Recombinant Gad c 1 improves diagnostic efficacy of cod allergy but not horse mackerel allergy.

BACKGROUND: Parvalbumin Gad c1 is a major cod allergen used as a follow-up marker of fish-allergic children. However, the diagnostic efficacy of recombinant Gad c 1 (rGad c 1) for fish allergy diagnosis remains controversial. This study aimed to evaluate the efficacy of rGad c1 for diagnosing cod and horse mackerel allergy. METHODS: This single-centered, retrospective study obtained oral food challenges (OFCs) information performed for cod and horse mackerel. Cod-, horse mackerel-, and rGad c1-specific immunoglobulins (sIgEs) were investigated. Diagnostic performances of these parameters were compared using areas under the curve (AUC). RESULTS: We enrolled 45 and 38 children with suspected cod and horse mackerel allergies, respectively. The median age (interquartile range) of children with suspected cod allergy was 5.7 (0.7-11.7) years and that of children with suspected horse mackerel allergy was 6.0 (1.0-12.3) years. Fourteen and 22 children reacted to OFCs with 25 (10-40) g of cooked pacific cod and 40 (10-40) g of cooked horse mackerel, respectively. The cod sIgE and rGad c 1 sIgE AUCs for cod allergy diagnosis were 0.85 and 0.90, respectively. For horse mackerel allergy diagnosis, AUCs of horse mackerel and rGad c 1 sIgE were 0.76 and 0.72, respectively. Both AUCs for cod and mackerel allergy were significantly different. CONCLUSION: rGad c 1 sIgE is more effective than cod sIgE as a diagnostic marker of cod allergy, but less effective than horse mackerel sIgE as a diagnostic marker of horse mackerel allergy. Further studies are warranted to explore the potential applications of rGad c 1 sIgE in the diagnosis of various fish allergies.

Time course changes in insulin sensitivity during cardiac surgery: A retrospective study on intraoperative glycemic management using an artificial pancreas.

INTRODUCTION: Glycemic control is essential for improving the prognosis of cardiac surgery, although precise recommendations have not yet been established. Under a constant blood glucose level, the insulin infusion rate correlates with insulin resistance during glycemic control using an artificial pancreas (AP). We conducted this retrospective study to elucidate changes in intraoperative insulin sensitivity as a first step to creating glycemic control guidelines. METHODS: Fifty-five cardiac surgery patients at our hospital who underwent intraoperative glycemic control using an AP were enrolled. Twenty-three patients undergoing surgical procedures requiring cardiac arrest under hypothermic cardiopulmonary bypass (CPB) with minimum rectal temperatures lower than 32°C, 13 patients undergoing surgical procedures requiring cardiac arrest under hypothermic CPB with minimum rectal temperatures of 32°C, eight patients undergoing on-pump beating coronary artery bypass grafting and 11 patients undergoing off-pump coronary artery bypass were assigned to groups A, B, C and D, respectively. We analyzed the time course of changes in the data derived from glycemic control using the AP. RESULTS: Significant time course changes were observed in groups A and B, but not in groups C and D. Insulin resistance was induced after the start of hypothermic CPB in groups A and B, and the induced change was not resolved by the rewarming procedure, remaining sustained until the end of surgery. CONCLUSIONS: Hypothermia is the predominant factor of the induced insulin resistance during cardiac surgery. Thus, careful glycemic management during hypothermic CPB is important. Prospective clinical studies are required to confirm the findings of this study.

Exogenous ANP Treatment Ameliorates Myocardial Insulin Resistance and Protects against Ischemia-Reperfusion Injury in Diet-Induced Obesity.

