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Multi-principal element alloys (MPEAs) have attracted rapidly growing attention from both research institutions and industry due to their unique microstructures and outstanding physical and chemical properties. However, the fabrication of MPEAs with desired microstructures and properties using conventional manufacturing techniques (e.g., casting) is still challenging. With the recent emergence of additive manufacturing (AM) techniques, the fabrication of MPEAs with locally tailorable microstructures and excellent mechanical properties has become possible. Therefore, it is of paramount importance to understand the key aspects of the AM processes that influence the microstructural features of AM fabricated MPEAs including porosity, anisotropy, and heterogeneity, as well as the corresponding impact on the properties. As such, this review will first present the state-of-the-art in existing AM techniques to process MPEAs. This is followed by a discussion of the microstructural features, mechanisms of microstructural evolution, and the mechanical properties of the AM fabricated MPEAs. Finally, the current challenges and future research directions are summarized with the aim to promote the further development and implementation of AM for processing MPEAs for future industrial applications.

Background Only one large series has been reported on fat embolism syndrome (FES), a condition caused by fat globules release into the circulation, primarily as consequence of bone fracture. Thus, more data on clinical features, therapies, and prognosis are needed. Methods and results The study screened 1090 manuscripts in PubMed and Web of Science on cases of FES published from June 2010 to June 2020. The authors identified 124 studies and included in the pooled-analysis 135 patients (>14 years), plus one additional unpublished case managed in Tongji hospital. All had confirmed diagnosis of FES with complete clinical data. The median age at presentation was 39 years, and 82 (61.8%) were men. FES was predominantly associated with bone fractures (78, 57.4%), particularly femur fracture (59, 43.4%). The most common clinical finding at the onset was respiratory abnormalities in 34.6% of all clinical presentations. Therapies included respiratory supportive care in 127 (93.4%) patients, application of corticosteroids in 22 (16.2%) and anticoagulant in 5 (3.7%) cases. Overall mortality was 30.2% (N = 41), and logistic regression analysis showed that corticosteroid therapy was significantly associated with reduced mortality with an OR of 0.143 (95%CI 0.029–0.711), while age ≥ 65 years and non-orthopedic conditions were significantly associated with increased mortality with an OR of 4.816 (95%CI 1.638–14.160) and 4.785 (95%CI 1.019–22.474). Conclusions FES has been associated with a larger mortality rate than previously observed, although publication bias can have led to overestimation of mortality. Finally, a potential protective effect of corticosteroid therapy has been suggested by the current analysis.

Thoracic aortic aneurysm (TAA), a life-threatening cardiovascular disease, is considered a common cause of death in older individuals. Studies on the molecular mechanism of TAA are very limited. The aim of this study is to explore the expression pattern of autophagy-related genes (ARGs) in TAA, and the related immune infiltration landscape, using bioinformatics analysis. Differentially expressed genes (DEGs) in GSE26155 and differentially expressed miRNAs in GSE110527 were screened by R software. GO annotation and KEGG pathway enrichment analysis were performed on these DEGs. STRING database was employed for the PPI network establishment which was visualized by Cytoscape software. The differentially expressed ARGs were obtained by merging these DEGs with ARGs in autophagy databases HAMDb and HADb. The expression patterns of these differentially expressed ARGs are shown by violin diagram, correlation heatmap, PPI network and enrichment analysis. ROC analysis was used to evaluated the diagnostic value of these differentially expressed ARGs in TAA. Genes with area under the curve (AUC) > 0.7 were considered as TAA biomarkers. TargetScan, miRDB and miRWalk databases were used to predict miRNAs that target these ARGs. Intersection of predicted miRNAs and differentially expressed miRNAs to screen miRNAs that have a clear regulatory relationship with genes. Then a miRNA-mRNA regulatory network was constructed. Following this, the immune infiltration landscape of TAA and the correlation between these ARGs and immunity were further analyzed. In this study, 15 differentially expressed ARGs were screened and the expression patterns of these ARGs were investigated. A miRNA-mRNA regulatory network was constructed. 13 genes with AUC>0.7 in these differentially expressed ARGs were recognized as TAA biomarkers. Finally, the immune infiltration landscape of TAA was shown.

