Cellular and molecular characteristics of stromal Lkb1 deficiency-induced gastrointestinal polyposis based on single-cell RNA sequencing.

Liver kinase B1 (Lkb1), encoded by serine/threonine kinase (Stk11), is a serine/threonine kinase and tumor suppressor that is strongly implicated in Peutz-Jeghers syndrome (PJS). Numerous studies have shown that mesenchymal-specific Lkb1 is sufficient for the development of PJS-like polyps in mice. However, the cellular origin and components of these Lkb1-associated polyps and underlying mechanisms remain elusive. In this study, we generated tamoxifen-inducible Lkb1flox/flox;Myh11-Cre/ERT2 and Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, performed single-cell RNA sequencing (scRNA-seq) and imaging-based lineage tracing, and aimed to investigate the cellular complexity of gastrointestinal polyps associated with PJS. We found that Lkb1flox/+;Myh11-Cre/ERT2 mice developed gastrointestinal polyps starting at 9 months after tamoxifen treatment. scRNA-seq revealed aberrant stem cell-like characteristics of epithelial cells from polyp tissues of Lkb1flox/+;Myh11-Cre/ERT2 mice. The Lkb1-associated polyps were further characterized by a branching smooth muscle core, abundant extracellular matrix deposition, and high immune cell infiltration. In addition, the Spp1-Cd44 or Spp1-Itga8/Itgb1 axes were identified as important interactions among epithelial, mesenchymal, and immune compartments in Lkb1-associated polyps. These characteristics of gastrointestinal polyps were also demonstrated in another mouse model, tamoxifen-inducible Lkb1flox/flox;PDGFRα-Cre/ERT2 mice, which developed obvious gastrointestinal polyps as early as 2-3 months after tamoxifen treatment. Our findings further confirm the critical role of mesenchymal Lkb1/Stk11 in gastrointestinal polyposis and provide novel insight into the cellular complexity of Lkb1-associated polyp biology. © 2024 The Pathological Society of Great Britain and Ireland.

Renal and cardiac effects of the PDE9 inhibitor BAY 73-6691 in 5/6 nephrectomized rats.

It has been suggested that the novel selective phosphodiesterase 9 (PDE9) inhibitor may improve cardiac and renal function by blocking 3',5'-cyclic guanosine monophosphate (cGMP) degradation. 5/6 nephrectomized (5/6Nx) rats were used to investigate the effects of the PDE9 inhibitor (BAY 73-6691) on the heart and kidney. Two doses of BAY 73-6691 (1 mg/kg/day and 5 mg/kg/day) were given for 95 days. The 5/6Nx rats developed albuminuria, a decrease in serum creatinine clearance (Ccr), and elevated serum troponin T levels. Echocardiographic data showed that 5/6 nephrectomy resulted in increased fractional shortening (FS), stroke volume (SV), and left ventricular ejection fraction (EF). However, 95 days of PDE9 inhibitor treatment did not improve any cardiac and renal functional parameter. Histopathologically, 5/6 nephrectomy resulted in severe kidney and heart damage, such as renal interstitial fibrosis, glomerulosclerosis, and enlarged cardiomyocytes. Telmisartan attenuated renal interstitial fibrosis and glomerulosclerosis as well as improved cardiomyocyte size. However, except for cardiomyocyte size and renal perivascular fibrosis, BAY 73-6691 had no effect on other cardiac and renal histologic parameters. Pathway enrichment analysis using RNA sequencing data of kidney and heart tissue identified chronic kidney disease pathways, such as phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway, complement and coagulation cascades, and nuclear factor kappa B (NF-κB) signaling pathway. PDE9i did not affect any of these disease-related pathways. Two dosages of the PDE9 inhibitor BAY 73-6691 known to be effective in other rat models have only limited cardio-renal protective effects in 5/6 nephrectomized rats.

Assessment of six surrogate insulin resistance indexes for predicting cardiometabolic multimorbidity incidence in Chinese middle-aged and older populations: Insights from the China health and retirement longitudinal study.