Increasing evidence suggests natriuretic peptides (NPs) coordinate interorgan metabolic crosstalk. We recently reported exogenous ANP treatment ameliorated systemic insulin resistance by inducing adipose tissue browning and attenuating hepatic steatosis in diet-induced obesity (DIO). We herein investigated whether ANP treatment also ameliorates myocardial insulin resistance, leading to cardioprotection during ischemia-reperfusion injury (IRI) in DIO. Mice fed a high-fat diet (HFD) or normal-fat diet for 13 weeks were treated with or without ANP infusion subcutaneously for another 3 weeks. Left ventricular BNP expression was substantially reduced in HFD hearts. Intraperitoneal-insulin-administration-induced Akt phosphorylation was impaired in HFD hearts, which was restored by ANP treatment, suggesting that ANP treatment ameliorated myocardial insulin resistance. After ischemia-reperfusion using the Langendorff model, HFD impaired cardiac functional recovery with a corresponding increased infarct size. However, ANP treatment improved functional recovery and reduced injury while restoring impaired IRI-induced Akt phosphorylation in HFD hearts. Myocardial ultrastructural analyses showed increased peri-mitochondrial lipid droplets with concomitantly decreased ATGL and HSL phosphorylation levels in ANP-treated HFD, suggesting that ANP protects mitochondria from lipid overload by trapping lipids. Accordingly, ANP treatment attenuated mitochondria cristae disruption after IRI in HFD hearts. In summary, exogenous ANP treatment ameliorates myocardial insulin resistance and protects against IRI associated with mitochondrial ultrastructure modifications in DIO. Replenishing biologically active NPs substantially affects HFD hearts in which endogenous NP production is impaired.

Possible Association Between Body Temperature and B-Type Natriuretic Peptide in Patients With Cardiovascular Diseases.

BACKGROUND: In addition to various biological effects of natriuretic peptides (NP) on cardiovascular systems, we recently reported that NP raises intracellular temperature in cultured adipocytes. We herein examined the possible thermogenic action of NP in consideration of hemodynamic parameters and inflammatory reaction by proposing structural equation models. METHODS AND RESULTS: The study population consisted of 1985 consecutive patients who underwent cardiac catheterization. Covariance structure analyses were performed to clarify the direct contribution of plasma B-type NP (BNP) to body temperature (BT) by excluding other confounding factors. A hierarchical path model showed increase in BNP, increase in C-reactive protein and decrease in left ventricular ejection fraction were mutually associated. As expected, C-reactive protein was positively correlated with BT. Importantly, despite a negative correlation between BNP and left ventricular ejection fraction, a decrease in the left ventricular ejection fraction was associated with BT decrease, whereas elevation in BNP level was associated with BT increase independently of C-reactive protein level (P = .007). CONCLUSIONS: Patients with LV dysfunction tend to manifest a decrease in BT, whereas BNP elevation is associated with an increase in BT independently of inflammatory response. These findings suggest the adaptive heat-retaining property of NP (and/or NP-associated factors) when BT falls owing to unfavorable hemodynamic conditions in a state of impaired cardiac function.

Cardiac ischemia-reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity.

BACKGROUND: Recent large-scale clinical trials have shown that SGLT2-inhibitors reduce cardiovascular events in diabetic patients. However, the regulation and functional role of cardiac sodium-glucose cotransporter (SGLT1 is the dominant isoform) compared with those of other glucose transporters (insulin-dependent GLUT4 is the major isoform) remain incompletely understood. Given that glucose is an important preferential substrate for myocardial energy metabolism under conditions of ischemia-reperfusion injury (IRI), we hypothesized that SGLT1 contributes to cardioprotection during the acute phase of IRI via enhanced glucose transport, particularly in insulin-resistant phenotypes. METHODS AND RESULTS: The hearts from mice fed a high-fat diet (HFD) for 12 weeks or a normal-fat diet (NFD) were perfused with either the non-selective SGLT-inhibitor phlorizin or selective SGLT2-inhibitors (tofogliflozin, ipragliflozin, canagliflozin) during IRI using Langendorff model. After ischemia-reperfusion, HFD impaired left ventricular developed pressure (LVDP) recovery compared with the findings in NFD. Although phlorizin-perfusion impaired LVDP recovery in NFD, a further impaired LVDP recovery and a dramatically increased infarct size were observed in HFD with phlorizin-perfusion. Meanwhile, none of the SGLT2-inhibitors significantly affected cardiac function or myocardial injury after ischemia-reperfusion under either diet condition. The plasma membrane expression of GLUT4 was significantly increased after IRI in NFD but was substantially attenuated in HFD, the latter of which was associated with a significant reduction in myocardial glucose uptake. In contrast, SGLT1 expression at the plasma membrane remained constant during IRI, regardless of the diet condition, whereas SGLT2 was not detected in the hearts of any mice. Of note, phlorizin considerably reduced myocardial glucose uptake after IRI, particularly in HFD. CONCLUSIONS: Cardiac SGLT1 but not SGLT2 plays a compensatory protective role during the acute phase of IRI via enhanced glucose uptake, particularly under insulin-resistant conditions, in which IRI-induced GLUT4 upregulation is compromised.

