Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid ß-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM), a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes, accounts for 20% of sudden cardiac death and lacks effective treatment. It is often caused by mutations in desmosome proteins, with Desmoglein-2 (DSG2) mutations as a common etiology. However, the mechanism underlying the accumulation of fibrofatty in ACM remains unknown, which impedes the development of curative treatment. Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2 (CS-Dsg2 -/-). Heart failure and cardiac lipid accumulation were observed in CS-Dsg2 -/- mice. We demonstrated that these phenotypes were caused by decline of fatty acid (FA) ß-oxidation resulted from impaired mammalian target of rapamycin (mTOR) signaling. Rapamycin worsened while overexpression of mTOR and 4EBP1 rescued the FA ß-oxidation pathway in CS-Dsg2 -/- mice. Reactivation of PPARα by fenofibrate or AAV9-Pparα significantly alleviated the lipid accumulation and restored cardiac function. Our results suggest that impaired mTOR-4EBP1-PPARα-dependent FA ß-oxidation contributes to myocardial lipid accumulation in ACM and PPARα may be a potential target for curative treatment of ACM.

Prevalence of sarcopenia and its association with clinical outcomes in heart failure: An updated meta-analysis and systematic review.

BACKGROUND: Sarcopenia is thought to be strongly associated with heart failure, but meta-analyses with sufficient samples are still lacking to accurately address its clinical situation. HYPOTHESIS: Sarcopenia has a high prevalence in patients with heart failure and is closely related to adverse clinical outcomes. METHODS: Relevant databases were systematically searched in October 2021 and updated in July 2022. The data with high heterogeneity were combined with random effects model. RESULTS: Twenty-one studies with 68,556 HF patients were included. The combined prevalence of sarcopenia in HF patients was 31%. Subgroup analysis found that the prevalence of sarcopenia in HF patients was 35% in Asia, 31% in Europe, 25% in the Americas, 31% in people aged ≥65 years, 25% in people with age <65 years, 28% in HF with reduced ejection fraction (HFrEF) patients and 18% in HF with preserved ejection fraction (HFpEF) patients. In addition, our analysis shows that sarcopenia in patients with HF is associated with an increased risk of poor prognosis, with a combined hazard ratio [HR] of 1.64 (95% confidence interval [CI] = 1.20-5.25), sarcopenia was also associated with poor outcomes in HFrEF patients with pooled HR of 2.77 (95% CI = 1.29-5.95). However, it was not associated with poor outcomes in HFpEF patients with pooled HR of 1.61 (95% CI = 0.82-3.16). CONCLUSIONS: The prevalence of sarcopenia is high in HF patients, and patients with HF, particularly those with reduced ejection fraction, are at high risk of adverse outcomes from sarcopenia. Therefore, early identification and intervention for sarcopenia were beneficial for improving the prognosis of HF patients.

Handgrip Measurement Method Affects Asymmetry but Not Weakness Identification in Community-Dwelling Older Adults.

OBJECTIVES: The Asian Working Group for Sarcopenia (AWGS) 2019 recommends different measurement protocols for handgrip strength (HGS). We aimed to explore (1) whether these protocols induce a significant difference in HGS; (2) whether these differences be clinically meaningful; and (3) whether these protocols affect the identification of HGS weakness or asymmetry. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: A total of 356 community-dwelling older adults (mean age 67.9 years; 146 women). METHODS: Maximal HGS was measured according to protocols from the National Health and Nutrition Examination Survey (Method A, standing with full elbow extended) and the American Society of Hand Therapists (Method B, sitting with elbow flexed at 90°). HGS was analyzed using the maximal value of 2 or 3 repetitions of the dominant hand or 4 or 6 repetitions of both hands. RESULTS: The difference in maximal HGS between Method A and Method B might have clinical meaning in approximately half of the participants. When measured using Method A, respective proportions of individuals with differences in HGS between the 6 repetitions group and the other repetition groups beyond the noninferiority threshold were 42%, 20%, and 25% in men and 39%, 21%, and 17% in women. Using Method B, the corresponding percentages were 25%, 18%, and 6% in men, and 27%, 20%, and 5% in women, respectively. Different protocols did not significantly affect the identification of HGS weakness, as different protocols reached diagnostic accuracies of 0.910 to 0.967 in men and 0.911 to 0.986 in women when using Method A (6 repetitions) as the reference standard. However, different protocols significantly affected the identification of HGS asymmetry, as different protocols had diagnostic accuracies of 0.667 to 0.886 in men and 0.658 to 0.863 in women. CONCLUSIONS AND IMPLICATIONS: The different protocols recommended by the AWGS 2019 update significantly affect maximal HGS values and the identification of HGS asymmetry but not HGS weakness.

