Background and Objectives: To investigate prognostic risk factors and determine the incidence, clinical characteristics, and predictors of heart failure (HF) development in pediatric patients with end-stage kidney disease (ESKD) secondary to steroid-resistant nephrotic syndrome (SRNS). Materials and Methods: We conducted a retrospective cohort study of pediatric patients diagnosed with ESKD secondary to nephrotic syndrome (NS) between 2014 and 2020. Patients were stratified based on clinical outcomes and the occurrence of HF during follow-up. Comparative analyses of clinical characteristics, laboratory parameters, and cardiac assessments were performed across groups. Multivariate logistic regression was used to identify independent risk factors for HF development within the first year and for adverse prognosis at five years. Results: The cohort comprised 172 children with ESKD secondary to NS. Multivariate logistic regression identified HF as an independent risk factor for adverse long-term outcomes in pediatric patients with ESKD. During follow-up, HF developed in 27 patients (15.7%) within the first year after ESKD diagnosis, and in 45 patients (26.2%) by the end of five years. Early HF onset (within the first year) was associated with a significantly reduced five-year survival rate. Independent risk factors for HF development included elevated cardiac troponin I levels (OR = 6.786, 95% CI: 2.326-19.799), a history of cardiac arrhythmias (OR = 2.951, 95% CI: 1.260-6.912), and the presence of left heart enlargement (OR = 23.669, 95% CI: 2.876-194.827), and valvular regurgitation at the initial post-ESKD diagnosis evaluation. Conclusions: HF is associated with markedly reduced survival. Crucially, our findings demonstrate that pre-existing cardiovascular structural abnormalities-specifically left heart enlargement-and elevated cTnI are robust, early predictors of HF. These findings necessitate a paradigm shift in pediatric ESKD management, we advocate for the implementation of systematic baseline echocardiographic and biomarker screening at the immediate onset of ESKD. Identifying these subclinical, yet modifiable, structural changes provide a critical therapeutic window for targeted anti-remodeling interventions to significantly improve long-term prognosis.

BackgroundStress hyperglycemia ratio (SHR) is a commonly used predictor of acute hyperglycemia. The present study aimed to evaluate the prognostic significance of SHR in acute myocardial infarction (AMI) patients who underwent percutaneous coronary intervention (PCI).MethodsA total of 3,212 consecutive AMI patients who underwent PCI were recruited and assigned to three groups, according to SHR tertiles. Then, the total number of major adverse cardiovascular and cerebrovascular events (MACCEs) and various cardiovascular events were recorded. The SHR was determined, as follows: admission blood glucose (mmol/L)/[1.59 × hemoglobin A1c (%) −2.59].ResultsThe incidence of MACCEs was positively correlated to SHR during the median follow-up of 36 months. The multivariate COX regression analysis identified SHR as an independent predictor of composite MACCEs [hazard ratio: 2.279, 95% confidence interval (CI): 1.569–3.311, p < 0.001] and target vessel revascularization (hazard ratio: 1.998, 95% CI: 1.299–3.074, p = 0.002). In terms of gender, age, type of AMI, body mass index, left ventricular ejection fraction, and diabetes mellitus, SHR >1.45 was significantly associated to MACCEs across all subgroups (all, p < 0.001), except for patients with ejection fraction <50%. Furthermore, the area under the receiver operating characteristic curve for SHR in predicting MACCEs was 0.636 (95% CI: 0.613–0.659, p < 0.05), with a cut-off value of 1.317.ConclusionsStress hyperglycemia, as indicated by SHR, is significantly correlated to MACCEs, and independently predicts the prognosis of AMI patients undergoing PCI. These findings highlight the potential of SHR as an effective prognostic marker for AMI patients undergoing PCI.

