Michio Shimabukuro

Echocardiographic Epicardial Adipose Tissue Thickness Is Associated with Symptomatic Coronary Vasospasm during Provocative Testing

Background: Epicardial adipose tissue (EAT) is the ectopic visceral fat surrounding the heart, which plays an important role in atherosclerosis of the coronary arteries via endothelial damage. Several studies have also suggested that vasospasm with angina (VSA) causes endothelial dysfunction in the coronary arteries. The aim of this study was to evaluate the thickness of EAT in the anterior interventricular groove (EAT‐AIG) using echocardiography in patients who had no obstructive coronary artery disease and were suspected of having VSA. Methods: Sixty‐five patients who underwent intracoronary acetylcholine provocation testing for clinical indications were prospectively enrolled. VSA was diagnosed by coronary artery stenosis increase of >90% and the presentation of chest pain with ischemic changes on electrocardiography. Results: Subjects were divided into two groups, with and without significant coronary spasm (VSA group, 30 patients; non‐VSA group, 35 patients), consistent with acetylcholine provocation testing. EAT‐AIG thickness was significantly greater in the VSA group than in the non‐VSA group (8.2 ± 2.7 vs 6.1 ± 2.5 mm, P = .002). By receiver operating characteristic analysis, EAT‐AIG thickness had a high C statistic (area under the curve = 0.81, P < .001) after adjustment for conventional risk factors (smoking, diabetes mellitus, and dyslipidemia). EAT‐AIG thickness had incremental diagnostic value over other conventional risk factors (area under the curve = 0.81 vs 0.64, P for comparison = .020). Conclusions: EAT‐AIG thickness, which is noninvasively and easily measured using transthoracic echocardiography, can be one of multiple clinical variables associated with VSA. HighlightsTo the best of our knowledge, this is the first report of echocardiographic EAT‐AIG thickness to help diagnose VSA in patients with chest pain or discomfort.EAT‐AIG thickness is noninvasively and easily measured using transthoracic echocardiography and can be one of multiple clinical variables associated with VSA.EAT‐AIG thickness may be useful as a risk factor and for follow‐up of patients with presumptive VSA.

Activity of xanthine oxidase in plasma correlates with indices of insulin resistance and liver dysfunction in patients with type 2 diabetes mellitus and metabolic syndrome: A pilot exploratory study

There is controversy as to whether hyperuricemia is an independent risk factor for cardiometabolic diseases. The serum level of uric acid is affected by a wide variety of factors involved in its production and excretion. In contrast, evidence has accumulated that locally‐ and systemically‐activated xanthine oxidase (XO), a rate‐limiting enzyme for production of uric acid, is linked to metabolic derangement in humans and rodents. We therefore explored the clinical implication of plasma XO activity in patients with type 2 diabetes mellitus and metabolic syndrome (MetS).

Adiponectin and T-Cadherin: a Tree for Biomarkers in ST-Elevation or Non-ST-Elevation Myocardial Infarction

Patients with suspected acute coronary syndromes (ACS) are differentiated based on their electrocardiogram (ECG) results as follows : (1) ST-elevation myocardial infarction (STEMI): patients with acute chest pain and persistent (20 min) ST segment elevation indicating acute total coronary occlusion and generally requiring immediate reperfusion with primary percutaneous coronary intervention (PPCI) or (2) nonST-elevation myocardial infarction (NSTEMI): patients with acute chest pain but no persistent ST-segment elevation and who may show a clinical spectrum from no symptoms at presentation to ongoing ischemia, electrical or hemodynamic instability, or cardiac arrest, indicating cardiomyocyte necrosis or less frequently, myocardial ischemia without cell loss (unstable angina). In the therapeutic strategy for ACS, biomarkers may improve the diagnostic accuracy and risk stratification by clinical assessment based on ECG and identify subgroups of patients who would benefit from a specific therapeutic modality in the acute phase. The new-generation cardiac troponin (cTn) assays, which reflect the presence of myocardial necrosis, provide considerably sensitive and specific diagnosis of ACS compared with less sensitive cTn and creatine kinase (CK) with its MB isoenzyme (CK-MB). The newgeneration cTn assays reduce the proportion of cases with unstable angina and increase that of cases with NSTEMI in the patients with NSTE-ACS (Fig.1). Consequently, this reclassification is believed to guide appropriate decisions of treatment. However, the longterm benefit of an invasive approach and its subsequent medical treatment in subgroups of patients reclassified from unstable angina to NSTE myocardial infarction has not been fully clarified (Fig.1) . Meanwhile, the diagnosis and acute management of STEMI are considered to be simple compared with those of NSTEMI, with the main decision of whether to perform immediate revascularization, pharmacological or mechanical, solely based on ST-segment elevation and symptoms . The prognosis of patients with STEMI who are promptly revascularized with PPCI is widely perceived to be good and is largely dependent on the efficacy of reperfusion and rescue of viable myocardial tissues. Although there is a striking decrease in acute mortality in patients with STEMI, an unacceptable rate of recurrent events still occurs after ACS including STEMI, prompting us identify biomarkers of STEMI. The current issue by Natsukawa et al. may provide an insight into a strategy for the diagnosis and risk stratification of STEMI. In 49 Japanese subjects who underwent PPCI for STEMI, the area under the curve (AUC) for serum CK-MB levels was associated with serum adiponectin levels on admission and Δ serum adiponectin levels at the acute phase. The present study may indicate that serum adiponectin levels are useful in the prediction of prognosis after PCItreated STEMI subjects. Adiponectin, an adipocyte-specific secretory protein, abundantly exists in the blood stream. Serum adiponectin levels paradoxically decrease in patients with visceral fat obesity and are associated with endothelial dysfunction, presence of ischemic heart diseases, and complexity of coronary lesion. The current study found that serum adiponectin levels decreased from admission to after 24 h and gradually recovered to baseline levels, and Δ serum adiponectin levels at the acute phase were negatively associated with serum AUC of CK-MB levels, suggesting that accumulation or consumption of adiponectin in the local area at the risk for myocardial necrosis may protect from myocardial damage and result in the reducAdiponectin and T-Cadherin: a Tree for Biomarkers in ST-Elevation or Non-ST-Elevation Myocardial Infarction