Mesoporous waffle-like N-doped carbon with embedded Co nanoparticles for efficiently electrocatalytic oxygen reduction and evolution.

Rational design and facile preparation of high-performance carbon-based eletrocatalysts for both oxygen reduction and evolution reactions (ORR and OER) is crucial for practical applications of rechargeable zinc-air batteries. Inspired by the fact that the metallic Co catalysis on the formation of carbon nanotubes (CNTs), this work develops a facial compression-pyrolysis route to synthesize a mesoporous waffle-like N-doped carbon framework with embedded Co nanoparticles (Co@pNC) using a Co metal-organic framework and melamine as precursors. The unique porous waffle-like carbon framework is built up of interwoven N-doped CNTs and graphene nanosheets, which offers abundant catalytic-active sites and rapid diffusion channels for intermediates and electrolyte. The optimized Co@pNC shows excellent bifunctional ORR/OER electrocatalytic activity in alkaline media with a half-wave potential (E1/2) of 0.85 V for ORR and a small potential gap of 0.70 V between ORR E1/2 and OER potential at 10 mA cm-2. Its assembled battery exhibits a peak power density up to 150.3 mW cm-2, an energy density of 928 Wh kgZn-1 and superb rate capability. It highlights a facile component and architecture strategy to design high-performance carbon-based eletrocatalysts.

SGLT2 inhibitor dapagliflozin attenuates cardiac fibrosis and inflammation by reverting the HIF-2α signaling pathway in arrhythmogenic cardiomyopathy.

Excessive cardiac fibrosis and inflammation aberrantly contribute to the progressive pathogenesis of arrhythmogenic cardiomyopathy (ACM). Whether sodium-glucose cotransporter-2 inhibitor (SGLT2i), as a new hypoglycemic drug, benefits ACM remains unclear. Cardiomyocyte-specific Dsg2 exon-11 knockout and wild-type (WT) littermate mice were used as the animal model of ACM and controls, respectively. Mice were administered by gavage with either SGLT2i dapagliflozin (DAPA, 1 mg/kg/day) or vehicle alone for 8 weeks. HL-1 cells were treated with DAPA to identify the molecular mechanism in vitro. All mice presented normal glucose homeostasis. DAPA not only significantly ameliorated cardiac dysfunction, adverse remodeling, and ventricular dilation in ACM but also attenuated ACM-associated cardiac fibrofatty replacement, as demonstrated by the echocardiography and histopathological examination. The protein expressions of HIF-2α and HIF-1α were decreased and increased respectively in cardiac tissue of ACM, which were compromised after DAPA treatment. Additionally, NF-κB P65 and IκB phosphorylation, as well as fibrosis indicators (including TGF-ß, α-SMA, Collagen I, and Collagen III) were increased in ACM. However, these trends were markedly suppressed by DAPA treatment. Consistent with these results in vitro, DAPA alleviated the IκB phosphorylation and NF-κB p65 transcriptional activity in DSG2-knockdown HL-1 cells. Interestingly, the elective HIF-2α inhibitor PT2399 almost completely blunted the DAPA-mediated downregulation of indicators concerning cardiac fibrosis and inflammation. SGLT2i attenuated the ACM-associated cardiac dysfunction and adverse remodeling in a glucose-independent manner by suppressing cardiac fibrosis and inflammation via reverting the HIF-2α signaling pathway, suggesting that SGLT2i is a novel and available therapy for ACM.

Gut Microbiota Interact With the Brain Through Systemic Chronic Inflammation: Implications on Neuroinflammation, Neurodegeneration, and Aging.

