3,3',5-tri-iodothyroacetic acid (TRIAC) transporters.

Introduction Thyroid hormone transporters are essential for thyroid hormones to enter target cells. Monocarboxylate transporter MCT8 is a key transporter and expressed at the blood-brain barrier, in neural cells and many other tissues. Patients with MCT8 deficiency have severe neurodevelopmental delays due to cerebral hypothyroidism and chronic sequelae of peripheral thyrotoxicosis. The T3 analog 3,3,5-triiodothyroacetic acid (TRIAC) rescued neurodevelopmental features in animal models mimicking MCT8 deficiency and improved key metabolic features in patients with MCT8 deficiency. However, the identity of the transporter(s) that facilitate TRIAC transport are unknown. Here, we screened candidate transporters that are expressed at the human blood-brain barrier and/or brain-cerebrospinal fluid barrier and known thyroid hormone transporters for TRIAC transport. Materials and methods Plasma membrane expression was determined by cell surface biotinylation assays. Intracellular accumulation of 1 nM TRIAC was assessed in COS-1 cells expressing candidate transporters in Dulbecco's phosphate buffered saline (DPBS)/0.1% glucose or Dulbecco's modified Eagle's medium (DMEM) with or without 0.1% bovine serum albumin (BSA). Expression of Slc22a8 was determined by fluorescent in situ hybridization (FISH) in brain sections from wild-type and Mct8/Oatp1c1 knock-out mice at postnatal day 12, 21 and 120. Results Fifty-nine plasma membrane transporters were selected for screening of TRIAC accumulation (n=40 based on expression at the human blood-brain barrier and/or brain-cerebrospinal fluid barrier and having small organic molecules as substrates; n=19 known thyroid hormone transporters). Screening of the selected transporter panel showed that 18 transporters facilitated significant intracellular accumulation of TRIAC in DPBS/0.1% glucose or DMEM in the absence of BSA. In the presence of BSA, substantial transport was noted for SLCO1B1 and SLC22A8 (in DPBS/0.1% glucose and DMEM) and SLC10A1, SLC22A6 and SLC22A24 (in DMEM). The zebrafish and mouse orthologues of these transporters similarly facilitated intracellular accumulation of TRIAC. Highest Slc22a8 mRNA expression was detected in mouse brain capillary endothelial cells and choroid plexus epithelial cells at early postnatal time points, but wasreduced at P120. Conclusions Human SLC10A1, SLCO1B1, SLC22A6, SLC22A8 and SLC22A24 as well as their mouse and zebrafish orthologues are efficient TRIAC transporters. These findings contribute to the understanding of TRIAC treatment in patients with MCT8 deficiency and animal models thereof.

Identification of Diagnostic Genes of Aortic Stenosis That Progresses from Aortic Valve Sclerosis.

Background: Aortic valve sclerosis (AVS) is a pathological state that can progress to aortic stenosis (AS), which is a high-mortality valvular disease. However, effective medical therapies are not available to prevent this progression. This study aimed to explore potential biomarkers of AVS-AS advancement. Methods: A microarray dataset and an RNA-sequencing dataset were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened from AS and AVS samples. Functional enrichment analysis, protein-protein interaction (PPI) network construction, and machine learning model construction were conducted to identify diagnostic genes. A receiver operating characteristic (ROC) curve was generated to evaluate diagnostic value. Immune cell infiltration was then used to analyze differences in immune cell proportion between tissues. Finally, immunohistochemistry was applied to further verify protein concentration of diagnostic factors. Results: A total of 330 DEGs were identified, including 92 downregulated and 238 upregulated genes. The top 5% of DEGs (n = 17) were screened following construction of a PPI network. IL-7 and VCAM-1 were identified as the most significant candidate genes via least absolute shrinkage and selection operator (LASSO) regression. The diagnostic value of the model and each gene were above 0.75. Proportion of anti-inflammatory M2 macrophages was lower, but the fraction of pro-inflammatory gamma-delta T cells was elevated in AS samples. Finally, levels of IL-7 and VCAM-1 were validated to be higher in AS tissue than in AVS tissue using immunohistochemistry. Conclusion: IL-7 and VCAM-1 were identified as biomarkers during the disease progression. This is the first study to analyze gene expression differences between AVS and AS and could open novel sights for future studies on alleviating or preventing the disease progression.

A Comparison of the Association of Septal Scar Burden on Responses to LBBAP-CRT and BVP-CRT.

