Cardiac-specific deletion of FDPS induces cardiac remodeling and dysfunction by enhancing the activity of small GTP-binding proteins.

The mevalonate pathway is essential for cholesterol biosynthesis. Previous studies have suggested that the key enzyme in this pathway, farnesyl diphosphate synthase (FDPS), regulates the cardiovascular system. We used human samples and mice that were deficient in cardiac FDPS (c-Fdps-/- mice) to investigate the role of FDPS in cardiac homeostasis. Cardiac function was assessed using echocardiography. Left ventricles were examined and tested for histological and molecular markers of cardiac remodeling. Our results showed that FDPS levels were downregulated in samples from patients with cardiomyopathy. Furthermore, c-Fdps-/- mice exhibited cardiac remodeling and dysfunction. This dysfunction was associated with abnormal activation of Ras and Rheb, which may be due to the accumulation of geranyl pyrophosphate. Activation of Ras and Rheb stimulated downstream mTOR and ERK pathways. Moreover, administration of farnesyltransferase inhibitors attenuated cardiac remodeling and dysfunction in c-Fdps-/- mice. These results indicate that FDPS plays an important role in cardiac homeostasis. Deletion of FDPS stimulates the downstream mTOR and ERK signaling pathways, resulting in cardiac remodeling and dysfunction. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A rare long-term undetected pheochromocytoma leading to Takotsubo syndrome in an older male patient: a case report.

BACKGROUND: Takotsubo syndrome is an uncommon, acute, and reversible cardiomyopathy that occurs primarily in postmenopausal females. The clinical presentation of the syndrome resembles acute coronary syndrome, but coronary angiography reveals no obstructive coronary artery disease. Rarely, a catecholamine surge due to pheochromocytoma may induce Takotsubo syndrome. The clinical features of pheochromocytoma include paroxysmal hypertension, headache, palpitations, and profuse sweating. However, owing to the episodic, rather than continued, symptoms and signs of pheochromocytoma, its timely diagnosis poses a challenge for clinicians. Here, we report a rare case of long-term undetected pheochromocytoma leading to Takotsubo syndrome in an older male patient. CASE PRESENTATION: A 70-year-old man presented with paroxysmal chest distress and chest pain. Examinations revealed acute coronary syndrome with normal coronary arteries, heart failure, reversible left ventricular regional wall motion abnormalities, labile blood pressure, a giant left adrenal mass, and extremely high levels of metanephrine and normetanephrine. Clinical manifestations, laboratory reports, and imaging findings suggested a diagnosis of Takotsubo syndrome caused by pheochromocytoma. Supportive therapy, administration of alpha- adrenergic receptor blockers, and left adrenal mass resection resolved the patient's symptoms. A histological examination confirmed the presence of pheochromocytoma. We reviewed his history of midbrain hemorrhage 6 years prior and found a mass in the left adrenal region by reviewing the computed tomography images of the lung that were also taken 6 years prior, on which the pheochromocytoma was evident. CONCLUSIONS: Our case illustrates the importance of understanding the link between pheochromocytoma and Takotsubo syndrome. A diagnosis of pheochromocytoma-induced Takotsubo syndrome should be considered during the differential diagnosis of acute coronary syndrome, especially in patients with labile blood pressure and normal coronary angiography findings; meanwhile, assessments of catecholamines and its metabolites and abdominal computed tomography scan should be performed at the right time. Clinicians should also be alert to potential pheochromocytoma in patients with unexplained cerebral hemorrhage, even in the absence of symptoms of catecholamine excess.