Aims Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance. Methods and results We used untargeted metabolomics and mass spectrometry to determine plasma succinate concentrations in 40 and 1665 individuals of the discovery and validation cohorts, respectively. Three different murine AAD models were used to determine the role of succinate in AAD development. We further examined the role of oxoglutarate dehydrogenase (OGDH) and its transcription factor cyclic adenosine monophosphate-responsive element-binding protein 1 (CREB) in the context of macrophage-mediated inflammation and established p38αMKO Apoe –/– mice. Succinate was the most upregulated metabolite in the discovery cohort; this was confirmed in the validation cohort. Plasma succinate concentrations were higher in patients with AAD compared with those in healthy controls, patients with acute myocardial infarction (AMI), and patients with pulmonary embolism (PE). Moreover, succinate administration aggravated angiotensin II-induced AAD and vascular inflammation in mice. In contrast, knockdown of OGDH reduced the expression of inflammatory factors in macrophages. The conditional deletion of p38α decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38α in macrophages reduced angiotensin II-induced AAD. Conclusion Plasma succinate concentrations allow to distinguish patients with AAD from both healthy controls and patients with AMI or PE. Succinate concentrations are regulated by the p38α–CREB–OGDH axis in macrophages.

The association among plasma trimethylamine-N-oxide (TMAO), FMO3 polymorphisms, and chronic heart failure (CHF) remains to be elucidated. TMAO is a microbiota-dependent metabolite from dietary choline and carnitine. A prospective study was performed including 955 consecutively diagnosed CHF patients with reduced ejection fraction, with the longest follow-up of 7 years. The concentrations of plasma TMAO and its precursors, namely, choline and carnitine, were determined by liquid chromatography-mass spectrometry, and the FMO3 E158K polymorphisms (rs2266782) were genotyped. The top tertile of plasma TMAO was associated with a significant increment in hazard ratio (HR) for the composite outcome of cardiovascular death or heart transplantation (HR = 1.47, 95% CI = 1.13-1.91, P = 0.004) compared with the lowest tertile. After adjustments of the potential confounders, higher TMAO could still be used to predict the risk of the primary endpoint (adjusted HR = 1.33, 95% CI = 1.01-1.74, P = 0.039). This result was also obtained after further adjustment for carnitine (adjusted HR = 1.33, 95% CI = 1.01-1.74, P = 0.039). The FMO3 rs2266782 polymorphism was associated with the plasma TMAO concentrations in our cohort, and lower TMAO levels were found in the AA-genotype. Thus, higher plasma TMAO levels indicated increased risk of the composite outcome of cardiovascular death or heart transplantation independent of potential confounders, and the FMO3 AA-genotype in rs2266782 was related to lower plasma TMAO levels.

Thoracic aortic dissection (TAD) without familial clustering or syndromic features is known as sporadic TAD (STAD). So far, the genetic basis of STAD remains unknown. Whole exome sequencing was performed in 223 STAD patients and 414 healthy controls from the Chinese Han population (N = 637). After population structure and genetic relationship and ancestry analyses, we used the optimal sequence kernel association test to identify the candidate genes or variants of STAD. We found that COL3A1 was significantly relevant to STAD (P = 7.35 × 10-6) after 10 000 times permutation test (P = 2.49 × 10-3). Moreover, another independent cohort, including 423 cases and 734 non-STAD subjects (N = 1157), replicated our results (P = 0.021). Further bioinformatics analysis showed that COL3A1 was highly expressed in dissected aortic tissues, and its expression was related to the extracellular matrix (ECM) pathway. Our study identified a profile of known heritable TAD genes in the Chinese STAD population and found that COL3A1 could increase the risk of STAD through the ECM pathway. We wanted to expand the knowledge of the genetic basis and pathology of STAD, which may further help in providing better genetic counseling to the patients.

We performed a cross-sectional study using the National Health Examination and Nutrition Survey (NHANES) data and a Mendelian randomisation (MR) study using the GWAS summary statistics from European populations. The T2D-related indices (fasting plasma glucose (FPG), fasting insulin (FI), and insulin resistance (IR)) were found to associate with elevated bone mineral density (BMD). The known associations amongst FPG, FI, IR, and BMD remain inconsistent. This study aims to explore the abovementioned associations by using cross-sectional and MR designs. Data from adults aged ≥ 20 years (n = 7170) in four rounds of the U.S. NHANES (2005–2010 and 2013–2014) were analysed in this cross-sectional study. Multiple linear and logistic regression models were used for statistical analyses. A two-sample MR study was performed using the genome-wide association study summary statistics obtained from the Meta-analyses of Glucose and Insulin-related traits Consortium (n = 108,557) and Genetic Factors for Osteoporosis Consortium (n = 32,735) to examine the causality of the FI–BMD association. Multiple linear regression revealed that FPG was positively associated with the BMDs at the hip, femur neck, and 1st lumbar spine (L1). Multiple logistic regressions revealed that FPG levels were associated with elevated BMDs at the hip and L1, and FI and IR levels were associated with elevated BMD at the hip. Patients with type 2 diabetes had higher hip BMD than those without diabetes. In the MR study, the lumbar spine BMD increased by 0.49 g/cm2 (95% confidence interval: 0.01, 0.97) in response to per unit increase in log-transformed FI. Findings from our cross-sectional and MR studies revealed the associations between the studied diabetic indices and BMD measurements in the US and European adults.