Diabetes is a predictor of coronary artery stenosis in patients hospitalized with heart failure.

In patients with heart failure, coronary artery disease is the most common underlying heart disease, and is associated with increased mortality. However, estimating the presence or absence of coronary artery disease in patients with heart failure is sometimes difficult without coronary imaging. We reviewed 155 consecutive patients hospitalized with heart failure who underwent coronary angiography. The patients were divided into two groups: patients with (N = 59) and without (N = 96) coronary artery stenosis. The clinical characteristics and blood sampling data were compared between the two groups. The patients with coronary artery stenosis were older than those without. The prevalence of diabetes mellitus (DM), dyslipidemia and a history of revascularization was higher in the patients with coronary artery stenosis. Patients with coronary artery stenosis tended to have wall motion asynergy more frequently than those without. On the other hand, the prevalence of atrial fibrillation (AF) was lower in patients with coronary artery stenosis. The serum hemoglobin level and estimated glomerular filtration rate were lower in patients with coronary artery stenosis than in those without. In the multivariate analysis, DM (odds ratio 3.517, 95 % CI 1.601-7.727) was found to be the only the predictor of the presence of coronary artery stenosis in patients with heart failure. In conclusion, coronary imaging is strongly recommended for heart failure patients with DM to confirm the presence of coronary artery stenosis.

Incidence of drug interaction when using proton pump inhibitor and warfarin according to cytochrome P450 2C19 (CYP2C19) genotype in Japanese.

OBJECTIVES: The US Food and Drug Administration has suggested that proton pump inhibitors (PPIs) increase the international normalized ratio (INR) when used concomitantly with warfarin (WF) because of being metabolized by cytochrome P450 2C19 (CYP2C19). We assessed whether CYP2C19 genotypes and type of PPI accentuated the drug interaction. METHODS AND RESULTS: The study group was 82 patients who needed WF after surgery and had their CYP2C19 genotypes analyzed in advance. We randomly divided them into two groups: group I (n = 41) included patients who had lansoprazole 15 mg/day and group II (n = 41) included patients who had rabeprazole 10 mg/day. The dose of WF was controlled by the doctor in charge as a target INR of 1.6 to 2.6 during the 2 months after surgery. The maximum INR was significantly higher in group I (3.36 ± 0.98) than in group II (2.29 ± 0.55, p < 0.0001). The incidence of over-INR (> 3.5) was significantly higher in group I (15 cases) than in group II (2 cases, p = 0.0001). Several bleeding events complicated 10 patients in group I, but none in group II (p = 0.015). Logistic regression analysis revealed that over-INR (odds ratio [OR] 3.58, 95% confidence interval [CI]: 3.48-368.25, p < 0.0001), and pair of lansoprazole and CYP2C19 intermediate metabolizer (OR 2.39, 95% CI: 1.108-29.491, p = 0.0009) were independent predictors of bleeding events. CONCLUSION: If a patient has had the intermediate metabolizer CYP2C19 genotype and concomitant use of WF and a PPI after open heart surgery, lansoprazole intensifies the effects of WF and is associated with bleeding events.

[Desflurane anesthesia without muscle relaxant for a patient with myasthenia gravis undergoing laparoscopic high anterior resection: a case report].

Myasthenia gravis (MG) is an autoimmune disease affecting neuromuscular junction, which is characterized by fluctuating muscle weakness and abnormal fatigability. The use of muscle relaxants is major concern in anesthetic management for patients with MG. Muscle relaxant is a practical tool to assure immobilization during surgery under general anesthesia Anesthetic management without muscle relaxants for patients with MG is challenging, because it is difficult to assure immobilization. However, pharmacological effects of muscle relaxants can be prolonged in patients with MG, resulting in the increased incidence of postoperative respiratory support. We, here, describe an anesthetic management of an 82-year-old man with MG undergoing laparoscopic surgery. Anesthesia was induced with propofol and remifentanil Desflurane was administered via a face mask, and the patient was manually ventilated for 10 min, and the trachea was intubated safely without muscle relaxants. Anesthesia was maintained with desflurane and remifentanil. We did not administer muscle relaxants to the patient during surgery. Throughout laparoscopic procedures, no movements of the patient were observed, and there were no problems concerning the laparoscopic view of the operation filed. The surgery was uneventful. The patient emerged from anesthesia smoothly, and was extubated safely. The postoperative course of the patient was also uneventful.