It has been noticed in recent years that the unfavorable effects of the gut microbiota could exhaust host vigor and life, yet knowledge and theory are just beginning to be established. Increasing documentation suggests that the microbiota-gut-brain axis not only impacts brain cognition and psychiatric symptoms but also precipitates neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). How the blood-brain barrier (BBB), a machinery protecting the central nervous system (CNS) from the systemic circulation, allows the risky factors derived from the gut to be translocated into the brain seems paradoxical. For the unique anatomical, histological, and immunological properties underpinning its permeable dynamics, the BBB has been regarded as a biomarker associated with neural pathogenesis. The BBB permeability of mice and rats caused by GM dysbiosis raises the question of how the GM and its metabolites change BBB permeability and causes the brain pathophysiology of neuroinflammation and neurodegeneration (NF&ND) and brain aging, a pivotal multidisciplinary field tightly associated with immune and chronic systemic inflammation. If not all, gut microbiota-induced systemic chronic inflammation (GM-SCI) mainly refers to excessive gut inflammation caused by gut mucosal immunity dysregulation, which is often influenced by dietary components and age, is produced at the interface of the intestinal barrier (IB) or exacerbated after IB disruption, initiates various common chronic diseases along its dispersal routes, and eventually impairs BBB integrity to cause NF&ND and brain aging. To illustrate the immune roles of the BBB in pathophysiology affected by inflammatory or "leaky" IB resulting from GM and their metabolites, we reviewed the selected publications, including the role of the BBB as the immune barrier, systemic chronic inflammation and inflammation influences on BBB permeability, NF&ND, and brain aging. To add depth to the bridging role of systemic chronic inflammation, a plausible mechanism indispensable for BBB corruption was highlighted; namely, BBB maintenance cues are affected by inflammatory cytokines, which may help to understand how GM and its metabolites play a major role in NF&ND and aging.

QTL identification, fine mapping, and marker development for breeding peanut (Arachis hypogaea L.) resistant to bacterial wilt.

KEY MESSAGE: A major QTL, qBWA12, was fine mapped to a 216.68 kb physical region, and A12.4097252 was identified as a useful KASP marker for breeding peanut varieties resistant to bacterial wilt. Bacterial wilt, caused by Ralstonia solanacearum, is a major disease detrimental to peanut production in China. Breeding disease-resistant peanut varieties is the most economical and effective way to prevent the disease and yield loss. Fine mapping the QTLs for bacterial wilt resistance is critical for the marker-assisted breeding of disease-resistant varieties. A recombinant inbred population comprising 521 lines was used to construct a high-density genetic linkage map and to identify QTLs for bacterial wilt resistance following restriction-site-associated DNA sequencing. The genetic map, which included 5120 SNP markers, covered a length of 3179 cM with an average marker distance of 0.6 cM. Four QTLs for bacterial wilt resistance were mapped on four chromosomes. One major QTL, qBWA12, with LOD score of 32.8-66.0 and PVE of 31.2-44.8%, was stably detected in all four development stages investigated over the 3 trial years. Additionally, qBWA12 spanned a 2.7 cM region, corresponding to approximately 0.4 Mb and was fine mapped to a 216.7 kb region by applying KASP markers that were polymorphic between the two parents based on whole-genome resequencing data. In a large collection of breeding and germplasm lines, it was proved that KASP marker A12.4097252 can be applied for the marker-assisted breeding to develop peanut varieties resistant to bacterial wilt. Of the 19 candidate genes in the region covered by qBWA12, nine NBS-LRR genes should be further investigated regarding their potential contribution to the resistance of peanut against bacterial wilt.

Association between daytime nap duration and risks of frailty: Findings from the China Health and Retirement Longitudinal Study.