BACKGROUND: Left bundle branch area pacing (LBBAP) is an alternative to biventricular pacing (BVP) for cardiac resynchronization therapy (CRT). However, despite the presence of left bundle branch block, whether cardiac substrate may influence the effect between the 2 strategies is unclear. OBJECTIVES: This study aims to assess the association of septal scar on reverse remodeling and clinical outcomes of LBBAP compared with BVP. METHODS: We analyzed patients with nonischemic cardiomyopathy who had CRT indications undergoing preprocedure cardiac magnetic resonance examination. Changes in left ventricular ejection fraction (LVEF) and echocardiographic response (ER, ≥5% absolute LVEF increase) were assessed at 6 months. The clinical outcome was the composite of all-cause mortality, heart failure hospitalization, or major ventricular arrhythmia. RESULTS: There were 147 patients included (51 LBBAP and 96 BVP). Among patients with low septal scar burden (below median 5.7%, range: 0 to 5.3%), LVEF improvement was higher in the LBBAP than the BVP group (17.5% ± 10.9% vs 12.3% ± 11.8%; P = 0.037), with more than 3-fold increased odds of ER (odds ratio: 4.35; P = 0.033). In high sepal scar subgroups (≥5.7%, range: 5.7% to 65.9%), BVP trended towards higher LVEF improvement (9.2% ± 9.4% vs 6.4% ± 12.4%; P = 0.085). Interaction between septal scar burden and pacing strategy was significant for ER (P = 0.002) and LVEF improvement (P = 0.011) after propensity score adjustment. During median follow-up of 33.7 (Q1-Q3: 19.8 to 42.1) months, the composite clinical outcome occurred in 34.7% (n = 51) of patients. The high-burden subgroups had worse clinical outcomes independent of CRT method. CONCLUSIONS: Remodeling response to LBBAP and BVP among nonischemic cardiomyopathy patients is modified by septal scar burden. High septal scar burden was associated with poor clinical prognosis independent of CRT methods.

Genetically predicted systemic inflammation and the risk of atrial fibrillation: A bidirectional two-sample Mendelian randomization study.

Background: Systemic inflammation has been proposed to be associated with the incidence of atrial fibrillation (AF), but whether it is a cause or a consequence of AF remains uncertain. We sought to explore the causal associations between systemic inflammation and AF using bidirectional Mendelian randomization (MR) analysis. Methods: Independent genetic variants strongly associated with AF were selected as instrumental variables from the largest genome-wide association study (GWAS) with up to 1,030,836 individuals. Regarding inflammation traits, genetic associations with 41 inflammatory cytokines and 5 inflammatory biomarkers were obtained from their corresponding GWASs databases. Effect estimates were primarily evaluated using the inverse-variance weighted (IVW) method, supplemented by sensitivity analyses using MR-Egger, weighted median, and MR-PRESSO methods. Results: In our initial MR analyses, we observed suggestive associations of genetically predicted interleukin-17 (IL-17), interleukin-2 receptor subunit alpha (IL-2rα), and procalcitonin (PCT) with AF. One standard deviation (SD) increase in IL-17, IL-2rα, and PCT caused an increase in AF risk by 6.3 % (OR 1.063, 95 %CI 1.011---1.118, p = 0.018), 4.9 % (OR 1.049, 95 %CI 1.007---1.094, p = 0.023) and 3.4 % (OR 1.034, 95 %CI 1.005---1.064, p = 0.022), respectively. Furthermore, our reverse MR analyses indicated that genetically predicted AF contributed to a suggestive increase in the levels of macrophage inflammatory protein-1ß (MIP1ß) (ß 0.055, 95 %CI 0.006 to 0.103, p = 0.028), while a decrease in the levels of fibrinogen (Fbg) (ß -0.091, 95 %CI -0.140 to -0.041, p < 0.001), which remained significant after multiple test correction. Conclusions: Our MR study identified several inflammatory biomarkers with suggestive causal associations regarding the upstream and downstream regulation of AF occurrence, offering new insights for therapeutic exploitation of AF. Further research is required to validate the underlying link between systemic inflammation and AF in larger cohorts.

Two novel in vitro assays to screen chemicals for their capacity to inhibit thyroid hormone transmembrane transporter proteins OATP1C1 and OAT4.

