Sympathetic neuropeptide Y protects from obesity by sustaining thermogenic fat.

Human mutations in neuropeptide Y (NPY) have been linked to high body mass index but not altered dietary patterns1. Here we uncover the mechanism by which NPY in sympathetic neurons2,3 protects from obesity. Imaging of cleared mouse brown and white adipose tissue (BAT and WAT, respectively) established that NPY+ sympathetic axons are a smaller subset that mostly maps to the perivasculature; analysis of single-cell RNA sequencing datasets identified mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains the proliferation of mural cells, which are a source of thermogenic adipocytes in both BAT and WAT4-6. We found that diet-induced obesity leads to neuropathy of NPY+ axons and concomitant depletion of mural cells. This defect was replicated in mice with NPY abrogated from sympathetic neurons. The loss of NPY in sympathetic neurons whitened interscapular BAT, reducing its thermogenic ability and decreasing energy expenditure before the onset of obesity. It also caused adult-onset obesity of mice fed on a regular chow diet and rendered them more susceptible to diet-induced obesity without increasing food consumption. Our results indicate that, relative to central NPY, peripheral NPY produced by sympathetic nerves has the opposite effect on body weight by sustaining energy expenditure independently of food intake.

Post-translational control of beige fat biogenesis by PRDM16 stabilization.

Compelling evidence shows that brown and beige adipose tissue are protective against metabolic diseases1,2. PR domain-containing 16 (PRDM16) is a dominant activator of the biogenesis of beige adipocytes by forming a complex with transcriptional and epigenetic factors and is therefore an attractive target for improving metabolic health3-8. However, a lack of knowledge surrounding the regulation of PRDM16 protein expression hampered us from selectively targeting this transcriptional pathway. Here we identify CUL2-APPBP2 as the ubiquitin E3 ligase that determines PRDM16 protein stability by catalysing its polyubiquitination. Inhibition of CUL2-APPBP2 sufficiently extended the half-life of PRDM16 protein and promoted beige adipocyte biogenesis. By contrast, elevated CUL2-APPBP2 expression was found in aged adipose tissues and repressed adipocyte thermogenesis by degrading PRDM16 protein. Importantly, extended PRDM16 protein stability by adipocyte-specific deletion of CUL2-APPBP2 counteracted diet-induced obesity, glucose intolerance, insulin resistance and dyslipidaemia in mice. These results offer a cell-autonomous route to selectively activate the PRDM16 pathway in adipose tissues.

Efficacy of Computed Tomography-Based Evaluation of Myocardial Extracellular Volume Combined With Red Flags for Early Screening of Concealed Cardiac Amyloidosis in Patients With Atrial Fibrillation.

BACKGROUND: The prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM) in atrial fibrillation (AF) patients remains unclear. We explored the efficacy of computed tomography-based myocardial extracellular volume (CT-ECV) combined with red flags for the early screening of concealed ATTR-CM in AF patients undergoing catheter ablation. METHODS AND RESULTS: Patients referred for AF ablation at Oita University Hospital were prescreened using the red-flag signs defined by echocardiographic or electrocardiographic findings, medical history, symptoms, and blood biochemical findings. Myocardial CT-ECV was quantified in red flag-positive patients using routine pre-AF ablation planning cardiac CT with the addition of delayed-phase cardiac CT scans. Patients with high (>35%) ECV were evaluated using technetium pyrophosphate (99 mTc-PYP) scintigraphy. A cardiac biopsy was performed during the planned AF ablation procedure if 99 mTc-PYP scintigraphy was positive. Between June 2022 and June 2023, 342 patients were referred for AF ablation. Sixty-seven (19.6%) patients had at least one of the red-flag signs. Myocardial CT-ECV was evaluated in 57 patients because of contraindications to contrast media, revealing that 16 patients had high CT-ECV. Of these, 6 patients showed a positive 99 mTc-PYP study, and 6 patients were subsequently diagnosed with wild-type ATTR-CM via cardiac biopsy and genetic testing. CONCLUSIONS: CT-ECV combined with red flags could contribute to the systematic early screening of concealed ATTR-CM in AF patients undergoing catheter ablation.