Rationale: Maladaptive cardiac remodeling is a critical step in the progression of heart failure. Low-density lipoprotein receptor-related protein 6 (LRP6), a co-receptor of Wnt, has been implicated in cardiac protection. We aimed to study the role of cardiomyocyte-expressed LRP6 in cardiac remodeling under chronic pressure overload. Methods: Cardiac parameters were analyzed in inducible cardiac-specific LRP6 overexpressing and control mice subjected to transverse aortic constriction (TAC). Results: Cardiac LRP6 was increased at an early phase after TAC. Cardiomyocyte-specific LRP6 overexpression improved cardiac function and inhibited cardiac hypertrophy and fibrosis four weeks after TAC. The overexpression significantly inhibited β-catenin activation, likely contributing to the inhibitory effect on cardiac hypertrophy after TAC. LRP6 overexpression reduced the expression and secretion of Wnt5a and Wnt11 by cardiomyocytes, and knockdown of Wnt5a and Wnt11 greatly inhibited cardiac fibrosis and dysfunction under pressure overload in vitro and in vivo. Cardiomyocyte-expressed LRP6 interacted with cathepsin D (CTSD, a protease) and promoted the degradation of Wnt5a and Wnt11, inhibiting cardiac fibrosis and dysfunction induced by TAC. The protease inhibitor leupeptin attenuated the interaction between LRP6 and CTSD, enhanced the expression of Wnt5a and Wnt11, and deteriorated cardiac function and fibrosis in cardiomyocyte-specific LRP6-overexpressing mice under pressure overload. Mutants from human patients, P1427Q of LRP6 and G316R of CTSD significantly inhibited the interaction between LRP6 and CTSD and increased Wnt5a and Wnt11 expression. Conclusion: Cardiomyocyte-expressed LRP6 promoted the degradation of Wnt5a and Wnt11 by regulating CTSD and inhibited cardiac fibrosis under pressure overload. Our study demonstrated a novel role of LRP6 as an anti-fibrosis regulator.

Background Cardiac injury, as measured by troponin elevation, has been reported among hospitalized coronavirus disease 2019 (COVID-19) patients and portends a poor prognosis. However, how the dynamics of troponin elevation interplay with inflammation and coagulation biomarkers over time is unknown. We assessed longitudinal follow-up of cardiac injury, inflammation and coagulation markers in relation to disease severity and outcome. Methods We retrospectively assessed 2068 patients with laboratory-confirmed COVID-19 between January 29 and April 1, 2020 at Tongji Hospital in Wuhan, China. We defined cardiac injury as an increase in high sensitivity cardiac troponin-I (hs-cTnI) above the 99th of the upper reference limit. We explored the dynamics of elevation in hs-cTnI and the relationship with inflammation (interleukin [IL]-6, IL-8, IL-10, IL-2 receptor, tumor necrosis factor-α, C-reactive protein) and coagulation (d-dimer, fibrinogen, international normalized ratio) markers in non-critically ill versus critically ill patients longitudinally and further correlated these markers to survivors and non-survivors. Results Median age was 63 years (first to third quartile 51–70 years), 51.4% of whom were women. When compared to non-critically ill patients (N = 1592, 77.0%), critically ill (defined as requiring mechanical ventilation, in shock or multiorgan failure) patients (N = 476, 23.0%), had more frequent cardiac injury on admission (30.3% vs. 2.3%, p, Graphical abstract Unlabelled Image, Highlights • In COVID-19 patients increased levels of hs-cTnI beyond day 3 since admission portend a poor prognosis. • A consistent positive correlation of hs-cTnI with IL-6 and d-dimer could suggest nonspecific cytokine-mediated cardiotoxicity. • The risk for cardiac arrest and rhythm disturbances in patients with elevated hs-cTnI suggest an arrhythmogenic nature.