Purpose: The neuropathologic mechanisms of sudden sensorineural hearing loss (SSNHL) are unknown. The aim of this study was to investigate the alterations of neurovascular coupling (NVC) in patients with SSNHL and its association with hematologic inflammatory factors. Methods: The amplitude of low-frequency fluctuations (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were calculated in 48 patients with SSNHL and 54 age-, gender-, and education-matched healthy control (HC), and also utilized the arterial spin labeling imaging (ASL) to calculate cerebral blood flow (CBF). Four indices of NVC (CBF-ALFF, CBF-fALFF, CBF-ReHo, and CBF-DC) in the whole brain gray matter as well as the NVC ratio were compared between two groups. In addition, correlation analyses were performed with inflammatory factors for the NVC indexes at the global level and regional level, respectively. Results: The NVC at global level was lower in SSNHL group than in HC, except for CBF-ALFF. At the regional level, most of the brain regions with abnormal NVC in SSNHL patients involved auditory and sensorimotor language centers and limbic system compared to HC. In addition, both at the global and regional levels, NVC metrics were shown to correlate with partial inflammatory factors or hematologic parameters, including platelet- lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), systemic immunoinflammatory index (SII), blood platelet count (PLT), and lymphocyte count (Lym). Conclusion: From the view of the NVC metrics, these findings provide new perspectives on the neuropathologic mechanisms and clinical treatment of SSNHL.

Early detection of juvenile clinical deterioration in acute care settings remains a significant problem in modern healthcare. This paper presents an AI-powered predictive analytics platform that combines transcriptome biomarker signals with structured vital signs, laboratory data, and unstructured clinical notes to improve early warning capabilities. The system uses ClinicalBERT to extract insights from clinical narratives, XGBoost to analyze tabular clinical information, and long short-term memory (LSTM) networks to simulate temporal dynamics. A meta-classifier combines multimodal data to produce real-time risk ratings for clinical deterioration. The performance evaluation utilizing five-fold cross-validation showed great accuracy, with an AUROC of 0.91, AUPRC of 0.83, and an average early warning lead time of 5.6 hours. Predictive markers included higher lactate levels, heart rate patterns, SpO₂ variability, and transcriptome signals indicating systemic inflammatory activation. Ablation investigations proved the importance of multimodal data fusion in increasing prediction robustness. The suggested strategy provides a scalable, interpretable, and high-performing hospital integration system that enables biomarker-informed, precision-based pediatric intervention options.

Oxidative stress-associated proximal tubular cells (PTCs) damage is an important pathogenesis of hypertensive renal injury. We previously reported the protective effect of VEGFR3 in salt-sensitive hypertension. However, the specific mechanism underlying the role of VEGFR3 in kidney during the overactivation of the renin-angiotensin-aldosterone system remains unclear. In the present study, hypertensive nephropathy was established by angiotensin II (Ang II). We found that VEGFR3 was highly increased in PTCs of Ang II-infused mice. Activation of VEGFR3 mitigated renal dysfunction, pathological damage, and oxidative stress in Ang II-induced hypertensive mice. Moreover, we found that VEGFR3 restored mitophagy deficiency induced by Ang II both in vivo and in vitro to alleviate oxidative stress injury in PTCs. Furthermore, in vitro experiment demonstrated that VEGFR3 improved abnormal mitophagy by enhancing PARKIN mitochondrial translocation. LC-MS/MS and Co-IP assays identified HSPA1L as the interacted protein of VEGFR3, which promoted the mitochondrial translocation of PARKIN. Mechanistically, VEGFR3 disorder domain bound to HSPA1L, and crotonylation modification of HSPA1L at K130 by VEGFR3 was required for mitophagy regulation in the context of Ang II-induced PTCs. Finally, the protective effect of VEGFR3 on mitophagy and oxidative stress were attenuated by transfection K130 (HSPA1L-K130R) mutant plasmid in vivo and in vitro. These findings indicated that VEGFR3 alleviated oxidative stress by promoting PARKIN-dependent mitophagy pathway via regulating HSPA1L crotonylation at K130 site in Ang II-induced PTCs, which provided a mechanistic basis for the therapeutic target in hypertensive renal injury.