Comparison of transesophageal echocardiography findings after different anticoagulation strategies in patients with atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: High risk of embolic events exists in both patients with chronic atrial fibrillation (AF) and patients in the perioperative period of ablation (effective treatment for AF). Therefore, anticoagulant therapy is important. Oral anticoagulants can be divided into two major categories: vitamin K antagonists (VKAs) and non-vitamin K antagonist oral anticoagulants (NOACs). VKAs, represented by warfarin, have been widely used as traditional anticoagulants, whereas NOACs have been used in clinical practice, but their anticoagulant effects and side effects are still the focus of research. We used a meta-analysis to compare the incidence of left atrial thrombi (LAT) between different anticoagulants. METHODS: We searched PubMed, EMBASE, Web of Science, and the Cochrane Library databases for observational studies that compared the transesophageal echocardiography (TEE) findings for patients treated with NOACs and VKAs. The incidence of LAT and dense spontaneous echocardiographic contrast (dense SEC) were extracted as the basis of the meta-analysis. RESULTS: Fifteen studies were included in the meta-analysis. We found that patients anticoagulated with NOACs and VKAs had similar incidence of LAT (OR = 0.74, 95%CI: 0.55-1.00). After excluding the heterogeneous article by sensitivity analysis, we found the incidence of LAT in patients anticoagulated with NOACs is lower than VKAs (OR = 0.59, 95%CI: 0.42-0.84). The results of subgroup analysis showed that the incidence of LAT among three types of NOACs have no significant difference (dabigatran vs. rivaroxaban, OR = 1.16 [0.75, 1.81]; rivaroxaban vs. apixaban, OR = 0.97 [0.54, 1.74]; dabigatran vs. apixaban, OR = 1.09 [0.55, 2.16]). CONCLUSION: Patients anticoagulated with NOACs may have lower incidence of LAT than VKAs. The incidence of LAT among different type of NOACs are similar.

The Role of RhoA in Neovascular-Related Functions of Endothelial Progenitor Cells Induced by Angiotensinâ ¡.

BACKGROUND/AIMS: Interference with endothelial progenitor cell (EPC) neovascularization is a novel therapeutic target for neovascular-related diseases. Angiotensin Ⅱ (Ang Ⅱ) was found to enhance new vessel formation and aggravated neovascular-related diseases. In this study, we investigated the effects of Ang Ⅱ on EPC neovascular-related functions and explored the underlying mechanisms. METHODS: EPCs were cultured from bone marrow derived mononuclear cells. The effects of Ang Ⅱ on EPC proliferation, adhesion, migration, and in vitro tube formation were investigated using the MTT assay, adhesion assay, transwell chamber assay, and in vitro tube formation assay respectively. The underlying mechanisms were explored using Western blotting assay. RESULTS: EPC adhesion, migration and in vitro tube formation were promoted by Ang Ⅱ, and the effects were reversed by RhoA/Rho-associated kinases (ROCK) signaling pathway inhibitors including C3 exoenzyme, GGTI-286 and Y-27632. The active form of RhoA was up-regulated by Ang Ⅱ and this effect was abolished by C3 exoenzyme. Moreover, RhoA silencing resulted in a notable inhibition of EPC adhesion, migration and in vitro tube formation, suggesting that RhoA activation played a pivotal role in Ang Ⅱ angiogenic effect. The results also demonstrated that phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun-NH2 kinase was elevated by Ang Ⅱ and attenuated by C3 exoenzyme, GGTI-286 and Y-27632. The enhancing effects of Ang Ⅱ on EPC adhesion, migration and in vitro vasculogenesis were reversed by p38 inhibitor SB202190 and JNK inhibitor SP600125. CONCLUSION: Ang Ⅱ may enhance EPC neovascular-related functions through activating RhoA/ ROCK and MAPK signaling pathway.

Effect of Geranylgeranyl Pyrophosphate Synthase on Hypoxia/Reoxygenation-Induced Injury in Heart-Derived H9c2 Cells.