[Anesthetic management of laparoscopic cholecystectomy for a patient with Churg-Strauss syndrome: a case report].

Churg-Strauss syndrome (CSS) is an uncommon disease characterized by bronchial asthma, eosinophilia and systemic vasculitis. Many patients with CSS are suffering from cardiovascular disorders, neurological disorders and/or renal disorders which are associated with systemic vasculitis. Cardiac diseases are considered as the main cause of the death in patients with CSS. Steroid administration is the standard pharmacological therapy for CSS. There are very few clinical reports concerning anesthetic management for the patients with CSS. We suppose that precise perioperative managements are required for the patients with CSS, including the appropriate control of bronchial asthma and the careful treatments of disorders in cardiovascular system, neurological system and/or kidney. In addition, we believe that the steroid cover should be considered during the perioperative period of the patients with CSS. Here, we describe an anesthetic management of a 28-year-old man with CSS undergoing laparoscopic cholecystectomy. General anesthesia was induced with midazolam and fentanyl. Rocuronium was administered to facilitate tracheal intubation. After tracheal intubation, anesthesia was maintained with sevoflurane and remifentanil. Prior to the surgery, 100 mg of hydrocortisone was administered for the steroid cover. The surgery was uneventful. The patient emerged from general anesthesia smoothly, and was extubated safely.

Effects of angiotensin receptor-neprilysin inhibitor on ketone body metabolism in pre-heart failure/heart failure patients.

Recently, a mild elevation of the blood ketone levels was found to exert multifaceted cardioprotective effects. To investigate the effect of angiotensin receptor neprilysin inhibitors (ARNIs) on the blood ketone body levels, 46 stable pre-heart failure (HF)/HF patients were studied, including 23 who switched from angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to ARNIs (ARNI group) and 23 who continued treatment with ACE inhibitors or ARBs (control group). At baseline, there were no significant differences in the total ketone body (TKB) levels between the two groups. Three months later, the TKB levels in the ARNI group were higher than the baseline values (baseline to 3 months: 71 [51, 122] to 92 [61, 270] µmol/L, P < 0.01). In the control group, no significant change was observed between the baseline and 3 months later. A multiple regression analysis demonstrated that the initiation of ARNI and an increase in the blood non-esterified fatty acid (NEFA) levels at 3 months increased the percentage changes in the TKB levels from baseline to 3 months (%ΔTKB level) (initiation of ARNI: P = 0.017, NEFA level at 3 months: P < 0.001). These results indicate that ARNI administration induces a mild elevation of the blood TKB levels in pre-HF/HF patients.

Blunted increase in plasma BNP during acute coronary syndrome attacks in obese patients.

Background: Unexpectedly low natriuretic peptide (NP) levels in proportion to heart failure severity are often observed in obese individuals. However, the magnitude of NP elevation in response to acute cardiac stress in obesity has not yet been extensively studied. This study aimed to determine the impact of obesity on the increase in plasma NP in response to cardiac hemodynamic stress during acute coronary syndrome (ACS) attacks. Methods and Results: The study population included 557 consecutive patients with ACS for whom data were collected during emergency cardiac catheterization. To determine the possible impact of body mass index (BMI) on the relationship between left ventricular ejection fraction (LVEF) and plasma B-type NP (BNP) levels, the study population was divided into two groups (Group 1: BMI <25, Group 2: BMI ≥25 [kg/m2]). Both BMI and LVEF were significantly and negatively correlated with BNP. Although a significant negative correlation between LVEF and BNP was observed in both groups, the regression line of Group 2 was significantly less steep than that of Group 1. Accordingly, BNP/LVEF ratio in Group 2, which indicates the extent of BNP increase in response to LVEF change, was significantly lower than that in Group 1. Conclusions: Blunted increase in plasma BNP in response to cardiac hemodynamic stress during ACS attacks was observed in obese individuals. In addition to the relatively low plasma BNP levels at baseline in obese individuals, the blunted response of BNP elevation to ACS attacks may have important pathophysiological implications for hemodynamic regulation and myocardial energy metabolism.

Long-term outcomes of patients undergoing extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock.