Introduction: Night sleep duration and total sleep duration are associated with frailty. However, the association between daytime nap duration and the risks of frailty has not been explored thoroughly. Methods: This study used data from the China Health and Retirement Longitudinal Study (CHARLS). Participants aged 60 years and older at baseline were included in this study. Individuals with daytime nap duration were categorized into four groups: no napping, short napping (< 30 min), moderate napping (30-89 min), and extended napping (≥90 min). Frailty was assessed using a modified Physical Frailty Phenotype (PFP) scale. Non-frail participants at baseline were followed up for 4 years. The association between nap duration and risks of frailty at baseline and incident frailty was evaluated by logistic regression and discrete-time Cox regression analyses, respectively. Results: In total, 5,126 participants were included in this study. For individuals with night sleep duration of ≥9 h, short nappers showed higher odds [odds ratio (OR) = 4.08, 95% confidence interval (CI): 1.30-12.78] for frailty compared with non-habitual nappers at baseline, while moderate nappers were less likely to be frail (OR = 0.18, 95% CI: 0.04-0.73). In the follow-up study, short nappers showed higher risks for frailty compared with participants of the no napping group with night sleep duration of < 6 h [hazard ratio (HR) = 1.91, 95% CI: 1.07-3.43] or 6-9 h (HR = 1.97, 95% CI: 1.18-3.30). Compared with short nappers, older adults with extended napping (HR = 0.41, 95% CI: 0.22-0.77) showed lower risks for frailty in those with night sleep duration of 6-9 h. For individuals with night sleep duration of ≥9 h, moderate napping (HR = 0.20, 95% CI: 0.05-0.77) decreased the risks for frailty compared with short napping. Conclusion: Among older adults with night sleep duration of < 9 h, short nappers posed higher risks for frailty compared with non-habitual nappers. Extended naps for those with a night sleep duration of 6-9 h or moderate naps for those with night sleep duration of ≥9 h could lower the risk of frailty compared with short naps. Future studies on the timing, purpose, frequency, and quality of daytime napping and objectively measured nap duration are needed to explore the association between daytime napping and risks of frailty.

Digenic heterozygous mutations of KCNH2 and SCN5A induced young and early-onset long QT syndrome and sinoatrial node dysfunction.

INTRODUCTION: Long QT syndrome (LQTS) is a life-threatening inherited channelopathy, and prolonged QT intervals easily trigger malignant arrhythmias, especially torsades de pointes and ventricular fibrillation. MATERIALS AND METHODS: The proband with overlapped phenotypes of LQTS and sinoatrial node dysfunction underwent some necessary examinations, including echocardiography, electrocardiogram (ECG), and Holter monitoring. Next, whole-exome sequencing was performed, and candidate genes were validated by Sanger sequencing. RNA secondary structure and protein physical-chemical parameter analyses were used to predict the possible structural change of the proteins induced by the mutations. RESULTS: We identified the digenic heterozygous mutations of KCNH2 p.307_308del (NM_001204798, c.921_923del) and SCN5A p.R1865H (NM_001160160, c.G5594A) in the female and young proband (II: 1) of LQTS and ventricular fibrillation with repeat syncope at rest. Subsequently, she occurred with obvious sinus arrest with persistent ventricular pacing of implantable cardioverter-defibrillator. The heterozygous SCN5Ap.R1865H was carried by her father and sister but not carried by I:2. II:1 carried with KCNH2 p.307_308del as a de novo mutation, but not existed in other family members. RNA secondary structure of KCNH2 p.307_308del showed a false regional double helix, and its amino acids' hydrophobicity was significantly weakened. For the Nav 1.5 protein property, SCN5A p.R1865H slightly increased the molecular weight and aliphatic index but reduced the instability index. CONCLUSIONS: The digenic heterozygous KCNH2 and SCN5A mutations were associated with young early-onset long QT syndrome and sinoatrial node dysfunction.

Overlap phenotypes of the left ventricular noncompaction and hypertrophic cardiomyopathy with complex arrhythmias and heart failure induced by the novel truncated DSC2 mutation.

BACKGROUND: The left ventricular noncompaction cardiomyopathy (LVNC) is a rare subtype of cardiomyopathy associated with a high risk of heart failure (HF), thromboembolism, arrhythmia, and sudden cardiac death. METHODS: The proband with overlap phenotypes of LVNC and hypertrophic cardiomyopathy (HCM) complicates atrial fibrillation (AF), ventricular tachycardia (VT), and HF due to the diffuse myocardial lesion, which were diagnosed by electrocardiogram, echocardiogram and cardiac magnetic resonance imaging. Peripheral blood was collected from the proband and his relatives. DNA was extracted from the peripheral blood of proband for high-throughput target capture sequencing. The Sanger sequence verified the variants. The protein was extracted from the skin of the proband and healthy volunteer. The expression difference of desmocollin2 was detected by Western blot. RESULTS: The novel heterozygous truncated mutation (p.K47Rfs*2) of the DSC2 gene encoding an important component of desmosomes was detected by targeted capture sequencing. The western blots showed that the expressing level of functional desmocollin2 protein (~ 94kd) was lower in the proband than that in the healthy volunteer, indicating that DSC2 p.K47Rfs*2 obviously reduced the functional desmocollin2 protein expression in the proband. CONCLUSION: The heterozygous DSC2 p.K47Rfs*2 remarkably and abnormally reduced the functional desmocollin2 expression, which may potentially induce the overlap phenotypes of LVNC and HCM, complicating AF, VT, and HF.

