Exercise-Induced Post-Ischemic Left Ventricular Delayed Relaxation or Diastolic Stunning Is it a Reliable Marker in Detecting Coronary Artery Disease?

ObjectivesThe aim of this study was to determine whether post-ischemic left ventricular (LV) delayed relaxation could be detected by using strain imaging (SI) derived from 2-dimensional speckle-tracking echocardiography in patients with stable effort angina.BackgroundRegional LV delayed relaxation during early diastole is a sensitive sign of acute myocardial ischemia and may persist beyond recovery of exercise-induced ischemia.MethodsRegional LV transverse strain changes during the first one-third of diastole duration (strain imaging diastolic index [SI-DI]) were determined at baseline and 5 and 10 min after the exercise test in 162 patients with stable effort angina. The ratio of SI-DI before and after exercise (SI-DI ratio) was used to identify regional LV delayed relaxation.ResultsA total of 117 patients had significant (≥50% of luminal diameter) coronary stenoses. The mean SI-DI decreased from 78.0 ± 9.7% to 27.6 ± 16.0% (p < 0.0001) in 191 territories perfused by coronary arteries with significant stenoses 5 min after the treadmill exercise, whereas it remained unchanged in 280 territories perfused by arteries with nonsignificant stenoses. Ten minutes after exercise, regional delayed relaxation was still observed in 85% of territories perfused by stenotic coronary arteries. An SI-DI ratio with a cutoff value of 0.74 had a sensitivity of 97% and a specificity of 93% to detect significant coronary stenosis in the receiver-operator characteristic curve.ConclusionsDetection of post-ischemic regional LV delayed relaxation or diastolic stunning after treadmill exercise using SI is a sensitive and reliable method for the detection of coronary artery disease

セイタイ ノ テイサンソ オウトウ ト ビョウタイ : ケッカン リモデリング ニオケル テンシャ インシ HIF ノ カンヨ「

Recent studies have shown that the cellular immune response to the hypoxic microenvironment constructed by vascular remodeling development modulates the resulting pathologic alterations. A major mechanism mediating adaptive responses to reduced oxygen availability is the regulation of transcription by hypoxia-inducible factor１（HIF‐１）. Impairment of HIF‐１‐ dependent inflammatory responses in T cells causes an augmented vascular remodeling induced by arterial injury, which is shown as prominent neointimal hyperplasia and increase in infiltration of inflammatory cells at the adventitia in mice lacking Hif‐１α specifically in T cells. Studies to clarify the mechanism of augmented vascular remodeling in the mutant mice have shown enhanced production of cytokines in activated T cells and augmented antibody production in response to a T-dependent antigen in the mutant mice. This minireview shows that HIF‐１α in T cells plays a crucial role in vascular inflammation and remodeling in response to cuff injury as a negative regulator of the T cell-mediated immune response and suggests potential new therapeutic strategies that target HIF‐１α

Rho-associated protein kinase and cyclophilin a are involved in inorganic phosphate-induced calcification signaling in vascular smooth muscle cells

Arterial calcification, a risk factor of cardiovascular events, develops with differentiation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells. Cyclophilin A (CypA) is a peptidyl-prolyl isomerase involved in cardiovascular diseases such as atherosclerosis and aortic aneurysms, and rho-associated protein kinase (ROCK) is involved in the pathogenesis of vascular calcification. CypA is secreted in a ROCK activity-dependent manner and works as a mitogen via autocrine or paracrine mechanisms in VSMCs. We examined the involvement of the ROCK-CypA axis in VSMC calcification induced by inorganic phosphate (Pi), a potent cell mineralization initiator. We found that Pi stimulated ROCK activity, CypA secretion, extracellular signal-regulated protein kinase (ERK) 1/2 phosphorylation, and runt-related transcription factor 2 expression, resulting in calcium accumulation in rat aortic smooth muscle cells (RASMCs). The ROCK inhibitor Y-27632 significantly suppressed Pi-induced CypA secretion, ERK1/2 phosphorylation, and calcium accumulation. Recombinant CypA was found to be associated with increased calcium accumulation in RASMCs. Based on these results, we suggest that autocrine CypA is mediated by ROCK activity and is involved in Pi-induced ERK1/2 phosphorylation following calcification signaling in RASMCs

Plasma levels of matrix metalloproteinase‐9 (MMP‐9) are associated with cognitive performance in patients with schizophrenia

