Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity including different phenotypes of near normal, normal, and supernormal left ventricular (LV) function. The aim of this study was to assess the value of resting LV elastance (also known as force) using transthoracic echocardiography to identify HFpEF phenotypes. Methods: In a prospective, observational, multicenter study, 2,380 patients with HFpEF were recruited from July 2016 to May 2024. Systolic blood pressure (SBP) was measured. LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction, force (SBP/LVESV), stroke volume (SV), arterial elastance, ventricular-arterial coupling, and left atrial volume index were assessed. Global longitudinal strain was available in 1,164 patients (48.9%). Six hundred eighty patients finished follow-up with a composite endpoint of major adverse cardiac events (MACEs). Patients were divided into three groups: group 1, low force (<25th percentile, <3.24 mm Hg/mL); group 2, intermediate force (>= 25th percentile and #75th percentile, 3.24-5.48 mm Hg/mL); and group 3, high force (>75th percentile, >5.48 mmHg/mL). Results: The three groups showed a gradient with descending values (group 3> group 2 > group 1) for SBP, LV ejection fraction, global longitudinal strain, arterial elastance, and ventricular-arterial coupling, with the opposite gradient (group 1 > group 2 > group 3) for LVEDV, LVESV, SV, and left atrial volume index values (P < .01 for all). After a median follow-up period of 16 months, 205 MACEs occurred in 138 patients. The cumulative MACE rate was lowest in group 2 (14.7% person-years) and higher in groups 1 (16.1% person-years) and 3 (22.9% person-years; log-rank P = .036). Conclusions: Patients with HFpEF present with different LV contractile phenotypes, easily identified with resting LV force and volumetric transthoracic echocardiography. The dominant hemodynamic feature of hypo-contractile phenotype is a preload recruitment with larger LVEDV and normal SV, while the hypercontractile phenotype is characterized by a small left ventricle with reduced SV. The hypercontractile and hypocontractile phenotypes are associated with a higher risk for subsequent events. (J Am Soc Echocardiogr 2025;38:409-20.)

Telomere repeat binding factor 2 (TRF2), a critical element of the shelterin complex, plays a vital role in the maintenance of genome integrity. TRF2 overexpression is found in a wide range of malignant cancers, whereas its down-regulation could cause cell death. Despite its potential role, the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown. Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis. Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits. Moreover, FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends, leading to the destruction of T-loop structure. Consequently, FKB04 promoted liver cancer cell senescence without modulating apoptosis levels. In corroboration with these findings, FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model, with no obvious side effects. These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2, showing promise in the treatment of liver cancer.

Endoscopy is the primary modality for detecting asymptomatic esophageal squamous cell carcinoma (ESCC) and precancerous lesions. Improving detection rate remains challenging. We developed a system based on deep convolutional neural networks (CNNs) for detecting esophageal cancer and precancerous lesions [high-risk esophageal lesions (HrELs)] and validated its efficacy in improving HrEL detection rate in clinical practice (trial registration ChiCTR2100044126 at www.chictr.org.cn ). Between April 2021 and March 2022, 3117 patients ≥50 years old were consecutively recruited from Taizhou Hospital, Zhejiang Province, and randomly assigned 1:1 to an experimental group (CNN-assisted endoscopy) or a control group (unassisted endoscopy) based on block randomization. The primary endpoint was the HrEL detection rate. In the intention-to-treat population, the HrEL detection rate [28 of 1556 (1.8%)] was significantly higher in the experimental group than in the control group [14 of 1561 (0.9%), P = 0.029], and the experimental group detection rate was twice that of the control group. Similar findings were observed between the experimental and control groups [28 of 1524 (1.9%) versus 13 of 1534 (0.9%), respectively; P = 0.021]. The system’s sensitivity, specificity, and accuracy for detecting HrELs were 89.7, 98.5, and 98.2%, respectively. No adverse events occurred. The proposed system thus improved HrEL detection rate during endoscopy and was safe. Deep learning assistance may enhance early diagnosis and treatment of esophageal cancer and may become a useful tool for esophageal cancer screening.

Acquired long QT syndrome caused by hypopituitarism and transient ST-segment elevation has not been reported in cardiac arrest patients. We report a case of extremely dangerous acquired long QT syndrome and transient ST-segment elevation. A 44-year-old Chinese woman with renal failure experienced sudden cardiac arrest in the haemodialysis room. Subsequent electrocardiogram showed QT prolongation and transient ST-segment elevation. This patient's medical history, subsequent laboratory results and pituitary magnetic resonance imaging suggested hypopituitarism. Transient ST-segment elevation on the electrocardiogram was considered to be caused by repeated direct current shocks. The patient was diagnosed with acquired long QT syndrome and was not taking any antiarrhythmic drugs. Her corrected QT interval normalized after hormone replacement therapy. This case highlights the importance of the awareness of hypopituitarism; early identification and intervention can prevent the occurrence of this life-threatening arrhythmia. ST-segment elevation is not always due to acute myocardial infarction, and a variety of other causes, especially electrical cardioversion, should be considered.