Indicators and prediction models for the severity of Covid-19.

OBJECTIVES: Coronavirus disease 2019 (Covid-19) is outbreaking globally. We aimed to analyse the clinical characteristics, cardiac injury, electrocardiogram and computed tomography (CT) features of patients confirmed Covid-19 and explored the prediction models for the severity of Covid-19. METHODS: A retrospective and single-centre study enrolled 98 laboratory-confirmed Covid-19 patients. Clinical data, electrocardiogram and CT features were collected and analysed using Statistical Package for the Social Sciences software. RESULTS: There were 46 males and 52 females, with a median age of 44 years, categorised into three groups, including mild, moderate and severe/critical Covid-19. The rate of abnormal electrocardiograms in severe/critical group (79%) was significantly higher than that in the mild group (17%) (P = .027), which (r = 0.392, P = .005) positively related to the severity of Covid-19 (OR: 5.71, 95% CI: 0.45-3.04, P = .008). Age older than 60 years old, comorbidities, whether had symptoms on admission, fatigue, CT features, laboratory test results such as platelet count, lymphocyte cell count, eosinophil cell count, CD3+ cell count, CD4+ cell count, CD8+ cell count, the ratio of albumin/globulin decreased and D-dimer, C-reactive protein (CRP), B-type natriuretic peptide (BNP), cardiac troponin I (cTnI) elevated were the risk factors for the increased severity of Covid-19. The logistic model, adjusted by age, lobular involvement score and lymphocyte cell count, could be applied for assessing the severity of Covid-19 (AUC, 0.903; Sensitivity, 90.9%; Specificity, 78.1%). CONCLUSIONS: Age >60 years old, chronic comorbidities, lymphocytopoenia and lobular involvement score were associated with the Covid-19 severity. The inflammation induced by Covid-19 caused myocardial injury with elevated BNP and cTnI level and abnormal electrocardiograms.

Identification of rare heterozygous linkage R965C-R1309H mutations in the pore-forming region of SCN5A gene associated with complex arrhythmia.

BACKGROUND: We examined the genetic background of a Chinese Han family in which some members presented with complex arrhythmias including sick sinus syndrome, progressive conduction block, atrial fibrillation, atrial standstill and Brugada syndrome. The possible underlying mechanism associated with the genetic mutation was explored. METHODS: Targeted capture sequencing was conducted in the probands in the coding and splicing regions of genes implicated in inherited arrhythmias. Stable cell lines overexpressing wild type (WT) or mutant SCN5A were generated in HEK293T cells. Whole-cell recording was performed to evaluate the functional changes in sodium channels. RESULTS: The rare heterozygous linkage mutations, SCN5A R965C and R1309H, were found in these patients with complex familial arrhythmias. Compared to WT, R965C or R1309H, the peak current of sodium channel was dramatically reduced in HEK293T cell with linkage R965C-R1309H mutation when testing potentials ranging from -45 to 15 mV. Notably, the maximum peak current of sodium channels with R1309H and linkage R965C-R1309H displayed significant decreases of 31.5% and 73.34%, respectively, compared to WT. Additionally, compared to R965C or R1309H alone, the linkage mutation R965C-R1309H demonstrated not only a more obvious depolarisation-shifted activation and hyperpolarisation-shifted inactivation, but also a more significant alteration in the time constant, V1/2 and the slope factor of activation and inactivation. CONCLUSIONS: The linkage mutation SCN5A R965C-R1309H led to a more dramatically reduced current density, as well as more significant depolarisation-shifted activation and hyperpolarisation-shifted inactivation in sodium channels than R965C or R1309H alone, which potentially explain this complex familial arrhythmia syndrome.

GPR4 signaling is essential for the promotion of acid-mediated angiogenic capacity of endothelial progenitor cells by activating STAT3/VEGFA pathway in patients with coronary artery disease.

