Shoichi Miyamoto

Histone Acetyltransferase Activity of p300 Is Required for the Promotion of Left Ventricular Remodeling After Myocardial Infarction in Adult Mice In Vivo

Background— Left ventricular (LV) remodeling after myocardial infarction is associated with hypertrophy of surviving myocytes and represents a major process that leads to heart failure. One of the intrinsic histone acetyltransferases, p300, serves as a coactivator of hypertrophy-responsive transcriptional factors such as a cardiac zinc finger protein GATA-4 and is involved in its hypertrophic stimulus-induced acetylation and DNA binding. However, the role of p300-histone acetyltransferase activity in LV remodeling after myocardial infarction in vivo is unknown. Methods and Results— To solve this problem, we have generated transgenic mice overexpressing intact p300 or mutant p300 in the heart. As the result of its 2–amino acid substitution in the p300-histone acetyltransferase domain, this mutant lost its histone acetyltransferase activity and was unable to activate GATA-4–dependent transcription. The two kinds of transgenic mice and the wild-type mice were subjected to myocardial infarction or sham operation at the age of 12 weeks. Intact p300 transgenic mice showed significantly more progressive LV dilation and diminished systolic function after myocardial infarction than wild-type mice, whereas mutant p300 transgenic mice did not show this. Conclusions— These findings demonstrate that cardiac overexpression of p300 promotes LV remodeling after myocardial infarction in adult mice in vivo and that histone acetyltransferase activity of p300 is required for these processes.

Effects of posture on cardiac autonomic nervous activity in patients with congestive heart failure.

OBJECTIVES We aimed to clarify which recumbent position is preferred by patients with congestive heart failure (CHF) and to evaluate whether cardiac autonomic nervous activity is different among three recumbent positions (supine, left lateral decubitus, right lateral decubitus) in patients with CHF. BACKGROUND It remains unclear whether cardiac autonomic nervous activity is different among three recumbent positions in patients with CHF. METHODS We studied 17 male CHF patients (66+/-7 years) and 17 age- and gender-matched healthy subjects (66+/-7 years). Each subject underwent 24-h ambulatory electrocardiographic monitoring. A channel was used to record the CM5 lead, and another to record the signal of the patients posture with use of a newly developed small-sized detector (3.2 cm x 3.2 cm). By using spectral analysis of heart rate variability, frequency-domain measures were calculated and compared among the three recumbent positions. Normalized high-frequency (HF: 0.15 to 0.40 Hz) power was used as an index of vagal activity and the low frequency (0.04 to 0.15 Hz)/HF power ratio was used as an index of sympathovagal balance. RESULTS In patients with CHF, the time for the right lateral decubitus position was two-fold longer than that for the supine and left lateral decubitus positions. The increased cardiac sympathetic activity and decreased vagal tone in CHF patients were normalized in the right lateral decubitus position. CONCLUSIONS The right lateral decubitus position in patients with CHF may be a self-protecting mechanism of attenuating the imbalance of cardiac autonomic nervous activity.

Effects of posture on sympathetic nervous modulation in patients with chronic heart failure

We investigated which recumbent position is preferred by patients with chronic heart failure (CHF) and whether sympathetic nervous modulation differs in three recumbent positions. We assessed 12 patients with CHF by spectral analysis of heart-rate variability and measurement of plasma norepinephrine concentrations. The right lateral decubitus position was preferred for significantly longer periods than the left lateral decubitus and supine positions. Sympathetic nervous modulation was most attenuated in the right lateral decubitus position. The right lateral decubitus position preferred by patients with CHF may be a self-protective mechanism to control increased sympathetic nervous modulation.

Increased serum levels and expression of S100A8/A9 complex in infiltrated neutrophils in atherosclerotic plaque of unstable angina

Background: The S100A8/A9 complex is expressed in a subset of activated neutrophils and macrophages in acute inflammatory lesions associated with various diseases. Objective: To investigate (a) whether serum S100A8/A9 levels are increased in patients with unstable angina (UA); and (b) whether S100A8/A9 expression is upregulated in coronary atherosclerotic plaques of patients with UA. Design: Serum S100A8/A9 levels in 39 patients with stable angina (SA) and 53 patients with UA were measured. In addition, the presence of the S100A8/A9 complex in directional coronary atherectomy specimens was studied immunohistochemically. Cell types which stain positive for S100A8/A9 were identified by immunodouble staining with neutrophils and macrophages. Results: Mean (SD) serum S100A8/A9 levels were significantly higher in patients with UA than in those with SA (3.25 (3.08) μg/ml vs 0.77 (0.31) μg/ml, p<0.05). In patients with UA, immunodouble staining clearly showed that the S100A8/A9 complex was expressed in infiltrated neutrophils and occasional macrophages. The S100A8/A9-positive area was significantly higher in UA than in SA (mean (SD) 18.3 (14.2)% vs 1.3 (2.4)%, respectively, p<0.001). Conclusions: The S100A8/A9 complex may be involved in the inflammatory process of coronary atherosclerotic plaques in patients with UA.