Reduction of bleeding complications on puncture site after percutaneous coronary intervention using a 6.5-French sheathless guiding catheter.

BACKGROUND: Reducing complications at the puncture site after percutaneous coronary intervention (PCI) is important. The diameter of a 6.5-French (Fr) sheathless guiding catheter (GC) is smaller by approximately 2-Fr compared to a 6-Fr conventional sheath. In the present study, we investigated the post-PCI puncture site complications of a transradial approach in each gender while using a 6.5-Fr sheathless GC. METHODS AND RESULTS: Our study consisted of 332 patients who underwent transradial coronary intervention (TRI) between August 2017 and July 2019. We classified the patients into either the 6.5-Fr sheathless GC (Asahi, Intecc, Aichi, Japan) Group (Sheathless group: n = 182 males, 58 females) or the 6-Fr sheathed GC Group (Sheathed group: n = 150 males, 36 females). We determined the complications at the puncture site: oozing, subcutaneous hemorrhage, formation of hematoma, pseudoaneurysms, and peripheral neuropathy. The body mass index of the patients was greater in the sheathless GC group compared to the sheathed GC group (24.5 ± 3.5 kg/m2 vs. 23.6 ± 3.7 kg/m2, p = 0.02). In males, there was no significant difference in the complication rate at the puncture site between the sheathless GC and sheathed GC groups (19.3% vs. 18.6%, p = 0.88). However, the complication rate at the puncture site in females was higher in the sheathed GC group than in the sheathless GC group (36% vs. 15.5%, p = 0.02). A multiple logistic regression analysis revealed that the use of a 6.5-Fr sheathless GC independently reduced the complications in female patients (p = 0.006). CONCLUSION: The use of the 6.5-Fr sheathless GC system in a transradial approach reduced the complications at the puncture site in female patients. The 6.5-Fr sheathless GC system may be a safe option for them compared to the conventional sheath system.

Factors associated with bleeding events during catheter ablation with uninterrupted periprocedural edoxaban for atrial fibrillation: a subanalysis of the KYU-RABLE study.

BACKGROUND: Data are limited on patient background characteristics associated with catheter ablation (CA)-related bleeding events in Japanese patients with non-valvular atrial fibrillation receiving uninterrupted periprocedural edoxaban. This subanalysis of the KYU-RABLE study focused on univariate and multivariate analyses to identify correlations between bleeding events and baseline patient demographics and CA-related characteristics. METHODS: Patients with non-valvular atrial fibrillation (NVAF) enrolled from the KYU-RABLE study were included in the study. We performed univariate and multivariate analyses to investigate the correlation of major, minor, and clinically relevant non-major bleeding events with the patient baseline data at enrollment, and with CA procedures. RESULTS: A total of 513 NVAF patients were included in the full analysis set. Univariate analysis showed that the incidence of the bleeding events was higher in patients with HAS-BLED score ≥ 3 compared with those with a score < 3 (odds ratio [OR]: 9.48, 95% CI: 2.36-38.01; p = 0.002), in those with creatinine clearance (CrCL) ≤50 mL/min compared with those with CrCL > 50 mL/min (OR: 10.59, 95% CI: 3.65-30.79; p < 0.0001), and in those receiving edoxaban 30 mg compared with those receiving edoxaban 60 mg (OR: 3.49, 95% CI: 1.18-10.38; p = 0.025). Multivariate analysis showed that HAS-BLED score ≥ 3 (OR: 7.93, 95% CI: 1.66-37.88; p = 0.0094) and CrCl ≤ 50 mL/min (OR: 7.78, 95% CI: 2.17-27.90; p = 0.0016) were significant predictors of bleeding events among KYU-RABLE patients. CONCLUSIONS: These predictors of CA-related bleeding events may allow informed decision-making and better AF patient selection for CA with uninterrupted periprocedural edoxaban. TRIAL REGISTRATION: KYU-RABLE, UMIN000029693 . Registered 1 December 2017.

