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BACKGROUND: Dilated cardiomyopathy (DCM) is a genetically heterogeneous cardiac disorder characterized by left ventricular dilation and contractile dysfunction. The substantial genetic heterogeneity evident in patients with DCM contributes to variable disease severity and complicates overall prognosis, which can be very poor. AIM: To identify pathogenic genes in DCM through pedigree analysis. METHODS: Our research team identified a patient with DCM in the clinic. Through investigation, we found that the family of this patient has a typical DCM pedigree. High-throughput sequencing technology, next-generation sequencing, was used to sequence the whole exomes of seven samples in the pedigree. RESULTS: A novel and potentially pathogenic gene mutation-ANK2p.F3067L-was discovered. The mutation was completely consistent with the clinical information for this DCM pedigree. Sanger sequencing was used to further verify the locus of the mutation in pedigree samples. These results were consistent with those of high-throughput sequencing. CONCLUSIONS: ANK2p.F3067L is considered a novel and potentially pathogenic gene mutation in DCM.
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Dysregulation of bone homeostasis is closely related to the pathogenesis of osteoporosis. Suppressing bone resorption by osteoclasts to attenuate bone loss has been widely investigated, but far less effort has been poured toward promoting bone formation by osteoblasts. Here, we aimed to explore magnesium ascorbyl phosphate (MAP), a hydrophilic and stable ascorbic acid derivative, as a potential treatment option for bone loss disorder by boosting osteoblastogenesis and bone formation. We found that MAP could promote the proliferation and osteoblastic differentiation of human skeletal stem and progenitor cells (SSPCs) in vitro. Moreover, MAP supplementation by gavage could alleviate bone loss and accelerate bone defect healing through promoting bone formation. Mechanistically, we identified Calcium/calmodulin-dependent serine/threonine kinase IIα (CaMKIIα) as the target of MAP, which was found to be directly bound and activated by MAP, then with a concomitant activation in the phosphorylation of ERK1/2 (Extracellular regulated kinase 1/2) and CREB (cAMP-response element binding protein) as well as an elevation of C-FOS expression. Further, blocking CaMKII signaling notably abolished these effects of MAP on SSPCs and bone remodeling. Taken together, our data indicated that MAP played an important role in enhancing bone formation through the activation of CaMKII/ERK1/2/CREB/C-FOS signaling pathway and may be used as a novel therapeutic option for bone loss disorders such as osteoporosis.
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Diuretics are drugs that promote the excretion of water and electrolytes in the body and produce diuretic effects. Clinically, they are often used in the treatment of edema caused by various reasons and hypertension. In sports, diuretics are banned by the World Anti-Doping Agency (WADA). Therefore, in order to monitor blood drug concentration, identify drug quality and maintain the fairness of sports competition, accurate, rapid, highly selective and sensitive detection methods are essential. This review provides a comprehensive summary of the pretreatment and detection of diuretics in various samples since 2015. Commonly used techniques to extract diuretics include liquid-liquid extraction, liquid-phase microextraction, solid-phase extraction, solid-phase microextraction, among others. Determination methods include methods based on liquid chromatography, fluorescent spectroscopy, electrochemical sensor method, capillary electrophoresis and so on. The advantages and disadvantages of various pretreatment and analytical techniques are elaborated. In addition, future development prospects of these techniques are discussed.
HIGHLIGHTSPretreatment and determination methods of diuretics in diverse samples are reviewed.Applications of novel materials and technologies for SPE and sensors are highlighted.Pros and cons of recent pretreatment and analysis techniques used for diuretics are discussed.Applications of high-resolution mass spectrometry are described in detail.
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With the rapid development of poultry industry and the highly intensive production management, there are an increasing number of stress factors in poultry production. Excessive stress will affect their growth and development, immune function, and induce immunosuppression, susceptibility to a variety of diseases, and even death. In recent years, increasing interest has focused on natural components extracted from plants, among which plant polysaccharides have been highlighted because of their various biological activities. Plant polysaccharides are natural immunomodulators that can promote the growth of immune organs, activate immune cells and the complement system, and release cytokines. As a green feed additive, plant polysaccharides can not only relieve stress and enhance the immunity and disease resistance of poultry, but also regulate the balance of intestinal microorganisms and effectively alleviate all kinds of stress faced by poultry. This paper reviews the immunomodulatory effects and molecular mechanisms of different plant polysaccharides (Atractylodes macrocephala Koidz polysaccharide, Astragalus polysaccharides, Taishan Pinus massoniana pollen polysaccharide, and alfalfa polysaccharide) in poultry. Current research results reveal that plant polysaccharides have potential uses as therapeutic agents for poultry immune abnormalities and related diseases.