ABSTRACT Young and middle‐aged adults with hypertension develop the disease earlier and accrue longer exposure to elevated blood pressure, conferring higher lifetime cardiovascular risk. However, reliable markers predicting long‐term major adverse cardiovascular events (MACEs) in this group remain unclear. Insulin resistance (IR) is crucial to hypertensive pathophysiology, but direct measurement is impractical. We evaluated the prognostic value of three laboratory‐derived IR indices, the triglyceride—glucose (TyG) index, the triglyceride (TG) to high‐density lipoprotein cholesterol (HDL‐C) ratio (TG/HDL‐C), and the metabolic score for IR (METS‐IR), in predicting MACEs. In this retrospective cohort of 4861 patients aged 18–65 years with primary hypertension, baseline indices were calculated and classified into tertiles. Patients were followed for a median of 73 months, during which 372 MACEs occurred. Multivariable Cox regression showed that higher TyG, TG/HDL‐C, and METS‐IR were independently associated with increased MACEs risk. In fully adjusted models, each standard deviation increase in METS‐IR conferred a 55.7% higher risk (HR = 1.557, 95% CI: 1.154–2.101, p < 0.01), and patients in the highest tertile had more than double the risk vs. the lowest. METS‐IR showed superior discrimination (AUC = 0.803, 95% CI: 0.774–0.886) and significant net reclassification improvement (NRI = 0.147, 95% CI: 0.073–0.239, p = 0.001) and integrated discrimination improvement (IDI = 0.006, 95% CI: 0.002–0.010, p = 0.002), whereas TyG showed borderline benefit and TG/HDL‐C offered no incremental value. These findings highlight METS‐IR as a pragmatic predictor of long‐term cardiovascular risk in younger hypertensive patients, supporting its integration into clinical risk stratification.

BACKGROUND AND AIMS:Histologic studies indicated that healed plaque, characterized by a multilayered pattern, is indicative of prior atherothrombosis and subsequent healing. However, longitudinal in vivo data on healed plaque formation in non-culprit plaques are limited. This study aimed to investigate serial changes and clinical significance of new layered pattern formation in non-culprit plaques in patients with acute coronary syndromes (ACS) using serial optical coherence tomography (OCT) imaging. METHODS:ACS patients who underwent two OCTs at baseline and 1-year follow-up were included. Serial changes in morphologic characteristics of non-culprit plaques were evaluated. New layered pattern was defined as a new signal-rich layer on the plaque surface at follow-up that was not present at baseline. RESULTS:Among 553 non-culprit plaques observed in 222 patients, 82 (14.8 %) exhibited a new layered pattern at follow-up. Thin-cap fibroatheroma, macrophage, and thrombus were identified as independent predictors of the new layered pattern. Plaques with new layered pattern formation showed a greater significant reduction in luminal area and lipid content, as well as a greater increase in fibrous cap thickness compared to those without. The incidence of 6-year non-culprit-related major adverse cardiac events was higher in patients with new layered pattern than in those without (25.4 % vs. 10.8 %, p = 0.011), mainly due to clinically driven coronary revascularization. CONCLUSIONS:Plaque destabilization and subsequent healing frequently occur in non-culprit plaques after ACS. The formation of a new layered pattern may contribute to temporary plaque stabilization, but results in luminal stenosis and worse clinical outcomes.