Usefulness of subcutaneous implantable cardioverter-defibrillator therapy in patients with Brugada syndrome.

Implantable cardioverter-defibrillators (ICDs) are the main therapy to prevent sudden cardiac death in patients with Brugada syndrome (BrS). The subcutaneous ICD (S-ICD) can eliminate lead-associated complications compared with transvenous ICD (TV-ICD). However, S-ICD is susceptible to T-wave oversensing (TWOS) and may result in more frequent inappropriate shocks in patients with BrS. This study aimed to compare inappropriate shocks between TV-ICD and S-ICD in patients with BrS. We enrolled 32 patients with BrS (including one woman; mean age 52 ± 18 years) who were implanted with ICD (23 TV-ICDs and 9 S-ICDs) between January 2002 and November 2018 in Oita University Hospital. We carried out a standard surface electrocardiogram (ECG) screening tests in both supine and standing positions prior to S-ICD implantation. The patients received routine clinical review every month and device monitoring every 4 months. The period of follow-up was 129 ± 51 months. Six patients with BrS and TV-ICDs experienced inappropriate shocks (26%) with their ICD therapy. In contrast, two patients with BrS and S-ICDs experienced inappropriate shocks (22%). There was no significant difference between the two groups (P = 0.82). Although one case in the S-ICD group experienced TWOS-induced inappropriate shock, SMART Pass (new high-pass filter) prevented the subsequent recurrence of inappropriate shocks during ICD therapy. Our results suggest that S-ICD is not inferior to TV-ICD in the incidence of inappropriate shocks. SMART Pass may be a useful tool to prevent inappropriate ICD shocks by TWOS in patients with BrS.

Hyponatraemia aggravates cardiac susceptibility to ischaemia/reperfusion injury.

Hyponatraemia is defined as a serum sodium concentration of <135 mEql/L and is the most common electrolyte disturbance in patients with chronic heart failure. We hypothesize that hyponatraemia may induce Ca2+ overload and enhance reactive oxygen species (ROS) production, which will exacerbate myocardial injury more than normonatraemia. We investigated the effect of hyponatraemia on the ability of the heart to recover from ischaemia/reperfusion episodes. Cardiomyocytes were obtained from 1- to 3-day-old Sprague Dawley rats. After isolation, cardiomyocytes were placed in Dulbecco's modified Eagle's medium (DMEM) containing low sodium concentration (110, 120, or 130 mEq/L) or normal sodium concentration (140 mEq/L) for 72 hours. Exposure of cardiomyocytes to each of the low-sodium medium significantly increased both ROS and intracellular Ca2+ levels compared with the exposure to the normal-sodium medium. In vivo, 8-week-old male Sprague Dawley rats were divided into four groups: control group (Con), furosemide group (Fur), low-sodium diet group (Lsd) and both furosemide and low-sodium diet group (Fur + Lsd). The hearts subjected to global ischaemia exhibited considerable decrease in left ventricular developed pressure during reperfusion, and the size of infarcts induced by ischaemia/reperfusion significantly increased in the Fur, Lsd and Fur + Lsd compared with that in the Con. Hyponatraemia aggravates cardiac susceptibility to ischaemia/reperfusion injury by Ca2+ overload and increasing in ROS levels.

Assessment of coronary flow reserve predicts long-term outcome of responders to cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) has been established as a treatment for patients with chronic heart failure (HF). We tested the hypothesis that assessment of coronary flow reserve (CFR) predicts the long-term outcome of CRT. The study consisted of 114 HF patients implanted with a CRT device for the treatment of advanced HF between April 2010 and April 2018. After excluding patients that withdrew from long-term follow-up and patients missing a baseline CFR measurement, we enrolled 53 eligible patients. CFR was determined non-invasively by transthoracic echocardiography. Based on the ROC curve for predicting the appearance of major adverse cerebral and cardiovascular events (MACCE), the level of preserved CFR was set at >1.35 in responders. Accurate follow-up information (mean 873 ± 498 days) was obtained in 23 patients with a preserved CFR (16 females; mean age 71 ± 7.9 years) and 11 patients with a depressed CFR (5 females; mean age, 73 ± 7.6 years) in responders. Kaplan-Meier survival analysis demonstrated that the depressed CFR group had a higher prevalence of MACCE than the preserved CFR group (log rank, 9.83; p = 0.0021). Multivariate analysis revealed that depressed CFR was associated with MACCE (hazard ratio 4.88, 95% confidence interval 1.13-26.5, p = 0.0329). Our results suggest that the assessment of CFR predicts the outcome in responders to CRT. Preservation of coronary circulation flow might underlie one of the mechanisms for a better response to CRT in responders.

