i) play an important role in the mechanism of apoptosis induced by oxidative stress, however, it is unknown the relationship between [mP] and [Ca2+]i upon oxidative stress and their modification by medication. Methods: Isolated neonatal cardiomyocytes were exposed to H2O2 for 16hours and apoptotic nuclei were detected by TUNEL method. Laser confocal microscopy was used to evaluate the time lapse-changes of [Ca2+]i and [mP] in cardiomyocytes loaded with fluo-3AM and TMRE. Results: The percentage of apoptotic cells was 24 ± 5%, 37 ± 8% and 44 ± 9% induced with 50, 100 and 200μmol/L H2O2 and carvedilol (10μmol/L) decreased the apoptotic cells to 17 ± 4%, 27 ± 5% and 32 ± 5% (p < 0.05 v.s. no carvedilol group) in each concentration of H2O2, respectively. The increase of [Ca2+]i preceded the change of [mP] (time to the onset: 21.4 ± 4.6 minutes for [Ca2+]i v.s. 38 ± 5.6 minutes for [mP], p < 0.01) after the addition of H2O2. Carvedilol delayed the onset of [mP] loss (1μmol/L group 46.0 ± 3.0 minutes, 5μmol/L group 57.0 ± 6.7 minutes, 10μmol/L group 86.5 ± 9.7 minutes, p < 0.05) and also delayed the onset of [Ca2+]i increase (5μmol/L group 27.2 ± 6.3, 10μmol/L group 45.4 ± 7.7 min, p < 0.05) respectively. Conclusion: Upon oxidative stress-induced apoptosis, the increase of [Ca2+]i preceded the depolarization of [mP] and carvedilol delayed [Ca2+]i overload and inhibited the collapse of [mP], which may contribute to the inhibition of apoptosis.

Purpose: In heart failure or ischemia-reperfusion injury, intracellular calcium overload occurs in the myocardium. However, mitochondrial functions during calcium overload are not well known. Additionally failing myocardium have source of oxygen free radicals from mitochondrial electron transport complex 1. Recently, a beta-blocker is known to be useful for heart failure, and also suggested the difference between the drugs depending on the lipid solubility, and with or without antioxidant effect. Methods: Isolated mitochondria from SD rat hearts were loaded in the cuvette mounted by Clark oxygen sensor to measure the mitochondrial oxygen consumption. The amount of malondialdehyde (MDA) was measured as an index of superoxide production. Calcium concentration was varied at 10, 100 μM and carvedilol and metoprolol concentration was varied at 1, 10, 100 μM. Rotenone was used for injuring complex 1. Result: The oxygen consumption was significantly augmented by increasing the calcium concentration from 10 to 100 μM (p Conclusion: These data strongly suggest the distinct effect of carvedilol on superoxide production and oxygen consumption from metoprolol, which may be beneficial for the protection of cardiomyocyte from oxidant stress.

We investigated the effect of inhibition of protein phosphatase 1 (PP1) in heart failure. We used in vivo high efficiency cardiac gene delivery system to express a human inhibitor-2 (I-2), an endogenous specific inhibitor of PP1, in UM-X7.1 cardiomyopathic hamster. Before cardiac gene delivery, we characterized time course of PP1 and protein kinase A (PKA) activity in progression of cardiomyopathy of UM-X7.1 hamster. Not only PP1 activity but also PKA activity was significantly elevated at 10 to 28weeks old of age in UM-7.1 hamster compared with normal hamster. We delivered recombinant adenovirus encoding I-2 or lacZ to UM-X7.1 hamster at 14 weeks old (I-2 and lacZ, n = 9 in each group). Seven days after gene delivery, we assessed echocardiography, hemodynamics, biochemical and histological data of hearts. In echocardiography, left ventricular (LV) dimension significantly decreased with subtle increase % fractional shortening of the LV in I-2 treated hamsters, whereas lacZ treated hearts showed further progression of cardiomyopathy. Induction of brain natriuretic peptide was alleviated and PKA activity was significantly reduced in I-2 treated hearts, suggesting mitigated β-adrenergic signaling. In conclusion, these data indicate that inhibition of PP1 is beneficial for preventing progressive LV dysfunction by modifying excessive β-adrenergic stimulation and can be a potential target for treatment of genetic cardiomyopathy and associated heart failure.