AIMS: Insulin resistance (IR) is associated with cardiometabolic multimorbidity (CMM). We aimed to explore the predictive value of six surrogate IR indexes-Chinese visceral adiposity index (CVAI), lipid accumulation product (LAP), triglyceride-glucose (TyG), atherogenic index of plasma (AIP), TyG-body mass index (TyGBMI), and TyG-waist circumference (TyGwaist)-to establish the CMM incidence in Chinese middle-aged and older populations. MATERIAL AND METHODS: To estimate the odds ratio (OR) with a 95% confidence interval (95% CI) for incident CMM using six surrogates, we analysed data from the China Health and Retirement Longitudinal Study using multivariate logistic regression models. The nonlinear dose-response correlation was evaluated using restricted cubic spline analysis; predictive performance was assessed using receiver operator characteristic curves. RESULTS: Among 6451 eligible participants, 268 (4.2%) developed CMM during the 4-year follow-up period. The ORs (95% CI) for incident CMM increased with increasing CVAI quartiles (Q) [Q2: 1.71, 1.03-2.90; Q3: 2.72, 1.70-4.52; Q4: 5.16, 3.29-8.45; all p < 0.05] after full adjustment, with Q1 as the reference. Other indexes yielded similar results. These associations remained significant in individuals with a normal body mass index. Notably, CVAI, AIP, and TyG exhibited a linear dose-response relationship with CMM (Pnonlinear ≥0.05), whereas LAP, TyGBMI, and TyGwaist displayed significant nonlinear correlations (Pnonlinear <0.05). The area under the curve for the CVAI (0.691) was significantly superior to that of other indexes (all p < 0.05). CONCLUSIONS: The six IR surrogates were independently associated with CMM incidence. CVAI may be the most appropriate indicator for predicting CMM in middle-aged and older Chinese populations.

Insight into endothelial cell-derived extracellular vesicles in cardiovascular disease: Molecular mechanisms and clinical implications.

The endothelium is crucial in regulating vascular function. Extracellular vesicles (EVs) serve as membranous structures released by cells to facilitate intercellular communication through the delivery of nucleic acids, lipids, and proteins to recipient cells in an paracrine or endocrine manner. Endothelial cell-derived EVs (EndoEVs) have been identified as both biomarkers and significant contributors to the occurrence and progression of cardiovascular disease (CVD). The impact of EndoEVs on CVD is complex and contingent upon the condition of donor cells, the molecular cargo within EVs, and the characteristics of recipient cells. Consequently, elucidating the underlying molecular mechanisms of EndoEVs is crucial for comprehending their contributions to CVD. Moreover, a thorough understanding of the composition and function of EndoEVs is imperative for their potential clinical utility. This review aims provide an up-to-date overview of EndoEVs in the context of physiology and pathophysiology, as well as to discuss their prospective clinical applications.

The survival benefit of metastasectomy for metastatic non-clear cell renal cell carcinoma: a retrospective cohort study.

PURPOSE: The aim of this study was to explore the benefit the metastasectomy for patients with metastatic non-clear cell carcinoma (non-ccRCC). METHODS: This study enrolled 120 patients with confirmed metastatic non-ccRCC from the RCC database of our center from 2008 to 2021. Patients without metastasectomy were grouped as radical nephrectomy without metastasectomy patients. The clinical outcomes included overall survival (OS) and progression-free survival (PFS). Cox regression and Kaplan-Meier analyses were used to assess potential factors that predict clinical benefits from metastasectomy. RESULTS: A total of 100 patients received radical nephrectomy alone, while the remaining 20 patients underwent both radical nephrectomy and metastasectomy. There was no significant difference in age between the two groups. Out of 100 patients who underwent radical nephrectomy, 60 were male, and out of 20 patients who had both radical nephrectomy and metastasectomy, 12 were male. Patients who underwent systemic therapy plus radical nephrectomy and metastasectomy had significantly better PFS (27.1 vs. 14.0, p = 0.032) and OS (67.3 vs. 24.0, p = 0.043) than those who underwent systemic therapy plus radical nephrectomy alone. Furthermore, for patients without liver metastasis (n = 54), systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.028) and OS (p = 0.043). Similarly, for patients with metachronous metastasis, systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.043) and OS (p = 0.032). None of the patients experienced serious perioperative complications (Clavien-Dindo Classification ≥ III grade). CONCLUSION: Metastasectomy in patients with metastatic non-ccRCC may provide clinical benefits in terms of improved PFS and OS, especially in patients without liver metastasis and those with metachronous metastasis.

Impact of Low Voltage Threshold Adjustment on Activation Mapping Interpretation for Atrial Tachycardia in Low-Voltage Left Atrium.