Recent studies have revealed that geranylgeranyl pyrophosphate synthase (GGPPS), a key enzyme involved in protein prenylation, plays a critical role in postnatal heart growth by regulating cardiomyocyte size. However, the role of GGPPS in myocardial ischemia/reperfusion (MIR) injury is still not clear. The objective of this work was to investigate the effect of GGPPS on MIR injury in H9c2 cells subjected to hypoxia/reoxygenation (HR) to mimic MIR. Prior to HR, the cells were transfected with GGPPS, shGGPPS, or shGFP. The results showed that cell viability was reduced, and cell injury and cell apoptosis were increased as a result of overexpression of GGPPS. Knockdown of GGPPS improved cell viability, and decreased cell injury and cell apoptosis. Furthermore, overexpression of GGPPS increased Rac1 activity and ROS generation, while GGPPS silencing decreased Rac1 activity and ROS generation. Based on these findings, we propose that the alteration of GGPPS expression changed the Rac1 activity and ROS production, and finally led to the different severity of HR-induced injury in H9c2 cells. These findings indicate that GGPPS might be a potential target in preventing H9c2 cells from HR-induced injury.

Knock-down of farnesyl pyrophosphate synthase protects heart-derived H9c2 cells against hypoxia/reoxygenation-induced injury.

Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. Our previous studies have indicated that cardiac-specific overexpression of FPPS induces cardiac hypertrophy and dysfunction in mice, and inhibition of FPPS prevents angiotensin (Ang) II-induced hypertrophy in cardiomyocytes. However, the role for FPPS in myocardial ischemia/reperfusion (MIR) injury is still not clear. The objective of this work was to investigate the effect of FPPS on MIR injury in H9c2 cells which were subjected to hypoxia/reoxygenation (HR) to mimic MIR. Prior to HR, cells were transfected with pE-mFPPS, shFPPS, or pE-GFP. Our results showed that the overexpression of FPPS reduced cell proliferation, increased cell injury and cell apoptosis, and knock-down of FPPS improved cell proliferation, decreased cell injury, and cell apoptosis after HR. Besides, overexpression of FPPS increased Rac1 activity and reactive oxygen species (ROS) generation, while FPPS silencing decreased Rac1 activity and ROS generation. Based on these findings, we propose that knock-down of FPPS reduces Rac1 activity and ROS production, and finally leads to the decrease of HR-induced injury in H9c2 cells. These findings point that FPPS might be a potential target in preventing H9c2 cells from HR-induced injury.

Abnormal expression of long non-coding RNAs in myocardial infarction.

Myocardial infarction (MI) is the leading cause of fatality worldwide. Our study aimed to investigate the dysregulated long non-coding RNA (lncRNA) in MI and elucidate the mechanism of it in MI. The lncRNA and mRNA expression profiling of the whole left ventricular tissue of MI mice model (8 mice) and Sham group (8 mice) was obtained based on microarray analysis. Differentially expressed lnRNAs/mRNA (DELs/DEMs) were identified in MI. DELs/DEMs co-expression network construction, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted to predict the biological functions of DEMs. Quantitative real-time polymerase chain reaction (qRT-PCR) was subjected to validate the abnormally expressed DELs in left ventricular tissues of MI mice model. Total of 168 DELs (37 up- and 131 down-regulated) and 126 DEMs (87 up- and 39 down-regulated) were identified in MI compared with Sham group. The co-expression network of candidate DELs and DEMs was constructed, which covered 219 nodes and 1775 edges. The qRT-PCR validation results indicated that ENSMUST00000124047 was significantly down-regulated in MI group and AK166279 was significantly up-regulated in MI group. ENSMUST00000121611 and NR_015515 had the up-regulated tendency in MI group compared with Sham group. The DEMs in MI were significantly enriched in 41 signaling pathways including complement and coagulation cascades, cytokine-cytokine receptor interaction and chemokine signaling pathway. The expression profiling of dysregulated DELs in MI was identified. Our results might provide useful information for exploring the pathogenesis mechanism of MI.

Estrogen and testosterone in concert with EFNB3 regulate vascular smooth muscle cell contractility and blood pressure.

