Hidetoshi Momii

Role of nitric oxide and peroxynitrite in the cytokine-induced sustained myocardial dysfunction in dogs in vivo.

Studies in vitro suggested that inflammatory cytokines could cause myocardial dysfunction. However, the detailed mechanism for the cytokine-induced myocardial dysfunction in vivo remains to be examined. We thus examined this point in our new canine model in vivo, in which microspheres with and without IL-1beta were injected into the left main coronary artery. Left ventricular ejection fraction (LVEF) was evaluated by echocardiography for 1 wk. Immediately after the microsphere injection, LVEF decreased to approximately 30% in both groups. While LVEF rapidly normalized in 2 d in the control group, it was markedly impaired in the IL-1beta group even at day 7. Pretreatment with dexamethasone or with aminoguanidine, an inhibitor of inducible nitric oxide synthase, prevented the IL-1beta-induced myocardial dysfunction. Nitrotyrosine concentration, an in vivo marker of the peroxynitrite production by nitric oxide and superoxide anion, was significantly higher in the myocardium of the IL-1beta group than in that of the control group or the group cotreated with dexamethasone or aminoguanidine. There was an inverse linear relationship between myocardial nitrotyrosine concentrations and LVEF. These results indicate that IL-1beta induces sustained myocardial dysfunction in vivo and that nitric oxide produced by inducible nitric oxide synthase and the resultant formation of peroxynitrite are substantially involved in the pathogenesis of the cytokine-induced sustained myocardial dysfunction in vivo.

Role of superoxide anion in the pathogenesis of cytokine-induced myocardial dysfunction in dogs in vivo.

OBJECTIVE Although studies in vitro have implicated oxygen-derived free radicals as possible mediators of inflammatory cytokine-induced cell injury, the role of the radicals in the cytokine-induced myocardial dysfunction in vivo remains unclear. The present study was designed to address this point in our novel canine model of cytokine-induced myocardial dysfunction in vivo. METHODS Studies were performed in mongrel dogs, in which microspheres (MS, 15 microns in diameter) with and without interleukin-1 beta (IL-1 beta) were injected into the left main coronary artery (control and IL-1 beta group). Left ventricular ejection fraction (LVEF) was evaluated by echocardiography for 1 week. RESULTS Immediately after the intracoronary injection of MS (10(6)/kg), LVEF equally decreased to approximately 30% in both the control and IL-1 beta group. While LVEF rapidly recovered within 2 days in the control group, it remained depressed in the IL-1 beta group until day 7 (p < 0.0001 vs. control group). Pretreatment with OPC-6535 (an inhibitor of superoxide production) before (2 mg/kg i.v.) and 1 and 2 days after IL-1 beta MS application (1 mg/kg i.v.) prevented the IL-1 beta-induced myocardial dysfunction. Superoxide production in the myocardium was significantly higher in the IL-1 beta group than in the control group at day 2 (p < 0.01), and OPC-6535 significantly suppressed the IL-1 beta-induced superoxide production (p < 0.01). An HPLC assay showed that nitrotyrosine, a marker of the formation of peroxynitrite by superoxide anion and nitric oxide, was present in the myocardium treated with IL-1 beta but not in that with control MS. OPC-6535 abolished the IL-1 beta-induced formation of myocardial nitrotyrosine. CONCLUSION These results indicate that superoxide anion and the resultant formation of peroxynitrite may substantially be involved in the pathogenesis of the cytokine-induced myocardial dysfunction in dogs in vivo.

A new electrocardiographic criterion to differentiate between Takotsubo cardiomyopathy and anterior wall ST-segment elevation acute myocardial infarction.