INTRODUCTION:Long noncoding RNA PMS2L2 can inhibit inflammation induced by LPS, while LPS plays an important role in sepsis, indicating the possible involvement of PMS2L2 in sepsis.METHODS:Expressions of miR-21 and PMS2L2 in patients with acute kidney injury (AKI), sepsis patients without induced AKI, and healthy controls were determined by performing RT-qPCR. Overexpression assay was performed to explore the crosstalk between miR-21 and PMS2L2. Methylation-specific PCR (MSP) was performed to explore the role of PMS2L2 in regulating the methylation of miR-21 gene. The role of miR-21 and PMS2L2 in the apoptosis of CIHP-1 cells induced by LPS was assessed by cell apoptosis assay.RESULTS:PMS2L2 was downregulated in AKI patients induced by sepsis compared to sepsis patients without AKI and healthy controls. MiR-21 was also downregulated in AKI induced by sepsis and positively correlated with PMS2L2. In addition, in cells of human podocyte cell line (CIHP-1), overexpression of PMS2L2 promoted the expression of miR-21, while miR-21 did not affect the expression of PMS2L2. MSP analysis showed that overexpression of PMS2L2 decreased methylation of miR-21. LPS treatment downregulated PMS2L2 and miR-21 in a time-dependent manner. PMS2L2 and miR-21 decreased the apoptosis of CIHP-1 cells induced by LPS, and co-overexpression of PMS2L2 and miR-21 showed stronger inhibitory effect.CONCLUSION:PMS2L2 is downregulated in AKI induced by sepsis and inhibits LPS-induced apoptosis of podocytes.

Abstract Objective to evaluate the clinical efficacy and safety of sacubitril valsartan in the treatment of heart failure (HF) with midrange ejection fraction after acute myocardial infarction (AMI) in diabetic patients. From January 2015 to July 2020, HF patients with diabetes mellitus complicated with AMI were retrospectively analyzed. According to the medication, they were divided into 2 groups, that is, sacubitril valsartan group (84 cases) and valsartan group (86 cases). Valsartan group took valsartan capsule (80 mg/capsule, Beijing Novartis Pharmaceutical Co., Ltd) 80 mg, qd, on the basis of routine treatment. On the basis of routine treatment, the sacubitril valsartan group took sacubitril valsartan sodium tablets (50 mg/tablet, Beijing Novartis Pharmaceutical Co., Ltd), the initial dose was 25 mg, bid, and gradually increased to the target dose according to the patient's blood pressure. After 12 months of treatment, the independent sample t test showed that the left ventricular end diastolic dimension in the sacubitril valsartan group was lower than that in the valsartan group [(47.26 ± 4.71) mm vs (50.05 ± 5.62) mm, P < .001]. The left ventricular ejection fraction in the sacubitril valsartan group was higher than that in the valsartan group [(54.76 ± 4.24)% vs (49.28 ± 3.74)%, P < .001]. χ2 inspection showed that the readmission rate in the sacubitril valsartan group was lower than that in the valsartan group (7.14% vs 18.60%, P < .05). Sacubitril valsartan has good safety and tolerability in patients with diabetes mellitus complicated with AMI who have HF with midrange ejection fraction. Compared with valsartan, sacubitril valsartan can improve the left ventricular function better and reduce the readmission rate due to HF in these patients.