BACKGROUND: Patients with coronary artery disease (CAD) are characterized by a decline in vascular regeneration, which is related to the dysfunction of endothelial progenitor cells (EPCs). G-protein-coupled receptor 4 (GPR4) is a proton-sensing G-protein-coupled receptor (GPCR) that contributes to neovascularization in acidic microenvironments. However, the role of GPR4 in regulating the angiogenic capacity of EPCs from CAD patients in response to acidity generated in ischemic tissue remains completely unclear. METHODS: The angiogenic capacity of EPCs collected from CAD patients and healthy subjects was evaluated in different pH environments. The GPR4 function of regulating EPC-mediated angiogenesis was analyzed both in vitro and in vivo. The downstream mechanisms were further investigated by genetic overexpression and inhibition. RESULTS: Acidic environment prestimulation significantly enhanced the angiogenic capacity of EPCs from the non-CAD group both in vivo and in vitro, while the same treatment yielded the opposite result in the CAD group. Among the four canonical proton-sensing GPCRs, GPR4 displays the highest expression in EPCs. The expression of GRP4 was markedly lower in EPCs from CAD patients than in EPCs from non-CAD individuals independent of acid stimulation. The siRNA-mediated knockdown of GPR4 with subsequent decreased phosphorylation of STAT3 mimicked the impaired function of EPCs from CAD patients at pH 6.4 but not at pH 7.4. Elevating GPR4 expression restored the neovessel formation mediated by EPCs from CAD patients in an acidic environment by activating STAT3/VEGFA signaling. Moreover, the beneficial impact of GPR4 upregulation on EPC-mediated angiogenic capacity was abrogated by blockade of the STAT3/VEGFA signaling pathway. CONCLUSIONS: Our present study demonstrated for the first time that loss of GPR4 is responsible for the decline in proton sensing and angiogenic capacity of EPCs from CAD patients. Augmentation of GPR4 expression promotes the neovessel formation of EPCs by activating STAT3/VEGF signaling. This finding implicates GPR4 as a potential therapeutic target for CAD characterized by impaired neovascularization in ischemic tissues.

Correction to: Systemic microvascular rarefaction is correlated with dysfunction of late endothelial progenitor cells in mild hypertension: a substudy of EXCAVATION-CHN1.

Upon publication of the original article [1], it was noticed that Jun Tao's affiliation information is not complete. The full affiliation information for Jun Tao can be found below and in the complete affiliation list of this Correction article.

Declined circulating Elabela levels in patients with essential hypertension and its association with impaired vascular function: A preliminary study.

Background: Elabela (ELA) is a newly identified endogenous ligand of apelin receptor (APJ) which has been confirmed to be implicated in the pathogenesis of hypertension. Previous experiments have revealed the critical role of ELA in eliciting vasodilation and lowering blood pressure. However, the role of plasma ELA levels in hypertensive patients and its relationship with vascular function have not been investigated.Method: Thirty-one patients with essential hypertension (EH) and 31 age-matched healthy subjects as controls were recruited in the study. Plasma ELA concentration and vascular function parameters including brachial artery flow-mediated dilation (FMD) and brachial-ankle pulse wave velocity (baPWV) were measured.Results: We observed remarkably lower plasma ELA concentration in hypertensive patients as compared with controls (1.29 ± 0.56 ng/ml vs. 1.79 ± 0.55 ng/ml; P = 0.001). Linear correlation analysis showed that ELA was negatively correlated with systolic blood pressure (r = -0.388, P = 0.002) and diastolic blood pressure (r = -0.321, P = 0.011) and positively correlated with FMD (r = 0.319, P = 0.011). There was no statistically significant relationship between ELA and baPWV (r = 0.234, P = 0.067). Stepwise multiple linear analysis also identified a close association of plasma ELA levels with endothelial function.Conclusion: The present study demonstrates for the first time that circulating ELA levels are reduced in patients with EH. The fall in endogenous ELA levels may be involved in the pathogenesis of hypertension-related vascular damage.

Berberine reduces endothelial injury and arterial stiffness in spontaneously hypertensive rats.

