A Clinical Study of Ninjin'yoeito With Regard to Frailty.

Frailty in older people is strongly associated with poor nutrition, which is particularly important in the present-day superaging society. This study initially investigated a number of cases of frailty where there was a speedy recovery after administration of a dual deficiency of qi and blood preparation, ninjin'yoeito (NYT), formulated for frail patients who suffer from kiketuryokyo status. Based on these observations, a more extensive investigation involving a greater number of cases was completed. The findings of the effects of NYT on frailty are reported here.

Familial hypercholesterolemia with multiple large tendinous xanthomas and advanced coronary artery atherosclerosis.

We herein report the case of a 53-year-old man with severe coronary ischemia who underwent successful coronary artery bypass surgery. Of note, he had hypercholesterolemia and presented with multiple large tendinous xanthomas and thickened Achilles tendons that had been present for more than two decades. Together with a family history of dyslipidemia, the patient was diagnosed as having familial hypercholesterolemia. Irrespective of an extensive search for possible mutations in the genes presumably involved in the patient's pathophysiology, including low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), autosomal recessive hypercholesterolemia (ARH) and apolipoprotein B (APOB), we were not able to identify the gene mutations responsible for the phenotype observed in the present case.

Enhanced expression of the ubiquitin-proteasome system in the myocardium from patients with dilated cardiomyopathy referred for left ventriculoplasty: an immunohistochemical study with special reference to oxidative stress.

The ubiquitin (Ub)-proteasome system (UPS) is an important proteolytic mechanism for selecting and digesting cytotoxic proteins. The aim of this study is to elucidate expression and in situ localization of the UPS in the myocardium from patients with dilated cardiomyopathy (DCM) with refractory heart failure. The expression profile of the oxidative stress-induced cytotoxic proteins was also examined. Myocardium was obtained from 26 patients with DCM at the left ventriculoplasty. Ten normal autopsied hearts served as controls. Myocardial expressions of Ub and proteasomes were studied immunohistochemically. Oxidative stresses were examined in point of localization of the oxidation-induced modifier molecules (OMM). The relationship between immunohistochemical results and clinical parameters was also evaluated. Both Ub and proteasomes were stained positive in granular structures accumulating between the myofibrils and adjacent to nuclei in cardiomyocytes. The OMMs were also positive in the same Ub-positive granular structures. The area fraction of Ub, proteasomes and OMM was significantly higher in DCM hearts than in normal controls. Significant positive correlation was observed between the area fractions of Ub and plasma levels of brain natriuretic peptide (p = 0.046) in DCM hearts. In conclusion, enhanced expression of the UPS colocalized with OMM in cardiomyocytes may be involved in the pathophysiology of DCM hearts.

High prevalence of chronic myocarditis in dilated cardiomyopathy referred for left ventriculoplasty: expression of tenascin C as a possible marker for inflammation.

The objectives of this study were to analyze the incidence of chronic myocarditis in dilated cardiomyopathy and to evaluate the diagnostic value of tenascin C for assessing inflammatory activity in the resected myocardium. Dilated cardiomyopathy patients with chronic myocarditis have a poor clinical outcome despite recent advances in medical treatments. Therefore, a precise diagnosis of inflammatory activity is critical to ensuring appropriate therapy. Tenascin C is an extracellular matrix glycoprotein that plays an important role in tissue remodeling in various heart diseases. Myocardial samples obtained during left ventriculoplasty from 64 patients (50 +/- 13 years, 56 men and 8 women) with dilated cardiomyopathy were examined by immunostaining for tenascin C. Histologic diagnosis was based on the Dallas criteria modified by the International Society and Federation of Cardiology task force. Nine cases (14%) had active myocarditis, 21 (33%) had borderline myocarditis, and 34 (53%) had no myocarditis. Intense tenascin C expression was observed at the site of active inflammation, with abundant cell accumulation, and in organized granulation tissue during the resolving phase but not in scar tissue during the healing phase. The ratio of tenascin C-positive area to the whole myocardium in the active and borderline myocarditis groups was significantly greater than that in the noninflammatory group. These findings suggest a high prevalence of chronic myocarditis in dilated cardiomyopathy patients and that tenascin C may prove to be a useful marker for distinguishing inflammatory cardiomyopathy from other types of dilated cardiomyopathy.

Enhanced expression of type 1 helper T-cell cytokines in the myocardium of active cardiac sarcoidosis.