BACKGROUND:Gastric cancer (GC), a multifactorial disease, is caused by pathogens, such as Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), and genetic components.AIM:To investigate microbiomes and host genome instability by cost-effective, low-coverage whole-genome sequencing, as biomarkers for GC subtyping.METHODS:Samples from 40 GC patients were collected from Taizhou Hospital, Zhejiang Province, affiliated with Wenzhou Medical University. DNA from the samples was subjected to low-coverage whole-genome sequencing with a median genome coverage of 1.86 × (range: 1.03 × to 3.17 ×) by Illumina × 10, followed by copy number analyses using a customized bioinformatics workflow ultrasensitive chromosomal aneuploidy detector.RESULTS:Of the 40 GC samples, 20 (50%) were found to be enriched with microbiomes. EBV DNA was detected in 5 GC patients (12.5%). H. pylori DNA was found in 15 (37.5%) patients. The other 20 (50%) patients were found to have relatively higher genomic instability. Copy number amplifications of the oncogenes, ERBB2 and KRAS, were found in 9 (22.5%) and 7 (17.5%) of the GC samples, respectively. EBV enrichment was found to be associated with tumors in the gastric cardia and fundus. H. pylori enrichment was found to be associated with tumors in the pylorus and antrum. Tumors with elevated genomic instability showed no localization and could be observed in any location. Additionally, H. pylori-enriched GC was found to be associated with the Borrmann type II/III and gastritis history. EBV-enriched GC was not associated with gastritis. No statistically significant correlation was observed between genomic instability and gastritis. Furthermore, these three different molecular subtypes showed distinct survival outcomes (P = 0.019). EBV-positive tumors had the best prognosis, whereas patients with high genomic instability (CIN+) showed the worst survival. Patients with H. pylori infection showed intermediate prognosis compared with the other two subtypes.CONCLUSION:Thus, using low-coverage whole-genome sequencing, GC can be classified into three categories based on disease etiology; this classification may prove useful for GC diagnosis and precision medicine.

Background: Hyperglycemia-associated inflammation contributes to adverse remodeling and fibrosis in diabetic heart. MyD88 is an adapter protein of many Toll-like receptors (TLRs) and is recruited to TLRs to initiate inflammatory signalling pathway in endotoxin-activated innate immunity. However, the role of MyD88 in diabetic cardiomyopathy is unknown. Methods: For genetic deficiency, cardiomyocyte-specific MyD88 knockout and littermate control mice were induced type 1 diabetes (T1D) by intraperitoneal injection of 50 mg/kg/day streptozotocin for five days consecutive and then fed for 4 moths. For pharmacological inhibition, MyD88 inhibitor LM8 were administered daily for 8 weeks by oral gavage in T1D and T2D (db/db) mice. The effect of genetic and pharmacological inhibition MyD88 to myocardial injure which were induced by 33 mM glucose in vivo. Results: In this study, we first found that MyD88 expression was increased in cardiomyocytes of diabetic mouse hearts. Cardiomyocyte-specific MyD88 knockout protected mice against hyperglycemia-induced cardiac inflammation, injury, hypertrophy, and fibrosis in T1D model. In cultured cardiomyocytes, MyD88 inhibition either by siRNA or by small-molecular inhibitor LM8 markedly blocked TLR4-MyD88 complex formation, reduced pro-inflammatory MAPKs/NF-κB cascade activation and decreased pro-inflammatory cytokine expression under high glucose condition. Moreover, pharmacologic inhibition of MyD88 by LM8 showed significantly anti-inflammatory, anti-hypertrophic and anti-fibrotic effects in the hearts of both T1D and T2D mice. These beneficial effects of MyD88 inhibition were correlated to the reduced activation of TLR4-MyD88-MAPKs/NF-κB signaling pathways in the hearts. Conclusion: Taken together, MyD88 in cardiomyocytes mediates diabetes-induced cardiac inflammatory injuries and genetic or pharmacologic inhibition of MyD88 shows significantly cardioprotective effects, indicating MyD88 as a potential therapeutic target for diabetic cardiomyopathy.

Objective Ischemic stroke subtypes such as patients with large artery atherosclerosis, cardioembolism and embolic stroke of undetermined source were investigated. This study was performed aimed to determine mean platelet volume (MPV) and mean platelet volume/platelet count (MPV/Plt) Ratio in nonvalvular atrial fibrillation (AF) stroke and large artery atherosclerosis (LAA) stroke.Methods We conducted a retrospective study of consecutive patients for treatment of acute ischemic stroke at Ruian People's Hospital from March 2017 to October 2018. The patients with ischemic stroke caused by AF and LAA were recruited to this study. Ischemic stroke was confirmed by MRI and MRA, ischemic lesions on diffusion-weighted imaging were measured in terms of size, composition, and pattern. MPV and platelet count were examined and (MPV/Plt) Ratio was calculated.Results 371 patients were enrolled composing of 177 (47.7%) nonvalvular AF and 194 (52.2%) with LAA. The MPV (11.3 ± 1.3 vs. 10.8 ±1.0, p﹤0.001) and MPV/Plt ratio (0.066±0.025 vs. 0.055±0.20, p﹤0.001) were much higher in AF group than LAA group. ROC analysis showed MPV (AUC: 0.624, confidence interval:0.567-0.68,p﹤0.001) and MPV/Plt (AUC: 0.657, confidence interval:0.601-0.713,p﹤0.001) predicted AF between the two groups. MPV/Plt ratio was negatively associated with lesion volume (r = -0.161, p = 0.033) in AF. The analyses of subtypes of composition of infarcts and infarct pattern showed that MPV/Plt ratio was almost higher in AF than LAA except for subcortical-only pattern. Multivariable regression analyses demonstrated NIHSS score (r = 2.74; p﹤0.001), LAD (r = -1.15; P = 0.025) and MPV/Plt ratio (r = -180.64; P = 0.021) were correlated with lesion volume.Conclusion Our results indicated elevated MPV and MPV/Plt ratio for the identification of difference between AF and LAA in patients with ischemic stroke.