Early brain development depends on adequate transport of thyroid hormones (THs) from the maternal circulation to the fetus. To reach the fetal brain, THs have to cross several physiological barriers, including the placenta, blood-brain-barrier and blood-cerebrospinal fluid-barrier. Transport across these barriers is facilitated by thyroid hormone transmembrane transporters (THTMTs). Some endocrine disrupting chemicals (EDCs) can interfere with the transport of THs by THTMTs. To screen chemicals for their capacity to disrupt THTMT facilitated TH transport, in vitro screening assays are required. In this study, we developed assays for two THTMTs, organic anion transporter polypeptide 1C1 (OATP1C1) and organic anion transporter 4 (OAT4), both known to play a role in the transport of THs across barriers. We used overexpressing cell models for both OATP1C1 and OAT4, which showed an increased uptake of radiolabeled T4 compared to control cell lines. Using these models, we screened various reference and environmental chemicals for their ability to inhibit T4 uptake by OATP1C1 and OAT4. Tetrabromobisphenol A (TBBPA) was identified as an OATP1C1 inhibitor, more potent than any of the reference chemicals tested. Additionally perfluorooctanesulfonic acid (PFOS), perfluoroctanic acid (PFOA), pentachlorophenol and quercetin were identified as OATP1C1 inhibitors in a similar range of potency to the reference chemicals tested. Bromosulfophthalein, TBBPA, PFOA and PFOS were identified as potent OAT4 inhibitors. These results demonstrate that EDCs commonly found in our environment can disrupt TH transport by THTMTs, and contribute to the identification of molecular mechanisms underlying TH system disruption chemicals.

Inclusion of reeling wastewater-derived sericin peptides in high-protein nutrition bars for antihardening and storage stability.

The utilization of agroindustrial wastes to enrich food protein resources and the exploration of their broader applications are crucial for addressing the food crisis and achieving sustainable development goals. In this study, reeling wastewater-derived sericin was hydrolyzed using papain and trypsin to prepare sericin peptide (SRP) and was used as an antihardening ingredient of high-protein nutrition bars (HPNBs). The mechanism of the antihardening effect of SRP was elucidated by investigating the content of advanced glycation end products and protein oxidation products (carbonyl and free sulfhydryl), and the molecular weight change of HPNBs during storage before and after the addition of SRP. Our results confirmed the fortification of HPNBs with SRP, which is beneficial for the promotion and expansion of sericin applications in the food industry, with positive implications for the rational utilization of protein resources and the enrichment of food protein sources.

Prognostic implications of premature ventricular contractions and non-sustained ventricular tachycardia in light-chain cardiac amyloidosis.

AIMS: Premature ventricular contractions (PVC) and non-sustained ventricular tachycardia (NSVT) are commonly observed in light chain cardiac amyloidosis (AL-CA), but their association with prognosis is still unclear. We aimed to evaluate the prognostic value of PVCs and NSVT in patients with moderate-to-advanced AL-CA. METHODS AND RESULTS: We retrospectively included patients with AL-CA at modified 2004 Mayo stages II-IIIb between February 2014 and December 2020. Twenty-four-hour Holter recordings were assessed on admission. The outcomes included (i) new onset of adverse ventricular arrhythmia (VA) or sudden cardiac death (SCD) and (ii) cardiac death during follow-up. Of the 143 patients studied (60.41 ± 11.06 years, male 64.34%), 132 (92.31%) had presence of PVC, and 50 (34.97%) had NSVT on Holter. Twelve (8.4%) patients died in hospital and 131 patients were followed up (median 24.4 months), among whom 71 patients had cardiac death, and 15 underwent adverse VA/SCD. NSVT [hazard ratio (HR): 13.57, 95% confidence interval (CI): 3.06-60.18, P < 0.001], log-transformed PVC counts (HR: 1.46, 95%CI: 1.15-1.86, P = 0.002) and PVC burden (HR: 1.43 95%CI:1.14-1.80, P = 0.002) were predictive of new onset of adverse VA/SCD. The highest tertile of PVC counts (HR: 2.33, 95%CI: 1.27-4.28, P = 0.006) and PVC burden (HR: 2.58, 95%CI: 1.42-4.69, P = 0.002), rather than NSVT (HR: 1.16, 95%CI: 0.67-1.98, P = 0.603), was associated with cardiac death. Higher PVC counts/burden provided incremental value on modified 2004 Mayo stage in predicting cardiac death, with C index increasing from 0.681 to 0.712 and 0.717, respectively (P values <0.05). CONCLUSION: PVC count, burden, and NSVT significantly correlated with adverse VA/SCD during follow-up in patients with AL-CA. Higher PVC counts/burdens added incremental value for predicting cardiac death.