Background: Changes in circulating endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) are considered as a new perspective reflection of the endothelial injury and repair status. Our previous studies have demonstrated that berberine improved endothelial function and arterial stiffness in healthy subjects. In this study, we further investigated the effects of berberine on regulating the circulating EMPs and EPCs, and preventing endothelial dysfunction and arterial stiffness in spontaneously hypertensive rats (SHRs). Methods: Twenty male SHRs were randomly divided into two groups: Berberine-treated SHR group and vehicle-treated SHR group. The SHR rats were intragastrically treated with physiologic saline, berberine 50 mg/kg.d or vehicle for 4 weeks, respectively. Ten male Wistar-Kyoto (WKY) rats treated with vehicle served as normotensive controls. Tail systolic blood pressure was monitored every 2 weeks. At the end of the study, aortic pulse wave velocity (aPWV) was measured in vivo, and aorta were collected for measurement of endothelium-dependent vasodilation and immunohistological staining of elastic fiber. Peripheral blood was collected for circulating EMP detection and EPC culture. Results: Compared to normotensive rats, hypertensive rats displayed significantly higher circulating CD31+/CD42- MPs, lower number and colony-forming units (CFUs) of EPCs, worse endothelium-dependent vasodilation, and faster aPWV. Berberine treatment in SHRs partly reduced the blood pressure and circulating EMPs, and augmented EPC numbers and CFUs. In addition, berberine preserved arterial elasticity by lowering aPWV and increasing the content of arterial media elastin fiber, and improved endothelial function by maintaining better endothelium-dependent vasodilation. Robust relationship was observed among circulating CD31+/CD42- MPs, EPC numbers and aPWV. Conclusions: Abnormal changes of circulating EMPs and EPCs in SHRs are associated with endothelial dysfunction and arterial stiffness. Berberine may be a novel therapeutic option for the hypertension-related vascular injury in SHRs.

Compound and heterozygous mutations of KCNQ1 in long QT syndrome with familial history of unexplained sudden death: Identified by analysis of whole exome sequencing and predisposing genes.

INTRODUCTION: Long QT syndrome (LQTS) increases the risk of life-threatening arrhythmia in young individuals with structurally normal hearts. Sixteen genes such as the KCNQ1, KCNH2, and SCN5A have been reported for association with LQTS. CASE PRESENTATION: We identified the compound heterozygous mutations in the KCNQ1 gene at c. G527A (p.W176X) and c.G1765A (p.G589S) predicted as "damaging." The in-silico analysis showed that when compared to the characteristics of mRNA and protein of wild-type KCNQ1, the mRNA of c.G527A mutation was significantly different in the centroid secondary structure. The subunit coded by W176X would lose the transmembrane domains S3-S6 and helices A-D. The protein secondary structure of G589S was slightly shortened in helix structure; the protein physics-chemical parameters of W176X and G589S significantly and slightly changed, respectively. CONCLUSIONS: The compound heterozygous mutations of W176X and G589S coexisting in KCNQ1 gene of homologous chromosomes, resulting in more severe phenotype, are the likely pathogenic and genetic risks of LQTS and USD in this Chinese family.

Systemic microvascular rarefaction is correlated with dysfunction of late endothelial progenitor cells in mild hypertension: a substudy of EXCAVATION-CHN1.

BACKGROUND: Hypertension often presents with microvascular rarefaction (MVR), which is closely associated with impaired angiogenesis. Early detection of MVR is essential for systemic assessment in patient with hypertension. We aimed to determine the systemic MVR through both optical coherence tomography angiography (OCTA) and intravital capillaroscopy, and to investigate their respective efficacies and related mechanisms associated with late endothelial progenitor cells (LEPCs) dysfunction. METHODS: Seventy-one hypertensive and sixty-nine age-match normotensive subjects were included in this study. All subjects received intravital capillaroscopy for skin capillary density (SCD) and OCTA for retinal capillary density (RCD) and non-perfused areas (R-NPA). Subsequently, correlation of LEPCs activities and microvascular rarefaction were examined. RESULTS: Compared with normotensive subjects, hypertensive patients had significantly lower RCD [(52.9 ± 2.9)% vs. (57.8 ± 1.6)%, P < 0.01] and higher R-NPA [(0.12 ± 0.07) mm2 vs. (0.053 ± 0.020) mm2, P < 0.01]. SCD correlated positively with RCD but negatively with R-NPA [(RCD: OR = 0.40, 95% CI 0.25-0.67, P < 0.01); (R-NPA: OR = 0.39, 95% CI - 0.0029 to 0.0011, P < 0.01)]. The discriminative powers of RCD performed best (AUC 0.79 versus SCD AUC 0.59, P < 0.001) followed by R-NPA (AUC 0.73 versus SCD AUC 0.59, P < 0.001) for systolic blood pressure. Similar pattern is also found for diastolic blood pressure (RCD AUC 0.80 versus SCD AUC 0.54, P < 0.001; R-NPA AUC 0.77 versus SCD AUC 0.54, P < 0.001). Furthermore, LEPCs tube formation was impaired in hypertensive patients (36.8 ± 2.3 vs. 28 ± 3.7, P < 0.01). After multivariate adjustments, positive correlation existed between RCD or R-NPA with LEPCs tube formation (RCD: ß = 0.64, 95% CI 0.34-0.91, P < 0.01; R-NPA: ß = - 24.67, 95% CI - 43.14 to - 4.63, P < 0.05) but not with SCD (ß = 0.082, 95% CI 0.01-0.18, P = 0.085). CONCLUSION: Compared to intravital capillaroscopy, OCTA is a more precise technique for early detection of hypertensive microvascular rarefaction, which is associated with the fall in LEPC-mediated angiogenesis. Both of OCTA and LEPCs function can help identify hypertension-related capillary abnormality. Trail Registration The trial is a substudy of EXCAVATION-CHN1, registered at clinicaltrials.gov as NCT02817204 (June 26, 2016).