Background: The misinterpretation of activation propagation within low voltage zone (LVZ) can complicate atrial tachycardia (AT) mechanism analysis, especially in patients with remodeled atrial substrate. This study investigated the impact of low voltage threshold adjustment (LVTA) on left atrial (LA) tachycardia activation mapping interpretation. Methods: We identified 55 ATs in 42 patients undergoing catheter ablation for LA tachycardia, with a mean LA voltage of < 0.5 mV. Activation mapping of LA or both atria was used to evaluate AT mechanisms before and after LVTA. Patients underwent regular clinic follow-up after the procedure. Results: Comparing activation mapping before and after LVTA revealed four categories: (1) complete change in AT circuit and ablation design in 9 ATs; (2) an unchanged AT circuit but tailored ablation design in 16 ATs; (3) identification of bystander gaps in 3 ATs; (4) an unchanged AT circuit and ablation design in 27 ATs. Effective ablation, defined as AT termination or circuit change, was obtained in all 9 Type 1 ATs and 15 of 16 Type 2 ATs by targeting the critical area identified by activation mapping after LVTA. After a median follow-up of 16.5 months, the cumulative freedom from AT was 69.3%. Conclusions: In patients with low LA voltage, conduction propagation hidden within LVZ was not uncommon, but is often excluded from activation mapping. LVTA can uncover this subtle conduction propagation with reliable accuracy, improving the veracity of activation mapping, and helping guide subsequent ablation.

Endothelial dysfunction: molecular mechanisms and clinical implications.

Cardiovascular disease (CVD) and its complications are a leading cause of death worldwide. Endothelial dysfunction plays a crucial role in the initiation and progression of CVD, serving as a pivotal factor in the pathogenesis of cardiovascular, metabolic, and other related diseases. The regulation of endothelial dysfunction is influenced by various risk factors and intricate signaling pathways, which vary depending on the specific disease context. Despite numerous research efforts aimed at elucidating the mechanisms underlying endothelial dysfunction, the precise molecular pathways involved remain incompletely understood. This review elucidates recent research findings on the pathophysiological mechanisms involved in endothelial dysfunction, including nitric oxide availability, oxidative stress, and inflammation-mediated pathways. We also discuss the impact of endothelial dysfunction on various pathological conditions, including atherosclerosis, heart failure, diabetes, hypertension, chronic kidney disease, and neurodegenerative diseases. Furthermore, we summarize the traditional and novel potential biomarkers of endothelial dysfunction as well as pharmacological and nonpharmacological therapeutic strategies for endothelial protection and treatment for CVD and related complications. Consequently, this review is to improve understanding of emerging biomarkers and therapeutic approaches aimed at reducing the risk of developing CVD and associated complications, as well as mitigating endothelial dysfunction.

The functional impact on donor vessel following transcatheter closure of coronary artery fistulas-a retrospective study using QFR analysis.

Background: The impact of transcatheter closure of coronary artery fistula (CAF) and residual shunt after occlusion on improving blood flow in the donor vessel remains uncertain. Objectives: To evaluate the functional impact on the donor vessel following CAFs closure using QFR (Quantitative Flow Ratio) analysis. Methods: A total of 46 patients with 48 CAFs who underwent transcatheter closure at Shanghai Chest Hospital and Shuguang Hospital between March 2015 and August 2023 were included in the review. The clinical, angiographic details, and QFR data were subjected to analysis. The size of the fistulae was defined according to the ratio between the diameters of the fistulae and the largest diameter of the coronary vessel not feeding the coronary fistula. Results: Among 48 CAFs, the average diameter of the fistulae ostium was 3.19 ± 1.04 mm, while the mean diameter of the donor vessel segment following fistulae was 3.45 ± 1.01 mm. The mean QFR value of the donor vessels with medium CAFs was found to be significantly lower than those with small CAFs (0.93 ± 0.10 vs. 0.98 ± 0.03; p < 0.05). Furthermore, the mean QFR value of donor vessels with medium CAFs was observed to be significantly improved after occlusion (0.99 ± 0.01 vs. 0.93 ± 0.10; p = 0.01). However, there was no statistical difference in the mean QFR value of donor vessels with small CAFs before and after occlusion (0.98 ± 0.03 vs. 0.98 ± 0.02; p > 0.05). Moreover, the changes in QFR were more pronounced in donor vessels with medium CAFs compared to those with small CAFs after occlusion (0.06 ± 0.10 vs. 0.005 ± 0.012; p = 0.01). There is no statistical difference in the mean QFR variation and QFR variation rate between donor vessels with CAFs that occurred residual shunt and those without residual shunt after occlusion (p > 0.05). Conclusions: The presence of medium CAFs has a significant impact on the blood flow of the donor vessel, as compared to small CAFs, and may benefit from occlusion. A small residual shunt has no significant impact on the effectiveness of CAFs occlusion in enhancing donor blood flow.