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Prime Editor (PE) is a precise genome manipulation technology based on the CRISPR-Cas9 system, while its application in human induced pluripotent stem cells (iPSCs) remains limited. Here, we established a repaired hiPS cell line (SKLRMi001-A-1) from hiPSCs with androgen receptor (AR) mutation (c.2710G > A; p.V904M). The repaired iPSC line expressed pluripotency markers, retained normal karyotype, showed the capability of differentiating into three germ layers and was absence of mycoplasma infection. The repaired iPSC line will help to elucidate the mechanism of androgen insensitivity syndrome (AIS) and benefit treatment for AIS in the future.
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Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin lymphoma with highly heterogeneous clinical courses. Paired-box 5 (PAX5), the regulator of B cell differentiation and growth, is abnormally expressed in several types of cancers. Herein, we explored the prognostic value of PAX5 in MCL by comprehensively analyzing the clinical features and laboratory data of 82 MCL cases. PAX5 positivity was associated with shorter overall survival (OS; p = 0.011) and was identified as an independent prognostic factor in MCL patients. The elevated ß2-MG (p = 0.027) and advanced Mantle Cell Lymphoma International Prognostic Index (MIPI) score (p = 0.014) were related to positive PAX5 expression. The MIPI-SP risk scoring system was established and exhibited a superior prognostic value for OS depending on an area under the curve (AUC) of 0.770 (95% CI, 0.658-0.881) than MIPI score. Bioinformatic analysis of PAX5-related genes supported the mechanistic roles of PAX5 in MCL. This study provides insight into the potential role of PAX5 in MCL, and the novel risk scoring system MIPI-SP optimizes the risk stratification and facilitates prognosis evaluation in MCL patients. KEY MESSAGES: ⢠Paired-box 5 positivity indicated adverse prognosis in mantle cell lymphoma patients. ⢠Positive PAX5 expression was related to MIPI score and ß2-MG in MCL patients. ⢠MIPI-SP risk scoring system has superior prognostic value than MIPI score in MCL.
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Linfoma de Células del Manto , Adulto , Humanos , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/genética , Factor de Transcripción PAX5/genéticaRESUMEN
RNA-binding proteins (RBPs) containing intrinsically disordered domains undergo liquid-liquid phase separation to form nuclear bodies under stress conditions. This process is also connected to the misfolding and aggregation of RBPs, which are associated with a series of neurodegenerative diseases. However, it remains elusive how folding states of RBPs changes upon the formation and maturation of nuclear bodies. Here, we describe SNAP-tag based imaging methods to visualize the folding states of RBPs in live cells via time-resolved quantitative microscopic analyses of their micropolarity and microviscosity. Using these imaging methods in conjunction with immunofluorescence imaging, we demonstrate that RBPs, represented by TDP-43, initially enters the PML nuclear bodies in its native state upon transient proteostasis stress, albeit it begins to misfolded during prolonged stress. Furthermore, we show that heat shock protein 70 co-enters the PML nuclear bodies to prevent the degradation of TDP-43 from the proteotoxic stress, thus revealing a previously unappreciated protective role of the PML nuclear bodies in the prevention of stress-induced degradation of TDP-43. In summary, our imaging methods described in the manuscript, for the first time, reveal the folding states of RBPs, which were previously challenging to study with conventional methods in nuclear bodies of live cells. This study uncovers the mechanistic correlations between the folding states of a protein and functions of nuclear bodies, in particular PML bodies. We envision that the imaging methods can be generally applied to elucidating the structural aspects of other proteins that exhibit granular structures under biological stimulus.