Several studies have examined the ability of electrocardiography to differentiate between takotsubo cardiomyopathy (TC) and anterior wall acute ST-segment elevation myocardial infarction (AA-STEMI). In those studies, the magnitude of ST-segment elevation was not measured at the J point. The American Heart Association, American College of Cardiology Foundation, and Heart Rhythm Society guidelines recommend that the magnitude of ST-segment elevation should be measured at the J point. Accordingly, the aim of this study was to retrospectively examine whether electrocardiography, using the magnitude of ST-segment elevation measured at the J point, could differentiate 62 patients with TC from 280 with AA-STEMI. Patients with AA-STEMI were divided into following subgroups: 140 with left anterior descending coronary artery occlusions proximal to the first diagonal branch (AA-STEMI-P), 120 with left anterior descending occlusions distal to the first diagonal branch and proximal to the second diagonal branch (AA-STEMI-M), and 20 with left anterior descending occlusions distal to the second diagonal branch (AA-STEMI-D). TC had a much lower prevalence of ST-segment elevation ≥1 mm in lead V(1) (19.4%) compared to AA-STEMI (80.4%, p <0.01), AA-STEMI-P (80.7%, p <0.01), AA-STEMI-M (80%, p <0.01), and AA-STEMI-D (80%, p <0.01). ST-segment elevation ≥1 mm in ≥1 of leads V(3) to V(5) without ST-segment elevation ≥1 mm in lead V(1) identified TC with sensitivity of 74.2% and specificity of 80.6%. Furthermore, this criterion could differentiate TC from each AA-STEMI subgroup, with similar diagnostic values. In conclusion, using the magnitude of ST-segment elevation measured at the J point, a new electrocardiographic criterion is proposed with an acceptable ability to differentiate TC from AA-STEMI.

Patient Factors against Stable Control of Warfarin Therapy for Japanese Non-valvular Atrial Fibrillation Patients

INTRODUCTION Effectiveness and safety of warfarin therapy for non-valvular atrial fibrillation (NVAF) patients are strongly associated with its stability presented such as time in therapeutic range (TTR) of PT-INR. However, the factors that affect TTR have not been fully elucidated in Japan where majority of patients are controlled within the range of 1.6-2.6 of PT-INR irrespective of the age. METHODS We retrospectively analyzed 163 NVAF patients taking warfarin to determine the factors that affect TTR including metabolic enzymes polymorphisms after TTR calculation with both the standard PT-INR range and the actual control range of 1.6-2.6. RESULTS Overall TTR calculated using Japanese Guideline was 69.7 ± 25.1% (<70 and ≥ 70 years; 49.6 ± 24.8% and 77.8 ± 20.3%, respectively). After confirming that PT-INR values in patients < 70 years distributed in the same range as in those ≥ 70 years, as in a Japanese large cohort, we recalculated TTR of those < 70 years with 1.6-2.6 of PT-INR and found that it was 79.5 ± 20.1%. Poor control of this new TTR were significantly associated with the lower height, the higher serum creatinine, the lower creatinine clearance, female gender, and presence of congestive heart failure, (p<0.05 respectively). Multivariate analysis revealed female gender and presence of congestive heart failure as independent predictor of the lower TTR (p<0.05, p<0.01, respectively). Polymorphism of CYP2C9 and VKORC1 were related to the dosage of warfarin but not determinant of TTR. CONCLUSIONS When evaluated using a range of PT-INR actually used in Japan, TTR is generally well controlled and female gender and presence of congestive heart failure significantly affected the poorer TTR control.

Diagnostic performance of cardiac fusion images from myocardial perfusion imaging and multislice computed tomography coronary angiography for assessment of hemodynamically significant coronary artery lesions: an observational study.

BackgroundIn detecting coronary artery disease (CAD), fusion images obtained by combining myocardial perfusion imaging (MPI) and computed tomography coronary angiography (CTCA) have shown a higher accuracy and clinical usefulness than these modalities used separately or a simple comparison of individual images. However, the clinical use of fusion images has been restricted by the necessity of obtaining images with an integral type device or with devices made by the same manufacturer. Thus, we evaluated the detection of hemodynamically significant CAD by fusion images created with a newly developed general-purpose application that can be used with any type of device. Methods and resultsIn 49 patients, MPI during exercise and at rest and CTCA were obtained separately and combined into fusion images using the new application. As the reference standard, a comparative interpretation of MPI and the conventional coronary arteriography (CAG) was adopted. Hemodynamically significant CAD were diagnosed when MPI showed a reversible perfusion defect in a region with greater than 50% luminal stenosis on CAG. The capability of fusion images to detect CAD was compared with that of CTCA images alone. Fusion images showed a higher ability to detect CAD (sensitivity 80%, specificity 94%, positive predictive value 77%, and negative predictive value 95%) than CTCA alone (77, 77, 46, and 93%, respectively; fusion vs. CTCA: specificity P=0.0002, positive predictive value P=0.0001). ConclusionFusion images obtained with a general-purpose application were superior to CTCA images alone for detecting hemodynamically significant CAD.