Two specific domains within ryanodine receptor (RyR) in sarcoplasmic reticulum (SR) {{N-terminal (N:0-600) and Central (C:2000-2500)}} have been recently shown to interact with each other as a regulatory switch for channel gating. Here, we assessed the role of the inter-domain interaction in the pathogenesis of heart failure. Methods and Results: SR vesicles were isolated from dog LV muscles (n = 6), then RyR was labeled in a site-directed fashion with the fluorescent conformational probe methylcoumarin acetate (MCA) using the following synthetic peptide as a site-directing carrier. 1) The peptide corresponding to Gly2460-Pro2495 of RyR (that contains a potential mutation site in pVT), designated DPc10 (10-100 u M), induced unzipping mode of N- and C-domain interaction (assessed by chemical quenching of MCA fluorescence), and Ca 2+ leak. 2) RyR channel stabilizer, JTV519 normally restored domain zipping, and prevented DPc10-induced Ca 2+ leak. 3) In the SR isolated from pacing-induced dog failing hearts (n = 5), the domain unzipping has already occurred, but JTV519 shifted back the mode from unzipping to zipping, and prevented spontaneous Ca 2+ leak from occurring. Conclusions: The defectiveness of specific domain interaction within RyR may play a key role in the pathogenesis of heart failure, and restoration of the inter-domain interaction could be a new therapeutic strategy against heart failure.

ObjectivesThis study theoretically examined the longitudinal structural determinants of plaque vulnerability using a color-coded stress mapping technique for several hypothetical vessel models as well as three-dimensional intravascular ultrasound (IVUS) images with use of a finite element analysis.BackgroundIt has been shown that an excessive concentration of stress is related to atherosclerotic plaque rupture. However, the local determinants of in-plaque longitudinal stress distribution along the coronary arterial wall remain unclear.MethodsUsing a finite element analysis, we performed a color mapping of equivalent stress distribution within plaques for three-dimensional vessel models as well as longitudinal IVUS plaque images (n = 15). Then, the effects of plaque size, shape, expansive remodeling, calcification, and lipid core on the equivalent stress distribution were examined.ResultsThe color mapping of vessel models revealed a concentration of equivalent stress at the top of the hills and the shoulders of homogeneous fibrous plaques. Expansive remodeling and the lipid core augmented the surface equivalent stress, whereas luminal stenosis and superficial calcification attenuated the equivalent stress. The location of excessive stress concentration was modified by the distribution of the lipid core and calcification. The thickness of the fibrous cap was inversely related to the equivalent stress within the fibrous cap. However, the color mapping of IVUS plaque images showed that the equivalent stress value at the fibrous cap varied with changes in plaque shape and superficial calcification, even when the thickness of the fibrous cap remained constant.ConclusionsA distribution analysis of longitudinal stress revealed specific effects of plaque shape, size, and remodeling, as well as effects of the interior distribution of tissue components, on the concentration of stress at the plaque surface. Moreover, fibrous caps of the same thickness did not consistently represent the same vulnerability to rupture.

ObjectivesWe sought to assess the effects of low density lipoprotein (LDL)-apheresis (LDL-A) for regression of coronary plaque in familial hypercholesterolemia (FH), we set up a one-year follow-up multicenter trial using coronary angiography and intravascular ultrasound (IVUS).BackgroundIt is still unclear whether aggressive lipid-lowering therapy by LDL-A leads to the regression of coronary plaque in patients with FH.MethodsEighteen patients with FH were assigned to one of two groups: medication + LDL-A (LDL-A group, n = 11) and medication only (medication group, n = 7). Total cholesterol, triglycerides, high density lipoprotein cholesterol and LDL cholesterol were measured in all subjects at the outset of treatment (baseline) and every three months thereafter. Coronary angiography and IVUS were performed at the outset and after the one-year follow-up period to measure minimal lumen diameter (MLD) by coronary angiogram and plaque area (PA) by IVUS.ResultsThe LDL-A group showed 28.4% reduction in total cholesterol (from 275 ± 27 mg/dl to 197 ± 19 mg/dl) and 34.3% reduction in LDL cholesterol (from 213 ± 25 mg/dl to 140 ± 27 mg/dl) after one-year follow-up, while the medication group showed no changes in cholesterol levels. There were significant interactions between both treatments in total cholesterol (p = 0.0001), LDL cholesterol (p = 0.0001), MLD (p = 0.008) and PA (p = 0.017) using two-way repeated-measures analysis of variance by the SAS system (SAS Institute Inc., Cary, North Carolina). Significant differences were seen in net change in MLD (p = 0.004) and PA (p = 0.008) during the one-year follow-up period between both groups.ConclusionsThese results suggest that aggressive lipid-lowering therapy using the combination of LDL-A and lipid-lowering drugs may induce regression of coronary atherosclerotic plaque in FH patients.