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OBJECTIVES: The application of deep learning to medical image segmentation has received considerable attention. Nevertheless, when segmenting thyroid ultrasound images, it is difficult to achieve good segmentation results using deep learning methods because of the large number of nonthyroidal regions and insufficient training data. METHODS: In this study, a Super-pixel U-Net, designed by adding a supplementary path to U-Net, was devised to boost the segmentation results of thyroids. The improved network can introduce more information into the network, boosting auxiliary segmentation results. A multi-stage modification is introduced in this method, which includes boundary segmentation, boundary repair, and auxiliary segmentation. To reduce the negative effects of non-thyroid regions in the segmentation, U-Net was utilized to obtain rough boundary outputs. Subsequently, another U-Net is trained to improve and repair the coverage of the boundary outputs. Super-pixel U-Net was applied in the third stage to assist in the segmentation of the thyroid more precisely. Finally, multidimensional indicators were used to compare the segmentation results of the proposed method with those of other comparison experiments. DISCUSSION: The proposed method achieved an F1 Score of 0.9161 and an IoU of 0.9279. Furthermore, the proposed method also exhibits better performance in terms of shape similarity, with an average convexity of 0.9395. an average ratio of 0.9109, an average compactness of 0.8976, an average eccentricity of 0.9448, and an average rectangularity of 0.9289. The average area estimation indicator was 0.8857. CONCLUSION: The proposed method exhibited superior performance, proving the improvements of the multi-stage modification and Super-pixel U-Net.
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Nanozyme, with enzyme-mimicking activity and excellent stability, has attracted extensive attention. However, some inherent disadvantages, including poor dispersion, low selectivity, and insufficient peroxidase-like activity, still limit its further development. Therefore, an innovative bioconjugation of a nanozyme and natural enzyme was conducted. In the presence of graphene oxide (GO), histidine magnetic nanoparticles (H-Fe3O4) were first synthesized by a solvothermal method. The GO-supported H-Fe3O4 (GO@H-Fe3O4) exhibited superior dispersity and biocompatibility because GO was the carrier and possessed outstanding peroxidase-like activity because of the introduction of histidine. Furthermore, the mechanism of the peroxidase-like activity of GO@H-Fe3O4 was the generation of â¢OH. Uric acid oxidase (UAO) was selected as the model natural enzyme and covalently linked to GO@H-Fe3O4 with hydrophilic poly(ethylene glycol) as a linker. UAO could specifically catalyze the oxidation of uric acid (UA) to generate H2O2, and subsequently, the newly produced H2O2 oxidized the colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue ox-TMB under the catalysis of GO@H-Fe3O4. Based on the above cascade reaction, the GO@H-Fe3O4-linked UAO (GHFU) and GO@H-Fe3O4-linked ChOx (GHFC) were used for the detection of UA in serum samples and cholesterol (CS) in milk, respectively. The method based on GHFU exhibited a wide detection range (5-800 µM) and a low detection limit (1.5 µM) for UA, and the method based on GHFC exhibited a wide detection range (4-400 µM) and a low detection limit (1.13 µM) for CS. These results demonstrated that the proposed strategy had great potential in the field of clinical detection and food safety.
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The chemokine CCL5 plays a potential role in the occurrence and development of colorectal cancer (CRC). Previous studies have shown that CCL5 directly acts on tumor cells to change tumor metastatic rates. In addition, CCL5 recruits immune cells and immunosuppressive cells into the tumor microenvironment (TME) and reshapes the TME to adapt to tumor growth or increase antitumor immune efficacy, depending on the type of secretory cells releasing CCL5, the cellular function of CCL5 recruitment, and the underlying mechanisms. However, at present, research on the role played by CCL5 in the occurrence and development of CRC is still limited, and whether CCL5 promotes the occurrence and development of CRC and its role remain controversial. This paper discusses the cells recruited by CCL5 in patients with CRC and the specific mechanism of this recruitment, as well as recent clinical studies of CCL5 in patients with CRC.Key MessagesCCL5 plays dual roles in colorectal cancer progression.CCL5 remodels the tumor microenvironment to adapt to colorectal cancer tumor growth by recruiting immunosuppressive cells or by direct action.CCL5 inhibits colorectal cancer tumor growth by recruiting immune cells or by direct action.
