Ryo Araki

Impact of contrast-induced acute kidney injury on outcomes in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

PURPOSE The purpose of this study was to identify predictors of contrast-induced acute kidney injury (CI-AKI) and the effect of CI-AKI on cardiovascular outcomes after hospital discharge in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). METHODS AND MATERIALS We retrospectively reviewed 194 STEMI consecutive patients who underwent primary PCI to evaluate the predictors for CI-AKI and 187 survivors to examine all-cause mortality and cardiovascular events. Outcomes were compared between patients with CI-AKI and those without CI-AKI, which was defined as an increase >50% or >0.5mg/dl in serum creatinine concentration within 48hours after primary PCI. RESULTS CI-AKI occurred in 23 patients (11.9%). Multivariate analysis identified pre-procedural renal insufficiency as a predictor of CI-AKI, and this predictor was independent from hemodynamic instability and excessive contrast volume. Receiver-operator characteristics analysis demonstrated that patients with an estimated glomerular filtration rate (eGFR) of ≤43.6ml/min per 1.73m(2) had the potential for CI-AKI. Patients who developed CI-AKI had higher mortality and cardiovascular events than did those without CI-AKI (27.8% vs. 4.7%; log-rank P=.0003, 27.8% vs. 11.2%; log-rank P=.0181, respectively). Cox proportional hazards model analysis identified CI-AKI as the independent predictor of mortality and cardiovascular events [hazard ratio [HR]=5.36; P=.0076, HR=3.10; P=.0250, respectively]. CONCLUSIONS The risk of CI-AKI is increased in patients with pre-procedural renal insufficiency, and eGFR is clinically useful in the emergent setting for CI-AKI risk stratification before primary PCI.

Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction

RATIONALE Doxorubicin is an effective chemotherapeutic agent for cancer, but its use is often limited by cardiotoxicity. Doxorubicin causes endoplasmic reticulum (ER) dilation in cardiomyocytes, and we have demonstrated that ER stress plays important roles in the pathophysiology of heart failure. OBJECTIVE We evaluated the role of ER stress in doxorubicin-induced cardiotoxicity and examined whether the chemical ER chaperone could prevent doxorubicin-induced cardiac dysfunction. METHODS AND RESULTS We confirmed that doxorubicin caused ER dilation in mouse hearts, indicating that doxorubicin may affect ER function. Doxorubicin activated an ER transmembrane stress sensor, activating transcription factor 6, in cultured cardiomyocytes and mouse hearts. However, doxorubicin suppressed the expression of genes downstream of activating transcription factor 6, including X-box binding protein 1. The decreased levels of X-box binding protein 1 resulted in a failure to induce the expression of the ER chaperone glucose-regulated protein 78 which plays a major role in adaptive responses to ER stress. In addition, doxorubicin activated caspase-12, an ER membrane-resident apoptotic molecule, which can lead to cardiomyocyte apoptosis and cardiac dysfunction. Cardiac-specific overexpression of glucose-regulated protein 78 by adeno-associated virus 9 or the administration of the chemical ER chaperone 4-phenylbutyrate attenuated caspase-12 cleavage, and alleviated cardiac apoptosis and dysfunction induced by doxorubicin. CONCLUSIONS Doxorubicin activated the ER stress-initiated apoptotic response without inducing the ER chaperone glucose-regulated protein 78, further augmenting ER stress in mouse hearts. Cardiac-specific overexpression of glucose-regulated protein 78 or the administration of the chemical ER chaperone alleviated the cardiac dysfunction induced by doxorubicin and may facilitate the safe use of doxorubicin for cancer treatment.

