Neointimal hyperplasia, a key pathological feature of many cardiovascular diseases, is driven by vascular smooth muscle cells (SMCs), yet the role of specific SMC subtypes remains unclear. This study identifies a smooth muscle-derived transient progenitor cell (STPC) population, marked by CD34 expression, which emerges after artery injury. These STPCs exhibit high proliferative capacity and generate the majority of neointimal SMCs. Genetic ablation of STPCs significantly reduces neointimal SMC accumulation and attenuates hyperplasia. Mechanistically, SMC-specific knockdown of DCLK1 markedly suppresses STPC generation and mitigates pathological remodeling. These findings establish STPCs as a critical progenitor population responsible for neointimal hyperplasia, identifying them as a novel therapeutic target for vascular diseases.

Bone morphogenetic proteins (BMPs) participate in the energy metabolism. BMP receptor type 2 (BMPR2) is expressed in the liver. Whether BMPR2 is involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD) has not been studied. In this study, we analyzed the RNA-sequence data of several patient cohorts and found that BMPR2 expression decreases at the stages of advanced fibrosis. A mouse model featuring BMPR2 knockout demonstrate that BMPR2 knockout in the liver produces profibrotic effect upon long-term high-fat and high-fructose (HFF) diet challenge. BMP signaling promotes biosynthesis of unsaturated fatty acids, which is repressed under BMPR2 knockout condition. The most affected unsaturated fatty acid, palmitoleic acid (POA), is found to activate CD169 macrophages. Moreover, CD169 macrophages is revealed to have high levels of lysosomal enzyme along with matrix metalloproteinase 8, which degrades collagen and alleviates fibrosis. Our study demonstrates that BMPR2 influences over the progression of liver fibrosis induced by the HFF diet through fatty acid-regulated CD169 macrophages. POA-primed macrophages might be a potential therapeutic strategy for the treatment of liver fibrosis.

Maladaptive ventricular remodeling following myocardial infarction (MI) is governed by a dysregulated inflammatory-reparative sequence. Macrophages are central driver in cardiomyocyte death and cardiac fibrosis through mediating inflammatory responses. Triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane glycoprotein selectively expressed by tissue-resident macrophages, has merged as a critical immune checkpoint. However, its cell-autonomous role in post-MI cardiac remodeling remains unclear. By applying permanent left-anterior-descending coronary ligation in WT mice and TREM2-knockout (TREM2 KO) mice, we found that TREM2 expression was rapidly upregulated in cardiac macrophages at day 7 post-MI, coinciding with the transition from inflammatory to reparative phase. TREM2 KO mice exhibited preserved baseline cardiac function but developed larger infarcts, lower ejection fraction, and higher mortality after MI. Mechanistically, TREM2 deficiency promoted macrophages towards a pro-inflammatory M1 phenotype, amplified the generation of reactive oxygen species (ROS) and activation of the NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) inflammasome in vitro. Additionally, a transwell co-culture model of bone marrow-derived macrophages (BMDMs) and primary mouse cardiomyocytes revealed that TREM2 suppressed cardiomyocyte apoptosis via ROS-NLRP3 signaling. The ROS scavenger N-acetylcysteine (NAC) markedly inhibited inflammatory factor production in TREM2 deficient macrophages and attenuate cardiomyocyte apoptosis. TREM2 functions as a macrophage-intrinsic checkpoint that coordinates the initiation, escalation, and resolution of post-MI inflammation by restraining ROS-NLRP3 signaling. Augmenting TREM2 activity or supplementing soluble TREM2 may represent a novel immunomodulatory strategy to limit adverse remodeling and improve outcomes after MI.

