Yoshiyuki Kijima

Depressive Symptoms Predict 12-month Prognosis in Elderly Patients with Acute Myocardial Infarction

Background Several studies have associated depressive symptoms with an increased risk for cardiac events after the onset of acute myocardial infarction (AMI). The aim of the present study is to investigate the impact of the depressive symptoms on prognosis of the elderly patients with AMI. Method Depression was assessed in consecutive patients with AMI (n=1042; mean age 63 ± 11 years) using the Zung Self-Rating Depression Scale (SDS). Patient with a score ≥ 40 was classified as having depressive symptoms. Cardiac events (cardiac death, nonfatal re-MI, coronary angioplasty or bypass surgery, readmission for heart failure, unstable angina, or uncontrolled arrhythmia) were examined during 12 months follow-up period. Results Depressive symptoms were observed in 438 patients (42.0%). Prevalence of depression was not dependent of age (P=0.60) and gender (P=0.91). The rate of cardiac events was 31.2% per year in patients with depressive symptoms whereas 23.9% per year in patients without depressive symptoms. Multiple logistic regression analyses showed that depression was significantly associated with 1-year cardiac events (odds ratio 1.41, 95% CI 1.03 to 1.92, P=0.03) after controlling for age, gender, severity of myocardial infarction, coronary risk factors, e.g. hypertension, diabetes mellitus and smoking habits. Depression was a significant risk factor for the cardiac events (log rank, P=0.02) in the elderly patients (≥65 years old, 501 patients). However, the association of depression with cardiac events in the young patients (< 65 years old, 541 patients) was not statistically significant (P=0.11). Conclusion Depression after AMI is a significant predictor of 1-year cardiac events for Japanese population, and its presence augments the risk especially in the elderly patients.

Lipocalin-type prostaglandin D synthase is a powerful biomarker for severity of stable coronary artery disease

Lipocalin-type prostaglandin D synthase (L-PGDS), which is responsible for the biosynthesis of prostaglandin (PG) D(2), has been found to be present in the atherosclerotic plaque of the human coronary artery and also to be detectable in human serum. This multicenter cooperative study was designed to establish the diagnostic value of measuring serum L-PGDS for coronary artery disease. The study included 1013 consecutive patients suspected of having stable coronary artery disease who underwent diagnostic coronary angiography. Peripheral blood was collected prior to angiography. The serum level of L-PGDS, as determined by a sandwich ELISA, was 58.1 +/- 2.2, 62.0 +/- 1.8 and 80.6 +/- 2.6 microg/dl for patients with no stenotic lesion (N, n=241), single-vessel coronary artery disease (S, n=351), and multi-vessel coronary artery disease (M, n=421), respectively (N vs. S; P<0.001, S vs. M; P<0.01, N vs. M; P<0.001). Multiple regression analysis indicated that the most powerful independent predictor of the coronary severity score (Gensini Score) was the L-PGDS level (R=0.55, P<0.0001). The serum L-PGDS level is suitable to evaluate the severity of coronary artery disease. The measurement of serum L-PGDS can be a strategy for screening of stable coronary artery disease prior to coronary angiography.

Effects of monoclonal antibody against phospholamban on calcium pump ATPase of cardiac sarcoplasmic reticulum.

A monoclonal antibody against phospholamban has been reported to increase Ca2+ uptake by cardiac sarcoplasmic reticulum. We compared the effect of this antibody on Ca2+ pump ATPase activity of cardiac sarcoplasmic reticulum vesicles to the effect of cAMP-dependent phosphorylation of phospholamban. The antibody markedly stimulated the Ca(2+)-dependent ATPase activity in parallel to the increase in Ca2+ uptake by cardiac sarcoplasmic reticulum. When the Ca(2+)-dependent profile of the ATPase activity was compared, the KCa was shifted from 1.24 to 0.62 microM by the antibody, whereas cAMP-dependent phosphorylation of phospholamban shifted the KCa to 0.84 microM. When cardiac sarcoplasmic reticulum vesicles were treated with both cAMP-dependent protein kinase and the antibody, the stimulation was the same as that with the antibody alone. Thus, the Ca2+ pump ATPase seems to be fully activated by the antibody. The stoichiometry between Ca2+ uptake and ATPase rate was around 1 and no significant change was observed by the treatment with the antibody. Therefore, the stimulation of Ca2+ uptake of cardiac sarcoplasmic reticulum by the antibody occurred by the stimulation of Ca2+ pump ATPase, not by other mechanisms such as channel activity of phospholamban. These results indicate that the binding of the antibody to phospholamban produces essentially the same mode of action on Ca2+ pump ATPase as that of phospholamban phosphorylation. The antibody and phospholamban phosphorylation appear to release the inhibitory action of phospholamban on Ca2+ pump ATPase, resulting in the stimulation of Ca2+ pump.

