Background: 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. Aims: To explore the relationship between circulating HSP70 levels and activation of monocyte TLR4 and myocardial damage after AMI. Methods and results: This study examined circulating HSP70 and monocyte TLR4 levels in 52 patients with AMI and 20 controls, and analyzed ex vivo inflammatory cytokine productions using HSP70-stimulated monocytes. Circulating HSP70 levels were higher in AMI patients on day 1 after onset than in controls and remained elevated in AMI patients 14 days after onset. HSP70 levels were positively correlated with monocyte TLR4, plasma interleukin-6 and tumor necrosis factor-a levels in AMI patients. HSP70 levels 14 days after onset were higher in AMI patients with heart failure (n = 15) than in those without heart failure. In our in vitro study, HSP70-stimulated monocytes resulted in dose-dependent TLR4 expression and release of inflammatory cytokines. TLR4 antibody inhibited inflammatory cytokines release. Conclusions: Elevated circulating levels of HSP70 may be involved in TLR4 signal-mediated immune response and the progression of heart failure after AMI.
A study was performed on seven traumatic neurologically complete quadriplegic (QP) males and seven age-matched healthy males (control) while they were at rest in the supine position in a climatic chamber (temperature 30 degrees C, relative humidity 60%). Arterial blood pressure waveforms were measured by a continuous noninvasive blood pressure-monitoring system based on arterial tonometry. Furthermore, the spontaneous beat-to-beat systolic blood pressure (SBP) variabilities of subjects were investigated by means of autoregressive power spectral analysis. As shown by earlier studies with an invasive (intra-arterial) blood pressure-monitoring system, in the control group there were two major spectral components: a high-frequency (HF) component [center frequency 0.27 +/- 0.02 (SE) Hz eq, power 0.9 +/- 0.2 mmHg2] and a low-frequency (LF) component (0.10 +/- 0.01 Hz eq, 5.2 +/- 1.4 mmHg2). On the contrary, in the QP group only the HF component was observed (0.28 +/- 0.03 Hz eq, 3.2 +/- 1.4 mmHg2). The results suggest that 1) in the QP subject the disappearance of the LF component in the SBP variability (i.e., the Mayer waves in humans) is presumably caused by the interruption of the spinal pathways linking supraspinal cardiovascular centers with the peripheral sympathetic outflow and 2) the cervical spinal sympathetic pathways may be instrumental in the genesis of the Mayer waves in humans.
Background: Osteopontin (OPN), an extracellular matrix (ECM) protein, plays an important role in myocardial remodeling by promoting collagen synthesis and accumulation in experimental animal models. Aims: We hypothesized that OPN could be expressed in myocardial tissues and contribute to collagen accumulation and myocardial dysfunction in human dilated cardiomyopathy (DCM). Methods and results: Endomyocardial biopsy tissues were obtained from 51 patients with DCM and 15 controls by right ventricular endomyocardial biopsy. OPN, collagen types I (Col I) and III (Col III) mRNA levels were measured by real-time reverse transcriptase polymerase chain reaction (RT-PCR). The cellular source of OPN was analyzed using immunohistochemistry and in situ hybridization. Myocardial collagen volume fraction (CVF) was determined by digital planimetry. OPN, Col I and Col III mRNA levels were higher in DCM patients than in controls ( Pb0.01). OPN mRNA levels were positively correlated with Col I levels and CVF in DCM patients (OPN vs. Col I: r=0.60, Pb0.01; OPN vs. CVF: r=0.52, Pb0.001). Immunostaining of OPN was present in cardiomyocytes from DCM patients. In situ hybridization identified cardiomyocytes as the major source of OPN mRNA transcription in DCM patients. OPN and Col I mRNA levels were highly expressed in the DCM subgroup with large left ventricular (LV) end-systolic diameter (LVESDz54.5 mm) or low LV ejection fraction (LVEFb29.5%). There was a weak positive correlation between OPN mRNA levels and LV end-systolic diameter (r=0.39, Pb0.01). Levels of OPN mRNA were also negatively correlated with LV ejection fraction (r=À0.43, Pb0.01). Conclusions: These results suggest that OPN may play a pivotal role in the development of Col-I-induced cardiac fibrosis and dysfunction in human DCM.
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.
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