Seasonal variations of weather conditions on acute myocardial infarction onset: Oita AMI Registry.

The onset of acute myocardial infarction (AMI) has been reportedly related to weather conditions. The aim of this study was to investigate the impact of weather conditions on AMI onset. Our study population consisted of 274 patients enrolled in the Oita AMI Registry who were admitted with AMI between June 2012 and May 2013. We divided the 365 days of the year into the four seasons: spring (March, April, May), summer (June, July, August), autumn (September, October, November), and winter (December, January, February). We classified each day as a day of onset of AMI (onset day) or a day of non-onset of AMI (non-onset day). Information on maximum temperature, minimum temperature, mean humidity, and mean atmospheric pressure was obtained from the Japan Meteorological Agency. In summer, the temperatures and intraday temperature differences were significantly lower on onset days than on non-onset days. Receiver operating characteristic analysis for predicting AMI onset in each season showed that the maximum temperature 2 days before AMI onset in summer had the largest area under the curve (AUC = 0.72, p = 0.0005). Our analysis demonstrated that there exist specific weather conditions that influence AMI onset in each season in Oita prefecture. AMI onset in summer was particularly associated with the maximum temperature 2 days before AMI onset.

Mast Cells Play an Important Role in the Pathogenesis of Hyperglycemia-Induced Atrial Fibrillation.

BACKGROUND AND OBJECTIVES: Recently, it was reported that mast cells (MCs) could underlie the mechanisms of several cardiovascular diseases. However, the role of MCs in diabetes-induced atrial fibrillation (AF) has not been notably investigated. We tested the hypothesis that MC deficiency attenuates hyperglycemia-induced AF in mice. METHODS AND RESULTS: Mast cell-deficient W/W(v)  mice, and congenic +/+ littermates (WT) were divided into either the vehicle (VEH)-injection group or the streptozotocin (STZ)-injection group (MCKO-VEH, MCKO-STZ, WT-VEH, and WT-STZ groups). On day 28 of our studies, we observed that (1) STZ-induced hyperglycemia increased MC infiltration in the left atrium (LA) in WT mice (P < 0.01), (2) atrium isolated from the WT-STZ group showed inhomogeneous interstitial fibrosis, abundant infiltration of macrophages, and enhanced apoptosis compared to the WT-VEH group (P < 0.01, P < 0.01, P < 0.05, respectively). However, the changes observed in the WT-STZ group were significantly attenuated in the MCKO-STZ mice. In addition, we observed that (3) messenger RNA levels of tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-1ß, transforming growth factor-ß, and collagen-1 in the LA were increased in the WT-STZ group, but not in the MCKO-STZ group, (4) STZ-induced hyperglycemia increased AF induction and prolonged interatrial conduction time in the WT mice, which were not observed in the MCKO mice, and that (5) hyperglycemia-enhanced atrial production of reactive oxygen species (ROS) was equally observed in the WT and MCKO mice. CONCLUSIONS: Our results suggest that MCs contribute to the pathogenesis of hyperglycemia-induced AF via enhancement of inflammation and fibrosis.

Glucose Fluctuations Aggravate Cardiac Susceptibility to Ischemia/Reperfusion Injury by Modulating MicroRNAs Expression.