目的:观察ACS(急性冠状动脉综合征)患者社会支持程度对其死亡率及MACE(不良心血管事件)的影响.方法:纳入本院2017年4月-12月间诊疗ACS患者90例为研究对象,用简单随机化手段将其分为对照组 、实验组,每组45例,对应常规ACS对症治疗 、联合社会支持模式干预.比较两种干预模式下ACS患者社会支持度 、发生死亡和MACE概率等数据并以此归纳之间的联系性.结果:通过MSPSS量表对两组患者社会支持度情况进行评估,提示实验组患者高社会支持例数显著高于对照组且有统计学意义(P<0.05);分别于患者出院后的1、3、6、12个月通过随访掌握死亡和MACE事件,实验组患者显著低于对照组且有统计学意义(P<0.05).结论:对ACS患者应该重视社会支持程度,有利于提高其出院后生存质量,保障治疗的延续性和依从性.

Abstract Left atrial (LA) remodeling has been identified to predict atrial fibrillation (AF) and heart failure. However, the role of LA diameter (LAD) in patients with heart failure (HF) with preserved (HFpEF), mid-range (HFmrEF), and reduced ejection fraction (HFrEF) remains poorly understood. A total of 142 patients including 71 subjects with AF (21 of HFpEF, 22 of HFmrEF, and 28 of HFrEF) and 71 ejection fraction (EF)-matched subjects with sinus rhythm (SR) were included in the study. Baseline characteristics and echocardiographic parameters including LAD were compared between both groups as well as among HFpEF, HFmrEF, and HFrEF. In receiver-operating characteristic (ROC) analyses, LAD predicted AF in HFpEF, HFmrEF, and HFrEF [area under the curve (AUC): 0.646; P = .03]. LAD was negatively association with left ventricular ejection fraction while positively with Nt-proNP and left ventricular end-diastolic diameter (regression coefficient: −0.239, P = .004; regression coefficient: 0.191, P = .023; regression coefficient: 0.357, P < .001). In ROC analyses, LAD predicted HFrEF among the 3 categories (AUC: 0.629, P = .01). In the setting of HF, LAD was higher in AF than in and SR, and predicted AF. Furthermore, LAD was associated with severity of HF in HFpEF, HFmrEF, and HFrEF, and also predicted HFrEF.

Free fatty acids (FFAs) predicted the risk of heart failure (HF) and were elevated in HF with very low left ventricular ejection fraction (LVEF) compared to healthy subjects. The aim of this study was to investigate whether total levels of FFA in plasma differed in patients with HF with preserved (HFpEF), mid-range (HFmrEF), and reduced ejection fraction (HFrEF) and the association with the three categories.

Rationale: Nocardia species is known as conditional pathogenic bacteria. Disseminated infection caused by Nocardia species is rare and occurs primarily in immunosuppressed patients. Signs and symptoms of this infection are frequently nonspecific making early diagnosis and treatment difficult. Patient concerns: We report a case of subcutaneous and pulmonary nocardiosis due to Nocardia farcinica (N farcinica) in a patient with nephrotic syndrome who is undergoing long-term corticosteroid therapy. In this patient, systemic and pulmonary symptoms (usually found in nocaria infection) such as fever, cough, and expectoration were absent. Diagnoses: Early diagnosis was made by pus culture from subcutaneous abscesses and 16S rRNA gene sequencing, which confirm the diagnosis of N farcinica infection. Interventions: The patient was treated with combination therapy of cefatriaxone and trimethoprim-sulfamethoxazole (TMP-SMX) for 2 weeks, and the treatment with TMP-SMX continued to 6 months. Outcomes: The abscesses were cured in 4 weeks and a lesion in the upper lobe of left lung resolved in 3 months. Lessons: This case indicates that disseminated infection due to N farcinica could occur in patients with nephrotic syndrome, even during the period of maintenance therapy with a low-dose corticosteroid and common signs and symptoms of infections could be absent.