EPH kinases and their ligands, ephrins (EFNs), have vital and diverse biological functions, although their function in blood pressure (BP) control has not been studied in detail. In the present study, we report that Efnb3 gene knockout (KO) led to increased BP in female but not male mice. Vascular smooth muscle cells (VSMCs) were target cells for EFNB3 function in BP regulation. The deletion of EFNB3 augmented contractility of VSMCs from female but not male KO mice, compared with their wild-type (WT) counterparts. Estrogen augmented VSMC contractility while testosterone reduced it in the absence of EFNB3, although these sex hormones had no effect on the contractility of VSMCs from WT mice. The effect of estrogen on KO VSMC contractility was via a nongenomic pathway involving GPER, while that of testosterone was likely via a genomic pathway, according to VSMC contractility assays and GPER knockdown assays. The sex hormone-dependent contraction phenotypes in KO VSMCs were reflected in BP in vivo. Ovariectomy rendered female KO mice normotensive. At the molecular level, EFNB3 KO in VSMCs resulted in reduced myosin light chain kinase phosphorylation, an event enhancing sensitivity to Ca(2+)flux in VSMCs. Our investigation has revealed previously unknown EFNB3 functions in BP regulation and show that EFNB3 might be a hypertension risk gene in certain individuals.

Autophagy protects against senescence and apoptosis via the RAS-mitochondria in high-glucose-induced endothelial cells.

BACKGROUNDS: Autophagy is an important process in the pathogenesis of diabetes and plays a critical role in maintaining cellular homeostasis. However, the autophagic response and its mechanism in diabetic vascular endothelium remain unclear. METHODS AND RESULTS: We studied high-glucose-induced renin-angiotensin system (RAS)-mitochondrial damage and its effect on endothelial cells. With regard to therapeutics, we investigated the beneficial effect of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) against high-glucose-induced endothelial responses. High glucose activated RAS, enhanced mitochondrial damage and increased senescence, apoptosis and autophagic-responses in endothelial cells, and these effects were mimicked by using angiotensin II (Ang). The use of an ACEI or ARB, however, inhibited the negative effects of high glucose. Direct mitochondrial injury caused by carbonyl cyanide 3-chlorophenylhydrazone (CCCP) resulted in similar negative effects of high glucose or Ang and abrogated the protective effects of an ACEI or ARB. Additionally, by impairing autophagy, high-glucose-induced senescence and apoptosis were accelerated and the ACEI- or ARB-mediated beneficial effects were abolished. Furthermore, increases in FragEL™ DNA Fragmentation (TUNEL)-positive cells, ß-galactosidase activation and the expression of autophagic biomarkers were revealed in diabetic patients and rats, and the treatment with an ACEI or ARB decreased these responses. CONCLUSIONS: These data suggest that autophagy protects against senescence and apoptosis via RAS-mitochondria in high-glucose-induced endothelial cells.

Alteration of mevalonate pathway related enzyme expressions in pressure overload-induced cardiac hypertrophy and associated heart failure with preserved ejection fraction.

BACKGROUND: Abnormalities of the mevalonate pathway, an important cellular metabolic pathway, are common in many diseases including cardiovascular disease. The mevalonate pathway related enzyme expressions in pressure overload-induced cardiac hypertrophy and associated diastolic dysfunction remains largely unknown. This study aims to investigate whether the expression of mevalonate pathway related enzyme is altered during the progression of cardiac hypertrophy and associated diastolic dysfunction induced by pressure overload. METHODS: Male Sprague-Dawley (SD) rats were randomly divided into two groups: the suprarenal abdominal aortic coarctation (AAC) group and the sham group. RESULTS: Histological and echocardiographic assessments showed that there was a significant cardiovascular remodeling in the AAC group compared with the sham group after 3 weeks post-operatively, and the left ventricular (LV) diastolic function was reduced at 8 and 14 weeks post-operatively in the AAC group, without any change in systolic function during the study. The tissue of the heart and the abdominal aorta proximal to the coarctation showed over-expression of several enzymes, including 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), farnesyl diphosphate synthase (FDPS), farnesyltransferase-α (FNTA), farnesyltransferase-ß (FNTB), geranylgeranyltransferase type I (GGTase-I) and the activation of their downstream proteins was enhanced. CONCLUSIONS: AAC induced compensatory LV hypertrophy to decompensatory diastolic dysfunction, accompanied by altered expression of several key enzymes in the mevalonate pathway.