Aim: Matrix metalloproteinase‐9 (MMP‐9) has been shown to modulate synaptic plasticity and may contribute to the pathophysiology of schizophrenia. This study investigated the peripheral levels of MMP‐9 and its association with cognitive functions in patients with schizophrenia to see the possible involvement of MMP‐9 in pathophysiology of schizophrenia, especially in cognitive decline. Methods: We measured the plasma levels of MMP‐9 in 257 healthy controls and 249 patients with schizophrenia, including antipsychotic drug–free patients. We also explored the possible association between plasma MMP‐9 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition (WAIS‐ III), the Wechsler Memory Scale‐Revised (WMS‐R), and the Rey Auditory Verbal Learning Test (AVLT). Results: We found that the plasma levels of MMP‐9 were significantly higher in patients with schizophrenia, including antipsychotic drug–free patients, than in healthy controls. We found a significant negative association between plasma MMP‐9 levels and cognitive performance in controls and patients with schizophrenia. Conclusion: Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased MMP‐9 levels are associated with cognitive impairment

Plasma Levels of Soluble Tumor Necrosis Factor Receptor 2 (sTNFR2) Are Associated with Hippocampal Volume and Cognitive Performance in Patients with Schizophrenia

Background: An imbalance in the inflammatory tumor necrosis factor system, including soluble tumor necrosis factor receptor 2 (sTNFR2), may contribute to the pathophysiology of schizophrenia. Methods: We measured the plasma levels of sTNFR2 in 256 healthy controls and 250 patients with schizophrenia including antipsychotic drug-free patients and treatment-resistant patients. We also explored the possible association between plasma sTNFR2 levels and cognitive performance in healthy controls and patients with schizophrenia using the Wechsler Adult Intelligence Scale, Third Edition, the Wechsler Memory Scale-Revised, and the Rey Auditory Verbal Learning Test. An association between plasma sTNFR2 levels and hippocampal volume in controls and patients with schizophrenia was also investigated via MRI. Results: We found that the plasma levels of sTNFR2 were significantly higher in patients with schizophrenia, including both antipsychotic drug-free patients and treatment-resistant patients. We found a significant negative association between plasma sTNFR2 levels and cognitive performance in controls and patients with schizophrenia. Hippocampal volume was also negatively associated with plasma sTNFR2 levels in patients with schizophrenia. Conclusion: Together, these convergent data suggest a possible biological mechanism for schizophrenia, whereby increased sTNFR2 levels are associated with a smaller hippocampal volume and cognitive impairment

Deletion of H-ferritin in macrophages alleviates obesity and diabetes induced by high-fat diet in mice

Aims/hypothesis Iron accumulation affects obesity and diabetes, both of which are ameliorated by iron reduction. Ferritin, an iron storage protein, plays a crucial role in iron metabolism. H-ferritin exerts its cytoprotective action by reducing toxicity via its ferroxidase activity. We investigated the role of macrophage H-ferritin in obesity and diabetes. Methods Conditional macrophage-specific H-ferritin knockout (LysM-Cre FthKO) mice were used and divided into 4 groups; Wild-type (WT) and LysM-Cre FthKO mice with normal diet (ND), and WT and LysM-Cre Fth-KO mice with high-fat diet (HFD). Results Iron concentration reduced, and mRNA expression of ferroportin increased in macrophages from LysM-Cre FthKO mice. HFD-induced obesity was lower in LysM-Cre FthKO mice than in WT mice at 12 weeks (body weight (g); KO 34.6 ± 5.6 vs. WT 40.1 ± 5.2). mRNA expression of inflammatory cytokines, infiltrated macrophages, and oxidative stress increased in the adipose tissue of WT mice with HFD, but was not elevated in LysM-Cre FthKO mice with HFD. However, WT mice with HFD had elevated iron concentration in adipose tissue and spleen, which was not observed in LysM-Cre FthKO mice with HFD (adipose (μmol Fe/g protein); KO 1496 ± 479 vs. WT 2316 ± 866, spleen (μmol Fe/g protein); KO 218 ± 54 vs. WT 334 ± 83). Moreover, HFD administration impaired both glucose tolerance and insulin sensitivity in WT mice, which was ameliorated in LysM-Cre FthKO mice. In addition, energy expenditure, mRNA expression of thermogenic genes, and body temperature were higher in KO mice with HFD than WT mice with HFD. In vitro experiments showed that iron content was reduced, and LPS-induced TNF-α mRNA upregulation was inhibited in a macrophage cell line transfected with Fth siRNA. Conclusions/interpretation Deletion of macrophage H-ferritin suppresses the inflammatory response by reducing intracellular iron levels, resulting in the prevention of HFD-induced obesity and diabetes. The findings from this study highlight macrophage iron levels as a potential therapeutic target for obesity and diabetes