Coronavirus disease 2019 (COVID-19) is a global pandemic which has caused numerous deaths worldwide. The present study investigated the roles of hypoproteinemia in the clinical outcome and liver dysfunction of COVID-19 patients. In this retrospective study, we extracted data from 2,623 clinically confirmed adult COVID-19 patients (>18 years old) between January 29, 2020 and March 6, 2020 in Tongji Hospital, Wuhan, China. The patients were divided into three groups—non-critically ill, critically ill, and death groups—in accordance with the Chinese Clinical Guideline for COVID-19. Serum albumin, low-density lipoproteins cholesterol (LDL-C), and high-density lipoproteins cholesterol (HDL-C) concentrations and inflammatory cytokines levels were measured and compared among these three groups. The median age of these 2,623 patients was 64 years old (interquartile range (IQR), 52–71). Among the patients enrolled in the study, 2,008 (76.6%) were diagnosed as non-critically ill and 615 (23.4%) were critically ill patients, including 383 (14.6%) critically ill survivors and 232 (8.8%) critically ill deaths in the hospital. Marked hypoalbuminemia occurred in 38.2%, 71.2%, and 82.4% patients in non-critically ill, critically ill, and death groups, respectively, on admission and 45.9%, 77.7%, and 95.6% of these three groups, respectively, during hospitalization. We also discovered that serum low-density lipoprotein (LDL) and HDL levels were significantly lower in critically ill and death groups compared to non-critically ill group. Meanwhile, the patients displayed dramatically elevated levels of serum inflammatory factors, while a markedly prolonged activated partial thromboplastin time (APTT) in critically ill patients reflected coagulopathy. This study suggests that COVID-19-induced cytokine storm causes hepatotoxicity and subsequently critical hypoalbuminemia, which are associated with exacerbation of disease-associated inflammatory responses and progression of the disease and ultimately leads to death for some critically ill patients. Electronic Supplementary Material Supplementary material is available for this article at 10.1007/s11427-020-1733-4 and is accessible for authorized users.

Both ischemic cardiomyopathy (ICM) and non-ischemic cardiomyopathy (NICM) are characterized by left ventricular (LV) dysfunction and dilation. Differentiation between ICM and NICM using non-invasive image modalities is a clinical challenge. This study compared the myocardial deformation patterns of ICM and NICM using 2-D speckle tracking echocardiography (2-D STE) and sought to find parameters valuable in the diagnosis and management of dilated cardiomyopathy. The study population comprised 84 consecutive patients with LV end-diastolic dimension55 mm and ejection fraction (EF)45 %. Of these patients, 41 were diagnosed with ICM and 43 with NICM by coronary angiography. 2-D STE was performed in all patients. The LV dimension did not differ between ICM and NICM. Compared with patients with ICM, patients with NICM had lower EF (29.0% vs. 33.0%, p = 0.024), lower global longitudinal strain (-5.4 ± 2.6% vs. -7.0 ± 2.5%, p = 0.006) and lower global radial strain (7.5 ± 4.5% vs. 10.7 ± 4.7%, p = 0.019). In contrast, global longitudinal strains did not differ significantly. However, NICM patients had higher apical and lower basal longitudinal strains compared with those with ICM. The ratio of basal to sum of mid- and apical longitudinal strains could predict NICM with a sensitivity of 63.4% and specificity of 88.4% by receiver operating characteristic curve analysis (cutoff value: 0.47, area under the curve: 0.792). Moreover, the concomitant presence of non-significant coronary artery stenosis (50% and70%) had no significant influence on global longitudinal strain in NICM. In conclusion, LV dilation and systolic dysfunction, relative apical sparing and a basal worsening pattern of LV longitudinal strain by 2-D STE were observed in patients with NICM but not ICM. The ratio of basal to sum of mid- and apical longitudinal strains could help differentiate NICM from ICM.

Background Sudden cardiac death due to malignant arrhythmias is a common cause of death in dilated cardiomyopathy (DCM). Whether genetic variants increase the risk of arrhythmias in DCM is unknown. Objective The purpose of this study was to investigate the genetic causes of arrhythmias in DCM patients. Methods Whole-exome sequencing and high-depth targeted next-generation sequencing (142-gene panel) were used. Eight specific DCM pedigrees with arrhythmias and 2 separate cohorts of 1232 consecutive unrelated sporadic DCM patients from 3 medical centers (550 in the discovery cohort, 682 in the replication cohort) were analyzed; 470 (250 in the discovery cohort, 220 in the replication cohort) suffered from arrhythmias (DCM-A group) and 762 (300 in the discovery cohort, 462 in the replication cohort) did not (DCM-NA group). All identified causative variants were Sanger sequenced to eliminate false-positive results and then screened in 700 unrelated matched arrhythmia- and DCM-free healthy controls. Results We identified long QT syndrome (LQTS)-causative variants that independently cosegregated in 2 unrelated DCM-LQTS pedigrees. Pathogenic variants in arrhythmia-related genes (ion channelopathies) were identified in 4.9% (23/470) of sporadic DCM-A patients (4.0% in the discovery cohort, 5.9% in the replication cohort) but only 0.1% (1/762) of sporadic DCM-NA patients (P = 2.16 × 10–9). These arrhythmia-related pathogenic variants included long QT syndrome, atrial fibrillation, sick sinus syndrome, cardiac conduction disease, and Brugada syndrome. Conclusion Some arrhythmias in DCM patients are caused by arrhythmia-related pathogenic variants. For DCM patients with explicit arrhythmias, arrhythmia-causative genetic screening may help to explain the etiology and decision-making.