PURPOSE: Postcardiotomy cardiogenic shock is still associated with a poor prognosis. We reviewed patients undergoing extracorporeal membrane oxygenation (ECMO) support for postcardiotomy cardiogenic shock and assessed their long-term outcomes. METHODS: The subjects were 47 patients who received ECMO support for cardiogenic shock after open heart surgery. We analyzed the long-term survival and risk factors for early or late death. RESULTS: Twenty-nine patients were weaned off ECMO support, but 15 of these patients died during their hospital stay. An independent predictor of mortality during ECMO support was incomplete sternum closure (OR 4.089, 95 % CL 1.003-16.67, p = 0.049) and a predictor of mortality after weaning off ECMO was more than 48 h of support (OR 8.975, 95 % CL 1.281-62.896, p = 0.027). Fourteen patients were discharged from hospital, but seven of these patients died during the follow-up period owing to cardiac events (n = 2) or non-cardiac causes (n = 5). The actuarial survival rates were 34.0 % at 30 days, 29.8 % at 1 year, and 17.6 % at 10 years. CONCLUSION: Although postcardiotomy cardiogenic shock requiring ECMO support is associated with high morbidity and mortality, the long-term survival rate is acceptable.

[Modified infarct exclusion technique of postinfarction ventricular septal perforation].

Ventricular septal perforation is one of the most serious complications of acute myocardial infarction, and is often fatal unless treated surgically. Despite the development of various surgical techniques for repair of postinfarction ventricular septal perforation, the operative mortality remains high. We report 3 consecutive cases in which a modified infarct exclusion technique was used to repair ventricular septal rupture after anterior myocardial infraction. The septal rupture was closed by the 1st pericardial patch with buttressed mattress sutures. Then buttressed mattress sutures were passed sequentially through the septal portion of the 2nd patch, the ventricular septum, and the free wall of the right ventricle to exclude the infarcted myocardium and septal perforation. The pericardial patch was sutured to the free wall of the left ventricle with a continuous suture for reconstruction of the left ventricular cavity. The ventriculotomy was closed with buttressed mattress sutures and a continuous suture. All 3 patients had an acceptable postoperative course and were discharged in satisfactory conditions. This technique seems to achieve satisfactory early results when used in the acute phase of myocardial infarction.

URAT1 is expressed in cardiomyocytes and dotinurad attenuates the development of diet-induced metabolic heart disease.

We recently reported that the selective inhibition of urate transporter-1 (URAT1), which is primarily expressed in the kidneys, ameliorates insulin resistance by attenuating hepatic steatosis and improving brown adipose tissue function in diet-induced obesity. In this study, we evaluated the effects of dotinurad, a URAT1-selective inhibitor, on the hearts of high-fat diet (HFD)-fed obese mice for 16-20 weeks and on neonatal rat cardiomyocytes (NRCMs) exposed to palmitic acid. Outside the kidneys, URAT1 was also expressed in cardiomyocytes and indeed worked as a uric acid transporter. Dotinurad substantially attenuated HFD-induced cardiac fibrosis, inflammatory responses, and cardiac dysfunction. Intriguingly, among various factors related to the pathophysiology of diet-induced obesity, palmitic acid significantly increased URAT1 expression in NRCMs and subsequently induced apoptosis, oxidative stress, and inflammatory responses via MAPK pathway, all of which were reduced by dotinurad. These results indicate that URAT1 is a potential therapeutic target for metabolic heart disease.

Effects of angiotensin receptor-neprilysin inhibitor on insulin resistance in patients with heart failure.