Brown rice-specific γ-oryzanol as a promising prophylactic avenue to protect against diabetes mellitus and obesity in humans

Chronic overconsumption of animal fats causes a variety of health problems, including diabetes mellitus and obesity. Underlying molecular mechanisms encompass leptin resistance, a decrease in rewarding effects of physical activities, xanthine oxidase‐induced oxidative stress in vasculature and peripheral tissue, impaired activation of incretin signaling, deviation in food preference, and dysbiosis of gut microbiota. Based on our clinical observation that daily intake of brown rice effectively ameliorates bodyweight gain, impaired glucose tolerance/insulin resistance and dependence on fatty foods in obese, prediabetes men, a line of research on brown rice (rice bran)‐derived γ‐oryzanol in mice experiments, cultured cells and human clinical trials is underway in our laboratory. Our works in mice showed that γ‐oryzanol, an ester mixture of ferulic acid and several kinds of phytosterols, acts as a molecular chaperone, thereby attenuating the strong preference for animal fats through suppression of endoplasmic reticulum stress in the hypothalamus. In pancreatic islets from both high‐fat diet‐induced and streptozotocin‐induced diabetic mice, γ‐oryzanol ameliorates endoplasmic reticulum stress and protects β‐cells against apoptosis. Noticeably, γ‐oryzanol also acts as a potent inhibitor against deoxyribonucleic acid methyltransferases in the brain reward system (striatum) in mice, thereby attenuating, at least partly, the preference for a high‐fat diet through the epigenetic modulation of striatal dopamine D2 receptor. Because dopamine D2 receptor signaling in the brain reward system is considerably attenuated in obese humans and rodents, γ‐oryzanol might represent a unique property to ameliorate both hedonic and metabolic dysregulation of feeding behavior, highlighting a promising prophylactic avenue to protect against metabolic derangement.

Preliminary Evidence for Adipocytokine Signals in Skeletal Muscle Glucose Uptake

The cross talk between the adipose tissue and insulin target tissues is a key mechanism for obesity-associated insulin resistance. However, the precise role of the interaction between the skeletal muscle and adipose tissue for insulin signaling and glucose uptake is questionable. L6 myocytes were co-cultured with or without 3T3-L1 adipocytes (~5 × 103 cells/cm2) up to 24 h. Glucose uptake was evaluated by 2-[3H] deoxyglucose uptake assay. Levels of mRNA expression of Glut1 and Glut4 and mitochondrial enzymes were analyzed by quantitative real-time reverse transcription polymerase chain reaction. Levels of Glut1 and Glut4 protein and phosphorylation of Akt (Ser473 and Thr308) were analyzed by immunoblotting. Study 1: co-culture with 3T3-L1 adipocytes increased glucose uptake in dose- and time-dependent manner in L6 myocytes under insulin-untreated conditions. When co-cultured with 3T3-L1 cells, reactive oxygen species production and levels of Glut1 mRNA and protein were increased in L6 cells, while these changes were abrogated and the glucose uptake partially inhibited by antioxidant treatment. Study 2: co-culture with 3T3-L1 adipocytes suppressed insulin-stimulated glucose uptake in L6 myocytes. Insulin-induced Akt phosphorylation at Ser473 decreased, which was proportional to 3T3-L1 density. Antioxidant treatment partially reversed this effect. Interactions between skeletal muscle and adipose tissues are important for glucose uptake under insulin-untreated or -treated condition through oxygen stress mechanism.