BACKGROUND: Various cytokines are involved in the pathogenesis of sarcoidosis, but their expression in the myocardium has not been documented for cardiac sarcoidosis. METHODS AND RESULTS: Myocardial tissue was obtained from 12 patients with cardiac sarcoidosis at the time of left ventriculoplasty, biopsy or autopsy. mRNA expression of various inflammatory cytokines was analyzed using quantitative real-time polymerase chain reaction, as well as by immunohistochemistry. Ten patients with dilated cardiomyopathy (DCM) served as controls. Enhanced expression of interleukin (IL)-1alpha, IL-2, IL-12 p40 and interferon (IFN)-gamma mRNA was limited to the myocardium of cardiac sarcoidosis patients. Expression of IL-1beta, IL-8, IL-10, IL-15 and TNF-alpha occurred in both cardiac sarcoidosis and DCM patients, but IL-4 and IL-5 were not detected in either disease. Immunohistochemistry of the myocardial tissue of sarcoidosis revealed positive staining for IL-12 and IFN-gamma. IL-12 was localized in multinucleated giant cells and macrophages of the sarcoid granulomas, whereas IFN-gamma was detected in lymphocytes and vascular endothelial cells. CONCLUSIONS: Type 1 helper T-cell cytokines may be involved in the pathogenesis of cardiac sarcoidosis.

Cardiac sarcoidosis underlies idiopathic dilated cardiomyopathy: importance of mediastinal lymphadenopathy in differential diagnosis.

BACKGROUND: Cardiac sarcoidosis is frequently overlooked or misdiagnosed as idiopathic dilated cardiomyopathy (DCM), primarily because of difficulties in its diagnosis. This is a crucial issue because appropriate therapy with immunosuppressive agents can be initiated if early diagnosis is achieved. METHODS AND RESULTS: Thoracic computed tomography (CT) was retrospectively analyzed in detail with special reference to lymph node swelling (LNS) in the mediastinum of 8 patients diagnosed with idiopathic DCM who underwent left ventriculoplasty (LVP), and were later proven to have active cardiac sarcoidosis by histological evaluation of the resected myocardium. Twenty age-matched patients with idiopathic DCM who also underwent LVP served as controls. On conventional chest radiographs, none of the cardiac sarcoidosis patients exhibited lymph node involvement, including bilateral hilar lymphadenopathy. However, CT demonstrated significant mediastinal LNS in 7 (88%) of them and in only 1 (5%) of the 20 controls. There was a significant difference in the incidence of LNS in the 2 groups (p=0.00005). CONCLUSION: Evaluation of mediastinal lymphadenopathy by CT is an easy and valuable initial screening method for distinguishing cardiac sarcoidosis from idiopathic DCM.

Enhanced expression of myeloid-related protein complex (MRP8/14) in macrophages and multinucleated giant cells in granulomas of patients with active cardiac sarcoidosis.

BACKGROUND: The myeloid-related protein complex (MRP8/14) is expressed in activated human macrophages and reported to be involved in the inflammatory process. The expression of MRP8/14 in patients with cardiac sarcoidosis and idiopathic dilated cardiomyopathy (DCM) was investigated. METHODS AND RESULTS: Serum MRP8/14 levels were measured in 35 patients with sarcoidosis and 23 patients with DCM. Sera from 30 normal volunteers served as controls. Additionally, the expression profiles of MRP8/14 in the myocardium from 12 patients with active cardiac sarcoidosis and 10 DCM patients were examined immunohistochemically. Serum MRP8/14 levels were significantly higher in patients with sarcoidosis than in normal controls [515+/-549 (SD) ng/ml vs 230+/-115 ng/ml, p=0.0019]. In the sarcoidosis group, serum MRP8/14 levels in patients with definite cardiac involvement (n=10) were significantly higher than in those without (n=25) (974+/-878 ng/ml vs 332+/-204 ng/ml, p=0.0227) and they were also higher than in DCM patients (vs 252+/-108 ng/ml, p=0.0026). Immunohistochemically, MRP8/14 was specifically positive in the cytoplasm of macrophages and multinucleated giant cells in the myocardial granulomas. CONCLUSIONS: MRP8/14 may be involved in the pathogenesis of sarcoid granulomas. The measurement of serum MRP8/14 levels is useful for the diagnosis of sarcoidosis, and their higher levels suggest the cardiac involvement.

Right atrial blood cyst with total occlusion of the right coronary artery.