Mutation Analysis of 2009 Pandemic Influenza A(H1N1) Viruses Collected in Japan during the Peak Phase of the Pandemic

Background Pandemic influenza A(H1N1) virus infection quickly circulated worldwide in 2009. In Japan, the first case was reported in May 2009, one month after its outbreak in Mexico. Thereafter, A(H1N1) infection spread widely throughout the country. It is of great importance to profile and understand the situation regarding viral mutations and their circulation in Japan to accumulate a knowledge base and to prepare clinical response platforms before a second pandemic (pdm) wave emerges. Methodology A total of 253 swab samples were collected from patients with influenza-like illness in the Osaka, Tokyo, and Chiba areas both in May 2009 and between October 2009 and January 2010. We analyzed partial sequences of the hemagglutinin (HA) and neuraminidase (NA) genes of the 2009 pdm influenza virus in the collected clinical samples. By phylogenetic analysis, we identified major variants of the 2009 pdm influenza virus and critical mutations associated with severe cases, including drug-resistance mutations. Results and Conclusions Our sequence analysis has revealed that both HA-S220T and NA-N248D are major non-synonymous mutations that clearly discriminate the 2009 pdm influenza viruses identified in the very early phase (May 2009) from those found in the peak phase (October 2009 to January 2010) in Japan. By phylogenetic analysis, we found 14 micro-clades within the viruses collected during the peak phase. Among them, 12 were new micro-clades, while two were previously reported. Oseltamivir resistance-related mutations, i.e., NA-H275Y and NA-N295S, were also detected in sporadic cases in Osaka and Tokyo.

Secretion of Lipocalin-Type Prostaglandin D Synthase (β-Trace) from Human Heart to Plasma During Coronary Circulation

Prostaglandin (PG) D2 is actively formed in a variety of tissues and cells,1 and is involved in many physiological events; e.g., it regulates sleep and ocular pressure, prevents platelet aggregation, and induces vasodilation and bronchoconstriction.2,3 Two distinct types of PGD synthase (PGDS), which catalyzes the isomerization of PGH2 to PGD2, have been isolated and characterized:4 one is glutathione-independent, the lipocalin-type PGDS (L-PGDS);5 and the other is glutathione-requiring, the hematopoietic PGDS.6 L-PGDS is responsible for biosynthesis of PGD2 in the central nervous system and male genital organs of various mammals, and is secreted into the cerebrospinal fluid and seminal plasma, respectively, as “β-trace”.7,8 In this study, we found that mRNA for human L-PGDS was most intensely expressed in the heart among various tissues examined and that the L-PGDS-like immunoreactivity is localized in myocardial cells, atrial endocardial cells, and the synthetic state of smooth muscle cells in the arteriosclerotic plaques. We also demonstrated that the enzyme, β-trace, is secreted into the plasma of the coronary circulation of angina patients.9

Effect of Theophylline on Adaptation of the Heart to Myocardial Ischemia During Percutaneous Transluminal Coronary Angioplasty in Patients With Stable Angina Pectoris

This study was designed to examine whether theophylline, an adenosine receptor antagonist, affects cardiac adaptation to ischemia during progression of repetitive balloon inflations of percutaneous transluminal coronary angioplasty (PTCA). Theophylline abolished this cardiac adaptation, suggesting that endogenous adenosine is a key mediator for cardiac adaptation during PTCA.

Molecular structure and function of phospholamban: the regulatory protein of calcium pump in cardiac sarcoplasmic reticulum.

The excitation-contraction coupling of the myocardium represents a three-part process, involving three kinds of subcellular systems. These are sarcolemma, sarcoplasmic reticulum (SR), and myofibrillar proteins. Information transfer among these systems is exclusively carried out by Ca ions1 in that both membranes of sarcolemma and SR exhibit bi-directional Ca fluxes, and the myofibrillar system contains Ca receptor protein troponin. It is important to note that all of these three subcellular systems provide phosphorylation sites for protein kinases and, in addition, such phosphorylation reactions are thought to accompany profound alterations in Ca-related events in these systems. Among these, phosphorylation of phospholamban, a membrane protein in cardiac SR, and its functional consequences are extensively defined 2,3, in that phospholamban presumably serves to modulate Ca pump ATPase of SR by augmenting the key elementary steps of ATPase. Phospholamban of cardiac SR was purified to near homogeneity and was sequenced by amino acid and cDNA sequencing, demonstrating a unique molecular properties. This paper defines the functional and structural characteristics of the phospholamban-ATPase system and attemps to propose a molecular model for the functional unit of phospholamban, which provides a basic understanding for the regulatory mechanism of ion transport and bioenergetic transduction across biomembrane.