Age-dependent impairment of coronary collateral development in humans

Abstract The purpose of this study was to evaluate whether age influences collateral development in patients with coronary artery disease. The extent of collateral development to the area perfused by the infarct-related artery was graded, depending on the degree of opacification of the occluded infarct-related artery. We evaluated the extent of collateral development using coronary cineangiography in 102 patients with an acutely occluded infarct-related coronary artery within 12 h after the onset of the first acute myocardial infarction, and who had a history of long-standing effort angina. Well-developed collateral circulation was observed in 54 (53%) of the patients. The patients were divided into two groups based on their age. The prevalence of well-developed collateral circulation in the younger group (≤64 years, n = 48) was 69% (33 of 48), being significantly (P = 0.003) higher than 39% (21 of 54) in the older group (≥65 years, n = 54). We conclude that in the presence of stimuli for collateral development i.e., long-standing effort angina accompanied by severe coronary stenosis, the age of patients is a key determinant of collateral development.

Myocardial ischemia enhances the expression of acidic fibroblast growth factor in human pericardial fluid.

Abstract Acidic fibroblast growth factor (FGF) is a potent mitogen that can induce angiogenesis in vivo. We have recently reported a marked increase of basic FGF in the pericardial fluid of patients with severe coronary stenosis and an increase in vascular endothelial growth factor (VEGF) in the pericardial fluid of patients with severe myocardial ischemia. The purpose of this study was to evaluate whether acidic FGF levels in the pericardial fluid are associated with severe myocardial ischemia. Immediately after incision of the pericardium in 48 patients during open-heart surgery, 3–5 ml of pericardial fluid was obtained. Concentrations of basic FGF and VEGF in the pericardial fluid were measured using an enzyme-linked immunosorbent assay (ELISA). The ELISA system for human acidic FGF was newly developed using a rabbit antibovine acidic FGF antibody. The patients were divided into three groups (group A: 13 patients undergoing emergency coronary artery bypass grafting (CABG) for unstable angina; group B: 17 patients undergoing elective CABG for stable angina; group C: 18 patients undergoing nonischemic open-heart surgery). The VEGF level in the pericardial fluid in group A was 68 ± 59 pg/ml, which was significantly higher than 33 ± 9 pg/ml in group B and 31 ± 20 pg/ml in group C (P < 0.05). The concentrations of basic FGF in the pericardial fluid in groups A and B were 722 ± 601 and 773 ± 763 pg/ml, respectively, significantly higher than 263 ± 349 pg/ml in group C. The pericardial acidic FGF level in group A was 4 291 ± 2 336 pg/ml, which was also significantly higher than 2 386 ± 1 048 pg/ml in group B and 2 589 ± 990 pg/ml in group C (P < 0.05). The acidic FGF level correlated well with the level of VEGF (r = 0.61, P < 0.0001). It is concluded that the level of acidic FGF in pericardial fluid is associated with severe myocardial ischemia. This result indicates that the release of acidic FGF from the myocardial tissue into pericardial fluid is closely related to severe myocardial ischemia.

Pericardial fluid level of heart-type cytoplasmic fatty acid-binding protein (H-FABP) is an indicator of severe myocardial ischemia

BACKGROUND Heart-type cytoplasmic fatty acid-binding protein (H-FABP) has been reported as a sensitive and specific marker for the early diagnosis of acute myocardial infarction. Our hypothesis was that serum or pericardial fluid levels of H-FABP can reflect not only myocardial infarction but also myocardial ischemia. METHODS A total of 34 patients with unstable angina, who had anginal symptoms and/or ST-changes in ECG monitoring within 24 h before operation, were classified into group A (n=17), and those without these symptoms and changes into group B (n=17). Blood and pericardial fluid samples were obtained immediately after median sternotomy, and serum and pericardial fluid levels of creatine kinase-MB, cardiac troponin-T, and H-FABP were measured. RESULTS Serum H-FABP levels were slightly elevated compared with their normal values in both groups. While they showed no difference between groups A and B (group A vs. B: 8.5+/-1.0 vs. 7.1+/-0.7 ng/ml, P=0.25), pericardial fluid levels of H-FABP were significantly higher in group A than in group B (16.3+/-2.0 vs. 9.6+/-1.0 ng/ml, P=0.0046). H-FABP showed a weak correlation between its serum levels and pericardial fluid levels (r=0.40). CONCLUSIONS Pericardial fluid levels of H-FABP reflect myocardial ischemia occurring within 24 h of their measurements. H-FABP may be secreted into the interstitial space by increased permeability of the myocardial cell membrane associated with severe myocardial ischemia. Thus, pericardial fluid reflects pathophysiological conditions of cardiomyocytes more sensitively than circulating blood.