Efficacy of adjunctive ambrisentan treatment for digital ulcers in patients with systemic sclerosis: a case series studyAmbrisentan for digital ulcers.

Purpose: The efficacy of adjunctive ambrisentan treatment in patients with systemic sclerosis (SSc) suffering from digital ulcers (DUs) was investigated.Material and methods: Patients (4 males, 7 females) diagnosed with SSc at our hospital between 2017 and 2022 were enrolled. Ten of them had diffuse SSc, while one had limited SSc. These patients received daily 5 mg doses of ambrisentan in addition to their regular SSc treatment for 16 weeks. Parameters including the total number and size of existing and new DUs, Visual Analog Score (VAS), frequency of Raynaud's phenomenon (RP) attacks, and any adverse effects were assessed.Results: At baseline, the median number and size of DUs was 3.0 (interquartile range (IQR): 2.0-4.0 cm) and 0.4 cm (IQR: 0.3-0.5 cm), respectively. Following the intervention, seven patients with a median of 2.0 DUs and a size of 0.35 cm (IQR: 0.15-0.45 cm) at baseline achieved complete healing. Significant improvements were also observed in other patients. VAS scores decreased from a baseline median of 5.0-0.0 (IQR: 0.0-1.0), and both the frequency and duration of RP attacks notably reduced.Conclusion: Adjunctive ambrisentan therapy proved effective in promoting DU healing and preventing new DUs in SSc patients.

Association between circulating leukocytes and arrhythmias: Mendelian randomization analysis in immuno-cardiac electrophysiology.

Background: Cardiac arrhythmia is a common disease associated with high mortality and morbidity. Circulating leukocyte counts, which serve as a biomarker for assessing systemic immune status, have been linked to arrhythmias in observational studies. However, observational studies are plagued by confounding factors and reverse causality, whether alterations in circulating leukocyte components are causally associated with arrhythmias remains uncertain. The present study explored this question based on genetic evidence. Methods and findings: We performed Mendelian randomization (MR) analysis to evaluate whether alterations in leukocyte counts affect aggregated risk of all types of arrhythmia or risk of five specific types of arrhythmia. Single-nucleotide polymorphisms serving as proxies for leukocyte differential counts were retrieved from the Blood Cell Consortium, and statistical data on arrhythmias were obtained from the UK Biobank), FinnGenand a meta-analysis of genome-wide association studies for atrial fibrillation. We applied inverse variance-weighted method as the primary analysis, complemented by a series of sensitivity analyses. Bidirectional analyses were conducted to assess reverse causality. Finally, multivariable MR was performed to study the joint effects of multiple risk factors. We found that genetically predicted differential leukocyte counts were not significantly associated with aggregated occurrence of all types of arrhythmia. In contrast, each 1-standard deviation increase in lymphocyte count was associated with 46% higher risk of atrioventricular block (OR 1.46, 95% CI 1.11-1.93, p=0.0065). A similar effect size was observed across all MR sensitivity analyses, with no evidence of horizontal pleiotropy. Reverse MR analysis suggested that atrioventricular block was unlikely to cause changes in lymphocyte count. Primary MR analysis based on the inverse-variance weighted method suggested that changes in neutrophil count alter risk of right bundle branch block, and changes in basophil count alter risk of atrial fibrillation. However, these causal relationships were not robust in sensitivity analyses. We found no compelling evidence that neutrophil or lymphocyte counts cause atrial fibrillation. Conclusion: Our data support higher lymphocyte count as a causal risk factor for atrioventricular block. These results highlight the importance of immune cells in the pathogenesis of specific cardiac conduction disorders.