BACKGROUND:Pathological cardiac hypertrophy is a central driver of heart failure, yet targeted therapies remain lacking. This study aimed to investigate the role of retinoid homeostasis in cardiac hypertrophy, focusing on retinol-binding protein 1 (RBP1), the primary intracellular regulator of retinol homeostasis. We sought to elucidate the effects and underlying mechanisms of RBP1 in cardiac hypertrophy. METHODS:Cardiac retinol and all-trans retinoic acid (atRA) levels were quantified using LC-MS. A mouse model of pressure overload-induced cardiac hypertrophy was established via transverse aortic constriction (TAC) surgery. Cardiomyocyte-specific overexpression of RBP1 was achieved by intravenous injection of an adeno-associated virus 9 (AAV9) vector carrying RBP1 under the control of the cardiac troponin T (cTnT) promoter. An in vitro hypertrophy model was established by treating rat neonatal cardiomyocytes (NRCMs) with phenylephrine (PE). Gain- and loss-of-function approaches were applied to evaluate the effect of RBP1 on cardiomyocyte hypertrophy. Transcriptomic changes upon RBP1 knockdown in PE-treated NRCMs were analyzed by RNA sequencing. To dissect the signaling pathways involved, the retinoic acid receptors (RARs) inhibitor AGN193109 (AGN) and the Wnt signaling agonist Wnt3a were administered. A dual-luciferase reporter assay was performed to evaluate whether atRA regulates Wnt3a promoter activity. RESULTS:Retinol metabolism was impaired in mice subjected to TAC. Supplementation of atRA sufficiently ameliorated cardiac hypertrophy. RBP1 was upregulated in both hypertrophied myocardium and isolated cardiomyocytes. Cardiomyocyte-specific RBP1 overexpression effectively restored myocardial retinol and atRA pools and alleviated cardiac hypertrophy and fibrosis in TAC mice. RBP1 expression was significantly upregulated in PE-induced hypertrophic NRCMs. Knockdown of RBP1 in NRCMs aggravated hypertrophy, whereas its overexpression attenuated hypertrophy induced by PE stimulation. RNA sequencing analyses indicated that RBP1 knockdown disrupted retinol and retinoic acid metabolic processes. Pharmacological inhibition of atRA signaling using AGN partially reversed the protective effect of RBP1 overexpression on cardiomyocyte hypertrophy, indicating that the anti-hypertrophic effect of RBP1 is partially dependent on atRA signaling. Further analyses demonstrated that RBP1 inhibited cardiomyocyte hypertrophy by suppressing Wnt3a/β-catenin signaling. Mechanistically, atRA partially reversed Wnt3a/β-catenin activation induced by RBP1 knockdown, whereas AGN partially abolished the inhibitory effect of RBP1 overexpression on this pathway, indicating that RBP1 regulated Wnt3a/β-catenin signaling in an atRA-dependent manner. Moreover, luciferase reporter assays demonstrated that atRA suppressed Wnt3a promoter activity via retinoic acid response elements (RAREs) within its promoter region. CONCLUSIONS:RBP1 is upregulated in hypertrophic myocardium and exerts a protective role against cardiac hypertrophy. These results suggest that RBP1 may serve as a potential therapeutic target for cardiac hypertrophy and heart failure, offering a promising strategy to prevent and regress cardiac hypertrophy through RBP1/atRA/Wnt3a/β-catenin signaling.

BACKGROUND:The extent to which achieving multiple metabolic treatment targets confers sustained cardiorenal protection across all stages of cardiovascular - kidney - metabolic (CKM) syndrome remains uncertain. METHODS:This multicenter retrospective study used data from the China Renal Data System (CRDS) to investigate the association between achieving multiple metabolic targets (blood pressure, fasting blood glucose, LDL-C control) and cardiorenal outcomes across stages of CKM syndrome. RESULTS:The proportion of patients meeting all three metabolic targets decreased markedly with advancing CKM stage. Kaplan-Meier curves showed increasing risks of cardiovascular-renal events and mortality across higher stages (P < 0.001). After adjustment, higher metabolic scores were linked to lower risks: for cardiovascular-renal outcomes, HR 0.82 (95% CI 0.77-0.87) for score 1, 0.72 (0.68-0.77) for score 2, and 0.65 (0.57-0.73) for score 3. Stratified analysis showed significant risk reduction in early CKM stages but not in advanced stages. Restricted cubic spline models indicated nonlinear associations between LDL-C and both outcomes, and between FBG, systolic BP, and mortality, after full adjustment (all P < 0.05). CONCLUSIONS:The findings underscore the need for stage-specific management strategies in CKM syndrome.