Effects of right lateral decubitus position on plasma norepinephrine and plasma atrial natriuretic peptide levels in patients with chronic congestive heart failure

P with chronic congestive heart failure (CHF) have fatigue and dyspnea with exercise intolerance and a poor prognosis. Fluid retention along with peripheral vasoconstriction and reduced skeletal muscle perfusion provide the physiologic basis for the symptoms. Neurohormonal modulation by norepinephrine (NE), atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP) are heavily involved in the clinical manifestations of patients with CHF. We have recently reported that posture largely affects the autonomic nervous activity in patients with CHF. In the right lateral decubitus position, sympathetic tone decreased, whereas parasympathetic activity increased. In the present study, we hypothesized that neurohormonal environment of patients with CHF is ameliorated in the right lateral decubitus position because these patients prefer the position. • • • The study group consisted of 14 patients (8 men and 6 women, mean age 72 14 years) with CHF due to coronary artery disease (Table 1). Three patients had New York Heart Association functional class II CHF, 10 had class III, and 1 had class IV. The mean left ventricular ejection fraction was 39 18%. No patient had diabetes mellitus. A constant diuretic, digitalis, calcium antagonist, nitrate, angiotensin-converting enzyme inhibitor, and angiotensin II antagonist dosing regimen was continued. However, -blocking therapy had been withdrawn at least 7 days earlier. Eight ageand sex-matched New York Heart Association functional class I patients with normal left ventricular function (5 men, 3 women, mean age 69 13 years) were selected as the control group. In the early morning, each of the 3 positions (left lateral decubitus, supine, right lateral decubitus) was maintained for 1 hour before blood samples were drawn from a peripheral vein through an indwelling catheter. The order of each position was randomized. Plasma NE, ANP, and BNP levels were then measured by radioimmunoassay. All patients provided informed consent to the protocol, which was approved by the human subjects review committee of Takeda Hospital. Data are expressed as mean SD. Comparisons of variables between the 2 groups were conducted by Fisher’s exact test or unpaired Student’s t test. Multiple comparisons were performed by 2-way analysis of variance, followed by the Tukey-Kramer test for each parameter among the 3 recumbent positions of both groups of patients. Results were considered significant at p 0.05. Plasma NE concentrations were higher in patients with CHF than in those with normal LV function (Figure 1A). In addition, plasma NE concentrations were significantly lower in the right lateral decubitus position than those in the left lateral decubitus and supine positions. Plasma ANP and BNP concentrations were also higher in patients with CHF than in those with normal left ventricular function (Figures 1B and 1C). In addition, in patients with CHF, plasma ANP concentrations were higher in the right lateral decubitus position than those in the left lateral decubitus and supine positions, although plasma BNP levels did not significantly differ among the 3 recumbent positions. In patients with normal left ventricular function, there were no significant differences in these From the Departments of Cardiovascular Medicine and Cardiovascular Surgery, Kyoto University, Kyoto; Division of Cardiology, Takeda Hospital, Kyoto; Division of Cardiology, National Cardiovascular Center, Osaka; Department of Medicine, Division of Cardiology, Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Osaka; Second Department of Internal Medicine, Kansai Electric Power Hospital, Kanasi; and College of Medical Technology, Kyoto University, Kyoto, Japan. Dr. Fujita’s address is: College of Medical Technology, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: mfujita@kuhp.kyoto-u.ac.jp. Manuscript received June 29, 2001; revised manuscript received and accepted September 25, 2001. TABLE 1 Clinical Characteristics of Eight Patients With Normal Left Ventricular Function and 14 Patients With CHF

Trepopnea in patients with chronic heart failure.

This article will review the recumbent positions of patients with chronic congestive heart failure. The time for the right lateral decubitus position was two-fold longer than that for the supine and left lateral decubitus positions. Sympathetic nervous modulation was most attenuated and parasympathetic tone was most augmented in the right lateral decubitus position. The underlying mechanisms why heart failure patients prefer this position will be discussed. In conclusion, the right lateral decubitus position preferred by patients with chronic congestive heart failure may be a self-protecting mechanism to augment cardiac output and to attenuate the imbalance of cardiac autonomic nervous activity.

Circadian variation of cardiac autonomic nervous activity is well preserved in patients with mild to moderate chronic heart failure: effect of patient position

BACKGROUND It remains unclear whether circadian variation (CV) of cardiac autonomic nervous activity (CANA) is preserved in patients with chronic heart failure (CHF) as in healthy subjects. We have demonstrated that CANA in CHF patients is largely affected by patient recumbent position. METHODS We studied eight mild to moderate CHF patients and eight age, sex-matched healthy subjects. Each subject underwent 24-h ambulatory ECG monitoring. One channel was used to record the CM5 lead, and another to record the signal of patient position from a newly developed, small-sized detector. By using spectral analysis of heart rate variability, frequency-domain measures were calculated. Normalized high-frequency (HF: 0.15-0.40 Hz) power was used as an index of vagal activity and the low frequency (LF: 0.04-0.15 Hz)/HF power ratio was used as an index of sympathovagal balance. These indexes in the same recumbent position were compared between night (2:00-4:00 a.m.) and morning (6:00-8:00 a.m.). RESULTS In healthy subjects, a definite CV of CANA was observed in each recumbent position. In patients with CHF, in each position, normalized HF power was lower in the morning than at night, whereas LF/HF was higher in the morning than at night. Thus, CANA in CHF patients is influenced not only by patient position but also by the time of day. CONCLUSION CV of CANA in mild to moderate CHF patients is well preserved when taking patient position into consideration.