CMR feature tracking-based left atrial mechanics predicts response to cardiac resynchronization therapy and adverse outcomes.

BACKGROUND: Cardiac resynchronization therapy (CRT) is an established therapy for advanced heart failure (HF) with prolonged QRS duration. However, 30% of patients have shown no benefit from the treatment. OBJECTIVE: This study aimed to examine the value of left atrial (LA) mechanics by cardiac magnetic resonance (CMR) to predict response to CRT and clinical outcomes. METHODS: A total of 163 CRT recipients with preimplantation CMR examination were retrospectively recruited. CMR feature tracking was used to evaluate LA size and function. The end points include (1) improvement of at least 5% in left ventricular ejection fraction combined with a reduction of at least 1 New York Heart Association functional class at 6-month follow-up and (2) any all-cause death or HF hospitalization during follow-up. RESULTS: Overall, 82 (50.3%) were CRT responders. CRT nonresponders had larger LA and worse LA reservoir and booster pump function than did responders (P < .001 for all). LA structural (maximum volume index < 47 mL/m2) and functional (booster pump strain > 8.5%) criteria were incremental to traditional indicators in detecting CRT response (χ2, 40.83 vs 9.98; P < .001). During follow-up (median 41 months), survival free from death or HF hospitalization increased with the number of positive LA criteria (log-rank, P < .001). After adjustment for clinical confounders, the absence of the 2 criteria remained associated with a considerably increased risk of death or HF hospitalization (adjusted hazard ratio 6.2; 95% confidence interval 2.15-17.88; P = .001). CONCLUSION: The preprocedure LA mechanics evaluated using CMR may be useful to predict response to CRT and improve risk stratification in CRT recipients.

Development and Validation of a Novel Predictive Model for the Early Differentiation of Cardiac and Non-Cardiac Syncope.

Background: The diagnosis of cardiac syncope remains a challenge. This study sought to develop and validate a diagnostic model for the early identification of individuals likely to have a cardiac cause. Methods: 877 syncope patients with a determined cause were retrospectively enrolled at a tertiary heart center. They were randomly divided into the training set and validation set at a 7:3 ratio. We analyzed the demographic information, medical history, laboratory tests, electrocardiogram, and echocardiogram by the least absolute shrinkage and selection operator (LASSO) regression for selection of key features. Then a multivariable logistic regression analysis was performed to identify independent predictors and construct a diagnostic model. The receiver operating characteristic curves, area under the curve (AUC), calibration curves, and decision curve analysis were used to evaluate the predictive accuracy and clinical value of this nomogram. Results: Five independent predictors for cardiac syncope were selected: BMI (OR 1.088; 95% CI 1.022-1.158; P =0.008), chest symptoms preceding syncope (OR 5.251; 95% CI 3.326-8.288; P <0.001), logarithmic NT-proBNP (OR 1.463; 95% CI 1.240-1.727; P <0.001), left ventricular ejection fraction (OR 0.940; 95% CI 0.908-0.973; P <0.001), and abnormal electrocardiogram (OR 6.171; 95% CI 3.966-9.600; P <0.001). Subsequently, a nomogram based on a multivariate logistic regression model was developed and validated, yielding AUC of 0.873 (95% CI 0.845-0.902) and 0.856 (95% CI 0.809-0.903), respectively. The calibration curves showcased the nomogram's reasonable calibration, and the decision curve analysis demonstrated good clinical utility. Conclusion: A diagnostic tool providing individualized probability predictions for cardiac syncope was developed and validated, which may potentially serve as an effective tool to facilitate early identification of such patients.

Statins Prevent the Deleterious Consequences of Placental Chemerin Upregulation in Preeclampsia.