The Different Shades of Thermogenic Adipose Tissue.

PURPOSE OF REVIEW: By providing a concise overview of adipose tissue types, elucidating the regulation of adipose thermogenic capacity in both physiological contexts and chronic wasting diseases (a protracted hypermetabolic state that precipitates sustained catabolism and consequent progressive corporeal atrophy), and most importantly, delving into the ongoing discourse regarding the role of adipose tissue thermogenic activation in chronic wasting diseases, this review aims to provide researchers with a comprehensive understanding of the field. RECENT FINDINGS: Adipose tissue, traditionally classified as white, brown, and beige (brite) based on its thermogenic activity and potential, is intricately regulated by complex mechanisms in response to exercise or cold exposure. This regulation is adipose depot-specific and dependent on the duration of exposure. Excessive thermogenic activation of adipose tissue has been observed in chronic wasting diseases and has been considered a pathological factor that accelerates disease progression. However, this conclusion may be confounded by the detrimental effects of excessive lipolysis. Recent research also suggests that such activation may play a beneficial role in the early stages of chronic wasting disease and provide potential therapeutic effects. A more comprehensive understanding of the changes in adipose tissue thermogenesis under physiological and pathological conditions, as well as the underlying regulatory mechanisms, is essential for the development of novel interventions to improve health and prevent disease.

Prevalence and Risk Factors of Hyperuricemia Among Young and Middle-Aged Tibetan Men Living at Ultrahigh Altitudes: A Cross-Sectional Study.

He, Ben, Jiayue Feng, Yan Shu, Lichun Yang, Zepin He, Kanxiu Liao, Hui Zhuo, and Hui Li. Prevalence and risk factors of hyperuricemia among young and middle-aged Tibetan men living at ultrahigh altitudes: a cross-sectional study. High Alt Med Biol. 25:42-48, 2024. Background: Few studies have examined the prevalence or risk factors of hyperuricemia among populations living at ultrahigh altitudes. Here we examined the prevalence of hyperuricemia and factors associated with it among young and middle-aged Tibetan men living at ultrahigh altitudes. Methods: This cross-sectional study analyzed 672 Tibetan men 18-60 years old living on the Qinghai-Tibet Plateau (mean altitude 4,014 m) within the county of Litang in the Ganzi Tibetan autonomous prefecture of Sichuan Province, China. Demographic and clinical data were collected from self-administered questionnaires, physical examinations and laboratory tests. Participants whose blood uric acid (UA) contained >420 µmol/l were classified as having hyperuricemia. Results: Of the 672 men analyzed, 332 (49.4%) had hyperuricemia. Multivariate logistic regression showed risk of hyperuricemia to correlate positively with body mass index (per 1 U increase: odds ratio [OR] 1.172, 95% confidence interval [CI] 1.1066-1.243), triglycerides (OR 1.408, 95% CI 1.084-1.828), red blood cell count (OR 1.376, 95% CI 1.009-1.875), and creatinine level (per 1 U increase: OR 1.051, 95% CI 1.033-1.070). Conversely, risk of hyperuricemia correlated negatively with the presence of diabetes mellitus (OR 0.412, 95% CI 0.175-0.968). Subgroup analyses showed that prevalence of hyperuricemia was significantly higher among those with polycythemia than among those without it, and that UA levels correlated positively with hematocrit and hemoglobin levels. Conclusions: Hyperuricemia is an important public health problem among Tibetan men living at ultrahigh altitudes in Ganzi autonomous prefecture. The region urgently requires appropriate prevention and management efforts.

Combining catheter ablation and left atrial appendage occlusion in high-risk patients with atrial fibrillation: a propensity score-matched analysis.