As the master orchestrator of integrated stress response, activating transcription factor 4 (ATF4) operates as a central molecular switch that directs cellular fate toward survival or death by regulating genes associated with oxidative stress, endoplasmic reticulum stress, apoptosis, ferroptosis and metabolism. The functional outcome of ATF4 activation is critically dependent on the context: it usually contributes to cellular adaption and survival under mild or transient stress, yet triggers cell death when stress is severe or prolonged. Dysregulation of this dichotomous function has been implicated in a variety of diseases, such as cancer, neurodegenerative disease, metabolic disease, etc., highlighting ATF4 as a potential therapeutic target. Recently, growing evidence has further underscored the dual roles of ATF4 as the guardian or executioner in cardiovascular disorders, such as coronary heart disease, cardiomyopathy, arrhythmia, valvular heart disease, heart failure and cardiovascular aging. Here in this review, we systematically decode the context-dependent opposing roles of ATF4 in cardiovascular diseases and also highlight the underlying regulatory mechanisms, thereby providing a rationale for developing context-specific therapeutic strategies targeting ATF4 for the personalized management of cardiovascular disorders.

BACKGROUND:Direct cardiac reprogramming offers a promising therapeutic strategy for heart regeneration by converting endogenous fibroblasts to functional induced cardiomyocytes (iCMs) that integrate into the myocardium to restore heart structure and function. While ECM (extracellular matrix) plays critical roles in cardiac disease and repair, the dynamic changes and transcriptional regulation underlying ECM remodeling during reprogramming remain poorly understood. METHODS:We investigated ECM dynamics during iCM reprogramming using integrated transcriptomic, proteomic, and epigenetic analyses, focusing on cell type-specific ECM components. A loss-of-function screen was used to identify critical ECM components and regulators, including Itga8 (integrin alpha-8) and Grhl3 (grainyhead-like protein 3 homolog), respectively, as reprogramming barriers. Mechanistic studies integrated RNA sequencing, mass spectrometry, and Cleavage Under Targets and Tagmentation to define Grhl3-dependent regulation. Functional outcomes were evaluated in vitro using decellularized ECM and in vivo using a myocardial infarction model with genetic lineage tracing. RESULTS:Cardiac reprogramming induced dynamic ECM remodeling, with significant changes in collagen, fibrillar proteins, and integrins. Itga8 was identified as a pivotal ECM component that restricts iCM conversion via the TGF-β (transforming growth factor-β)/SMAD (small mothers against decapentaplegic) pathway. Grhl3 emerged as a key transcriptional regulator for ECM components, including Itga8. ECM derived from Grhl3-deficient fibroblasts enhanced iCM induction, while Grhl3 depletion also reduced fibroblast activation and increased cellular plasticity. These effects synergized with TF (transcription factor)-mediated reprogramming to improve iCM efficiency, structural organization, and functional maturation. In vivo, removing Grhl3 enhanced fibroblast-to-cardiomyocyte conversion, reduced scar formation, and improved cardiac function after myocardial infarction. CONCLUSIONS:Our findings establish ECM adaptation as a critical determinant of cardiac reprogramming and identify Grhl3 as a promising therapeutic target to advance myocardial repair strategies.