Background: Cardiac sialylation is involved in a variety of physiological processes in the heart. Altered sialylation has been implicated in heart failure (HF) mice. However, its role in patients with HF is unclear, and the potential effect of modulation of cardiac sialylation is worth exploring. Methods: We first assessed the association between plasma N-acetylneuraminic acid levels and the incidence of adverse cardiovascular events in patients with HF over a median follow-up period of 2 years. Next, immunoblot analysis and lectin histochemistry were performed in cardiac tissue to determine the expression levels of neuraminidases and the extent of cardiac desialylation. Finally, the therapeutic impact of a neuraminidase inhibitor was evaluated in animal models of HF. Results: Among 1699 patients with HF, 464 (27%) died of cardiovascular-related deaths or underwent heart transplantation. We found that the elevated plasma N-acetylneuraminic acid level was independently associated with a higher risk of incident cardiovascular death and heart transplantation (third tertile adjusted hazard ratio, 2.11 [95% CI, 1.67–2.66], P Conclusions: This study uncovered a significant association between elevated plasma N-acetylneuraminic acid level and an increased risk of a poor clinical outcome in patients with HF. Our data support the notion that desialylation represents an important contributor to the progression of HF, and neuraminidase inhibition may be a potential therapeutic strategy for HF.

Background Chronic chagasic cardiomyopathy (CCC) is the leading cause of heart failure in Latin America and often causes severe inflammation and fibrosis in the heart. Studies on myocardial function and its molecular mechanisms in patients with Chronic chagasic cardiomyopathy are very limited. In order to understand the development and progression of Chronic chagasic cardiomyopathy and find targets for its diagnosis and treatment, the field needs to better understand the exact molecular mechanisms involved in these processes. Methods The mRNA microarray datasets GSE84796 (human) and GSE24088 (mouse) were obtained from the Gene Expression Omnibus (GEO) database. Homologous genes between the two species were identified using the online database mining tool Biomart, followed by differential expression analysis, gene enrichment analysis and protein–protein interaction (PPI) network construction. Cytohubba plug-in of Cytoscape software was used to identify Hub gene, and miRNet was used to construct the corresponding miRNA–mRNA regulatory network. miRNA-related databases: miRDB, Targetscan and miRWalk were used to further evaluate miRNAs in the miRNA–mRNA network. Furthermore, Comparative Toxicogenomics Database (CTD) and L1000 Platform were used to identify hub gene-related drugs. Results A total of 86 homologous genes were significantly differentially expressed in the two datasets, including 73 genes with high expression and 13 genes with low expression. These differentially expressed genes were mainly enriched in the terms of innate immune response, signal transduction, protein binding, Natural killer cell mediated cytotoxicity, Tuberculosis, Chemokine signaling pathway, Chagas disease and PI3K−Akt signaling pathway. The top 10 hub genes LAPTM5, LCP1, HCLS1, CORO1A, CD48, TYROBP, RAC2, ARHGDIB, FERMT3 and NCF4 were identified from the PPI network. A total of 122 miRNAs were identified to target these hub genes and 30 of them regulated two or more hub genes at the same time. miRDB, Targetscan and miRWalk were further analyzed and screened out hsa-miR-34c-5p, hsa-miR-34a-5p and hsa-miR-16-5p as miRNAs regulating these hub genes. Finally, Progesterone, Flutamide, Nimesulide, Methotrexate and Temozolomide were identified to target these hub genes and might be targeted therapies for Chronic chagasic cardiomyopathy. Conclusions In this study, the potential genes associated with Chronic chagasic cardiomyopathy are identified and a miRNA–mRNA regulatory network is constructed. This study explores the molecular mechanisms of Chronic chagasic cardiomyopathy and provides important clues for finding new therapeutic targets.