BACKGROUND: The influence of glucose fluctuations (GF) on cardiovascular complications of diabetes mellitus (DM) has been attracting much attention. In the present study, whether GF increase susceptibility to ischemia/reperfusion in the heart was investigated. METHODS AND RESULTS: Male rats were randomly assigned to either a control, DM, and DM with GF group. DM was induced by an injection of streptozotocin, and glucose fluctuation was induced by starvation and insulin injection. One sequential program comprised 2 hypoglycemic episodes during 4 days. The isolated hearts were subjected to 20-min ischemia/30-min reperfusion. The infarct size was larger in hearts with GF than those with sustained hyperglycemia. Activities of catalase and superoxide dismutase were decreased, and expressions of NADPH oxidase and thioredoxin-interacting protein were upregulated by GF accompanied by an increase of reactive oxygen species (ROS). Swollen mitochondria with destroyed cristae were observed in diabetic hearts; they were further devastated by GF. Microarray analysis revealed that the expressions of microRNA (miRNA)-200c and miRNA-141 were abundant in those hearts with GF. Overexpression of miRNA-200c and miRNA-141 decreased mitochondrial superoxide dismutase and catalase activities, and increased ROS levels. Meanwhile, knockdown of miRNA-200c and miRNA-141 significantly decreased ROS levels in cardiomyocytes exposed to GF. CONCLUSIONS: GF increased ROS generation and enhanced ischemia/reperfusion injury in the diabetic heart. Upregulated miRNA-200c and miRNA-141 may account for the increased ROS.

Mitochondrial choline import regulates purine nucleotide pools via SLC25A48.

Choline is an essential nutrient for cellular metabolism, including the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism. A critical step of choline catabolism is the mitochondrial import and synthesis of chorine-derived methyl donors, such as betaine. However, the underlying mechanisms and the biological significance of mitochondrial choline catabolism remain insufficiently understood. Here, we report that a mitochondrial inner-membrane protein SLC25A48 controls mitochondrial choline transport and catabolism in vivo. We demonstrate that SLC25A48 is highly expressed in brown adipose tissue and required for whole-body cold tolerance, thermogenesis, and mitochondrial respiration. Mechanistically, choline uptake into the mitochondrial matrix via SLC25A48 facilitates betaine synthesis and one-carbon metabolism. Importantly, cells lacking SLC25A48 exhibited reduced synthesis of purine nucleotides and failed to initiate the G1-to-S phase transition, thereby leading to cell death. Taken together, the present study identified SLC25A48 as a mitochondrial carrier that mediates choline import and plays a critical role in mitochondrial respiratory capacity, purine nucleotide synthesis, and cell survival.

Impact of the COVID-19 Pandemic on the Long-Term Prognosis of Acute Myocardial Infarction in Japan.

Background During the early phase of the coronavirus disease 2019 (COVID-19) pandemic, a global reduction in hospitalizations for acute myocardial infarction (AMI) was observed. Generally, patients experienced increased severity of AMI with delays in time from symptom onset to treatment during the pandemic. However, the impact of the COVID-19 pandemic on in-hospital mortality among patients with AMI remains unclear. This study aimed to compare the long-term prognosis of patients with AMI during the COVID-19 pandemic to that observed in the pre-pandemic period and to evaluate the influence of the COVID-19 pandemic on the prognosis of patients with AMI. Methods We reviewed the data of patients admitted to our hospital for AMI treatment between April 1, 2018, and March 31, 2021. The time from admission to major adverse cardiac events (MACE), as well as the time from admission to all-cause death, were examined between the pandemic period (April 1, 2020, to March 31, 2021) and the pre-pandemic period (April 1, 2018, to March 31, 2020). Results Eighty patients were included in the study, and those admitted during the pandemic exhibited a higher likelihood of advanced age, lower levels of LDL-cholesterol, and a reduced prevalence of hypertension. The 2.5-year MACE-free survival and overall survival rates between the patients during the pre-pandemic and pandemic periods were not significantly different. Conclusion The long-term prognosis of patients with AMI during the COVID-19 pandemic remains unclear. In this study, we reported that the 2.5-year MACE-free survival and overall survival rates of the patients with AMI admitted during the COVID-19 pandemic were not significantly different from those during the pre-pandemic period. The impact of the COVID-19 pandemic on the prognosis of patients with AMI appears to vary according to the study population.