Effect of microRNA-34a in cell cycle, differentiation, and apoptosis: a review.

The tumor suppressor gene p53 was shown to directly regulate the expression of microRNA-34a (miR-34a). miR-34a regulates a plethora of target proteins, which are involved in cell cycle, apoptosis, differentiation, and cellular development.miR-34a resides in the region of chromosome 1p36.23, which is commonly deleted in many tumor types, while it results in the loss expression of miR-34a. The promoters of the miR-34a gene subject to inactivation by CpG methylation also induce the loss expression of miR-34a. Ectopic miR-34a expression induces apoptosis, cell cycle arrest, and differentiation or reduces migration. This review summarizes the progress regarding the role of miR-34a in cell cycle, differentiation, and apoptosis.

The Relationship between Uric Acid and the Development, Complication, and Prognosis of Atrial Fibrillation: The Views from a Clinical Study.

A large number of studies suggest that uric acid (UA) is related to the occurrence, complications, and prognosis of atrial fibrillation (AF). However, the guidelines did not clearly elaborate on this issue. The current research results need to be summarized to analyze the association between UA and AF. This study found that in the current clinical research on the relationship between UA and AF, studies mainly focus on the development or complications of AF. A lot of repetitive work does not deepen awareness of this question. In contrast, studies investigating the effects of UA-lowering therapy on the management of AF are limited. The only reports deny the protective effect of UA-lowering therapy. For now, we suggest that UA is close to the occurrence and progression of AF; therefore, it may have important significance as a clinical marker. The role of UA-lowering therapy in the management of AF is one of the next key issues to be explored. It will be a meaningful topic to focus on the latest research on AF ablation and to conduct a secondary analysis to explore the prognostic impact of UA on the latest treatment methods for AF. Multiomics techniques may allow us to have a deeper understanding of the role of UA in AF management in the future.

Alteration of enzyme expressions in mevalonate pathway: possible role for cardiovascular remodeling in spontaneously hypertensive rats.

BACKGROUND: The mevalonate pathway is an important metabolic pathway that plays a key role in multiple cellular processes. The aim of this study was to define whether the enzyme expression in mevalonate pathway changes during cardiovascular remodelling in spontaneously hypertensive rats (SHR). METHODS AND RESULTS: Hearts and thoracic aortas were removed for the study of cardiovascular remodeling in SHR and Wistar-Kyoto rats (WKY). The protein expression of the enzymes in hearts, aortas and livers was analyzed by western blot. The histological measurements showed that the mass and the size of cardiomyocytes, the media thickness and the media cross-sectional area (MCSA) of the thoracic aorta were all increased in SHR since 3 weeks of age. In the heart, there was overexpression of some enzymes, including 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), farnesyl diphosphate synthase (FDPS), and geranylgeranyltransferase type I (GGTase-I), and downregulation of squalene synthetase (SQS) in SHR since 3 weeks of age. In the aorta, besides similar expressions of HMGR, SQS, FDPS and GGTase-I as in the heart, there was upregulation of farnesyltransferase α at 16 and 25 weeks of age and of farnesyltransferase ß in 25-weeks-old SHR. Western blot demonstrated overexpression of HMGR and downregulation of SQS in SHR livers at all ages tested. CONCLUSIONS: The cardiovascular remodeling of SHR preceded the development of hypertension, and altered expression of several key enzymes in the mevalonate pathway may play a potential pathophysiological role in cardiovascular remodeling.

Establishment of transgenic mice carrying the gene for farnesyl pyrophosphate synthase.

Farnesyl pyrophosphate synthase (FPPS) is an essential enzyme in the mevalonate pathway and might be relevant to hypertension and other cardiovascular diseases. FPPS transgenic mice were produced by microinjecting a construct with the FPPS gene into fertilized eggs derived from an inbred C57BL/6 strain. Three mice were identified as carrying copies of the transgene using the PCR. Reverse transcription PCR and Western blotting showed that the transgene was expressed in heart, liver, lung, ear, brain, thymus, and blood vessels in the transgenic mouse. Pathological analysis (hematoxylin and eosin staining) showed that FPPS expression did not cause obvious pathological changes in multiple tissues of 6-week-old transgenic mice. This FPPS transgenic mouse model, may therefore, facilitate the investigation of the biological functions of FPPS in vivo.