Ablation of IL-33 gene exacerbate myocardial remodeling in mice with heart failure induced by mechanical stress

Background and purpose: ST2 is one of the interleukin (IL)‐1 receptor family members comprising of membrane‐bound (ST2L) and soluble (sST2) isoforms. Clinical trials have revealed that serum sST2 levels predict outcome in patient with myocardial infarction or chronic heart failure (HF). Meanwhile, we and others have reported that ablation of ST2 caused exaggerated cardiac remodeling in both ischemic and non‐ischemic HF. Here, we tested whether IL‐33, the ligand for ST2, protects myocardium against HF induced by mechanical overload using ligand specific knockout (IL‐33−/−) mice. Methods and results: Transverse aortic constriction (TAC)/sham surgery were carried out in both IL‐33 and WT‐littermates. Echocardiographic measurements were performed at frequent interval during the study period. Heart was harvested for RNA and histological measurements. Following mechanical overload by TAC, myocardial mRNA expressions of Th1 cytokines, such as TNF‐&agr; were enhanced in IL‐33−/− mice than in WT mice. After 8‐weeks, IL‐33−/− mice exhibited exacerbated left ventricular hypertrophy, increased chamber dilation, reduced fractional shortening, aggravated fibrosis, inflammation, and impaired survival compared with WT littermates. Accordingly, myocardial mRNA expressions of hypertrophic (c‐Myc/BNP) molecular markers were also significantly enhanced in IL‐33−/− mice than those in WT mice. Conclusions: We report for the first time that ablation of IL‐33 directly and significantly leads to exacerbate cardiac remodeling with impaired cardiac function and survival upon mechanical stress. These data highlight the cardioprotective role of IL‐33/ST2 system in the stressed myocardium and reveal a potential therapeutic role for IL‐33 in non‐ischemic HF.

An estimation method for a cellular-state-specific gene regulatory network along tree-structured gene expression profiles

BACKGROUND Identifying the differences between gene regulatory networks under varying biological conditions or external stimuli is an important challenge in systems biology. Several methods have been developed to reverse-engineer a cellular system, called a gene regulatory network, from gene expression profiles in order to understand transcriptomic behavior under various conditions of interest. Conventional methods infer the gene regulatory network independently from each of the multiple gene expression profiles under varying conditions to find the important regulatory relations for understanding cellular behavior. However, the inferred networks with conventional methods include a large number of misleading relations, and the accuracy of the inference is low. This is because conventional methods do not consider other related conditions, and the results of conventional methods include considerable noise due to the limited number of observation points in each expression profile of interest. RESULTS We propose a more accurate method for estimating key gene regulatory networks for understanding cellular behavior under various conditions. Our method utilizes multiple gene expression profiles that compose a tree structure under varying conditions. The root represents the original cellular state, and the leaves represent the changed cellular states under various conditions. By using this tree-structured gene expression profiles, our method more powerfully estimates the networks that are key to understanding the cellular behavior of interest under varying conditions. CONCLUSION We confirmed that the proposed method in cell differentiation was more rigorous than the conventional method. The results show that our assumptions as to which relations are unimportant for understanding the differences of cellular states in cell differentiation are appropriate, and that our method can infer more accurately the core networks of the cell types.

Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats.

Immunosuppressive agents are used for the treatment of immune-mediated myocarditis; however, the need to develop a more effective therapeutic approach remains. Nano-sized liposomes may accumulate in and selectively deliver drugs to an inflammatory lesion with enhanced vascular permeability. The aims of this study were to investigate the distribution of liposomal FK506, an immunosuppressive drug encapsulated within liposomes, and the drug’s effects on cardiac function in a rat experimental autoimmune myocarditis (EAM) model. We prepared polyethylene glycol-modified liposomal FK506 (mean diameter: 109.5 ± 4.4 nm). We induced EAM by immunization with porcine myosin and assessed the tissue distribution of the nano-sized beads and liposomal FK506 in this model. After liposomal or free FK506 was administered on days 14 and 17 after immunization, the cytokine expression in the rat hearts along with the histological findings and hemodynamic parameters were determined on day 21. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads had accumulated in myocarditic but not normal hearts on day 14 after immunization and thereafter. Compared to the administration of free FK506, FK506 levels were increased in both the plasma and hearts of EAM rats when liposomal FK506 was administered. The administration of liposomal FK506 markedly suppressed the expression of cytokines, such as interferon-γ and tumor necrosis factor-α, and reduced inflammation and fibrosis in the myocardium on day 21 compared to free FK506. The administration of liposomal FK506 also markedly ameliorated cardiac dysfunction on day 21 compared to free FK506. Nano-sized liposomes may be a promising drug delivery system for targeting myocarditic hearts with cardioprotective agents.