Chronic heart failure (CHF) has poor prognosis and polygenic heritability, and the genetic risk score (GRS) to predict CHF outcome has not yet been researched comprehensively. In this study, we sought to establish GRS to predict the outcomes of CHF. We re‐analysed the proteomics data of failing human heart and combined them to filter the data of high‐throughput sequencing in 1000 Chinese CHF cohort. Cox hazards models were used based on single nucleotide polymorphisms (SNPs) to estimate the association of GRS with the prognosis of CHF, and to analyse the difference between individual SNPs and tertiles of genetic risk. In the cohort study, GRS encompassing eight SNPs harboured in seven genes were significantly associated with the prognosis of CHF (P = 2.19 × 10−10 after adjustment). GRS was used in stratifying individuals into significantly different CHF risk, with those in the top tertiles of GRS distribution having HR of 3.68 (95% CI: 2.40‐5.65 P = 2.47 × 10−10) compared with those in the bottom. We developed GRS and demonstrated its association with first event of heart failure endpoint. GRS might be used to stratify individuals for CHF prognostic risk and to predict the outcomes of genomic screening as a complement to conventional risk and NT‐proBNP.

Background Spontaneous coronary artery dissection (SCAD) is defined as a splitting of the coronary artery wall exclusive of iatrogenesis or trauma. Since the last decades, our knowledge of the diagnosis and prognosis and therapy for SCAD has advanced; however, its causes remain unknown. Objectives This study sought to identify genes associated with SCAD development in the Chinese Han population. Methods Between November 2011 and January 2018, the authors enrolled 85 SCAD cases and 296 non-SCAD controls from the Chinese Han population. All 381 subjects enrolled underwent detection with whole exome sequencing, followed by Sanger sequencing for confirmation. Principle component analysis was used to evaluate the structure of the population. Haploview was used to analyze the linkage disequilibrium statistics of the variants. The author used 2 gene-based association tests, optimal sequence kernel association test and mixed effects score test, to identify the causal genes or variants of SCAD. Immunohistochemistry was used to detect the expression of TSR1 in coronary artery tissues. Results Four genes with a suggestive association with SCAD (p Conclusions This study describes the clinical characteristics of the Chinese Han population with SCAD and identified TSR1 as a potential causal gene, which might bring about a further progress in diagnosis and treatment of the disorder.

Fulminant myocarditis (FM) has unacceptable high mortality. This study aimed to evaluate the therapeutic efficacy of a life support-based comprehensive treatment regimen (LSBCTR), a completely novel treatment regimen, for FM. A total of 169 FM patients recruited from January 2008 to December 2018 were divided into two groups: patients receiving LSBCTR (81 cases), which includes (i) mechanical life support (positive pressure respiration, intra-aortic balloon pump with or without extracorporeal membrane oxygenation), (ii) immunomodulation therapy using sufficient doses of glucocorticoids and immunoglobulins, and (iii) application of neuraminidase inhibitors, and those receiving conventional treatment (88 cases). The endpoints were in-hospital death and heart-transplantation. Of all the population, 44 patients (26.0%) died in hospitals. In-hospital mortality was 3.7% (3/81) for LSBCTR group and 46.6% (41/88) for traditional treatment (P

A life support-based comprehensive treatment regimen, in which an intra-aortic balloon pump (IABP) unloads the left ventricle, has reduced the mortality of patients with fulminant myocarditis (FM). This study evaluated the efficacy of IABP in the treatment of patients with FM. A total of 100 patients diagnosed with FM were divided into two groups depending on the application of IABPs. 57 (57%) received IABPs within 30 min after admission (IABP group), whereas 43 (43%) did not (non-IABP group). In IABP group, 24.6% (14/57) died, compared to 34.9% (15/43) of those without IABPs (P

Background The genetic basis of a considerable fraction of hypertrophic cardiomyopathy (HCM) cases remains unknown. Whether the gene encoding RNA binding motif protein 20 (RBM20) is implicated in HCM and the correlation of clinical characteristics of RBM20 heterozygotes with HCM remain unresolved. We aimed to investigate the association between RBM20 variants and HCM. Methods We compared rare variants in the RBM20 gene by exome sequencing in 793 patients with HCM and 414 healthy controls. Based on a case-control approach, we used optimal sequence kernel association test (SKAT-O) to explore whether RBM20 is associated with HCM. The genetic distribution of RBM20 rare variants was then compared between HCM heterozygotes and dilated cardiomyopathy (DCM) heterozygotes. Clinical features and prognosis of RBM20 heterozygotes were compared with nonheterozygotes. Results Gene-based association analysis implicated RBM20 as a susceptibility gene for developing HCM. Patients with RBM20 variants displayed a higher prevalence of sudden cardiac arrest (SCA) (6.7% vs 0.9%, P = 0.001), increased sudden cardiac death (SCD) risk factor counts and impaired left ventricle systolic function. Further survival analysis revealed that RBM20 heterozygotes had higher incidences of resuscitated cardiac arrest, recurrent nonsustained ventricular tachycardia, and malignant arrhythmias. Mendelian randomization suggested that RBM20 expression in the left ventricle was causally associated with HCM and DCM with opposite effects. Conclusions This study identified RBM20 as a potential causal gene of HCM. RBM20 variants are associated with increased risk for SCA in HCM.