The Correlation Between Whole Blood Copper (Cu), Zinc (Zn) Levels and Cu/Zn Ratio and Sepsis-Induced Left Ventricular Systolic Dysfunction (SILVSD) in Patients with Septic Shock: A Single-Center Prospective Observational Study.

PURPOSE: This study aimed to explore relationships between whole blood copper (Cu), zinc (Zn) and Cu/Zn ratio and cardiac dysfunction in patients with septic shock. SUBJECTS AND METHODS: Between April 2018 and March 2020, septic shock patients with sepsis-induced left ventricular systolic dysfunction (SILVSD, left ventricular ejection fraction, LVEF<50%) and with no sepsis-induced myocardial dysfunction (non-SIMD, septic shock alone and LVEF>50%) and controls were prospectively enrolled. Whole blood Cu and Zn levels were measured using flame atomic absorption spectrophotometry. RESULTS: Eighty-six patients with septic shock including both 41 SILVSD and 45 non-SIMD and 25 controls were studied. Whole blood Cu levels and Cu/Zn ratio were significantly higher and Zn levels were lower in SILVSD compared with non-SIMD and controls (Cu, p=0.009, <0.001; Zn, p=0.029, <0.001; Cu/Zn ratio, p=0.003, <0.001). Both increased whole blood Cu and Cu/Zn ratio and reduced Zn were associated with lower LVEF (all p<0.001) and higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) (Cu, p=0.002; Zn, p<0.001; Cu/Zn ratio, p<0.001) and had predictive values for SILVSD (Cu, AUC=0.666, p=0.005; Zn, AUC=0.625, p=0.039; Cu/Zn ratio, AUC=0.674, p=0.029). Whole blood Cu levels and Cu/Zn ratio were increased but Zn levels were reduced in non-survivors compared with survivors (Cu, p<0.001; Zn, p<0.001; Cu/Zn ratio, p<0.001). Whole blood Cu and Zn displayed the value of predicting 28-day mortality (Cu, AUC = 0.802, p<0.001; Zn, AUC=0.869, p<0.001; Cu/Zn ratio, AUC=0.902, p<0.001). CONCLUSION: Findings of the study suggest that whole blood Cu levels and Cu/Zn ratio are increased in SILVSD patients and positively correlated with cardiac dysfunction, while whole blood Zn levels are reduced and negatively associated with cardiac dysfunction. Moreover, both whole blood Cu, Zn and Cu/Zn ratio might distinguish between SILVSD and non-SIMD in septic shock patients and predict 28-day mortality. TRIAL REGISTRATION: Registered at http://www.chictr.org.cn/ChiCTR1800015709.

New perspective on the risk markers for left atrial thrombosis in patients with atrial fibrillation.