SLC25A48 controls mitochondrial choline import and metabolism.

Choline is an essential nutrient for the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism with a critical step being its import into mitochondria. However, the underlying mechanisms and biological significance remain poorly understood. Here, we report that SLC25A48, a previously uncharacterized mitochondrial inner-membrane carrier protein, controls mitochondrial choline transport and the synthesis of choline-derived methyl donors. We found that SLC25A48 was required for brown fat thermogenesis, mitochondrial respiration, and mitochondrial membrane integrity. Choline uptake into the mitochondrial matrix via SLC25A48 facilitated the synthesis of betaine and purine nucleotides, whereas loss of SLC25A48 resulted in increased production of mitochondrial reactive oxygen species and imbalanced mitochondrial lipids. Notably, human cells carrying a single nucleotide polymorphism on the SLC25A48 gene and cancer cells lacking SLC25A48 exhibited decreased mitochondrial choline import, increased oxidative stress, and impaired cell proliferation. Together, this study demonstrates that SLC25A48 regulates mitochondrial choline catabolism, bioenergetics, and cell survival.

R-R' interval in the left bundle branch block predicts long-term outcomes after cardiac resynchronization therapy by estimating greater mechanical dyssynchrony and viable myocardium.

BACKGROUND: Typical left bundle branch block (LBBB) shows 2 peaks of the R wave, which reflect activation reaching the interventricular septum (R) and posterolateral wall (R') sequentially. OBJECTIVE: The purpose of this study was to investigate the relationship among R-R' interval (RR'), mechanical dyssynchrony, extent of viable myocardium, and long-term outcomes in cardiac resynchronization therapy (CRT) candidates. METHODS: The study enrolled 49 patients (34 men; mean age: 69 ± 11 years) with LBBB who received CRT. The LBBB definition used requires the presence of mid-QRS notching in leads V1, V2, V5, V6, I, and aVL. Baseline evaluations were QRS duration (QRSd) and RR' measured from the 12-lead electrocardiogram; eyeball dyssynchrony (apical rocking and septal flash) and opposing-wall delay by speckle tracking from echocardiography, and extent of viable myocardium assessed by thallium-201 single-photon emission computed tomography. Primary outcomes included the combination of all-cause death and heart failure-related hospitalization. RESULTS: RR' predicted volumetric response better than QRSd (area under the curve 0.73 vs 0.67, respectively). The long RR' group (≥48 ms) revealed more frequent eyeball dyssynchrony and significantly greater radial (SL) and circumferential dyssynchrony (AP and SL) and %viable segment than the short RR' group. In multivariate regression analysis, only RR' ≥48 ms was independently associated with higher event-free survival rates following CRT (hazard ratio 0.21; P = .014). CONCLUSION: These findings suggest that RR' in complete LBBB was associated with mechanical dyssynchrony, extent of viable myocardium, and long-term outcomes following CRT.

Conditional deficiency of Rho-associated kinases disrupts endothelial cell junctions and impairs respiratory function in adult mice.

The Ras homology (Rho) family of GTPases serves various functions, including promotion of cell migration, adhesion, and transcription, through activation of effector molecule targets. One such pair of effectors, the Rho-associated coiled-coil kinases (ROCK1 and ROCK2), induce reorganization of actin cytoskeleton and focal adhesion through substrate phosphorylation. Studies on ROCK knockout mice have confirmed that ROCK proteins are essential for embryonic development, but their physiological functions in adult mice remain unknown. In this study, we aimed to examine the roles of ROCK1 and ROCK2 proteins in normal adult mice. Tamoxifen (TAM)-inducible ROCK1 and ROCK2 single and double knockout mice (ROCK1flox/flox and/or ROCK2flox/flox;Ubc-CreERT2) were generated and administered a 5-day course of TAM. No deaths occurred in either of the single knockout strains, whereas all of the ROCK1/ROCK2 double conditional knockout mice (DcKO) had died by Day 11 following the TAM course. DcKO mice exhibited increased lung tissue vascular permeability, thickening of alveolar walls, and a decrease in percutaneous oxygen saturation compared with noninducible ROCK1/ROCK2 double-floxed control mice. On Day 3 post-TAM, there was a decrease in phalloidin staining in the lungs in DcKO mice. On Day 5 post-TAM, immunohistochemical analysis also revealed reduced staining for vascular endothelial (VE)-cadherin, ß-catenin, and p120-catenin at cell-cell contact sites in vascular endothelial cells in DcKO mice. Additionally, VE-cadherin/ß-catenin complexes were decreased in DcKO mice, indicating that ROCK proteins play a crucial role in maintaining lung function by regulating cell-cell adhesion.