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Quimiocina CCL5 , Neoplasias Colorrectales , Humanos , Línea Celular Tumoral , Microambiente TumoralRESUMEN
BACKGROUNDS: Intrahepatic infiltration of neutrophils is a character of alcoholic hepatitis (AH) and neutrophil extracellular traps (NETs) are an important strategy for neutrophils to fix and kill invading microorganisms. The gut-liver axis has been thought to play a critical role in many liver diseases also including AH. However, whether NETs appear in AH and play role in AH is still unsure. METHODS: Serum samples from AH patients were collected and LPS and MPO-DNA were detected. WT, NE KO, and TLR4 KO mice were used to build the AH model, and the intestinal bacteria were eliminated at the same time and LPS was given. Then the formation of NETs and AH-related markers were detected. RESULTS: The serum MPO-DNA and LPS concentration was increased in AH patients and a correlation was revealed between these two indexes. More intrahepatic NETs formed in AH mice. NETs formation decreased with antibiotic intervention and restored with antibiotic intervention plus LPS supplement. While NETs formation failed to change with gut microbiome or combine LPS supplement in TLR4 KO mice. As we tested AH-related characters, liver injury, intrahepatic fat deposition, inflammation, and fibrosis alleviated with depletion of NE. These related marks were also attenuated with gut sterilization by antibiotics and recovered with a combined treatment with antibiotics plus LPS. But the AH-related markers did show a difference in TLR4 KO mice when they received the same treatment. CONCLUSION: Intestinal-derived LPS promotes NETs formation in AH through the TLR4 pathway and further accelerates the AH process by NETs.
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Despite the successful application of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, the treatment efficacy in solid tumors remains unsatisfactory, largely due to the highly immunosuppressive tumor microenvironment and low density of specific tumor antigens. Natural killer group 2 member D (NKG2D) CAR-T cells have shown promising treatment effects on several cancers such as lymphoma and multiple myeloma. However, the application and efficacy of NKG2D-CAR-T cells in gastric cancer (GC) still needs further exploration. This study identified a novel combination immunotherapy strategy with Dickkopf-1 (DKK1) inhibition and NKG2D-CAR-T cells, exerting synergistic and superior antitumor effect in GC. We show that the baseline expression of NKG2D ligands (NKG2DLs) is at low levels in GC tissues from The Cancer Genome Atlas and multiple GC cell lines including NCI-N87, MGC803, HGC27, MKN45, SGC7901, NUGC4, and AGS. In addition, DKK1 inhibition by WAY-262611 reverses the suppressive tumor immune microenvironment (TIME) and upregulates NKG2DL expression levels in both GC cell lines and GC tissues from a xenograft NCG mouse model. DKK1 inhibition in GC cells markedly improves the immune-activating and tumor-killing ability of NKG2D-CAR-T cells as shown by cytotoxicity assays in vitro. Moreover, the combination therapy of NKG2D-CAR-T and WAY-262611 triggers superior antitumor effects in vivo in a xenograft NCG mouse model. In sum, our study reveals the role of DKK1 in remodeling GC TIME and regulating the expression levels of NKG2DLs in GC. We also provide a promising treatment strategy of combining DKK1 inhibition with NKG2D-CAR-T cell therapy, which could bring new breakthroughs for GC immunotherapy.
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The development of stable and efficient electrocatalysts for oxygen evolution reaction is of great significance for electro-catalytic water splitting. Bimetallic layered double hydroxides (LDHs) are promising OER catalysts, in which NiCu LDH has excellent stability compared with the most robust NiFe LDH, but the OER activity is not satisfactory. Here, we designed a NiCu LDH heterostructure electrocatalyst (Cu/NiCu LDH) modified by Cu nanoparticles which has excellent activity and stability. The Cu/NiCu LDH electrocatalyst only needs a low over-potential of 206 mV and a low Tafel slope of 86.9 mV dec-1 at a current density of 10 mA cm-2 and maintains for 70 h at a high current density of 100 mA cm-2 in 1M KOH. X-ray photoelectron spectroscopy (XPS) showed that there was a strong electronic interaction between Cu nanoparticles and NiCu LDH. Density functional theory (DFT) calculations show that the electronic coupling between Cu nanoparticles and NiCu LDH can effectively improve the intrinsic OER activity by optimizing the conductivity and the adsorption energy of oxygen-containing intermediates.