BACKGROUND:Pathogenic cardiac hypertrophy, often driven by mechanical stress, is a leading cause of heart failure. However, effective therapeutic targets remain limited. TMC6 (transmembrane channel-like protein 6) is abundant in healthy myocardium but downregulated in hypertrophic hearts; its role in cardiac hypertrophy remains undefined. METHODS:We combined cardiac-specific Tmc6 knockout mice subjected to transverse aortic constriction surgery, neonatal rat ventricular myocytes, and CRISPR/Cas9-edited human pluripotent stem cell-derived cardiomyocytes to assess hypertrophy and signaling readouts. Subcellular localization, protein-protein interaction, and competitive peptide assays were used to dissect the mechanism. Adeno-associated virus serotype 9 (AAV9)-cTnT (cardiac troponin T)-TMC6 was used for in vivo rescue. RESULTS:TMC6 deficiency increased cardiomyocyte size, fetal gene expression, and adverse remodeling in vivo and in vitro, whereas TMC6 overexpression blunted hypertrophic responses. Full-length TMC6 localized to the endoplasmic reticulum and bound CIB1 (calcium and integrin-binding protein 1) to sequester it in the endoplasmic reticulum, limiting CIB1 access to sarcolemmal Ca2+ microdomains required to scaffold calcineurin and activate NFAT (nuclear factor of activated T cells). A cell-permeable TMC6161-180 peptide competitively displaced CIB1 from TMC6 and augmented hypertrophy in wild-type but not Tmc6 knockout cardiomyocytes, indicating a dominant-negative mechanism. Therapeutically, AAV9-cTnT-TMC6 restored TMC6-CIB1 engagement, suppressed calcineurin/NFAT readouts, and improved function after pressure overload. CONCLUSIONS:TMC6 is an endogenous brake on pathological hypertrophy that restrains CIB1-calcineurin/NFAT signaling via endoplasmic reticulum sequestration of CIB1. Restoring full-length TMC6 mitigates pressure-overload remodeling, nominating the TMC6-CIB1 axis as a therapeutic target.

ABSTRACTBackgroundRight ventricular (RV) failure is a well‐recognized pivotal prognostic factor of adverse outcomes in pulmonary artery hypertension (PAH), while RV dilation provides significant implications for adaptive or maladaptive changes. PAH is a predominant cause of mortality among patients with connective tissue disease (CTD). This study aims to elucidate the prognostic significance of RV morphology, as assessed by echocardiography (ECHO), in with CTD associated with PAH (CTD‐PAH).MethodsIn this ambispective cohort study, 143 CTD‐PAH patients diagnosed by right‐sided heart catheterization (RHC) from 2013 to 2023 were enrolled. Clinical characteristics, laboratory data, echocardiographic parameters (right ventricular end‐diastolic basal diameter index (RVDDI), tricuspid annular plane systolic excursion (TAPSE) and pulmonary arterial systolic pressure (PASP)) and therapy were recorded. The primary endpoint was defined as clinical worsening within a five‐year timeframe. Analytical methods included Kaplan–Meier survival analyses, the log‐rank test, and multivariable Cox proportional hazards regression to evaluate prognostic factors.ResultsThe study enrolled a total of 143 patients with CTD‐PAH, with a notable female predominance (95.1%) and a median age of 41.67 years; SLE‐PAH (49%) and pSS‐PAH (34%) were the most common subtypes, and 94% of the participants were in WHO‐FC II‐III. Among the participants, 34 (23.8%) patients experienced clinical worsening during a median follow‐up period of 21 months. After adjusting for confounders such as age and sex, RVDDI, as determined by ECHO was correlated with clinical worsening (HR 1.090; 95% CI: 1.019–1.166; p = 0.012). RVDDI > 25.81 mm/m2 predicts higher incidence of clinical worsening in CTD‐PAH. In the subgroup of TAPSE/PASP > 0.19 mm/mmHg, patients with RVDDI > 25.81 mm/m2 had a higher incidence of clinical worsening. The estimated event‐free survival rates at 1 and 3 years were 93.5% and 53.7%, respectively.ConclusionThe study demonstrates that RVDDI, as evaluated by ECHO, is a significant prognostic indicator for clinical worsening in CTD‐PAH. Its inclusion in the assessment of RV function and risk stratification may provide valuable incremental prognostic information for this CTD‐PAH population.