Baicalin, a flavonoid glycoside separated from Scutellaria baicalensis, has cardioprotection against ischaemia/reperfusion (I/R) injury. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is considered as an endogenous protective mechanism against I/R injury depending on its anti-oxidant and anti-apoptotic characteristics. The present study demonstrates whether ALDH2 contributes to the cardioprotection of baicalin against hypoxia/reoxygenation (H/R)-inudced H9c2 cardiomyocytes injury. Our results observed that H/R treatment resulted in a significant decrease in cells viability and obvious increases in caspase-3 activity and apoptosis rate in H9c2 cells, while these alterations were evidently reversed by baicalin pretreatment. Simultaneously, baicalin mitigated H/R-induced the decreases in the levels of ALDH2 mRNA and protein as well as the activity of ALDH2 in H9c2 cells. However, we found that daidzin, an ALDH2 antagonist, remarkably attenuated baicalin-elicited inhibitory action on H/R-induced the downregulation of cells viability and Bcl-2 protein expression, and the upregulations of caspase-3 activity, apoptosis rate, cytochrome c and Bax proteins expressions in H9c2 cells. In addition, baicalin reversed H/R-induced oxidative stress as evidenced by the downregulation of malondialdehyde (MAD) and 4-hydroxy aldehydes (4-HNE) levels, the inhibition of endogenous reactive oxygen species (ROS) generation, and the downregulation of superoxide dismutase (SOD) activity induced by H/R treatment, while these effects were also blocked by daidzin. Furthermore, we found that Alda-1, an ALDH2 agonist, also abolished H/R-induced cytotoxicity, apoptosis, and oxidative stress, indicating that ALDH2 mediated H/R-induced H9c2 cell injury. Overall, these results suggested that baicalin prevents H/R-induced apoptosis and oxidative stress through enhancing ALDH activity and expression in H9c2 cardiomyocytes.

BACKGROUND:Multiple studies suggest anti-angiogenesis to be a promising and rational option in cancer treatment. Interestingly, the axonal sprouting inhibitor semaphorin 3A (Sema3A), a potent suppressor of tumor angiogenesis in various cancer models, is lowly expressed in human oral cancer. Thus, we hypothesized that overexpression of Sema3A in human oral cancer cells may have potential therapeutic effects.METHODS:The LentiSema3A-EGFP was first constructed and transduced to the tongue squamous cell carcinoma cell line SSC-9. Angiogenesis assay was performed with endothelial cell tube formation assay and chorioallantoic membrane (CAM) assay. Tumor xenografts model was used to evaluate the effect of Sema3a on the tumor growth. Finally, western blot was performed to study the mechanisms of inhibiting angiogenesis by Sema3A.RESULTS:In vitro and in vivo approaches revealed that Sema3A significantly inhibited tube formation of endothelial cells and reduced angiogenesis in CAM assay. In addition, overexpression of Sema3A in the tongue squamous cell carcinoma cell line SSC-9 resulted in significantly reduced angiogenesis and drastically suppressed tumor growth in mice. Mechanistically, Sema3A inhibited the phosphorylation of VEGFR2, as well as Src and FAK, downstream of the VEGF/VEGFR2 pathway.CONCLUSION:Our results demonstrated that overexpression of Sema3A in oral cancer cells drastically suppressed tumor growth by inhibiting angiogenesis. Our findings provide a basis for the development of novel therapeutics in the management of oral cancer.

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Objective Drug eluting stent (DES) with percutaneous coronary intervention is increasingly used to treat unprotected left main coronary artery (LMCA) disease. We undertook a meta analysis to assess outcomes for coronary artery bypass graft (CABG) and DES for unprotected LMCA disease. Methods We conducted a PubMed/EMBASE/CENTRAL search for RCTs evaluating CABG versus DES for unprotected LMCA. Primary outcome was survival. Secondary outcomes were major adverse cardiac and cerebrovascular event (MACCE) and target vessel revascularization (TVR). Results Four randomised controlled trials were identified evaluating a total of 2, 706 patients with unprotected LMCA. There was no significant difference between the CABG and DES groups in the risk for mortality (HR [hazard ratio]:0.76; 95% CI [confidence interval]: 0.47–1.23). The risks were lower for MACCE (0.78 [95% CI: 0.60–1.02]) and for TVR (0.73 [95% CI: 0.61–0.87]). Conclusions our meta-analysis of RCTs suggests that there are no significant differences in terms of survival and MACCE in patients with unprotected LMCA disease suitable for either DES or CABG, but CABG is superior to DES in reducing the incidence of TVR.