OBJECTIVESThis study aimed to investigate prospectively the protective effect of a first preinfarction angina attack against acute myocardial infarction (AMI) in human hearts without significant collaterals.BACKGROUNDSeveral retrospective studies and the prospective studies have demonstrated the existence of the preconditioning (PC) effect in humans. However, collaterals were not examined in the prospective studies. In animal models, the PC effect on myocardial infarct size appears soon after PC reperfusion (classic) but disappears within 1 to 2 h. It then reappears 24 to 48 h after reperfusion (the delayed PC effect). Meanwhile, the PC effect on stunning appears 12 h after PC reperfusion (the delayed PC effect). The concept of the classic and delayed PC effects has not been investigated in human AMI studies. If the above concept is also correct in humans, the infarct size and/or impairment of the left ventricular function should be inversely correlated with the time interval between the first preinfarction angina attack and the onset of AMI when that time interval is limited to between 2 and 48 h.METHODSThe subjects were 25 patients with first AMI of the proximal left anterior descending artery who underwent successful direct percutaneous transluminal coronary angioplasty (PTCA) 2 to 6 h after the onset and with no (or poor) collateral circulation (grade 0 or 1). They were divided into two groups: preinfarction angina (PA)(+) group: 11 patients with new onset preinfarction angina from 2 to 48 h before the onset, PA(−) group: 14 patients without angina before infarction. Peak creatine kinase (CK) and cumulative CK were examined, and the left ventricular ejection fraction (LVEF) and the regional wall motion (RWM) were determined from the left ventriculograms during the acute (immediately after the coronary reperfusion) and chronic (four weeks after the onset of AMI) phases. The RWM index (RWMI) was then calculated as the mean motion of chords (standard deviation [SD]/chord) lying in the area of chords of RWM ≤ −2 SD in the acute phase (ischemic risk area).RESULTSThe increase in the RWMI between the acute and chronic phases was significantly larger in the PA(+) group than in the PA(−) group (1.55 ± 1.32 and 0.69 ± 0.75, p < 0.05, respectively) although no significant difference in the enzymatic infarct size was seen between the two groups. The increases in the LVEF and the RWMI were significantly correlated with the time interval from the first preinfarction angina attack to the onset of AMI (r = 0.622, p < 0.05 and r = 0.646, p < 0.05, respectively), but the enzymatic infarct size was not.CONCLUSIONSThe beneficial effect of preinfarction angina on left ventricular wall motion, independently of collateral flows, indicates the existence of the PC effect in humans. The greater protective effect of a longer time interval between angina pectoris and AMI suggests that the protection is due to a delayed PC effect.

ObjectivesThis study sought to determine whether initial medical therapy (MT) only or percutaneous coronary intervention plus medical therapy (PCI+MT) is better for patients with low-risk stable coronary artery disease (CAD) indicated for intervention in Japan.BackgroundSeveral multicenter studies have suggested that in the above patients, an initial management strategy of PCI+MT does not reduce the long-term risk of cardiovascular events more effectively than initial MT only.MethodsWe conducted a randomized comparative study (JSAP [Japanese Stable Angina Pectoris] study) in the previously mentioned patients.ResultsThe patients were randomized to PCI+MT (n = 192) or initial MT only group (n = 192), and the patient characteristics were very similar in the 2 groups. During the 3.3-year follow-up, there was no significant difference in the cumulative death rate between PCI+MT (2.9%) and MT (3.9%). However, the cumulative risk of death plus acute coronary syndrome was significantly smaller in PCI+MT.ConclusionsIn stable low-risk CAD, PCI+MT may improve long-term prognosis more effectively than MT.