BACKGROUND AND PURPOSE:Postmenopausal women experience accelerated progression of atherosclerosis, yet the underlying mechanisms remain poorly understood and effective therapeutic strategies are limited. This study aimed to investigate the protective effects of quercetin (QCT) against postmenopausal atherosclerosis and to elucidate its mechanism through the KEAP1/NRF2 pathway-mediated inhibition of endothelial cell ferroptosis. EXPERIMENTAL APPROACH:A postmenopausal atherosclerosis model was established using bilateral ovariectomy (OVX) combined with a high-fat diet in ApoE-/- female mice. The therapeutic effects of QCT and a ferroptosis inhibitor Fer-1 were evaluated through histological, biochemical and molecular analyses. For in vitro studies, ox-LDL-induced endothelial cells were conducted to examine the antiferroptosis mechanism of QCT. The role of NRF2 was further validated using AAV-shNRF2 in vivo and ML385 (NRF2 inhibitor) in vitro. KEY RESULTS:Both QCT and Fer-1 significantly attenuated postmenopausal atherosclerosis progression, as evidenced by reduced lipid peroxidation, decreased iron deposition and suppressed endothelial cell ferroptosis in OVX mice. QCT treatment up-regulated GPX4 whilst down-regulating ACSL4 expression and reducing ROS accumulation in ox-LDL-induced endothelial cells. Mechanistically, QCT promoted KEAP1 ubiquitination and subsequent degradation, leading to NRF2 nuclear translocation and activation of downstream antioxidant pathways. The protective effects of QCT were significantly diminished by NRF2 inhibition, both in vitro and in vivo. CONCLUSION AND IMPLICATIONS:This study demonstrates that QCT alleviated postmenopausal atherosclerosis by inhibiting endothelial cell ferroptosis through KEAP1 ubiquitination-mediated activation of the NRF2/GPX4 pathway. These findings provide novel insights into the molecular mechanisms of postmenopausal atherosclerosis and suggest QCT as a potential therapeutic agent for this condition.

BACKGROUND AND AIMS:Clonal haematopoiesis of indeterminate potential (CHIP) can increase the risk of myocardial infarction (MI). Among various CHIP mutations, JAK2 V617F substantially elevated this risk. However, the specific associations between JAK2 V617F and two mechanisms of MI, plaque erosion and plaque rupture, remain unclear. METHODS:Case-control studies investigated these associations. A total of 728 erosion cases, 919 rupture cases, and 804 controls were included from our centre. Digital-drop polymerase chain reaction was performed on these individuals to identify the presence of JAK2 V617F. Previous experimental work has implicated neutrophils in the pathogenesis of erosion in the presence of this mutation. Thus, single-cell RNA sequencing of neutrophils from both JAK2 V617F carriers and healthy donors was performed to seek the potential mechanisms responsible for erosion associated with JAK2 V617F. RESULTS:Among the participants, 26 (3.57%) erosion patients, 7 (.76%) rupture patients, and 3 (.37%) controls were identified as JAK2 V617F carriers with a variant allele frequency (VAF) ≥1%. The carriers among the erosion patients exhibited higher platelet counts and lower glycated haemoglobin and blood lipid levels. Logistic regression analysis, considering erosion or rupture as separate cases, revealed that JAK2 V617F carriers with a VAF ≥1% showed a significant association with erosion [odds ratio (OR) 16.246, 95% confidence interval (CI) 4.624-57.080, P < .0001], but not with rupture (OR 1.677, 95% CI .379-7.415, P = .495). Single-cell RNA-sequencing data indicated that neutrophils from JAK2 V617F carriers displayed augmented expression levels of genes and gene sets associated with activation, adhesion, migration, and granule secretion. CONCLUSIONS:JAK2 V617F linked to a high risk of erosion, an association to which enhanced neutrophil activation may contribute.