BACKGROUND: Chemerin, an inflammatory adipokine, is upregulated in preeclampsia, and its placental overexpression results in preeclampsia-like symptoms in mice. Statins may lower chemerin. METHODS: Chemerin was determined in a prospective cohort study in women suspected of preeclampsia and evaluated as a predictor versus the sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio. Chemerin release was studied in perfused placentas and placental explants with or without the statins pravastatin and fluvastatin. We also addressed statin placental passage and the effects of chemerin in chorionic plate arteries. RESULTS: Serum chemerin was elevated in women with preeclampsia, and its addition to a predictive model yielded significant effects on top of the sFlt-1/PlGF ratio to predict preeclampsia and its fetal complications. Perfused placentas and explants of preeclamptic women released more chemerin and sFlt-1 and less PlGF than those of healthy pregnant women. Statins reversed this. Both statins entered the fetal compartment, and the fetal/maternal concentration ratio of pravastatin was twice that of fluvastatin. Chemerin constricted plate arteries, and this was blocked by a chemerin receptor antagonist and pravastatin. Chemerin did not potentiate endothelin-1 in chorionic plate arteries. In explants, statins upregulated low-density lipoprotein receptor expression, which relies on the same transcription factor as chemerin, and NO release. CONCLUSIONS: Chemerin is a biomarker for preeclampsia, and statins both prevent its placental upregulation and effects, in an NO and low-density lipoprotein receptor-dependent manner. Combined with their capacity to improve the sFlt-1/PlGF ratio, this offers an attractive mechanism by which statins may prevent or treat preeclampsia.

Cardiac magnetic resonance-derived myocardial scar is associated with echocardiographic response and clinical prognosis of left bundle branch area pacing for cardiac resynchronization therapy.

AIMS: Left bundle branch area pacing (LBBAP) is a novel approach for cardiac resynchronization therapy (CRT), but the impact of myocardial substrate on its effect is poorly understood. This study aims to assess the association of cardiac magnetic resonance (CMR)-derived scar burden and the response of CRT via LBBAP. METHODS AND RESULTS: Consecutive patients with CRT indications who underwent CMR examination and successful LBBAP-CRT were retrospectively analysed. Cardiac magnetic resonance late gadolinium enhancement was used for scar assessment. Echocardiographic reverse remodelling and composite outcomes (defined as all-cause death or heart failure hospitalization) were evaluated. The echocardiographic response was defined as a ≥15% reduction of left ventricular end-systolic volume. Among the 54 patients included, LBBAP-CRT resulted in a 74.1% response rate. The non-responders had higher global, septal, and lateral scar burden (all P < 0.001). Global, septal, and lateral scar percentage all predicted echocardiographic response [area under the curve (AUC): 0.857, 0.864, and 0.822; positive likelihood ratio (+LR): 9.859, 5.594, and 3.059; and negative likelihood ratio (-LR): 0.323, 0.233, and 0.175 respectively], which was superior to QRS morphology criteria (Strauss left bundle branch abnormality: AUC: 0.696, +LR 2.101, and -LR 0.389). After a median follow-up time of 20.3 (11.5-38.7) months, higher global, lateral and septal scar burdens were all predictive of the composite outcome (hazard ratios: 4.996, 7.019, and 4.741, respectively; P's < 0.05). CONCLUSION: Lower scar burden was associated with higher response rate of LBBAP-CRT. The pre-procedure CMR scar evaluation provides further useful information to identify potential responders and clinical outcomes.

Efficacy and Safety of Leadless Pacemakers for Atrioventricular Synchronous Pacing: A Systematic Review and Meta-Analysis.

Leadless pacemakers with an atrioventricular synchrony algorithm represent a novel technology for patients qualified for VDD pacing. The current evidence of their performance is limited to several small-scale observational studies. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of this new technology. We systematically searched the PubMed, Embase, and Cochrane library databases from their inception to 12 September 2022. The primary efficacy outcome was atrioventricular synchrony after implantation, whereas the secondary efficacy outcome was the change in cardiac output represented by the left ventricular outflow tract velocity time integral (LVOT-VTI). The primary safety outcome was major complications related to the procedures and the algorithm. Means or mean differences with 95% confidence interval (95% CI) were combined using a random-effects model or a fixed-effects model. Finally, 8 published studies with 464 participants were included in the qualitative analysis. The pooled atrioventricular synchrony proportion was 78.9% (95% CI 71.9-86.0%), and a further meta-regression did not screen factors that contributed significantly to the heterogeneity. Additionally, a significant increase in atrioventricular synchrony of 11.3% (95% CI 7.0-15.7%, p < 0.01) was achieved in patients experiencing programming optimization. LVOT-VTI was significantly increased by 1.9 cm (95% CI 1.2-2.6, p < 0.01), compared with the VVI pacing mode. The overall incidence of complications was approximately 6.3%, with major complications related to the algorithm being extremely low. Overall, leadless pacemakers with atrioventricular synchronous pacing demonstrated favorable safety and efficacy. Future data on their long-term performance are required to facilitate their widespread adoption in clinical practice.

Novel (sulfated) thyroid hormone transporters in the solute carrier 22 family.