Role of epicardial adipose tissue in human atrial fibrillation.

A recent meta-analysis among which four reports were conducted in Japan demonstrated that epicardial adipose tissue (EAT) is closely associated with an increased risk of atrial fibrillation (AF) recurrence after catheter ablation. We previously investigated the role of EAT in AF in humans. Left atrial (LA) appendage samples were obtained from AF patients during cardiovascular surgery. Histologically, the severity of fibrotic EAT remodeling was associated with LA myocardial fibrosis. Total collagen in the LA myocardium (i.e., LA myocardial fibrosis) was positively correlated with proinflammatory and profibrotic cytokines/chemokines, including interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α, in EAT. Human peri-LA EAT and abdominal subcutaneous adipose tissue (SAT) were obtained by autopsy. EAT- or SAT-derived conditioned medium was applied to the rat LA epicardial surface using an organo-culture system. EAT-conditioned medium induced atrial fibrosis in organo-cultured rat atrium. The profibrotic effect of EAT was greater than that of SAT. The fibrotic area of the organo-cultured rat atrium treated with EAT from patients with AF was greater than in patients without AF. Treatment with human recombinant angiopoietin-like protein 2 (Angptl2) induced fibrosis in organo-cultured rat atrium, which was suppressed by concomitant treatment with anti-Angptl2 antibody. Finally, we attempted to detect fibrotic EAT remodeling on computed tomography (CT) images, which demonstrated that the percent change in EAT fat attenuation was positively correlated with EAT fibrosis. Based on these findings, we conclude that the percent change in EAT fat attenuation determined using CT non-invasively detects EAT remodeling.

Role of polyunsaturated fatty acids in Japanese patients with coronary spastic angina.

BACKGROUND: n-3 polyunsaturated fatty acids (PUFAs) reduce the risk of ischemic heart disease. However, there are few reports of a relationship between n-3 PUFAs and coronary spastic angina (CSA). This study aimed to assess the age-dependent role of serum levels of fatty acid in patients with CSA. METHODS AND RESULTS: We enrolled 406 patients who underwent ergonovine tolerance test (ETT) during coronary angiography for evaluation of CSA. All ETT-positive subjects were diagnosed as having CSA. We categorized the patients by age and results of ETT as follows: (1) young (age ≤ 65 years) CSA-positive (n = 32), (2) young CSA-negative (n = 134), (3) elderly (age > 66 years) CSA-positive (n = 36), and (4) elderly CSA-negative (n = 204) groups. We evaluated the serum levels of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid, and dihomo-gamma-linolenic acid. In the young groups, the serum levels of EPA (64.3 ±â€¯37.7 µg/mL vs. 49.4 ±â€¯28.8 µg/mL, p = 0.015) and DHA (135.7 ±â€¯47.6 µg/mL vs. 117.4 ±â€¯37.6 µg/mL, p = 0.020) were significantly higher in the CSA-positive group than in the CSA-negative group, respectively. However, this was not the case with elderly groups. In the multivariate analysis in young groups, the serum levels of EPA (p = 0.028) and DHA (p = 0.049) were independently associated with the presence of CSA, respectively. CONCLUSION: Our results suggested that the higher serum levels of EPA and/or DHA might be involved in the pathophysiology of CSA in the young population but not in the elderly population.