Yudai Shimoda

Elevated circulating levels of heat shock protein 70 are related to systemic inflammatory reaction through monocyte Toll signal in patients with heart failure after acute myocardial infarction

Recent studies have shown that heat shock protein (HSP) 70 may serve as a “damage signal” to the immune system and could be the endogenous ligand for Toll‐like receptor (TLR) 4 mediating synthesis of inflammatory cytokines.

Myocardial osteopontin expression is associated with collagen fibrillogenesis in human dilated cardiomyopathy.

Osteopontin (OPN), an extracellular matrix (ECM) protein, plays an important role in myocardial remodeling by promoting collagen synthesis and accumulation in experimental animal models.

Expression of Toll-like receptor 4 is associated with enteroviral replication in human myocarditis

Previous studies have demonstrated that inflammatory cytokine expression associated with enteroviral (EV) infection may play an important role in human myocarditis. However, the mechanism of the host immune response against viral pathogens has not been fully understood. The aim of the present study was to determine whether Toll-like receptor 4 (TLR4) and EV RNA are present in human myocarditis. Endomyocardial biopsy samples were obtained from 44 patients with myocarditis and five controls. Levels of plus- and minus-strand EV RNAs and TLR4 mRNA were measured by real-time reverse transcriptase-PCR. Immunohistochemical analysis was performed to identify the cellular source of TLR4 and the EV capsid protein VP1. EV RNA was present in 21 patients with myocarditis and these patients were defined as having either active viral replication ( n =15) or latent viral persistence ( n =6). Neither strand of EV RNA was detected in controls. TLR4 mRNA expression levels were higher in myocarditis patients than in controls (TLR4/glyceraldehyde-3-phosphate dehydrogenase ratio 1.48+/-0.17 compared with 0.08+/-0.06, P <0.001). A positive correlation was found between EV RNA and TLR4 levels (plus-strand vs TLR4: r =0.66, P <0.001; minus-strand vs TLR4: r =0.48, P <0.001). TLR4 immunostaining was observed in infiltrating cells and myocytes in patients with myocarditis. The EV capsid protein VP1 was also found in myocytes. The myocarditis group with EV replication and high levels of TLR4 showed significantly lower systolic function. The present study has shown that increased expression of TLR4 is associated with EV replication and that these RNA levels are related to cardiac dysfunction in human myocarditis.

Toll-like receptor 4 is expressed with enteroviral replication in myocardium from patients with dilated cardiomyopathy

Expressions of innate immune response proteins, most notably proinflammatory cytokines, against enteroviral (EV) infection have been documented in the heart of human dilated cardiomyopathy (DCM). Toll-like receptor 4 (TLR4) activates signaling pathways leading to the expression of proinflammatory cytokines implicated the etiology of DCM. We sought to determine whether EV replication activates TLR4-dependent immune response in myocardium obtained from patients with DCM. Endomyocardial biopsy tissues were obtained from 56 patients with DCM and 10 controls. Levels of plus- and minus-strand EV RNA and TLR4 mRNA were measured by real-time RT-PCR. Immunohistochemical analysis was performed to identify the cellular source of EV capsid protein VP1 and TLR4. Both plus- and minus-strand EV RNA were detected in 19 DCM patients (34%). Neither strand of EV RNA was detected in controls. TLR4 mRNA levels were higher in DCM patients than in controls (P<0.001). A positive correlation was found between TLR4 levels and each strand type of EV RNA in EV RNA-positive patients (plus-strand vs TLR4: r=0.69, P<0.001; minus-strand vs TLR4: r=0.65, P=0.002). VP1/TLR4 double staining showed extensive colocalization of VP1 and TLR4 proteins in cytoplasm of cardiac myocytes in myocardium obtained from DCM patients. EV RNA-positive patients showed lower systolic function and larger ventricular volume compared with EV RNA-negative patients left ventricular ejection fraction (LVEF): P=0.002; left ventricular end-systolic diameter (LVESD): P=0.004). The DCM subgroup with high TLR4 levels showed lower LVEF and larger LVESD than the subgroup with TLR4 levels (both P<0.001). This study suggests that myocardial expression of TLR4 associates with EV replication in human DCM. EV RNA and TLR4 mRNA levels may correlate with LV dysfunction in DCM. The expression of TLR4 against EV replication may be involved in the pathogenesis of DCM.

C‐reactive protein co‐expresses with tumor necrosis factor‐α in the myocardium in human dilated cardiomyopathy

C‐reactive protein (CRP) has recently been reported to be present in cardiac tissue and to stimulate the production of proinflammatory cytokines. Cardiac expression of tumor necrosis factor‐α (TNF‐α) plays an important role in the pathogenesis of dilated cardiomyopathy (DCM).

Increased expression of tumor necrosis factor‐α converting enzyme and tumor necrosis factor‐α in peripheral blood mononuclear cells in patients with advanced congestive heart failure

Tumor necrosis factor‐α converting enzyme (TACE) has recently been identified as a metalloproteinase‐disintegrin, which converts pro‐tumor necrosis factor‐α (TNF‐α) to the mature form, and is an important mediator in the pathogenesis of CHF.