Objective: Thyroid hormone (TH) transport represents a critical first step in governing intracellular TH regulation. It is still unknown whether the full repertoire of TH transporters has been identified. Members of the solute carrier (SLC) 22 family have substrates in common with the known TH transporters of the organic anion-transporting peptide family. Therefore, we screened the SLC22 family for TH transporters. Methods: Uptake of 1 nM of iodothyronines or sulfated iodothyronines in COS1 cells expressing SLC22 proteins was performed. Results: We first tested 25 mouse (m) SLC22 proteins for TH uptake and found that the majority of the organic anion transporter (OAT) clade were capable of 3,3',5-triiodothyronine and/or thyroxine (T4) transport. Based on phylogenetic tree analysis of the mouse and human (h) SLC22 family, we selected eight hSLC22s that grouped with the newly identified mouse TH transporters. Of these, four tested positive for uptake of one or more substrates, particularly hSLC22A11 showed robust (3-fold over control) uptake of T4. Uptake of sulfated iodothyronines was strongly (up to 17-fold) induced by some SLC22s, most notably SLC22A8, hSLC22A9, mSLC22A27 and mSLC22A29. Finally, the zebrafish orthologues of SLC22A6/8 drOatx and drSlc22a6l also transported almost all (sulfated) iodothyronines tested. The OAT inhibitors lesinurad and probenecid inhibited most SLC22 proteins. Conclusions: Our results demonstrated that members of the OAT clade of the SLC22 family constitute a novel, evolutionary conserved group of transporters for (sulfated) iodothyronines. Future studies should reveal the relevance of these transporters in TH homeostasis and physiology.

MultiSimNeNc: A network representation learning-based module identification method by network embedding and clustering.

Accurate identification of gene modules based on biological networks is an effective approach to understanding gene patterns of cancer from a module-level perspective. However, most graph clustering algorithms just consider low-order topological connectivity, which limits their accuracy in gene module identification. In this study, we propose a novel network-based method, MultiSimNeNc, to identify modules in various types of networks by integrating network representation learning (NRL) and clustering algorithms. In this method, we first obtain the multi-order similarity of the network using graph convolution (GC). Then, we aggregate the multi-order similarity to characterize the network structure and use non-negative matrix factorization (NMF) to achieve low-dimensional node characterization. Finally, we predict the number of modules based on the bayesian information criterion (BIC) and use the gaussian mixture model (GMM) to identify modules. To testify to the efficacy of MultiSimeNc in module identification, we apply this method to two types of biological networks and six benchmark networks, where the biological networks are constructed based on the fusion of multi-omics data from glioblastoma (GBM). The analysis shows that MultiSimNeNc outperforms several state-of-the-art module identification algorithms in identification accuracy, which is an effective method for understanding biomolecular mechanisms of pathogenesis from a module-level perspective.

Radial and Circumferential CMR-Based RV Strain Predicts Low R Wave Amplitude after ICD Implantation in Patients with Arrhythmogenic Cardiomyopathy.

Inadequate R wave amplitude (RWA) after implantable cardiac defibrillator (ICD) implantation in patients with arrhythmogenic cardiomyopathy (ACM) was suspected to relate to right ventricle impairment. However, little data-based evidence was provided to quantify the association. We retrospectively enrolled ACM patients receiving CMR examinations before transvenous ICD implantation from Fuwai Hospital. The RWA was obtained within 24 h and at 2-6-month follow-up after the operation. Structural, functional, as well as tissue characterization of the left ventricle (LV) and right ventricle (RV), were analyzed in relation to RWA. Among the 87 ACM patients (median RWA: 8.0 mV), 19 (21.8%) patients were found with low initial RWA (<5 mV) despite attempts in multiple positions. RV end diastolic diameter (RVEDD), (r = -0.44), RV ejection fraction (RVEF, r = 0.43), RV end diastolic volume index (RVEDVi, r = -0.49), RV end systolic volume index (RVESVi, r = -0.53), RV global circumferential (RVGCS, r = -0.64), and radial strain (RVGRS, r = 0.61, all p < 0.001) rather than LV metrics correlated strongly with initial RWA. RVGCS, RVESVi, and RVGRS were decent predictors of low RWA (areas under the curve AUC: 0.814, 0.769, 0.757, respectively) early after implantation and during 2-6-month follow-up. To summarize, low RWA of ICD lead in ACM patients was associated with RV abnormalities. The RVGCS, RVGRS, and RVESVi can be valuable predictors for identifying low RWA prior to ICD implantation.