Background: Accumulating evidence has revealed that coronavirus disease 2019 (COVID-19) patients may be complicated with myocardial injury during hospitalization. However, data regarding persistent cardiac involvement in patients who recovered from COVID-19 are limited. Our goal is to further explore the sustained impact of COVID-19 during follow-up, focusing on the cardiac involvement in the recovered patients.Methods: In this prospective observational follow-up study, we enrolled a total of 40 COVID-19 patients (20 with and 20 without cardiac injury during hospitalization) who were discharged from Zhongnan Hospital of Wuhan University for more than 6 months, and 27 patients (13 with and 14 without cardiac injury during hospitalization) were finally included in the analysis. Clinical information including self-reported symptoms, medications, laboratory findings, Short Form 36-item scores, 6-min walk test, clinical events, electrocardiogram assessment, echocardiography measurement, and cardiac magnetic resonance imaging was collected and analyzed.Results: Among 27 patients finally included, none of patients reported any obvious cardiopulmonary symptoms at the 6-month follow-up. There were no statistically significant differences in terms of the quality of life and exercise capacity between the patients with and without cardiac injury. No significant abnormalities were detected in electrocardiogram manifestations in both groups, except for nonspecific ST-T changes, premature beats, sinus tachycardia/bradycardia, PR interval prolongation, and bundle-branch block. All patients showed normal cardiac structure and function, without any statistical differences between patients with and without cardiac injury by echocardiography. Compared with patients without cardiac injury, patients with cardiac injury exhibited a significantly higher positive proportion in late gadolinium enhancement sequences [7/13 (53.8%) vs. 1/14 (7.1%), p = 0.013], accompanied by the elevation of circulating ST2 level [median (interquartile range) = 16.6 (12.1, 22.5) vs. 12.5 (9.5, 16.7); p = 0.044]. Patients with cardiac injury presented higher levels of aspartate aminotransferase, creatinine, high-sensitivity troponin I, lactate dehydrogenase, and N-terminal pro–B-type natriuretic peptide than those without cardiac injury, although these indexes were within the normal range for all recovered patients at the 6-month follow-up. Among patients with cardiac injury, patients with positive late gadolinium enhancement presented higher cardiac biomarker (high-sensitivity troponin I) and inflammatory factor (high-sensitivity C-reactive protein) on admission than the late gadolinium enhancement–negative subgroup.Conclusions: Our preliminary 6-month follow-up study with a limited number of patients revealed persistent cardiac involvement in 29.6% (8/27) of recovered patients from COVID-19 after discharge. Patients with cardiac injury during hospitalization were more prone to develop cardiac fibrosis during their recovery. Among patients with cardiac injury, those with relatively higher cardiac biomarkers and inflammatory factors on admission appeared more likely to have cardiac involvement in the convalescence phase.

Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n = 1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has induced an ongoing global health crisis. Here we utilized a combination of targeted amino acids (AAs) and clinical biochemical profiling to analyze the plasma of coronavirus disease 2019 (COVID-19) subjects at the hospitalization stage and 1-month post-infection convalescent stage, respectively, to investigate the systematic injury during COVID-19 disease progress. We found the virus-induced inflammatory status and reduced liver synthesis capacity in hospitalized patients, which manifested with increased branched-chain AAs (BCAAs), aromatic AAs (AAAs), one-carbon related metabolites, and decreased methionine. Most of these disturbances during infection recover except for the increased levels of medium-chain acylcarnitines (ACs) in the convalescent subjects, implying the existence of incomplete fatty acids oxidation during recovery periods. Our results suggested that the imbalance of the AA profiling in COVID-19 patients. The majority of disturbed AAs recovered in 1 month. The incomplete fatty acid oxidation products suggested it might take longer time for convalescent patients to get complete recovery.