Low-Dose Erythropoietin in Patients With ST-Segment Elevation Myocardial Infarction (EPO-AMI-II) ― A Randomized Controlled Clinical Trial ―

BACKGROUND Erythropoietin (EPO) has antiapoptotic and tissue-protective effects, but previous clinical studies using high-dose EPO have not shown cardioprotective effects, probably because of platelet activation and a lack of knowledge regarding the optimal dose. In contrast, a small pilot study using low-dose EPO has shown improvement in left ventricular function without adverse cardiovascular events.Methods and Results:We performed a multicenter (25 hospitals), prospective, randomized, double-blind, placebo-controlled, dose-finding study to clarify the efficacy and safety of low-dose EPO in patients with ST-segment elevation myocardial infarction (STEMI) under the Evaluation System of Investigational Medical Care of the Ministry of Health, Labor and Welfare of Japan. In total, 198 STEMI patients with low left ventricular ejection fraction (LVEF <50%) were randomly assigned to receive intravenous administration of EPO (6,000 or 12,000 IU) or placebo within 6 h of successful percutaneous coronary intervention. At 6 months, there was no significant dose-response relationship in LVEF improvement among the 3 groups tested (EPO 12,000 IU: 5.4±9.3%, EPO 6,000 IU: 7.3±7.7%, Placebo: 8.1±8.3%, P=0.862). Low-dose EPO also did not improve cardiac function, as evaluated by 99 mTc-MIBI SPECT or NT-proBNP at 6 months and did not increase adverse events. CONCLUSIONS Administration of low-dose EPO did not improve LVEF at 6 months in STEMI patients (UMIN000005721).

Noninvasive Demonstration of Dual Coronary Artery Fistulas to Main Pulmonary Artery with 64-Slice Multidetector-Computed Tomography: A Case Report

Coronary artery fistulas, including coronary pulmonary fistulas, are usually discovered accidently among the adult population when undergoing invasive coronary angiographies. We report here a 58-year-old woman with dual fistulas originating from the left anterior descending coronary artery and right coronary sinus to the main pulmonary artery, demonstrating noninvasively with multidetector-computed tomography (MDCT) and transthoracic echocardiography (TTE).

Development of a novel one-step production system for injectable liposomes under GMP

Abstract There are few methods available for injectable liposome production under good manufacturing practices (GMP). Injectable liposome production processes under GMP generally consist of liposome formation, size homogenization, organic solvent removal, liposome concentration control and sterilization. However, these complicated and separate processes make it difficult to maintain scalability, reproducibility and sterility. To overcome these limitations, we developed a novel one-step in-line closed liposome production system that integrated all production processes by combining the in-line thermal mixing device with modified counterflow dialysis. To validate the system, we produced liposomal cyclosporine A (Lipo-CsA) and lyophilized the liposomes. The three independent pilot batches were highly reproducible and passed the quality specifications for injectable drugs, demonstrating that this system could be used under GMP. The accelerated stability test suggested that the liposomes would be stable in long-term storage. This one-step system facilitates a fully automated and unattended production of injectable liposomes under GMP.

THE RESIDUAL SYNTAX SCORE FOR MORTALITY RISK ASSESSMENT IN ACUTE CORONARY SYNDROME WITH CARDIOGENIC SHOCK

The SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score (SS) is a good predictor of adverse cardiovascular events and mortality in patients with acute coronary syndrome (ACS). The utility of risk stratifying patients with ACS complicated by cardiogenic

A case of coronary artery fistula diagnosed in the right decubitus position by transthoracic echocardiography.

A 70‐year‐old woman was admitted to our hospital for a continuous heart murmur in the fourth intercostal space at the right sternal border. Routine echocardiography demonstrated aneurismal dilatation at the origin of right coronary artery. These findings suggested a coronary artery fistula, although its drainage site could not be identified. By shifting the patient to the right decubitus position, we could observe an abnormal color Doppler signal going from the right coronary artery into the right atrium, confirming coronary artery fistula. The right decubitus position may be helpful for the evaluation of abnormal anatomic and auscultatory findings.