Immunotherapy has emerged as a highly promising strategy in the realm of cancer treatment, wherein immunogenic cell death (ICD) is considered a potential trigger for anti-tumor immunity by inducing adaptive immunity to dying cell antigens. This process is often accompanied by the exposure, active secretion, or passive release of a large number of damage-associated molecular patterns (DAMPs), which activate dendritic cells (DCs) and enhance their antigen-presenting capacity. Subsequently, it promotes the recruitment and activation of cytotoxic T lymphocytes, ultimately leading to tumor growth inhibition. In addition, polarizing the M2 phenotype of tumor-associated macrophages (TAMs) to the M1 phenotype is another way to activate anti-tumor immunity, which can further enhance the effect of anti-tumor immunotherapy. In this study, we engineered a composite nanoparticle of UiO-66-NH2@Gold nanoshells@GOx-P-Arg (denoted as UGsGP). The gold nano shells in UGsGP exhibit a broad Near-Infrared-II (NIR-II) absorption to give a high photothermal conversion efficiency and achieve photothermal therapy (PTT). The GOx in UGsGP involves the breakdown of glucose, which results in a decrease in ATP levels and an inhibition of HSP90 and HSP70 production, ultimately enhancing the heat sensitivity of the tumor for PTT. In addition, GOx-mediated starvation therapy by glucose exhaustion produces a substantial amount of hydrogen peroxide (H2O2), which can then react with P-Arg to produce intratumoral NO. Thus, the synergistic effect of PTT resensitization, the photothermally-enhanced GOx-mediated starvation, and NO-based gas therapy promote the induction of ICD and the polarization of TAMs. The combination therapy exhibits significant antitumor effects both in vitro and in vivo. Statement of Significance (1) Gold nanoshells on the surface of UiO-66-NH2 display a broad absorption spectrum ranging from 900 to 1700 nm, combined with a high photothermal conversion efficiency of 74.0%, demonstrating their remarkable ability to harness and convert light energy into heat for effective tumor ablation.(2) Under laser irradiation, GOx within the UGsGPs effectively consumes glucose, increasing intratumoral H2O2 levels, which then reacts with P-Arg to produce NO within the tumor. Concurrently, the reduction in ATP levels suppresses HSP90 and HSP70 production, thereby enhancing the tumor's sensitivity to photothermal therapy.(3) The synergistic combination of NO gas therapy, starvation therapy, and PTT promotes ICD induction and TAM polarization, thereby improving the therapeutic outcomes for primary and distant tumors.

Exercise can stimulate physiological cardiac growth and provide cardioprotection effect in ischemia/reperfusion (I/R) injury. MiR-210 is regulated in the adaptation process induced by exercise; however, its impact on exercise-induced physiological cardiac growth and its contribution to exercise-driven cardioprotection remain unclear. We investigated the role and mechanism of miR-210 in exercise-induced physiological cardiac growth and explored whether miR-210 contributes to exercise-induced protection in alleviating I/R injury. Here, we first observed that regular swimming exercise can markedly increase miR-210 levels in the heart and blood samples of rats and mice. Circulating miR-210 levels were also elevated after a programmed cardiac rehabilitation in patients that were diagnosed of coronary heart diseases. In 8-week swimming model in wild-type (WT) and miR-210 knockout (KO) rats, we demonstrated that miR-210 was not integral for exercise-induced cardiac hypertrophy but it did influence cardiomyocyte proliferative activity. In neonatal rat cardiomyocytes, miR-210 promoted cell proliferation and suppressed apoptosis while not altering cell size. Additionally, miR-210 promoted cardiomyocyte proliferation and survival in human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and AC16 cell line, indicating its functional roles in human cardiomyocytes. We further identified miR-210 target genes, cyclin-dependent kinase 10 (CDK10) and ephrin-A3 (EFNA3), that regulate cardiomyocyte proliferation and apoptosis. Finally, miR-210 KO and WT rats were subjected to swimming exercise followed by I/R injury. We demonstrated that miR-210 crucially contributed to exercise-driven cardioprotection against I/R injury. In summary, this study elucidates the role of miR-210, an exercise-responsive miRNA, in promoting the proliferative activity of cardiomyocytes during physiological cardiac growth. Furthermore, miR-210 plays an essential role in mediating the protective effects of exercise against cardiac I/R injury. Our findings suggest exercise as a potent nonpharmaceutical intervention for inducing miR-210, which can alleviate I/R injury and promote cardioprotection.