Activated tumour necrosis factor-α shedding process is associated with in-hospital complication in patients with acute myocardial infarction

TACE [TNF-alpha (tumour necrosis factor-alpha)-converting enzyme] plays an essential role in the shedding of TNF-alpha, which could affect the outcome of AMI (acute myocardial infarction). To investigate the clinical significance of the TACE-TNF-alpha system in AMI, we examined TACE-mediated TNF-alpha synthesis in PBMCs (peripheral blood mononuclear cells), which are a possible source of TNF-alpha in AMI. Forty-one patients with AMI and 15 healthy subjects (HS) were enrolled in the present study. PBMCs were isolated from peripheral blood on day 1 and 14 after the onset of AMI. TACE and TNF-alpha mRNA levels and intracellular median fluorescence intensity were measured by real-time RT (reverse transcriptase)-PCR and flow cytometry respectively. TACE-mediated TNF-alpha production was evaluated in cultured PBMCs with PMA, which is known to activate TACE. Spontaneous TACE and TNF-alpha levels were higher in AMI patients than in HS (P<0.001). TACE and TNF-alpha levels in PMA-stimulated PMBCs were markedly increased in AMI patients compared with HS (P<0.001). There was a positive correlation between TACE and TNF-alpha levels in AMI. Although spontaneous and stimulated levels of TACE and TNF-alpha decreased 14 days after the onset of AMI, levels in AMI patients were higher than in HS. In AMI patients with in-hospital complications (n=15; pump failure in ten, recurrent myocardial infarction in one, malignant ventricular arrhythmia in three and cardiac death in one), spontaneous and stimulated levels of TACE and TNF-alpha were higher than in patients without complications (P<0.01). These levels were higher in AMI patients with in-hospital complications 14 days after onset. These results demonstrate that TACE-mediated TNF-alpha maturation in PBMCs may play an important role in poor outcomes from AMI, suggesting that TACE may be a potential target for the inhibition of cellular TNF-alpha production in AMI.

A Low Early High-density Lipoprotein Cholesterol Level is an Independent Predictor of In-hospital Death in Patients with Acute Coronary Syndrome

Objective In patients with acute coronary syndrome (ACS), low high-density lipoprotein cholesterol (HDL-C) levels in samples collected after an overnight fast are diagnostic indicators and well-established predictors of adverse outcomes. However, the relationship between the HDL-C levels in samples collected just after arrival (early HDL-C) and in-hospital mortality remains unknown. The purposes of the present ACS study were to (1) evaluate the association between the early HDL-C levels of patients and in-hospital mortality and (2) compare the early HDL-C level with other well-known determinants associated with in-hospital mortality. Methods This retrospective study surveyed 638 consecutive ACS patients and then assessed the possible determinants of in-hospital mortality. All initial blood samples, including that for early HDL-C, were drawn within one hour of arrival. Results In the present study, the overall in-hospital mortality was 5.9%. A multivariable analysis showed that a low early HDL-C [odds ratio (OR) 2.53, 95% confidence interval (CI) 1.14-5.62], elevated troponin T (OR 4.40, 95% CI 1.26-15.29) and high Killip class (OR 15.41, 95% CI 7.29-32.59) were independent predictors of in-hospital mortality. A Kaplan-Meier survival analysis indicated that there the in-hospital outcome for the low early HDL-C group was significantly worse than that for the high early HDL-C group (age- and gender-adjusted hazard ratio 2.40, 95% CI 1.15-5.00, p=0.02). Conclusion ACS patients with low early HDL-C levels had higher in-hospital mortalities than those who did not have low early HDL-C levels. In addition to the already well-known determinants, low early HDL-C should also be considered as an independent predictor of in-hospital mortality in ACS patients who present to a cardiac care unit.

Spontaneous healing of saccular type aneurysm with ventricular septal lacerations after blunt chest trauma

We present a case of spontaneous healing of saccular type aneurysm with ventricular septal lacerations after blunt chest trauma. A 50-year-old Japanese man was transferred to our hospital diagnosed with ventricular septal lacerations after blunt chest trauma. Electrocardiogram (ECG) at admission showed ST elevations in I, II, III, aVL, aVF, V2-through to V6 were observed. Laboratory data showed elevated creatine kinase. Echocardiogram revealed normal ventricular contraction and a saccular type ventricular septal laceration with an influx blood flow without septal shunt flow. After admission, serial echocardiogram and cardiac computed enhancement tomography showed disappearance of a saccular type ventricular septal laceration. Gadolinium-enhanced magnetic resonance imaging (MRI) was performed at day 30. MRI showed an enhanced scar of saccular type aneurysm with ventricular septal laceration; this image suggested some residual damage of ventricular septal laceration. At discharge, ECG was resolved with normal ST-T level and no Q wave, but persistent complete right bundle branch block and left axis deviation. After one year, repeat MRI showed a scar of saccular type aneurysm with ventricular septal laceration. <Learning objective: To recognize spontaneous healing of saccular type aneurysm with ventricular septal lacerations after blunt chest trauma. This is a case of saccular type aneurysm with ventricular septal laceration after non-penetrating blunt chest trauma successfully healed with conservative therapy. There are many case reports of blunt chest trauma, however, there are few reports of treatment with conservative therapy.>.