Cardiac blood cysts are rarely seen in adult patients and in the right atrium. The origin of cardiac blood cysts is not understood, and several hypotheses have been proposed. We present a rare case of right atrial blood cyst with total occlusion of the right coronary artery (RCA). Inflammatory processes may have played an important role in the development of the cyst, because infiltration of inflammatory cells was observed in the cystic wall. Additionally, total obstruction of the proximal RCA indicated that ischemia and/or infarction in the right atrium might be related to formation of the cyst.

Higher serum tenascin-C levels reflect the severity of heart failure, left ventricular dysfunction and remodeling in patients with dilated cardiomyopathy.

BACKGROUND: Tenascin-C (TN-C), an extracellular matrix glycoprotein, is specifically expressed at high levels during embryonic development, but not in the adult heart. TN-C reappears at sites of inflammatory tissue remodeling or wound healing under various pathologic conditions, such as acute myocardial infarction, acute myocarditis, and some cases of cardiomyopathy. Therefore, the expression of TN-C might be useful for detecting the clinical characteristics of, and ventricular remodeling in, dilated cardiomyopathy (DCM). METHODS AND RESULTS: Circulating serum TN-C levels in 107 patients with DCM were measured using an ELISA kit. Clinical data were also assessed by Pearson's or Spearman's correlation analysis to estimate correlations between variables. Serum TN-C levels in DCM patients were higher than those in normal controls (p<0.001). TNC levels showed a significantly positive correlation with New York Heart Association functional class (p<0.001), B-type natriuretic peptide level (p<0.001), cardiothoracic ratio on chest X-ray (p<0.01), left ventricular end-diastolic diameter (p<0.05) and left ventricular end-systolic diameter (p<0.01), and a significantly negative correlation with left ventricular ejection fraction (p<0.01). CONCLUSIONS: The findings suggest that increased serum TN-C levels indicate the severity of heart failure, left ventricular dysfunction and remodeling in patients with DCM.

Comparative study of quantitative blood pool SPECT imaging with 180 degrees and 360 degrees acquisition orbits on accuracy of cardiac function.

BACKGROUND: Quantitative blood pool single photon emission computed tomography (SPECT) (QBS) can measure ejection fraction (EF) and volumes from gated blood pool single photon emission tomography (GBPS) working in fully automatic mode in 3-dimensional space. The effects of 180 degrees and 360 degrees data acquisition in GBPS have not been fully evaluated. This study compares the accuracy of 360 degrees and 180 degrees data acquisition for left ventricular (LV) systolic function in a clinical study and measures LV volume by GBPS compared with ultrasound echocardiography. METHODS AND RESULTS: The study population comprised 9 normal volunteers and 34 patients. GBPS data were acquired by use of 360 degrees rotation and 60 stops per head. All 60 (360 degrees ) and 30 (45 degrees right anterior oblique to 45 degrees left posterior oblique) pieces of projection data that were selected for reconstructing the 180 degrees data were reconstructed and both ventricular functional parameters were automatically obtained by QBS software. The contour of the LV septal wall was concave in 6 patients (14%) when processed at 180 degrees , whereas a concave septum at 360 degrees processing was observed in only 1 patient (2%). The coefficients of correlation between 180 degrees and 360 degrees were 0.467 for the end-diastolic volume (EDV) and 0.648 for the end-systolic volume (ESV). The mean 180 degrees EDV value (152.9 +/- 46.1 mL) was significantly smaller than that of the 360 degrees EDV (191 +/- 70.8 mL) ( P < .001). However, there was no significant difference between the 360 degrees EDV (0.623) and 180 degrees EDV (0.407) as compared by echocardiography ( P = .218). The agreement of the EF between both methods was close ( r = 0.894, P < .0001). The agreement of the right ventricular volumes between the 180 degrees and 360 degrees orbits was close ( r = 0.800 for EDV and 0.706 for ESV). The EF was relatively dispersed between the 180 degrees and 360 degrees methods ( r = 0.642). CONCLUSION: This study showed that SPECT image acquisition by use of both the 180 degrees method and the 360 degrees method considerably underestimated LV volume quantification. In addition, the LV volume with the 180 degrees method was significantly smaller than that with the 360 degrees method. Thus a 360 degrees acquisition orbit may be suitable for more quantitatively accurate results when blood pool imaging is performed with gated SPECT.

Mechanisms of combined treatment with celiprolol and candesartan for ventricular remodeling in experimental heart failure.