BACKGROUND: The safety and efficacy of a combined approach of catheter ablation (CA) and left atrial appendage occlusion (LAAO) compared to LAAO alone remain unknown. METHODS: Patients with atrial fibrillation (AF) at increased stroke risk who underwent LAAO were divided into either combined (CA and LAAO) procedures or LAAO alone group. Propensity score matching was utilized to balance baseline characteristics. The primary endpoint of the study was a composite of death, thromboembolic events, major bleeding, heart failure (HF) rehospitalization, and major periprocedural complications. RESULTS: A total of 707 AF patients who underwent LAAO were included. After 1:1 propensity score matching, 166 patients who underwent LAAO alone (n = 83) or the combined procedure (n = 83) were analyzed. Successful LAAO was achieved in all (100%) patients, with a low incidence of periprocedural complications in both groups (2.4% vs. 4.8%, LAAO vs. combined, p = 0.68). The incidence of peri-device leak post-LAAO was significantly higher in the combined group (25.3% vs. 43.4%, p = 0.01). After a median follow-up of 2 years, there were no significant differences in the rates of the primary composite endpoint between the two strategies (22.2% vs. 14.3%, HR: 1.24 [95% CI: 0.51-2.97], p = 0.63). However, the rate of HF rehospitalization was significantly lower in the combined group (19.6% vs. 3.6%, HR: 4.89 [95% CI: 1.50-15.97], p = 0.024). CONCLUSIONS: Combining CA and LAAO in a "one-stop" approach is safe and brings additional benefits in relieving symptoms of heart failure, although peri-device leak was more common compared to LAAO alone.

Selective deletion of E3 ubiquitin ligase FBW7 in VE-cadherin-positive cells instigates diffuse large B-cell lymphoma in mice in vivo.

During the maturation of hematopoietic stem/progenitor cells (HSPCs) to fully differentiated mature B lymphocytes, developing lymphocytes may undergo malignant transformation and produce B-cell lymphomas. Emerging evidence shows that through the endothelial-hematopoietic transition, specialized endothelial cells called the hemogenic endothelium can differentiate into HSPCs. However, the contribution of genetic defects in hemogenic endothelial cells to B-cell lymphomagenesis has not yet been investigated. Here, we report that mice with endothelial cell-specific deletion of Fbw7 spontaneously developed diffuse large B-cell lymphoma (DLBCL) following Bcl6 accumulation. Using lineage tracing, we showed that B-cell lymphomas in Fbw7 knockout mice were hemogenic endothelium-derived. Mechanistically, we found that FBW7 directly interacted with Bcl6 and promoted its proteasomal degradation. FBW7 expression levels are inversely correlated with BCL6 expression. Additionally, pharmacological disruption of Bcl6 abolished Fbw7 deletion-induced B-cell lymphomagenesis. We conclude that selective deletion of E3 ubiquitin ligase FBW7 in VE-cadherin positive endothelial cells instigates diffuse large B-cell lymphoma via upregulation of BCL6 stability. In addition, the mice with endothelial cell-specific deletion of Fbw7 provide a valuable preclinical platform for in vivo development and evaluation of novel therapeutic interventions for the treatment of DLBCL.

Impact of sequential (first- to third-generation) EGFR-TKI treatment on corrected QT interval in NSCLC patients.

Objective: To evaluate the impact of sequential (first- to third-generation) epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment on top-corrected QT interval (top-QTc) in non-small cell lung cancer (NSCLC) patients. Methods: We retrospectively reviewed the medical records of NSCLC patients undergoing sequential EGFR-TKI treatment at Shanghai Chest Hospital between October 2016 and August 2021. The heart rate (HR), top-QT interval, and top-QTc of their ECGs were extracted from the institutional database and analyzed. Logistic regression was performed to identify predictors for top-QTc prolongation. Results: Overall, 228 patients were enrolled. Compared with baseline (median, 368 ms, same below), both first-generation (376 ms vs. 368 ms, p < 0.001) and sequential third-generation EGFR-TKIs (376 ms vs. 368 ms, p = 0.002) prolonged top-QT interval to a similar extent (p = 0.635). Top-QTc (438 ms vs. 423 ms, p < 0.001) and HR (81 bpm vs.79 bpm, p = 0.008) increased after first-generation EGFR-TKI treatment. Further top-QTc prolongation (453 ms vs. 438 ms, p < 0.001) and HR increase (88 bpm vs. 81 bpm, p < 0.001) occurred after treatment advanced. Notably, as HR elevated during treatment, top-QT interval paradoxically increased rather than decreased, and the top-QTc increased rather than slightly fluctuated. Moreover, such phenomena were more significant after treatment advanced. After adjusting for confounding factors, pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation during sequential third-generation EGFR-TKI treatment. Conclusion: First-generation EGFR-TKI could prolong top-QTc, and sequential third-generation EGFR-TKI induced further prolongation. Top-QT interval paradoxically increased and top-QTc significantly increased as HR elevated, which was more significant after sequential EGFR-TKI treatment. Pericardial effusion and lower serum potassium levels were independent predictors of additional QTc prolongation after sequential EGFR-TKI treatment.

ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights.

Endoplasmic reticulum aminopeptidases ERAP1 and 2 are intracellular aminopeptidases that trim antigenic precursors and generate antigens presented by major histocompatibility complex class I (MHC-I) molecules. They thus modulate the antigenic repertoire and drive the adaptive immune response. ERAPs are considered as emerging targets for precision immuno-oncology or for the treatment of autoimmune diseases, in particular MHC-I-opathies. This perspective covers the structural and biological characterization of ERAP, their relevance to these diseases and the ongoing research on small-molecule inhibitors. We describe the chemical and pharmacological space explored by medicinal chemists to exploit the potential of these targets given their localization, biological functions, and family depth. Specific emphasis is put on the binding mode, potency, selectivity, and physchem properties of inhibitors featuring diverse scaffolds. The discussion provides valuable insights for the future development of ERAP inhibitors and analysis of persisting challenges for the translation for clinical applications.

SUMOylation of TEAD1 Modulates the Mechanism of Pathological Cardiac Hypertrophy.

Pathological cardiac hypertrophy is the leading cause of heart failure and has an extremely complicated pathogenesis. TEA domain transcription factor 1 (TEAD1) is recognized as an important transcription factor that plays a key regulatory role in cardiovascular disease. This study aimed to explore the role of TEAD1 in cardiac hypertrophy and to clarify the regulatory role of small ubiquitin-like modifier (SUMO)-mediated modifications. First, the expression level of TEAD1 in patients with heart failure, mice, and cardiomyocytes is investigated. It is discovered that TEAD1 is modified by SUMO1 during cardiac hypertrophy and that the process of deSUMOylation is regulated by SUMO-specific protease 1 (SENP1). Lysine 173 is an essential site for TEAD1 SUMOylation, which affects the protein stability, nuclear localization, and DNA-binding ability of TEAD1 and enhances the interaction between TEAD1 and its transcriptional co-activator yes-associated protein 1 in the Hippo pathway. Finally, adeno-associated virus serotype 9 is used to construct TEAD1 wild-type and KR mutant mice and demonstrated that the deSUMOylation of TEAD1 markedly exacerbated cardiomyocyte enlargement in vitro and in a mouse model of cardiac hypertrophy. The results provide novel evidence that the SUMOylation of TEAD1 is a promising therapeutic strategy for hypertrophy-related heart failure.

Activation of Nrf2 inhibits atherosclerosis in ApoE-/- mice through suppressing endothelial cell inflammation and lipid peroxidation.

BACKGROUND: Nuclear erythroid 2-related factor 2 (Nrf2), a transcription factor, is critically involved in the regulation of oxidative stress and inflammation. However, the role of endothelial Nrf2 in atherogenesis has yet to be defined. In addition, how endothelial Nrf2 is activated and whether Nrf2 can be targeted for the prevention and treatment of atherosclerosis is not explored. METHODS: RNA-sequencing and single-cell RNA sequencing analysis of mouse atherosclerotic aortas were used to identify the differentially expressed genes. In vivo endothelial cell (EC)-specific activation of Nrf2 was achieved by injecting adeno-associated viruses into ApoE-/- mice, while EC-specific knockdown of Nrf2 was generated in Cdh5CreCas9floxed-stopApoE-/- mice. RESULTS: Endothelial inflammation appeared as early as on day 3 after feeding of a high cholesterol diet (HCD) in ApoE-/- mice, as reflected by mRNA levels, immunostaining and global mRNA profiling, while the immunosignal of the end-product of lipid peroxidation (LPO), 4-hydroxynonenal (4-HNE), started to increase on day 10. TNF-α, 4-HNE, and erastin (LPO inducer), activated Nrf2 signaling in human ECs by increasing the mRNA and protein expression of Nrf2 target genes. Knockdown of endothelial Nrf2 resulted in augmented endothelial inflammation and LPO, and accelerated atherosclerosis in Cdh5CreCas9floxed-stopApoE-/- mice. By contrast, both EC-specific and pharmacological activation of Nrf2 inhibited endothelial inflammation, LPO, and atherogenesis. CONCLUSIONS: Upon HCD feeding in ApoE-/- mice, endothelial inflammation is an earliest event, followed by the appearance of LPO. EC-specific activation of Nrf2 inhibits atherosclerosis while EC-specific knockdown of Nrf2 results in the opposite effect. Pharmacological activators of endothelial Nrf2 may represent a novel therapeutic strategy for the treatment of atherosclerosis.