BACKGROUND: Anticoagulant therapy is one of the important aspects of atrial fibrillation (AF) management, which can effectively reduce the formation of left atrial thrombosis (LAT) and the occurrence of embolic events. The CHA2DS2-VASc score is a commonly used risk assessment tool for embolic events, and it has guiding significance for anticoagulant therapy. However, a large number of recent studies have clearly shown that some of the markers that are not included in the score affect the formation of LAT. OBJECTIVE: This single-center study probed for risk markers for LAT by analyzing the clinical features of patients who experienced AF. METHODS: We reviewed patients with AF who had undergone a transesophageal echocardiography exam over the past 6 years and used binary logistic regression analysis to identify risk markers other than CHA2DS2-VASc score. For the risk markers found, the propensity score matching (PSM) was used to further evaluate whether it was an independent risk marker for LAT. The newly discovered markers were added to the score, and receiver operating characteristic analysis was used to evaluate whether the ability of the model to predict LAT was improved. RESULTS: A total of 2246 patients were included in the study. In total, 838 of them were anticoagulated (314 with rivaroxaban, 57 with dabigatran, and 467 with warfarin) and 30 patients (1.33%) had LAT. Regression analysis revealed abnormal uric acid metabolism (abUA) and obesity were risk markers for LAT. Further PSM analysis found that abUA was an independent risk marker for LAT. After including abUA, the CHA2DS2-VASc score was more accurate for LAT prediction (area under the curve difference is 0.0651, 95% confidence interval: 0.0247, 0.1050, Z = 3.158, P = 0.0016). CONCLUSIONS: AbUA is an independent risk marker for LAT. After considering abUA, the CHA2DS2-VASc score for LAT is more accurate.

Identification and Functional Prediction of Long Non-Coding RNAs in Dilated Cardiomyopathy by Bioinformatics Analysis.

Dilated cardiomyopathy (DCM) is a relatively common cause of heart failure and the leading cause of heart transplantation. Aberrant changes in long non-coding RNAs (lncRNAs) are involved in DCM disorder; however, the detailed mechanisms underlying DCM initiation and progression require further investigation, and new molecular targets are needed. Here, we obtained lncRNA-expression profiles associated with DCM and non-failing hearts through microarray probe-sequence re-annotation. Weighted gene co-expression network analysis revealed a module highly associated with DCM status. Then eight hub lncRNAs in this module (FGD5-AS1, AC009113.1, WDFY3-AS2, NIFK-AS1, ZNF571-AS1, MIR100HG, AC079089.1, and EIF3J-AS1) were identified. All hub lncRNAs except ZNF571-AS1 were predicted as localizing to the cytoplasm. As a possible mechanism of DCM pathogenesis, we predicted that these hub lncRNAs might exert functions by acting as competing endogenous RNAs (ceRNAs). Furthermore, we found that the above results can be essentially reproduced in an independent external dataset. We observed the localization of hub lncRNAs by RNA-FISH in human aortic smooth muscle cells and confirmed the upregulation of the hub lncRNAs in DCM patients through quantitative RT-PCR. In conclusion, these findings identified eight candidate lncRNAs associated with DCM disease and revealed their potential involvement in DCM partly through ceRNA crosstalk. Our results facilitate the discovery of therapeutic targets and enhance the understanding of DCM pathogenesis.

Dual effects of sodium aescinate on vascular tension in rat thoracic aorta.

OBJECTIVE: Sodium aescinate (SA) is used as a vasoactive drug in clinical treatment. This study was designed to investigate the effects of SA on rat isolated thoracic aorta and the possible mechanisms. METHODS: Isometric tension was recorded in response to drugs in organ bath. RESULTS: The effects of SA obeyed an all-or-nothing response. SA in relatively low dose (> or = 50 microg/ml) had an endothelium-independent contractile effect in rat aorta (P<0.01), which depended on extracellular Ca(2+) influx via L-type Ca(2+) channel (P<0.05). SA in relatively high dose (> or = 100 microg/ml) also induced vasoconstriction in Ca(2+)-free medium (P<0.01), which was independent of the activity of inositol-1,4,5-trisphosphate receptor (IP(3)R), ryanodine receptor (RYR), and protein kinase C (PKC). SA in relatively high dose (> or = 100 microg/ml) dilated both endothelium-intact and endothelium-denuded aortic rings precontracted by phenylephrine (PE) or KCl (each P<0.01). SA inhibited extracellular Ca(2+) influx induced by PE or KCl (each P<0.01) and had no activation effect on K(+) channels on vascular smooth muscle. The relaxant effect of SA partly depended on the activity of NO synthase but not on the activity of cyclooxygenase. CONCLUSIONS: Taken together, this study indicated that SA had dual effects on vascular tension in rat isolated thoracic aorta.