OBJECTIVE:Thoracic aortic aneurysm (TAA) is a life-threatening condition that predisposes to aortic dissection (AD), yet its underlying pathophysiologic mechanisms remain poorly understood. METHODS:Tandem mass tag-based quantitative proteomics of plasma from type A AD patients was performed to identify dysregulated proteins. The β-aminopropionitrile-induced mouse model was used to experimentally recapitulate TAA progression, with disease mechanisms further characterized through RNA sequencing transcriptomics, complemented by comprehensive molecular analyses including immunohistochemistry, immunofluorescence, western blot, co-immunoprecipitation, and bioinformatics integration. RESULTS:Integrin αV and integrin αL were significantly downregulated proteins in plasma samples from patients with type A AD. Integrin αV abundantly expressed in the aortic media, particularly in smooth muscle cells (SMCs), with significantly reduced expression after dissection. Pharmacologic inhibition of integrin αV with cilengitide or SB273005 markedly aggravated ascending TAA development, accompanied by severe disorganization and loss of elastic fibers. Bulk RNA sequencing revealed that integrin αV inhibition exacerbated proinflammatory responses during TAA progression. Inhibiting integrin αV disrupted the SMC transition to a contractile phenotype, whereas STAT1 negatively regulated integrin αV-mediated SMC phenotypic modulation. CONCLUSIONS:These findings identify integrin αV as a promising molecular target for TAA intervention. However, they also highlight concerns regarding the clinical use of integrin αV inhibitors, which are currently under investigation in cancer trials because they may increase the risk of TAA or AD development.

Aims We aimed to examine the association between hypnotic agents and cardiovascular outcomes in general individuals with insomnia. Methods and results In a propensity score matched cohort of UK Biobank (UKB) participants with insomnia, Cox proportional hazard model was used to estimate the association between regular use of hypnotic agents and predetermined cardiovascular outcomes including incident coronary heart diseases (CHD), heart failure (HF), stroke, and cardiovascular death. Inverse probability of treatment weighting, competing risk models, and shared frailty models were further performed during sensitivity analysis. Drug-target Mendelian randomization (MR) analyses were employed for further evaluation of the association between therapeutic targets of hypnotics and cardiovascular diseases. During a median follow-up of 14.3 years, the matched cohort documented a total of 929 CHD cases, 360 HF cases, 262 stroke cases, and 180 cardiovascular deaths. No significant association was detected between Z-meds and CHD, stroke, and cardiovascular mortality. Benzodiazepine use was significantly associated with the increased risk of CHD, HF, and cardiovascular mortality. The inverse probability of treatment weighting, competing risk models, and shared frailty models didn’t alter the above associations. Moreover, drug-target MR analyses corroborated the safety of Z-meds in the general population regarding cardiovascular health. Conclusion Our findings suggested the heterogeneous associations between different categories of hypnotics and incident cardiovascular events in individuals with insomnia. Both observational and genetic evidence raised safety concerns regarding the cardiovascular impact of benzodiazepines. No cardiovascular hazard of Z-meds was discovered in the UKB population with insomnia.

Cardiovascular diseases (CVDs) remain the global leading cause of mortality, necessitating novel diagnostics and therapies. Extracellular vesicles (EVs)—including exosomes, microvesicles, and apoptotic bodies—serve as key intercellular communicators in cardiovascular system. As carriers of bioactive miRNAs/proteins, EVs regulate inflammation, fibrogenesis, angiogenesis, and cardiac/systemic communication. Their non-invasive accessibility and disease-specific molecular signatures enable diagnostic applications. Endogenous origin and targeting capacity make EV ideal drug delivery platforms, while engineering of surface/content properties enhances their therapeutic specificity. However, key challenges persist in reproducibility, long-term safety profiles, clearance mechanisms, and therapeutic applications. Therefore, we highlight the potential of EVs as engineered drug carriers and their therapeutic promise for CVDs such as myocardial infarction, atherosclerosis, and heart failure. Future clinical translation of EV-based tools offers transformative potential—from cardiovascular diagnostics to regenerative therapies—where collaborative efforts will accelerate the pipeline development of these emerging solutions for clinical CVDs management. Extracellular vesicles (EVs), including exosomes, microvesicles, and apoptotic bodies, have emerged as key players in disease progression, diagnostic biomarkers, and therapeutic tools in the field of CVDs. This review summarizes key aspects of EVs—including structure, biogenesis, and functions—along with current technological limitations and future clinical potential in CVDs.