Safety and efficacy of the DragonFly system for transcatheter valve repair of degenerative mitral regurgitation: one-year results of the DRAGONFLY-DMR trial.

BACKGROUND: Severe degenerative mitral regurgitation (DMR) can cause a poor prognosis if left untreated. For patients considered at prohibitive surgical risk, transcatheter edge-to-edge repair (TEER) has become an accepted alternative therapy. The DragonFly transcatheter valve repair system is an innovative evolution of the mitral TEER device family to treat DMR. AIMS: Herein we report on the DRAGONFLY-DMR trial (ClinicalTrials.gov: NCT04734756), which was a prospective, single-arm, multicentre study on the safety and effectiveness of the DragonFly system. METHODS: A total of 120 eligible patients with prohibitive surgical risk and DMR ≥3+ were screened by a central eligibility committee for enrolment. The study utilised an independent echocardiography core laboratory and clinical event committee. The primary endpoint was the clinical success rate, which measured freedom from all-cause mortality, mitral valve reintervention, and mitral regurgitation (MR) >2+ at 1-year follow-up. RESULTS: At 1 year, the trial successfully achieved its prespecified primary efficacy endpoint, with a clinical success rate of 87.5% (95% confidence interval: 80.1-92.3%). The rates of major adverse events, all-cause mortality, mitral valve reintervention, and heart failure hospitalisation were 9.0%, 5.0%, 0.8%, and 3.4%, respectively. MR ≤2+ was 90.4% at 1 month and 92.0% at 1 year. Over time, left ventricular reverse remodelling was observed (p<0.05), along with significant improvements in the patients' functional and quality-of-life outcomes, shown by an increase in the New York Heart Association Class I/II from 32.4% at baseline to 93.6% at 12 months (p<0.001) and increased Kansas City Cardiomyopathy Questionnaire (KCCQ) score of 31.1±18.2 from baseline to 12 months (p<0.001). CONCLUSIONS: The DRAGONFLY-DMR trial contributes to increasing evidence supporting the safety and efficacy of TEER therapy, specifically the DragonFly system, for treating patients with chronic symptomatic DMR 3+ to 4+ at prohibitive surgical risk.

Noninvasive evaluation of pulmonary hypertension using the second heart sound parameters collected by a mobile cardiac acoustic monitoring system.

Background: Pulmonary hypertension (PH) is linked to higher rates of morbidity and mortality worldwide. Early diagnosis of PH is important for clinical treatment. The estimated pulmonary artery systolic pressure (ePASP ≥ 35 mmHg) measured by echocardiography helps screen PH patients. In this paper, we report a novel PH screening method through a mobile cardiac acoustic monitoring system. Methods: In the retrospective study, patients admitted to our hospital between January 2022 and April 2023 were classified into PH and control groups using ePASP and compared with acoustic cardiographic parameters. According to ePASP, PH severity was classified as mild, moderate, and severe. We analyzed the first and second heart sound (S1, S2) characteristics, including amplitude (S1A, S2A), energy (S1E, S2E), and frequency (S1F, S2F). Results: The study included 209 subjects, divided into PH (n = 121) and control (n = 88) groups. Pearson correlation analysis confirmed the positive correlation between S2F and ePASP. The diagnostic performance of S2F as assessed by the area under the ROC curve was 0.775 for PH. The sensitivity and specificity of diagnosing ePASP ≥ 35 mmHg when S2F ≥ 36 Hz were found to be 79.34% and 67.05%, respectively, according to ROC analysis. Severity classification was performed using S2F, the area under the ROC curve was 0.712-0.838 for mild PH, 0.774-0.888 for moderate PH, and 0.826-0.940 for severe PH. Conclusions: S2F collected by the mobile cardiac acoustic monitoring system offers a convenient method for remote PH screening, potentially improving PH management and outcomes.