The association among plasma trimethylamine-N-oxide (TMAO), FMO3 polymorphisms, and chronic heart failure (CHF) remains to be elucidated. TMAO is a microbiota-dependent metabolite from dietary choline and carnitine. A prospective study was performed including 955 consecutively diagnosed CHF patients with reduced ejection fraction, with the longest follow-up of 7 years. The concentrations of plasma TMAO and its precursors, namely, choline and carnitine, were determined by liquid chromatography-mass spectrometry, and the FMO3 E158K polymorphisms (rs2266782) were genotyped. The top tertile of plasma TMAO was associated with a significant increment in hazard ratio (HR) for the composite outcome of cardiovascular death or heart transplantation (HR = 1.47, 95% CI = 1.13-1.91, P = 0.004) compared with the lowest tertile. After adjustments of the potential confounders, higher TMAO could still be used to predict the risk of the primary endpoint (adjusted HR = 1.33, 95% CI = 1.01-1.74, P = 0.039). This result was also obtained after further adjustment for carnitine (adjusted HR = 1.33, 95% CI = 1.01-1.74, P = 0.039). The FMO3 rs2266782 polymorphism was associated with the plasma TMAO concentrations in our cohort, and lower TMAO levels were found in the AA-genotype. Thus, higher plasma TMAO levels indicated increased risk of the composite outcome of cardiovascular death or heart transplantation independent of potential confounders, and the FMO3 AA-genotype in rs2266782 was related to lower plasma TMAO levels.

COVID-19 caused by SARS-COV-2 infection can lead to multi-organ injuries and significant mortality in severe and critical patients, especially among those individuals with type 2 diabetes (T2D) as a comorbidity. While attenuated mortality was observed with aggressive glucose control, it was unclear whether therapeutic regimens including insulin treatment were beneficial for patients with COVID-19 and T2D. This retrospective study investigated 689 patients with COVID-19 and T2D from a cohort of 3,305 cases from Wuhan, China. Unexpectedly, we found that insulin treatment for patients with COVID-19 and T2D was associated with a significant increase in mortality (27.2% versus 3.5%; adjusted HR, 5.38 [2.75–10.54]). Further analysis showed that insulin treatment was associated with enhanced systemic inflammation and aggravated injuries of vital organs. Therefore, insulin treatment for patients with COVID-19 and T2D should be used with caution., Graphical Abstract, Highlights • 689 patients with COVID-19 and T2D were retrospectively analyzed • Insulin treatment associated with increased mortality risk with COVID-19 • Insulin was associated with higher mortality compared to other anti-diabetics • Insulin treatment should be used with caution for patients with COVID-19 and T2D, Type 2 diabetes (T2D) is associated with poor outcome for patients with COVID-19. Here, Yu et al. demonstrated that among 689 patients with T2D from a cohort of 3,305 hospitalized COVID-19 cases, insulin treatment was associated with a significant increase in death rate in patients with COVID-19 and T2D.

ImportanceCoronavirus disease 2019 (COVID-19) is a pandemic with no specific drugs and high mortality. The most urgent thing is to find effective treatments.ObjectiveTo determine whether hydroxychloroquine application may be associated with a decreased risk of death in critically ill COVID-19 patients and what is potential mechanism.Design, Setting and PatientsThis retrospective study included all 568 critically ill COVID-19 patients who were confirmed by pathogen laboratory tests despite antiviral treatment and had severe acute respiratory distress syndrome, PAO2/FIO2 MAIN OUTCOMES AND MEASURESIn-hospital death and hospital stay time (day) were obtained, level of inflammatory cytokine (IL-6) was measured and compared between HCQ and NHCQ treatments.RESULTSThe median age of 568 critically ill patients is 68 (57, 76) years old with 37.0% being female. Mortalities are 18.8% (9/48) in HCQ group and 45.8% (238/520) in NHCQ group (pCONCLUSIONS AND RELEVANCEHydroxychloroquine treatment is significantly associated with a decreased mortality in critically ill patients with COVID-19 through attenuation of inflammatory cytokine storm. Therefore, hydroxychloroquine should be prescribed for treatment of critically ill COVID-19 patients to save lives.Key PointsQuestionCould hydroxychloroquine administration be beneficial in the treatment of critically ill patients with COVID-19?FindingsIn this retrospective study, a total of 568 critically ill patients with COVID-19 all received basic therapy and additionally 48 of them received hydroxychloroquine for 7–10 days (200 mg twice per day). Hydroxychloroquine treatment is significantly associated with a decreased mortality in critically ill COVID-19 patients and attenuated inflammatory cytokine IL-6 level.MeaningOur data suggest that hydroxychloroquine could be used to treat critically ill patients with COVID-19 which may save a lot of lives.