Therapeutic Hypothermia Inhibits Hypoxia-Induced Cardiomyocyte Apoptosis Via the MiR-483-3p/Cdk9 Axis.

Background Therapeutic hypothermia has a beneficial effect on cardiac function after acute myocardial infarction, but the exact mechanism is still unclear. Recent research has suggested that microRNAs participate in acute myocardial infarction to regulate cardiomyocyte survival. This study aimed to explore the ability of hypothermia-regulated microRNA-483-3p (miR-483-3p) to inhibit hypoxia-induced myocardial infarction. Methods and Results Primary cardiomyocytes were cultured under hypoxia at 32 °C to mimic therapeutic hypothermia, and the differentially expressed microRNAs were determined by RNA sequencing. Therapeutic hypothermia recovered hypoxia-induced increases in apoptosis, decreases in ATP levels, and decreases in miR-483-3p expression. Overexpression of miR-483-3p exhibited effects similar to those of therapeutic hypothermia on hypoxia in the treatment of cardiomyocytes to associate with maintaining the mitochondrial membrane potential, and cyclin-dependent kinase 9 (Cdk9) was identified as a target gene with downregulated expression by miR-483-3p. Knockdown of Cdk9 also promoted cardiac survival, ATP production, and mitochondrial membrane potential stability under hypoxia. In vivo, the expression of miR-483-3p and Cdk9 was tested in the cardiac tissue of the mice with acute myocardial infarction, and the expression of miR-483-3p decreased and Cdk9 increased in the region of myocardial infarction. However, miR-483-3p was overexpressed with lentivirus, which suppressed apoptosis, infarct size (miR-483-3p, 22.00±4.04% versus negative control, 28.57±5.44%, P<0.05), and Cdk9 expression to improve cardiac contractility. Conclusions MiR-483-3p antagonizes hypoxia, leading to cardiomyocyte injury by targeting Cdk9, which is a new mechanism of therapeutic hypothermia.

A novel predictive model for poor in-hospital outcomes in patients with acute kidney injury after cardiac surgery.

OBJECTIVE: Patients with cardiac surgery-associated acute kidney injury are at risk of renal replacement therapy and in-hospital death. We aimed to develop and validate a novel predictive model for poor in-hospital outcomes among patients with cardiac surgery-associated acute kidney injury. METHODS: A total of 196 patients diagnosed with cardiac surgery-associated acute kidney injury were enrolled in this study as the training cohort, and 32 blood cytokines were measured. Least absolute shrinkage and selection operator regression and random forest quantile-classifier were performed to identify the key blood predictors for in-hospital composite outcomes (requiring renal replacement therapy or in-hospital death). The logistic regression model incorporating the selected predictors was validated internally using bootstrapping and externally in an independent cohort (n = 52). RESULTS: A change in serum creatinine (delta serum creatinine) and interleukin 16 and interleukin 8 were selected as key predictors for composite outcomes. The logistic regression model incorporating interleukin 16, interleukin 8, and delta serum creatinine yielded the optimal performance, with decent discrimination (area under the receiver operating characteristic curve: 0.947; area under the precision-recall curve: 0.809) and excellent calibration (Brier score: 0.056, Hosmer-Lemeshow test P = .651). Application of the model in the validation cohort yielded good discrimination. A nomogram was generated for clinical use, and decision curve analysis demonstrated that the new model adds more net benefit than delta serum creatinine. CONCLUSIONS: We developed and validated a promising predictive model for in-hospital composite outcomes among patients with cardiac surgery-associated acute kidney injury and demonstrated interleukin-16 and interleukin-8 as useful predictors to improve risk stratification for poor in-hospital outcomes among those with cardiac surgery-associated acute kidney injury.

Asymmetrical Transport of Thyroxine Across Human Term Placenta.