Expression of SUMO1P3 Compared with SUMO1 is an Independent Predictor of Patient Outcome in Lung Adenocarcinoma.

BACKGROUND The small ubiquitin-like modifier 1 (SUMO1) and small ubiquitin-like modifier 1 pseudogene 3 (SUMO1P3) are long noncoding RNAs (lncRNAs). The prognostic significance of SUMO1 and SUMO1P3 expression in non-small cell lung cancer (NSCLC) remains unclear. This study aimed to use clinical, genetic, and survival data from the Cancer Genome Atlas (TCGA), to analyze the prognostic significance of SUMO1 and SUMO1P3 expression in the two main subtypes of NSCLC, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). MATERIAL AND METHODS Data were acquired from TCGA and in silico survival analysis was performed. SUMO1 and SUMO1P3 expression were compared between patients with LUAD and LUSC. Patient outcome was assessed as complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). Recurrence-free survival (RFS) was defined as the survival time from primary surgery to the time of locoregional or distant recurrence of lung cancer. RESULTS SUMO1P3 was significantly increased in LUSC and LUAD tissues compared with adjacent normal lung tissue and was significantly co-expressed with SUMO1. SUMO1P3 expression was significantly increased in patients with LUAD but not LUSC with reduced RFS after primary or follow-up treatment. Although patients with LUAD who had high SUMO1 or SUMO1P3 expression had reduced RFS compared with low expression groups, univariate and multivariate analysis showed that only SUMO1P3 expression was independently associated reduced RFS (HR, 1.418; 95% CI, 1.041-1.930; p=0.027). CONCLUSIONS SUMO1P3 expression was an independent indicator of reduced RFS in patients with LUAD.

The prevalence of 30-day readmission after acute myocardial infarction: A systematic review and meta-analysis.

OBJECTIVE: The 30-day readmission is associated with increased medical costs, which has become an important quality metric in several medical institutions. This current study is aimed at clarifying the prevalence, the underlying risk factors, and reasons of the 30-day readmission after acute myocardial infarction (AMI). METHODS: PubMed, Cochrane Library, and EMBASE were systematically searched to identify eligible studies. Random-effect models were employed to perform pooled analyses. Means and 95% confidence intervals (CIs) were used to estimate prevalence and reasons for 30-day readmission. We also used Odds ratios (ORs) to explore the potential significant predictors of risk factors of 30-day readmission after AMI. Potential publication bias was assessed using funnel plot and Begg'test. RESULTS: A total of 14 relevant studies were included in this systematic review and meta-analysis. The pooled 30-day readmission rate of AMI was 12% (95% CI 0.11-0.14). Acute coronary syndrome (ACS), angina and acute ischemic heart disease, and heart failure (HF) were the principal cardiovascular reasons of 30-day readmission. Meanwhile, non-specific chest pain was regarded as the significant cause among non-cardiovascular reasons. The common co-morbidities kidney disease, HF and diabetes mellitus were significant risk factors for 30-day readmission. No significant publication bias was found by funnel plot and statistical tests. CONCLUSIONS: The 30-day readmission rate of post-AMI ranged from 11% to 14% and can be mainly attributed to cardiovascular and non-cardiovascular events. The common co-morbidities, such as kidney disease, HF, and diabetes mellitus were significant risk factors for 30-day readmission.