Yuh Ishikawa

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.

Local expression of Toll-like receptor 4 at the site of ruptured plaques in patients with acute myocardial infarction

Several reports suggest that a chronic inflammatory process plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. In a previous study, we found that TLR4 (Toll-like receptor 4) mediates the synthesis of cytokines in circulating monocytes of patients with AMI (acute myocardial infarction); however, it remains unclear whether TLRs are expressed at the site of the ruptured plaque in these patients. The aim of the present study was to determine whether TLR2 and TLR4 are expressed at the site of ruptured plaques in patients with AMI and to compare this with systemic levels. The study included 62 patients with AMI, 20 patients with SA (stable angina) and 32 subjects with a normal coronary angiogram (control). Local samples from the site of the ruptured plaque were taken from patients with AMI using aspiration catheterization. Systemic blood samples from the aorta were taken from patients with AMI and SA and controls. Systemic levels of TLR2 and TLR4 were higher in patients with AMI than in patients with SA and controls. In patients with AMI, local TLR4 levels were higher than systemic levels. There was no significant difference in TLR2 levels between local and systemic samples. TLR4 immunostaining was positive in infiltrating macrophages in ruptured plaque material. Cardiac events were observed in 16 patients with AMI at the time of the 6-month follow-up study. Local and systemic levels of TLR4 were higher in patients with AMI with cardiac events than in those without. These results indicate an increase in monocytic TLR4 expression not only in the systemic circulation, but also at the site of plaque rupture. In conclusion, expression of both systemic and local plaque TLR4 may be one of the mechanisms responsible for the pathogenesis of AMI.

The expression of TNF-α converting enzyme at the site of ruptured plaques in patients with acute myocardial infarction

Background  Tumour necrosis factor‐α (TNF‐α) converting enzyme (TACE) plays an essential role in the TNF‐α shedding process, which could affect the outcome of acute myocardial infarction (AMI). However, it remains unclear whether it originates from the ruptured plaque or represents a systemic process. This study analysed TACE‐mediated TNF‐α shedding at the site of ruptured plaques in AMI patients and compared them with a systemic mechanism.

Role of Toll like receptor signaling pathway in ischemic coronary artery disease.

Inflammatory process plays a fundamental role in ischemic coronary artery disease (CAD) in terms of both the etiology of atherosclerosis and the pathophysiology of CAD. In particular, chronic inflammation plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. It is therefore important to clarify the mechanism underlying the activation of the immune response in the pathogenesis of CAD. Currently 10 toll-like receptors (TLRs) have been reported in mammalian species, and these appear to recognize distinct pathogen-associated molecular patterns controlling innate immune responses. In recent studies, signaling of two forms of human TLR (TLR2 and TLR4) has been shown to be involved in the pathogenesis of CAD, establishing a key link between the progression of coronary atherosclerosis and immune response to both foreign pathogens and endogenously generated inflammatory ligands. A better understanding of TLR signal may provide a novel therapeutic agent for the treatment of CAD. This review summarizes the relationship between the pathogenesis of ischemic coronary artery disease and the human TLR system.

Eplerenone inhibits tumour necrosis factor α shedding process by tumour necrosis factor α converting enzyme in monocytes from patients with congestive heart failure

Eplerenone, a selective mineralocorticoid receptor antagonist, attenuated the expression of systemic proinflammatory molecules in a rat model of congestive heart failure (CHF).1 However, the mechanisms by which eplerenone reduces proinflammatory molecule expression have not been elucidated. Our previous study was the first to show that expression of tumour necrosis factor α (TNFα) converting enzyme (TACE) in peripheral blood mononuclear cells may be responsible for the release of TNFα in CHF.2 To the best of our knowledge, the observation that peripheral monocytes can activate the TACE–TNFα system in CHF is without precedent. The objective of the present study was to examine whether monocytes have a role in the activated TACE–TNFα system and to determine whether eplerenone reduces the TNFα shedding process in monocytes from patients with CHF. Peripheral monocytes were isolated from blood samples at the time of admission (32 patients with CHF and 10 healthy subjects). The origin of left ventricular (LV) dysfunction was idiopathic dilated cardiomyopathy in all cases. Echocardiography …

109 Association between toll‐like receptor 8 expression and adverse clinical outcomes in patients with enterovirus‐associated dilated cardiomyopathy

BACKGROUND In recent reports, human toll-like receptor (TLR) 8 mediates the antiviral response by recognizing single-stranded RNA. The inflammatory response against enteroviral (EV) RNA replication may play an important role in dilated cardiomyopathy (DCM). The purpose of this study was to determine whether TLR8 was expressed with EV replication in patients with enterovirus-associated DCM. METHODS Reverse transcriptase-polymerase chain reaction analysis was performed to screen the detection of myocardial EV RNA in 198 consecutive patients with DCM. Seventy-two EV RNA-positive patients with DCM and 20 control samples constituted the study population of the present study. Levels of TLR8 and myeloid differentiation factor (MyD) 88 adaptor protein mRNA and EV RNA (plus- and minus-strand RNAs) were measured by real-time RT-PCR. Immunohistochemistry was performed to identify the cellular source of these molecules. RESULTS Toll-like receptor 8 and MyD88 mRNA levels were higher in patients with DCM than in controls (P < .001). Immunostainings of TLR8, MyD88, and EV protein showed localization of these proteins in cardiac myocytes in patients with DCM. After a mean follow-up of 426 days, clinical outcomes (development of heart failure n = 11, cardiac death n = 3) were associated with increased levels of TLR8 and MyD88 (P < .05). Multivariate analysis showed that TLR8 (relative risk 3.2, 95% CI 1.6-6.2) was a strong predictor of heart failure and cardiac death after adjustment for baseline characteristics. CONCLUSION Toll-like receptor 8 and MyD88 expressions may be involved in the immune response to EV replication in enterovirus-associated DCM. In addition, TLR8 may provide important prognostic information in patients with enterovirus-associated DCM.