Subclinical Anthracycline-Induced Cardiotoxicity in the Long - Term Follow-Up of Lymphoma Survivors: A Multi-Layer Speckle Tracking Analysis / Cardiotoxicidade Subclínica Induzida por Antraciclina no Seguimento a Longo Prazo de Sobreviventes de Linfoma: Uma Análise Speckle Tracking Multi-Layer

Abstract Background: Anthracycline generates progressive left ventricular dysfunction associated with a poor prognosis. Objectives: The purpose of this study was to evaluate whether layer-specific strain analysis could assess the subclinical left ventricular dysfunction after exposure to anthracycline. Methods: Forty-two anthracycline-treated survivors of large B-cell non-Hodgkin lymphoma, aged 55.83 ± 17.92 years (chemotherapy group) and 27 healthy volunteers, aged 51.39 ± 13.40 years (control group) were enrolled. The cumulative dose of epirubicin in chemotherapy group was 319.67 ± 71.71mg/m2. The time from last dose of epirubicin to the echocardiographic examination was 52.92 ± 22.32 months. Global longitudinal (GLS), circumferential (GCS) and radial strain (GRS), subendocardial, mid and subepicardial layer of longitudinal (LS-ENDO, LS-MID, LS-EPI) and circumferential strain (CS-ENDO, CS-MID, CS-EPI) values were analyzed. Transmural strain gradient was calculated as differences in peak systolic strain between the subendocardial and subepicardial layers. A value of p < 0.05 was considered significant. Results: Conventional parameters of systolic and diastolic function showed no significant difference between two groups. Compared with controls, patients had significantly lower GCS and GLS. Multi-layer speckle tracking analysis showed significant reduction of circumferential strain of subendocardial layer, transmural CS gradient and longitudinal strain of all three layers. In contrast, the two groups did not differ in transmural longitudinal strain gradient and radial strains. Conclusions: It proved the preferential impairment of subendocardial deformation in long-term survivors after exposure to anthracycline. Multi-layer speckle tracking echocardiography might facilitate the longitudinal follow-up of this at-risk patient cohort.

Resumo Fundamentos: A antraciclina gera uma disfunção ventricular esquerda progressiva associada a um prognóstico ruim. Objetivos: O propósito deste estudo foi avaliar se a análise layer específico de strain poderia avaliar disfunção ventricular esquerda subclínica após exposição a antraciclina. Métodos: Foram inscritos quarenta e dois sobreviventes tratados com antraciclina por linfoma não Hodgkin de células B grandes, de 55,83 ± 17,92 anos (grupo de quimioterapia) e 27 voluntários saudáveis, de 51,39 ± 13,40 anos (grupo controle). A dose cumulativa de epirrubicina no grupo de quimioterapia foi de 319,67 ± 71,71 mg/m2. O tempo desde a última dose de epirrubicina até o exame ecocardiográfico foi de 52,92 ± 22,32 meses. Analisaram-se o strain longitudinal global (GLS), o circunferencial (GCS) e o strain radial (GRS), os valores das camadas subendocárdica, média e subepicárdica so strain longitudinal (LS-ENDO, LS-MID, LS-EPI) e do strain circunferencial (CS-ENDO, CS-MID, CS-EPI). O gradiente de strain transmural foi calculado como a diferença no strain sistólico pico entre as camadas subendocárdicas e subepicárdicas. Um valor de p < 0,05 foi considerado significativo. Resultados: Os parâmetros convencionais da função sistólica e diastólica não mostraram diferenças significativas entre dois grupos. Comparados aos controles, os pacientes apresentaram GCS e GLS significativamente menores. A análise de speckle tracking multi-layer mostrou uma redução significativa no strain circunferencial da camada subendocárdica, o gradiente transmural CS e o strain longitudinal das três camadas. Em contraste, os dois grupos não diferiram no gradiente de strain longitudinal transmural e de strain radiais. Conclusões: Provou-se a deterioração preferencial do strain subendocárdico em sobreviventes de longa duração após exposição à antraciclina. O ecocardiograma de speckle tracking multi-layer pode facilitar o acompanhamento longitudinal dessa coorte de pacientes em risco. (Arq Bras Cardiol. 2018; 110(3):219-228)