Background: Phenotypic switching of vascular smooth muscle cells (VSMCs) greatly contributes to vascular remodeling in various vascular diseases. The underlying molecular mechanisms, however, remain incompletely understood. Microtubule-associated serine/threonine kinase doublecortin-like kinase 1 (DCLK1) is known to regulate the proliferation, migration, and differentiation of cancer cells. Yet, its role in VSMC phenotypic switching in neointimal formation during vascular injury is entirely unknown. This study aimed to examine the function of DCLK1 in VSMC phenotypic switching and neointima formation. Research Questions: This study aimed to examine the function of DCLK1 in VSMC phenotypic switching and neointima formation. Methods: Carotid artery ligation was performed in both wild-type and SMC-specific Dclk1-deficient mice. Single-cell RNA sequencing, bulk RNA sequencing, co-immunoprecipitation, mass spectrometry, AlphaFold modeling, and protein-protein docking analyses were performed to explore the potential role of DCLK1 in VSMC phenotypic switching and neointima formation. Results: DCLK1 expression in VSMCs was significantly upregulated in human carotid atherosclerotic samples and murine carotid artery ligation tissues (Figure A, B). SMC-specific deletion of Dclk1 markedly reduced neointima formation after carotid artery ligation (Figure C, D) , and the involvement of autophagy in VSMC phenotypic switching was revealed (Figure E, F). Mechanistically, DCLK1 directly interacted with the His368 site of tripartite motif-containing 21 (TRIM21) (Figure G). DCLK1 deficiency increased TRIM21-SQSTM1/P62 interaction, thereby decreasing autophagy and maintaining a contractile VSMC phenotype (Figure H). Moreover, the phenotypic switching of VSMCs was promoted by the dual knockdown of DCLK1 and TRIM21 in VSMCs. Conclusion: Our study reveals a pivotal role of DCLK1 in promoting VSMC phenotypic switching and neointimal remodeling in response to vascular injury. Therefore, inhibition of VSMC DCLK1 may represent a potential therapeutic target for vascular hyperplasia.

Cardiac fibrosis following myocardial infarction (MI) drives adverse ventricular remodeling and heart failure, with cardiac fibroblasts (CFs) playing a central role. GSTM1 is an important member of the glutathione S-transferase (GSTs) family, which plays an important role in maintaining cell homeostasis and detoxification. This study investigated the role and mechanism of GSTM1 in post-MI fibrosis. Multi-omics approaches (proteomics/scRNA-seq) identified GSTM1 as a dysregulated target in post-MI fibroblasts. Using a murine coronary ligation model, we assessed GSTM1 dynamics via molecular profiling, such as Western blotting, immunofluorescence, and real-time quantitative polymerase chain reaction. AAV9-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery. In vitro studies employed transforming growth factor-β (TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions. Mechanistic insights were derived from transcriptomics and lipid peroxidation assays. The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels. In human dilated cardiomyopathy (DCM) patients with severe heart failure, GSTM1 expression was decreased alongside aggravated fibrosis. Overexpression of GSTM1 in post-MI mice improved cardiac function, while significantly reducing infarct size and fibrosis compared with the control group. In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts, as well as suppressed their proliferation and migration. Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species (ROS) under pathological conditions, suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts. Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways. Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria, markedly decreased ferroptosis-related indicators, and alleviated oxidative lipid levels [such as 12-hydroxyeicosapentaenoic acid (HEPE) and 9-, 10-dihydroxy octadecenoic acid (DHOME)] under fibrotic conditions. GSTM1 enhanced the phosphorylation of STAT3, thereby upregulating the downstream expression of glutathione peroxidase 4 (GPX4), reducing ROS production, and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation. This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis, highlighting its ability to target ferroptosis through redox regulation. AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.