ObjectivesThis study examined the feasibility of using a wavelet analysis of radiofrequency (RF) intravascular ultrasound (IVUS) signals in detecting lipid-laden plaque.BackgroundWavelet analysis is a new mathematical model for assessing local changes in a geometrical profile of time-series signals.MethodsRadiofrequency IVUS signals of 85 arbitrarily selected vectors were acquired from 27 formalin-fixed noncalcified atherosclerotic plaques from human necropsy with a digitizer at 500 MHz with 8-bit resolution by use of a 40-MHz IVUS catheter. Wavelet analysis of these RF signals was performed using a Daubechies-2 wavelet to obtain a color-coded map of the correlation coefficient with the wavelet reconstructed over the x-y plane of the wavelet scale and the distance from the IVUS catheter. The plaque segment was then examined histologically after being stained with Masson’s trichrome stain. This technique also was applied in vivo in 29 human coronary plaque segments. These segments were excised subsequently by directional coronary atherectomy and processed for histologic analysis.ResultsIn the in vitro study, histologic examination revealed lipid-laden segments in 29 vectors. When performing a wavelet analysis with the Daubechies-2 wavelet, the color-coded mapping revealed a different pattern in lipid-laden plaques compared with other types of plaque. Using this wavelet analysis, lipid-laden plaque could be detected with a sensitivity of 83% (24 of 29) and a specificity of 82% (46 of 56). In the in vivo study, fatty plaque could be detected with a sensitivity of 81% (13 of 16) and a specificity of 85% (11 of 13) with this method.ConclusionsWavelet analysis of RF IVUS signals enabled in vitro as well as in vivo detection of lipid-laden plaque. This method may be useful in assessing plaque vulnerability in patients with coronary artery disease.

ObjectivesThe purpose of the present study was to assess the relationship between shear stress distribution and coronary plaque rupture by means of a new color-mapping program of shear stress with 3-dimensional intravascular ultrasound (IVUS).BackgroundVarious in-vitro studies have demonstrated that shear stress of the vascular lumen is one of the important determinants of coronary plaque vulnerability. However, the in-vivo relationship between shear stress and plaque rupture is still unclear.MethodsIn the present study, 3-dimensional IVUS was used to obtain spatial information on luminal geometry from 20 patients with acute coronary syndrome having a distinct ulcerative lesion. These 3-dimensional contours for each lumen were first reconstructed into mesh polygons, and then analyzed by means of a program for calculating the fluid dynamics. The flow was considered to be a constant laminar one. Then, colorized mappings of the distribution of the streamline, blood pressure, and shear stress were performed. The original luminal contour for each ruptured lesion was obtained by smoothing and extrapolation.ResultsAll patients had a coronary plaque rupture in the proximal or top portion of the plaque hill. In the color mapping, localized elevation of blood pressure and shear stress could be observed on each plaque surface. The shear stress concentration was frequently correlated with the plaque rupture site (kappa = 0.79).ConclusionsAlthough the absolute value of shear stress is not sufficient to directly provoke mechanical destruction of the fibrous cap, localized high shear stress might be a trigger of fibrous cap rupture.

ObjectivesThe objective of this study was to evaluate whether the regressive effects of aggressive lipid-lowering therapy with atorvastatin on coronary plaque volume (PV) in patients with acute coronary syndrome (ACS) are generalized for other statins in multicenter setting.BackgroundA previous single-center study reported beneficial regressive effects of atorvastatin in patients with ACS on PV of the nonculprit site by intravascular ultrasound (IVUS) evaluation. The effect of statins other than atorvastatin on PV has not been evaluated in the setting of ACS.MethodsThe JAPAN-ACS (Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome) study was a prospective, randomized, open-label, parallel group study with blind end point evaluation conducted at 33 centers in Japan. A total of 307 patients with ACS undergoing IVUS-guided percutaneous coronary intervention were randomized, and 252 patients had evaluable IVUS examinations at baseline and 8 to 12 months' follow-up. Patients were randomly assigned to receive either 4 mg/day of pitavastatin or 20 mg/day of atorvastatin. The primary end point was the percentage change in nonculprit coronary PV.ResultsThe mean percentage change in PV was −16.9 ± 13.9% and −18.1 ± 14.2% (p = 0.5) in the pitavastatin and atorvastatin groups, respectively, which was associated with negative vessel remodeling. The upper limit of 95% confidence interval of the mean difference in percentage change in PV between the 2 groups (1.11%, 95% confidence interval: −2.27 to 4.48) did not exceed the pre-defined noninferiority margin of 5%.ConclusionsThe administration of pitavastatin or atorvastatin in patients with ACS equivalently resulted in significant regression of coronary PV (Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome; NCT00242944).