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The Federal Highway Administration (FHWA) mandates biannual bridge inspections to assess the condition of all bridges in the United States. These inspections are recorded in the National Bridge Inventory (NBI) and the respective state's databases to manage, study, and analyze the data. As FHWA specifications become more complex, inspections require more training and field time. Recently, element-level inspections were added, assigning a condition state to each minor element in the bridge. To address this new requirement, a machine-aided bridge inspection method was developed using artificial intelligence (AI) to assist inspectors. The proposed method focuses on the condition state assessment of cracking in reinforced concrete bridge deck elements. The deep learning-based workflow integrated with image classification and semantic segmentation methods is utilized to extract information from images and evaluate the condition state of cracks according to FHWA specifications. The new workflow uses a deep neural network to extract information required by the bridge inspection manual, enabling the determination of the condition state of cracks in the deck. The results of experimentation demonstrate the effectiveness of this workflow for this application. The method also balances the costs and risks associated with increasing levels of AI involvement, enabling inspectors to better manage their resources. This AI-based method can be implemented by asset owners, such as Departments of Transportation, to better serve communities.
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BACKGROUND AND OBJECTIVES: Migraine is a major public health problem owing to its long disease duration and disease relapse. Non-invasive brain stimulation treatments were reported effective for the management of migraine, but the comparative effectiveness of three main NIBSs, rTMS, nVNS, and tDCS, has not been studied. We aimed to explore the relative efficacy of rTMS, tDCS, and nVNS in migraine prophylaxis by using network meta-analysis (NMA). METHODS: We searched OVID Medline, Embase, Cochrane Controlled Register of Trials, and Web of Science from inception to 1 January 2022. Randomized controlled trials that reported the efficacy of rTMS, tDCS or nVNS in the prophylactic treatment of migraine were included. The primary outcome was monthly migraine frequency, and secondary outcomes were headache intensity and the impact of headaches on daily life. The relative effects of the treatments in contrast to the others were measured by using standard mean difference (SMD). RESULTS: We included 31 trials with 1659 participants. Fourteen trials were rated as low risk of bias. The results showed that tDCS (SMD - 1.58; 95%CI, - 2.38 to - 0.79; P-score = 0.92) had the largest effect on migraine frequency when compared with sham interventions in reducing monthly migraine frequency, and tDCS had a larger effect than rTMS (SMD - 0.62; 95%CI, - 1.81 to 0.57) and nVNS (SMD - 1.39; 95%CI, - 3.27 to 0.49). tDCS had also the largest effect in reducing pain intensity when compared with sham intervention (SMD - 1.49; 95%CI, - 2.46 to - 0.52) and rTMS (SMD - 0.48; 95%CI, - 2.06 to 1.09). CONCLUSIONS: For the prophylactic treatment of migraine, tDCS was relatively more effective than rTMS and nVNS. Head-to-head comparison trials are needed to confirm the findings.
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BACKGROUND: Observational studies have shown that Helicobacter pylori (H. pylori) infection and H. pylori antibodies are associated with an increased risk of stroke. However, which and how H. pylori antibodies serve as the causal determinant of the development of stroke remains largely unknown. METHODS: Genome-wide association studies (GWAS) on seven different antibodies of H. pylori-specific proteins, stroke, and stroke subtypes were included in this study. Mendelian randomization (MR) and multivariable MR (MVMR) analysis were performed to assess the causal associations between H. pylori antibodies and the development of stroke and to determine the potential mechanisms underlying the associations. RESULTS: Genetically predicted serum H. pylori vacuolating cytotoxin-A (VacA) antibody level was associated with an increased risk of all-cause stroke (odds ratio [OR] = 1.04, 95% CI 1.01-1.07, P = 0.017) and cardioembolic stroke (CES, OR = 1.11, 95% CI 1.04-1.18, P = 0.001). The results of multivariable MR (MVMR) showed that C-reactive protein (CRP), but not monocyte chemoattractant protein-1 and peptic ulcer, mediated the causal effects of VacA-positive H. pylori infection on all-cause stroke and CES. No strong causal associations were found between other H. pylori antibodies and stroke and its subtypes. CONCLUSIONS: Our results demonstrate that H. pylori VacA antibody is the only causal determinant associated with the risk of stroke in the spectrum of H. pylori-related antibodies, in which CRP may mediate the association. This study suggests that inhibition of the CRP signaling pathway may reduce the risk of stroke in patients with VacA-positive H. pylori infection.