Experience of step-wise protocol using noninvasive positive pressure ventilation for treating cardiogenic pulmonary edema.

Initiating and weaning procedure of noninvasive positive pressure ventilation (NIPPV) on acute cardiogenic pulmonary edema (ACPE) has been determined empirically, and the total time of its use has been sometimes prolonged unnecessarily. A simple protocol for its use may facilitate initiation and avoids prolongation of the NIPPV treatment. We designed a step-wise protocol for NIPPV use and retrospectively examined the clinical outcome of our protocol for initiation and weaning of NIPPV in 45 patients with ACPE. Almost all patients recovered from respiratory distress successfully. There was no intubation nor complication related to NIPPV. In most of the cases, maximal-end expiratory pressure was less than 7-cm H2O. The mean duration of NIPPV was 19.5±28.0 h and the median duration was 8.0 h (interquartile range=14.0 h). This simple step-wise NIPPV protocol for ACPE can facilitate quick and safe initiation and termination of the treatment.

Effects of the L/N-type calcium channel antagonist cilnidipine on morning blood pressure control and peripheral edema formation.

The L/N-type calcium channel blocker cilnidipine has unique effects including sympathetic nerve suppression and the balanced vasodilatation of arteries and veins that may alleviate morning hypertension (MHT) or peripheral edema caused by calcium channel antagonists. We used ambulatory blood pressure monitoring (ABPM) and a unique peripheral edema measurement to evaluate the effect of morning and bedtime cilnidipine in patients with MHT. Forty-three patients with MHT (60 ± 12 years) were randomly assigned to a morning or bedtime cilnidipine (10-20 mg/day). MHT was defined as a mean systolic blood pressure (SBP) ≥ 135 mm Hg by ABPM within 2 hours after awaking. After 3 months, greater SBP reductions were observed in the bedtime administration group (versus the morning administration group) at 3:30-6:00 AM (-24 ± 20 mm Hg vs. -10 ± 4 mm Hg; P < .05) and at 6:30-9:00 AM (-26 ± 15 mm Hg vs. -14 ± 17 mm Hg; P < .05). Although physical examinations showed leg edema in 16% of the patients, quantitative evaluations did not reveal significant volume gains. Cilnidipine had a greater effect on MHT, without causing significant leg edema, when administered at bedtime.

Respiratory Management with Bi-level Positive Airway Pressure Ventilation for Acute Cardiogenic Pulmonary Edema

Non-invasive positive pressure ventilation (NIPPV) has long been used in the treatment of acute respiratory failure in patients with acute cardiogenic pulmonary edema (ACPE) and it has became a first line therapy for this kind of patients. Continuous positive airway pressure (CPAP) and bi-level positive airway pressure (bi-level PAP) are the two main NIPPV modalities. Though the results of meta-analysis of the difference in the effectiveness of these two modalities showed almost the same efficacy for ACPE patients, we have felt that bi-level PAP produces greater improvement in oxygenation parameters in some of the most severe type of ACPE patients. As the technique of using bi-level PAP is somewhat complex and requires more experience compared with CPAP, we designed a simple step-wise protocol for initiation and weaning of bi-level PAP. We have examined the clinical outcome of 45 patients with ACPE with whom this protocol was used and found that almost all patients successfully recovered from respiratory distress. There was no intubation nor complication related to their bi-level PAP treatment. In most of the cases, maximal end expiratory pressure was less than 7-cm H2O. The median duration was 8.0 hours. This simple step-wise bi-level PAP protocol for ACPE could be used even by co-medical staff safely and could facilitate quick and safe initiation and termination of the treatment.