AIMS: Although the haemodynamic effects of angiotensin receptor-neprilysin inhibitor (ARNI) on patients with heart failure have been demonstrated, the effect on glucose metabolism has not been fully elucidated. We retrospectively investigated the effect of ARNI on abnormal glucose metabolism in patients with stable chronic heart failure using an additional structural equation model (SEM) analysis. METHODS: We analysed 34 patients who regularly visited to the outpatient department of our institute with heart failure from October 2021 and July 2022 and who were taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Seventeen patients switched from ACE inhibitors or ARBs to an ARNI (ARNI group), and the other 17 patients continued treatment with ACE inhibitors or ARBs (control group). RESULTS: At baseline, although the ARNI group included fewer patients with heart failure with preserved ejection fraction in comparison with the control group (P = 0.004), patients with heart failure with mildly reduced ejection fraction, and heart failure with reduced ejection fraction were mostly biased towards the ARNI group (although not statistically significant). The baseline insulin resistance in the ARNI group was already significantly higher in comparison with the control group [fasting blood insulin, 9.7 (7.4, 11.6) vs. 7.8 (5.2, 9.2) µU/mL, P = 0.033; homoeostasis model assessment of insulin resistance (HOMA-IR), 3.10 (1.95, 4.19) vs. 2.02 (1.56, 2.42), P = 0.014]. Three months later, the fasting blood insulin and the HOMA-IR levels were both found to have decreased in comparison with the baseline values [baseline to 3 months: insulin, 9.7 (7.4, 11.6) to 7.3 (4.6, 9.4) µU/mL, P < 0.001; HOMA-IR, 3.10 (1.95, 4.19) to 1.96 (1.23, 3.09), P < 0.001]. An additional SEM analysis demonstrated that the initiation of ARNI had caused a reduction in the fasting blood insulin and the HOMA-IR levels at 3 months independently of the baseline fasting blood insulin and HOMA-IR levels, respectively. Similarly, the initiation of ARNI resulted in a significant reduction in serum uric acid levels (6.28 ± 0.35 to 5.80 ± 0.30 mg/dL, P = 0.008). CONCLUSIONS: In conclusion, even in a short period of only 3 months, the administration of ARNI improved insulin resistance and consequently reduced the serum uric acid levels in patients with stable chronic heart failure. Although the ARNI group already had high insulin resistance at baseline, an additional SEM analysis revealed that the decreased insulin resistance was truly due to the effect of ARNI.

Propagative α-synuclein seeds as serum biomarkers for synucleinopathies.

Abnormal α-synuclein aggregation is a key pathological feature of a group of neurodegenerative diseases known as synucleinopathies, which include Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA). The pathogenic ß-sheet seed conformation of α-synuclein is found in various tissues, suggesting potential as a biomarker, but few studies have been able to reliably detect these seeds in serum samples. In this study, we developed a modified assay system, called immunoprecipitation-based real-time quaking-induced conversion (IP/RT-QuIC), which enables the detection of pathogenic α-synuclein seeds in the serum of individuals with synucleinopathies. In our internal first and second cohorts, IP/RT-QuIC showed high diagnostic performance for differentiating PD versus controls (area under the curve (AUC): 0.96 (95% confidence interval (CI) 0.95-0.99)/AUC: 0.93 (95% CI 0.84-1.00)) and MSA versus controls (AUC: 0.64 (95% CI 0.49-0.79)/AUC: 0.73 (95% CI 0.49-0.98)). IP/RT-QuIC also showed high diagnostic performance in differentiating individuals with PD (AUC: 0.86 (95% CI 0.74-0.99)) and MSA (AUC: 0.80 (95% CI 0.65-0.97)) from controls in a blinded external cohort. Notably, amplified seeds maintained disease-specific properties, allowing the differentiation of samples from individuals with PD versus MSA. In summary, here we present a novel platform that may allow the detection of individuals with synucleinopathies using serum samples.

The effect of combined treatment with Impella(®) and landiolol in a swine model of acute myocardial infarction.

Cardiogenic shock is associated with a high mortality rate in patients with acute myocardial infarction (AMI). We developed a new treatment approach named heart rest therapy (HRT) for complete revascularization in the early stage of AMI using an ultra-short-acting ß-blocker (landiolol) and an Impella(®) left ventricular assist device and verified the effect of this therapy in a swine model. In 18 male pigs, AMI was induced by left anterior descending coronary artery occlusion at the level of the second diagonal branch for 120 min, followed by 240 min of reperfusion. The animals were divided into three groups: group A had no support, group B was supported with the Impella(®), and group C was treated with HRT from 90 min after ischemia to 240 min after reperfusion. Infarct ratio (percentage of the infarct area relative to the area at infarct risk) was significantly reduced in group C (group A 65.38 ± 6.07, group B 39.66 ± 11.16, group C 21.78 ± 7.29), with a significant difference between groups A and B (P < 0.001), A and C (P < 0.001), and B and C (P = 0.006). Heart rates were significantly lower in group C at 30 min (P = 0.01), 60 min (P = 0.022), and 240 min (P = 0.032) after reperfusion compared with group B, without development of hypotension. HRT at the early stage in AMI stabilized the hemodynamic conditions and reduced infarct size and complications in a swine model. These results suggest that HRT can improve the prognosis of patients with AMI.