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BACKGROUND: The aim of this study was to estimate the burden of rheumatic heart disease (RHD) and its trends in different countries, regions, genders and age groups globally. METHODS: Data were obtained from the Global Burden of Disease 2019 study. Age-standardized rates (ASRs) and the estimated annual percentage changes (EAPCs) in the ASRs were used to describe the burden of disease and its trends. Pearson's correlation was used to evaluate the correlation between sociodemographic index (SDI) values and the observed trends. RESULTS: In 2019, the ASRs of the incidence, prevalence, mortality and disability-adjusted life years (DALYs) of RHD were 37.39/105 (95%UI, 28.59/105 to 46.74/105), 513.68/105 (95%UI, 405.01/105 to 636.25/105), 3.85/105 (95%UI, 4.29/105 to 3.29/105) and 132.88/105 (95%UI, 115.02/105 to 150.34/105), respectively. From 1990 to 2019, the incidence and prevalence of RHD showed upward trends and the mortality and DALYs showed downward trends. Countries or regions in Africa, South America and South Asia had a greater burden of RHD. The burden of RHD was greater in women, where as men showed more obvious increasing trends in the incidence and prevalence. The incidence of RHD was highest in adolescents, and the prevalence was highest in young and middle-aged. The mortality and DALYs rate associated with RHD increased with age. The EAPCs in the ASRs were negatively correlated with the SDI value. CONCLUSION: Although the ASRs of mortality and DALYs attributable to RHD are decreasing globally, RHD remains an important public health problem that needs to be addressed urgently, especially in certain low- and middle-income countries and regions.
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Background: The noninvasive diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging. The role of left atrial (LA) functional changes in patients with HFpEF has attracted increased attention. This study aimed to evaluate LA deformation in patients with hypertension (HTN) using cardiac magnetic resonance tissue tracking and to investigate the diagnostic value of LA strain for HFpEF. Methods: This retrospective study consecutively enrolled 24 HTN patients with HFpEF (HTN-HFpEF) and 30 patients with pure HTN based on clinical indications. Thirty age-matched healthy participants were also enrolled. All participants underwent a laboratory examination and 3.0 T cardiovascular magnetic resonance (CMR). The LA strain and strain rate, including total strain (εs), passive strain (εe), active strain (εa), peak positive strain rate (SRs), peak early negative strain rate (SRe), and peak late negative strain rate (SRa), were evaluated using CMR tissue tracking and compared among the 3 groups. Receiver operating characteristic (ROC) analysis was used to identify HFpEF. Spearman correlation was used to analyze the correlation between LA strain and brain natriuretic peptide (BNP) level. Results: Patients with HTN-HFpEF had significantly lower εs (17.70%, IQR 14.65% to 19.70%, εe 7.83%±2.86%), εa (9.08%±3.19%), SRs (0.88±0.24 s-1), SRe (-0.60 s-1, IQR -0.90 to -0.50 s-1), and SRa (-1.10±0.47 s-1) than did patients with HTN and control participants (all P values <0.05). Compared to the control group, patients with HTN had lower εs (25.35%, IQR 21.80% to 27.25%), εe (11.49%±2.64%), SRs (1.10 s-1, IQR 1.00 to 1.48 s-1), and SRe (-1.11±0.37 s-1) (all P values <0.05). The values of εa and SRa were not significantly different between the HTN and control groups. LA total strain εs was independently associated with HFpEF (odds ratio 0.009; P<0.05) with a cutoff value of 19.55% (95% CI: 0.882-0.996), and the sensitivity and specificity were 75% and 97%, respectively. There was a good correlation between the LA strain parameters and BNP level (all P values <0.05). Conclusions: LA function impairment exists in patients with HFpEF. The LA strain parameter has potential value in diagnosing HFpEF.