Roles of Systemic Nitric Oxide Metabolites for Human Coronary Circulation

Several previous studies have suggested decreased bioactivity of nitric oxide (NO) in coronary artery diseases using NO synthase inhibitors. Nitrite is delivered as bioactive NO in the forearm circulation. However, the role(s) of NO metabolites in the systemic and coronary circulation are still unknown. The aim of this study was to investigate the role(s) of systemic NO metabolites for human coronary circulation in patients with and without coronary spastic angina (CSA). Twenty-nine patients with chest symptoms were enrolled to perform the acetylcholine (Ach) provocative test. Blood was sampled from the aorta at baseline, and from the great cardiac vein at baseline and after Ach to measure plasma levels of nitrate and nitrite (NOx). The epicardial left anterior descending artery was examined by quantitative angiography. The patients were divided into the two groups according to the Ach provocative test. In the non-CSA group, the NOx uptake across the coronary circulation correlated with the endothelium-dependent vasoresponse to Ach (r = −0.61, p < 0.05) and NOx levels of the aorta also correlated (r = −0.72, p < 0.005), which suggested the compensatory increase of systemic NOx levels for impaired endothelial function. In the CSA group, the NOx uptake across the coronary circulation did not correlate with the vasoresponse to Ach (r = 0.29, p = 0.28). However, NOx levels of the aorta correlated with vasosensitivity to Ach (r = 0.61, p < 0.005). The higher systemic NOx levels correlated well with the vasodilator responsiveness to Ach. These results suggest that systemic NOx is delivered into the coronary circulation as bioactive NO to preserve endothelial function in the non-CSA patients, and to attenuate Ach-induced vasoconstriction in the CSA patients. There is a possibility that systemic NOx plays a complementary role on impaired coronary vasoregulation.

Differences in the mode of presentation for acute coronary syndrome by pre-hospitalization medication, in relation to coronary risk factors, East-Osaka acute coronary syndrome (EACS) registry

BACKGROUND Pre-hospitalization medication such as aspirin and nitrates has been shown to affect the mode of presentation in acute coronary syndrome (ACS). However, it is not formally assessed whether other cardiovascular medications may be contributed to the differences in the mode of presentation, especially in relation to coronary risk factors. METHODS AND RESULTS We conducted a registration study of patients (M/F 850/323) with either ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) or unstable angina (UA), and examined the differences in the mode of presentation, pre-hospitalization medication, and coronary risk factors. The ratio of the incidence of STEMI and NSTEMI/UA was significantly reduced in patients having pre-hospitalization medication with aspirin, nitrates or statins, but not with other medications such as beta-blockers in multivariate analysis. Pre-hospitalization medication with aspirin and nitrates was significantly associated with the same reduction of the ratio in patients with male gender, hypertension, diabetes mellitus and a history of coronary artery disease. However, in patients who smoked, were obese and hypercholesterolemic, pre-hospitalization medication with nitrates was significantly associated with the reduced ratio. The ratio was significantly low in patients with males and hypercholesterolemia treated with statins before admission. CONCLUSION Depending on their coronary risk factors, pre-hospitalization medication with aspirin, nitrates or statins was associated with a different presentation and evolution of ACS.

Pharmacological Modification of Ischemic Preconditioning During Percutaneous Transluminal Coronary Angioplasty

In the progression of repetitive balloon inflations during percutaneous transluminal coronary angioplasty (PTCA), the heart becomes more tolerant to ischemia. The study reported here analyzed the effects of theophylline and nicorandil on this intriguing phenomenon. Twenty-one patients with stable angina pectoris due to a significant stenosis at the left anterior descending; artery were subjected to PTCA. The balloon was inflated twice for two minutes each with a three-minute reperfusion period. Theophyylline, an adenosine receptor antagonist, was intravenously administered (0.6mg/kg/hr) to six patients during PTCA (theophylline group). Nicorandil, a hybrid between nitrate and an ATP-sensitive potassium channel opener, was intravenously administered (6 mg/hr) to nine patients during PTCA (nicorandil group). The rest of the patients served as controls (ischemic preconditioning group, n = 6). Cardiac adaptation to the second ischemia was observed in the ischemic preconditioning group, judging from lactate metabolism and electrocardiography. In both the theophylline and nicorandil groups, the difference between the two ischemic events was abolished. In the nicorandil group, the severity of the first ischemia was less than that of the ischemic preconditioning group. In conclusion, signal transduction through the adenosine receptor and opening of the ATP-sensitive potassium channels might play key roles, interactively or independently, in the cardioprotection observed in the process of PTCA.