Sleep disorders and aortic dissection in a working population.

The aim of the present study was to assess the relationship between acute aortic dissection (AAD) and sleep disorders in a working population. Seventy (50.4%) of 139 younger subjects with AAD suffered from sleep disorders. Insomnia was reported by 35 patients (50%), sleep deprivation by 31 patients (44.3%), and sleep apnea syndrome was present in 43 patients (61.4%). The average apnea-hypopnea index was 22.0 ± 7.5 points, requiring appropriate treatment. Most of these patients had irregular daily schedules due to job pressure. Sixty-six (94.3%) complained of severe mental and physical stress in daily life. Sleep disorders are considered one of the risk factors for the occurrence of AAD at younger active ages. In primary care for patients with mental or physical stress due to their daily life, it is important to assess these individuals for the presence of sleep disorders.

URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice.

OBJECTIVE: Accumulating evidence indicates that high uric acid (UA) is strongly associated with obesity and metabolic syndrome and drives the development of nonalcoholic fatty liver disease (NAFLD) and insulin resistance. Although urate transporter-1 (URAT1), which is primarily expressed in the kidneys, plays a critical role in the development of hyperuricemia, its pathophysiological implication in NAFLD and insulin resistance remains unclear. We herein investigated the role and functional significance of URAT1 in diet-induced obese mice. METHODS: Mice fed a high-fat diet (HFD) for 16-18 weeks or a normal-fat diet (NFD) were treated with or without a novel oral URAT1-selective inhibitor (dotinurad [50 mg/kg/day]) for another 4 weeks. RESULTS: We found that URAT1 was also expressed in the liver and brown adipose tissue (BAT) other than the kidneys. Dotinurad administration significantly ameliorated HFD-induced obesity and insulin resistance. HFD markedly induced NAFLD, which was characterized by severe hepatic steatosis as well as the elevation of serum ALT activity and tissue inflammatory cytokine genes (chemokine ligand 2 (Ccl2) and tissue necrosis factor α (TNFα)), all of which were attenuated by dotinurad. Similarly, HFD significantly increased URAT1 expression in BAT, resulting in lipid accumulation (whitening of BAT), and increased the production of tissue reactive oxygen species (ROS), which were reduced by dotinurad via UCP1 activation. CONCLUSIONS: In conclusion, a novel URAT1-selective inhibitor, dotinurad, ameliorates insulin resistance by attenuating hepatic steatosis and promoting rebrowning of lipid-rich BAT in HFD-induced obese mice. URAT1 serves as a key regulator of the pathophysiology of metabolic syndrome and may be a new therapeutic target for insulin-resistant individuals, particularly those with concomitant NAFLD.

Substantial impact of 3-iodothyronamine (T1AM) on the regulations of fluorescent thermoprobe-measured cellular temperature and natriuretic peptide expression in cardiomyocytes.

There is growing interest in 3-iodothyronamine (T1AM), an active thyroid hormone metabolite, that induces negative inotropic and chronotropic actions in the heart and exerts systemic hypothermic action. We explored the direct impact of T1AM on cardiomyocytes with a focus on the regulation of the intracellular temperature and natriuretic peptide (NP) expression. A thermoprobe was successfully introduced into neonatal rat cardiomyocytes, and the temperature-dependent changes in the fluorescence intensity ratio were measured using a fluorescence microscope. After one-hour incubation with T1AM, the degree of change in the fluorescence intensity ratio was significantly lower in T1AM-treated cardiomyocytes than in equivalent solvent-treated controls (P < 0.01), indicating the direct hypothermic action of T1AM on cardiomyocytes. Furthermore, T1AM treatment upregulated B-type NP (BNP) gene expression comparable to treatment with endothelin-1 or phenylephrine. Of note, ERK phosphorylation was markedly increased after T1AM treatment, and inhibition of ERK phosphorylation by an MEK inhibitor completely cancelled both T1AM-induced decrease in thermoprobe-measured temperature and the increase in BNP expression. In summary, T1AM decreases fluorescent thermoprobe-measured temperatures (estimated intracellular temperatures) and increases BNP expression in cardiomyocytes by activating the MEK/ERK pathway. The present findings provide new insight into the direct myocardial cellular actions of T1AM in patients with severe heart failure.