Background: Fetal development is crucially dependent on thyroid hormone (TH). Maternal-to-fetal transfer of TH is a prerequisite for fetal TH availability, particularly in the first half of pregnancy. The mechanisms of transplacental transport of TH, however, are yet poorly understood. We, therefore, investigated the TH transport processes across human placentas using an ex vivo perfusion system. Methods: Intact cotyledons from term placentas of uncomplicated pregnancies were cannulated within 30 minutes after delivery and the maternal and fetal circulations were re-established. One hundred nanomolar thyroxine (T4) was added to either the maternal or fetal circulation and perfusions run up to three hours during which samples were taken from both circulations at different time points. Variables included addition of iopanoic acid (IOP) to block activity of the deiodinase type 3 (D3) and bovine serum albumin (BSA) to trap released T4. T4 and 3,3',5'-triiodothyronine concentrations in the perfusates were measured by radioimmunoassays. Results: Maternal-to-fetal transfer was slow, with T4 barely detectable in the fetal circulation unless D3 was blocked by IOP. Fetal T4 was detected after three hours perfusion (10.6 ± 0.6 nM) when BSA (34 g/L) was added in the fetal circulation to trap the released T4. In contrast, fetal-to-maternal transfer of T4 was rapid and maternal T4 increased to 43.6 ± 5.5 nM. Conclusions: Maternal-to-fetal T4 transport is limited, whereas fetal-to-maternal transport is rapid indicating that T4 transport across human term placenta is an asymmetrical process. With the high D3 activity, our observations are compatible with a protective role of the placental barrier. Future studies should reveal how the placenta exerts its gatekeeper function in ensuring optimal TH passage to the fetus.

Thyroid Hormone Transporters in Pregnancy and Fetal Development.

Thyroid hormone is essential for fetal (brain) development. Plasma membrane transporters control the intracellular bioavailability of thyroid hormone. In the past few decades, 15 human thyroid hormone transporters have been identified, and among them, mutations in monocarboxylate transporter (MCT)8 and organic anion transporting peptide (OATP)1C1 are associated with clinical phenotypes. Different animal and human models have been employed to unravel the (patho)-physiological role of thyroid hormone transporters. However, most studies on thyroid hormone transporters focus on postnatal development. This review summarizes the research on the thyroid hormone transporters in pregnancy and fetal development, including their substrate preference, expression and tissue distribution, and physiological and pathophysiological role in thyroid homeostasis and clinical disorders. As the fetus depends on the maternal thyroid hormone supply, especially during the first half of pregnancy, the review also elaborates on thyroid hormone transport across the human placental barrier. Future studies may reveal how the different transporters contribute to thyroid hormone homeostasis in fetal tissues to properly facilitate development. Employing state-of-the-art human models will enable a better understanding of their roles in thyroid hormone homeostasis.

Association of glucagon-like peptide-1 receptor agonists with cardiac arrhythmias in patients with type 2 diabetes or obesity: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been highly recommended for glycemic control and weight reduction. However, evidence has accumulated that GLP-1 RAs treatment is related to an increase in heart rate, which could potentially induce cardiac arrhythmias. This study aims to investigate the association of GLP-1 RAs therapy with incident arrhythmias in diabetic and obese patients. METHODS: MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were systematically searched from inception up to May 25, 2022. Randomized controlled trials (RCTs) comparing GLP-1 RAs with placebo or active control for adults with type 2 diabetes or obesity were included. The outcomes of interest were prespecified as incident atrial fibrillation (AF), atrial flutter (AFL), ventricular arrhythmias (VAs), and sudden cardiac death (SCD). Mantel-Haenszel relative risk (MH-RR) with a corresponding 95% confidence interval (95% CI) was estimated using a fixed-effects model. RESULTS: A total of 56 RCTs involving 79,720 participants (44,028 GLP-1 RAs vs 35,692 control: mean age 57.3 years) were included from 7692 citations. GLP-1 RAs use overall did not significantly increase the risk of AF (RR 0.97, 95% CI 0.83-1.12), AFL (RR 0.83, 95% CI 0.59-1.17), VAs (RR 1.24, 95% CI 0.92-1.67), and SCD (RR 0.89, 95% CI 0.67-1.19), compared with controls. In further subgroup analyses, we observed an increasing trend toward incident AF with dulaglutide (RR 1.40, 95% CI 1.03-1.90) while an inverse trend with oral semaglutide (RR 0.43, 95% CI 0.21-0.87). Additionally, higher doses of GLP-1 RAs (RR 1.63, 95% CI 1.11-2.40) and higher baseline BMI (RR 1.60, 95% CI 1.04-2.48) might significantly increase the risk of VAs. No significant differences were identified in other subgroup analyses. CONCLUSIONS: GLP-1 RAs therapy was not associated with an overall higher risk of arrhythmias, demonstrating an assuring cardiovascular safety profile. Further studies are required to determine whether the potential antiarrhythmic or arrhythmogenic effect of GLP-1 RAs is drug-specific and varies from doses or baseline BMI. TRIAL REGISTRATION: PROSPERO Identifier: CRD42022339389.