OBJECTIVES:Numerous studies have demonstrated impaired right ventricular (RV) synchronicity in pulmonary arterial hypertension (PAH). However, few studies have focused on connective tissue disease (CTD)-associated PAH. This study evaluates RV dyssynchrony and its prognostic value in CTD-associated PAH. METHODS:One hundred thirteen CTD patients and 32 healthy controls were consecutively recruited. The patients were further divided into two groups: the CTD-nonPAH group (sPAP ˂ 36 mmHg, n = 60) and the CTD-PAH group (sPAP ≥ 36 mm Hg, n = 53). RV dyssynchrony was evaluated by determining the standard deviation of the heart rate-corrected intervals from QRS onset to peak strain for the four segments (RV-SD4) using 2D speckle-tracking echocardiography (2D-STE). All patients were followed up, and the primary endpoint was clinical worsening. RESULTS:Compared to the health control, the CTD patients exhibited obviously prolonged RV-SD4 (13.3 ± 6.8 ms vs. 41.2 ± 36.5 ms, p < 0.001). Among 113 CTD patients, the CTD-PAH patients had longer RV-SD4 than the CTD-nonPAH patients (20.8 ± 9.9 ms vs. 64.3 ± 41.6 ms, p < 0.001). RV-SD4 was moderately positively correlated with RV longitudinal strain (r = 0.632, p < 0.001), sPAP (r = 0.644, p < 0.001), and were negatively correlated with TAPSE (r = -0.547, p < 0.001), and FAC (r = -0.611, p < 0.001). In the follow-up, 23 patients experienced clinical worsening. The ROC analysis suggested that RV-SD4 level >60.6 ms predicted clinical worsening with 91.3% sensitivity and 66.7% specificity (AUC = 0.891, p < 0.001). Multivariate Cox analysis showed that TAPSE (HR = 0.739; 95% CI 0.623-0.878; p = 0.001) and RV-SD4 (HR = 6.148; 95% CI 1.718-22.000; p = 0.005) were independent predictive parameters of clinical worsening. CONCLUSION:CTD patients exhibit impaired RV synchronicity, which is linked to RV function and pulmonary artery pressure. RV dyssynchrony could predict clinical worsening in CTD-PAH.

Management of patients with acute chest pain poses a significant challenge in identifying those requiring urgent coronary reperfusion. Electrocardiogram (ECG) constitutes the cornerstone in making prompt clinical decisions by identifying ST-segment elevation, commonly associated with ST-segment elevation myocardial infarction. It is important to note that ST-segment elevation can also be a manifestation of various cardiac and non-cardiac conditions, from acute myocarditis, early repolarization syndrome, acute pericarditis, and left bundle branch block to unknown origins. The similarity of ECG changes among these conditions complicates clinical differential diagnosis, necessitating a detailed medical history and thorough examinations. Here, we presented a case of a 52-year-old female with chest pain and unidentified convex ST-segment elevation. Considering the negative emergent coronary angiography results, normal echocardiography, and long-lasting ST-segment elevation for the following 1 year, the final diagnosis was non-myocardial infarction, probably related to a prior cerebral haemorrhage.

BACKGROUND:T-cell exhaustion (TEX), a condition characterized by impaired T-cell function, has been implicated in numerous pathological conditions, but its role in acute myocardial Infarction (AMI) remains largely unexplored. This research aims to identify and characterize all TEX-related genes for AMI diagnosis. METHODS:By integrating gene expression profiles, differential expression analysis, gene set enrichment analysis, protein-protein interaction networks, and machine learning algorithms, we were able to decipher the molecular mechanisms underlying TEX and its significant association with AMI. In addition, we investigated the diagnostic validity of the leading TEX-related genes and their interactions with immune cell profiles. Different types of candidate small molecule compounds were ultimately matched with TEX-featured genes in the "DrugBank" database to serve as potential therapeutic medications for future TEX-AMI basic research. RESULTS:We screened 1725 differentially expressed genes (DEGs) from 80 AMI samples and 71 control samples, identifying 39 differential TEX-related transcripts in total. Functional enrichment analysis identified potential biological functions and signaling pathways associated with the aforementioned genes. We constructed a TEX signature containing five hub genes with favorable prognostic performance using machine learning algorithms. In addition, the prognostic performance of the nomogram of these five hub genes was adequate (AUC between 0.815 and 0.995). Several dysregulated immune cells were also observed. Finally, six small molecule compounds which could be the future therapeutic for TEX in AMI were discovered. CONCLUSION:Five TEX diagnostic feature genes, CD48, CD247, FCER1G, TNFAIP3, and FCGRA, were screened in AMI. Combining these genes may aid in the early diagnosis and risk prediction of AMI, as well as the evaluation of immune cell infiltration and the discovery of new therapeutics.