BACKGROUND: Both beta-adrenergic blockers and angiotensin-II receptor blockers were reported to improve the prognosis of patients with heart failure, but the efficacy of combination therapy with these agents has not been fully elucidated. Also the efficacy of celiprolol, a beta1-selective adrenoceptor antagonist with partial beta2-agonist properties, for heart failure treatment is still controversial. We examined the cardioprotective effects and mechanisms of the therapy with celiprolol or candesartan, an angiotensin-II receptor blockers and their combination in heart failure induced by isoproterenol (ISO). METHODS AND RESULTS: ISO 300 mg/kg was injected in rats to produce heart failure. Two months after the injection, the ISO-injected rats were divided into 4 groups (8 rats each) and treated for 4 weeks as follows: (a) vehicle; (b) celiprolol 10 mg/kg per day (BB); (c) candesartan 0.2 mg/kg per day (ARB); and (d) their combination BB+ARB. ISO significantly elevated left ventricular (LV) end-diastolic pressure, decreased peak-negative dP/dt and LV ejection fraction. BB and ARB similarly ameliorated cardiac dysfunction due to ISO, but BB+ARB were more potent than the individual therapies. Separately, ARB preserved the histological structure in LV myocardium. In contrast, BB ameliorated calcium handling, as shown by the increased ratio of SERCA2 to phospholamban protein, despite having little effect on the histology. CONCLUSION: Both celiprolol and candesartan showed cardioprotective effects in this heart failure model. The potential use of the combination treatment in heart failure might result in a synergistic effect through the different cardioprotective mechanisms of celiprolol and candesartan.

Diphtheria toxin-induced autophagic cardiomyocyte death plays a pathogenic role in mouse model of heart failure.

It is still not clear whether loss of cardiomyocytes through programmed cell death causes heart failure. To clarify the role of cell death in heart failure, we generated transgenic mice (TG) that express human diphtheria toxin receptor in the hearts. A mosaic expression pattern of the transgene was observed, and the transgene-expressing cardiomyocytes (17.3% of the total cardiomyocytes) were diffusely scattered throughout the ventricles. Intramuscular injection of diphtheria toxin induced complete elimination of the transgene-expressing cardiomyocytes within 7 days, and approximately 80% of TG showed pathophysiological features characteristic of heart failure and were dead within 14 days. Degenerated cardiomyocytes of the TG heart showed characteristic features indicative of autophagic cell death such as up-regulated lysosomal markers and abundant autophagosomes containing cytosolic organelles like cardiomyocytes of human dilated cardiomyopathy. The heart failure-inducible TG are a useful model for dilated cardiomyopathy, and provided evidence indicating that myocardial cell loss through autophagic cell death plays of a causal role in the pathogenesis heart failure.

Long-term outcome of a residual scar from myocardial infarction after coronary artery bypass grafting: a 100-month study using myocardial perfusion scintigraphy.

The prognosis for patients with a residual scar from myocardial infarction (MI) after coronary artery bypass grafting surgery (CABG) has not been fully evaluated, so the present study retrospectively evaluated such patients with stress myocardial single photon emission computed tomography (SPECT) at 100 months after CABG. The study group consisted of 24 subjects (23 males, 1 female; mean age, 59+/-9 years) in whom CABG had been performed more than 100 months (mean follow-up period 135+/-25 months) previously. The 24 subjects were classified into 3 groups according to their summed stress score (SSS) and summed reversibility score (SRS) in the early period after CABG. Eight subjects with MI (SSS> or =2 and SRS<2) were classified into the group MI, 8 subjects with ischemic myocardium (SSS> or =2 and SRS> or =2) was classified into the group RE, and 8 subjects with normal perfusion (SSS<2 and SRS<2) was classified into group N. None of the subjects in group MI required revascularization. Cardiac events occurred in 4 of the group RE patients and all required revascularization. As to the SPECT scoring system, the long-term SSS of group MI (6.4+/-3.1) was not different from that in the early periods (4.3+/-4.0; NS). However, the long-term SSS values of group RE (8.8+/-6.2) were significantly greater than those soon after CABG (3.4+/-1.8; p=0.03). In group N, there was also no difference in the SSS values between the early period (0.3+/-0.5) and the long-term period (0.0+/-0.0; NS). Patients with a residual scar from MI in the early period after CABG did not worsen over a period of 100 months. Moreover, there was no significant difference in the SPECT score in the segment with the residual scar in the short or long term after CABG. However, the extent of reversibility was directly associated with the presence of clinical events. Therefore scintigraphic imaging remains an important and clinically relevant risk stratification tool. Stress myocardial SPECT, early after CABG, can be used to predict the possibility of future cardiac events or the need for revascularization.