Abstract Background Previous studies have shown an association between gut microbiota and cardiovascular diseases (CVDs). However, the underlying causal relationship remains unclear. This study aims to elucidate the causal relationship between gut microbiota and CVDs and to explore the pathogenic role of gut microbiota in CVDs. Methods In this two-sample Mendelian randomization study, we used genetic instruments from publicly available genome-wide association studies, including single-nucleotide polymorphisms (SNPs) associated with gut microbiota (n = 14,306) and CVDs (n = 2,207,591). We employed multiple statistical analysis methods, including inverse variance weighting, MR Egger, weighted median, MR pleiotropic residuals and outliers, and the leave-one-out method, to estimate the causal relationship between gut microbiota and CVDs. Additionally, we conducted multiple analyses to assess horizontal pleiotropy and heterogeneity. Results GWAS summary data were available from a pooled sample of 2,221,897 adult and adolescent participants. Our findings indicated that specific gut microbiota had either protective or detrimental effects on CVDs. Notably, Howardella (OR = 0.955, 95% CI: 0.913–0.999, P = .05), Intestinibacter (OR = 0.908, 95% CI:0.831–0.993, P = .03), Lachnospiraceae (NK4A136 group) (OR = 0.904, 95% CI:0.841–0.973, P = .007), Turicibacter (OR = 0.904, 95% CI: 0.838–0.976, P = .01), Holdemania (OR, 0.898; 95% CI: 0.810–0.995, P = .04) and Odoribacter (OR, 0.835; 95% CI: 0.710–0.993, P = .04) exhibited a protective causal effect on atrial fibrillation, while other microbiota had adverse causal effects. Similar effects were observed with respect to coronary artery disease, myocardial infarction, ischemic stroke, and hypertension. Furthermore, reversed Mendelian randomization analyses revealed that atrial fibrillation and ischemic stroke had causal effects on certain gut microbiotas. Conclusion Our study underscored the importance of gut microbiota in the context of CVDs and lent support to the hypothesis that increasing the abundance of probiotics or decreasing the abundance of harmful bacterial populations may offer protection against specific CVDs. Nevertheless, further research is essential to translate these findings into clinical practice.

Eph receptors, comprising the largest family of receptor tyrosine kinases (RTKs), exert profound influence on diverse biological processes and pathological conditions such as cancer. Interacting with their corresponding ligands, Ephrins, Eph receptors regulate crucial events like embryonic development, tissue boundary formation, and tumor cell survival. In addition to their well-established roles in embryonic development and cancers, emerging evidence highlights the pivotal contribution of the Ephrin/Eph family to cardiovascular physiology and pathology. Studies have elucidated their involvement in cardiovascular development, atherosclerosis, postnatal angiogenesis, and more recently, cardiac fibrosis and calcification, suggesting a promising avenue for therapeutic interventions in cardiovascular diseases. There remains a need for a comprehensive synthesis of their collective impact in the cardiovascular context. By exploring the intricate interactions between Eph receptors, ephrins, and cardiovascular system, this review aims to provide a holistic understanding of their roles and therapeutic potential in cardiovascular health and diseases.

Adipose tissue development begins in the fetal period, and continues to expand after birth. Dysregulation of adipose tissue during weaning may predispose individuals to lifelong metabolic disorders. However, the developmental remodeling of adipose tissue during weaning remains largely unexplored. Here we comprehensively compare the changes in mouse subcutaneous white adipose tissue from 7 days after birth to 7 days after weaning using single-cell RNA sequencing along with other molecular and histologic assays. We characterize the developmental trajectory of preadipocytes and indicate the commitment of preadipocytes with beige potential during weaning. Meanwhile, we find immune cells unique to weaning period, whose expression of extracellular matrix proteins implies potential regulation on preadipocyte. Finally, the strongest cell-cell interaction during weaning determined by the TGFβ ligand-receptor pairs is between preadipocytes and endotheliocytes. Our results provide a detailed and unbiased cellular landscape and offer insights into the potential regulation of adipose tissue remodeling during weaning.