BACKGROUND:Exercise-induced physiological cardiac growth regulators may protect the heart from ischemia/reperfusion (I/R) injury. Homeobox-containing 1 (Hmbox1), a homeobox family member, has been identified as a putative transcriptional repressor and is downregulated in the exercised heart. However, its roles in exercise-induced physiological cardiac growth and its potential protective effects against cardiac I/R injury remain largely unexplored. METHODS:We studied the function of Hmbox1 in exercise-induced physiological cardiac growth in mice after 4 weeks of swimming exercise. Hmbox1 expression was then evaluated in human heart samples from deceased patients with myocardial infarction and in the animal cardiac I/R injury model. Its role in cardiac I/R injury was examined in mice with adeno-associated virus 9 (AAV9) vector-mediated Hmbox1 knockdown and in those with cardiac myocyte-specific Hmbox1 ablation. We performed RNA sequencing, promoter prediction, and binding assays and identified glucokinase (Gck) as a downstream effector of Hmbox1. The effects of Hmbox1 together with Gck were examined in cardiomyocytes to evaluate their cell size, proliferation, apoptosis, mitochondrial respiration, and glycolysis. The function of upstream regulator of Hmbox1, ETS1, was investigated through ETS1 overexpression in cardiac I/R mice in vivo. RESULTS:We demonstrated that Hmbox1 downregulation was required for exercise-induced physiological cardiac growth. Inhibition of Hmbox1 increased cardiomyocyte size in isolated neonatal rat cardiomyocytes and human embryonic stem cell-derived cardiomyocytes but did not affect cardiomyocyte proliferation. Under pathological conditions, Hmbox1 was upregulated in both human and animal postinfarct cardiac tissues. Furthermore, both cardiac myocyte-specific Hmbox1 knockout and AAV9-mediated Hmbox1 knockdown protected against cardiac I/R injury and heart failure. Therapeutic effects were observed when sh-Hmbox1 AAV9 was administered after I/R injury. Inhibition of Hmbox1 activated the Akt/mTOR/P70S6K pathway and transcriptionally upregulated Gck, leading to reduced apoptosis and improved mitochondrial respiration and glycolysis in cardiomyocytes. ETS1 functioned as an upstream negative regulator of Hmbox1 transcription, and its overexpression was protective against cardiac I/R injury. CONCLUSIONS:Our studies unravel a new role for the transcriptional repressor Hmbox1 in exercise-induced physiological cardiac growth. They also highlight the therapeutic potential of targeting Hmbox1 to improve myocardial survival and glucose metabolism after I/R injury.

Pulmonary arterial hypertension (PAH) is associated with aberrant pulmonary vascular smooth muscle cell (PASMC) function and vascular remodeling. MiR-30d plays an important role in the pathogenesis of several cardiovascular disorders. However, the function of miR-30d in PAH progression remained unknown. Our study shows that circulating miR-30d level is significantly reduced in the plasma from PAH patients. In miR-30d transgenic (TG) rats, overexpressing miR-30d attenuates monocrotaline (MCT)-induced pulmonary hypertension (PH) and pulmonary vascular remodeling. Increasing miR-30d also inhibits platelet-derived growth factor-bb (PDGF-bb)-induced proliferation and migration of human PASMC. Metadherin (MTDH) and phosphodiesterase 5A (PDE5A) are identified as direct target genes of miR-30d. Meanwhile, nuclear respiratory factor 1 (NRF1) acts as a positive upstream regulator of miR-30d. Using miR-30d knockout (KO) rats treated with sildenafil, a PDE5A inhibitor that is used in clinical PAH therapies, it is further found that suppressing miR-30d partially attenuates the beneficial effect of sildenafil against MCT-induced PH and vascular remodeling. The present study shows a protective effect of miR-30d against PAH and pulmonary vascular remodeling through targeting MTDH and PDE5A and reveals that miR-30d modulates the beneficial effect of sildenafil in treating PAH. MiR-30d should be a prospective target to treat PAH and pulmonary vascular remodeling.

Background:Endothelial dysfunction, characterized by impaired flow-mediated vasodilation (FMD), is associated with atherosclerosis. However, the relationship between FMD, plaque morphology, and clinical outcomes in patients with acute coronary syndrome (ACS) remains underexplored. This study aims to investigate the influence of FMD on the morphology of culprit plaques and subsequent clinical outcomes in patients with ACS. Methods:This study enrolled 426 of 2482 patients who presented with ACS and subsequently underwent both preintervention FMD and optical coherence tomography (OCT) between May 2020 and July 2022. Impaired FMD was defined as an FMD% less than 7.0%. Major adverse cardiac events (MACEs) included cardiac death, nonfatal myocardial infarction, revascularization, or rehospitalization for angina. Results:Within a one-year follow-up, 34 (8.0%) patients experienced MACEs. The median FMD% was 4.0 (interquartile range 2.6-7.0). Among the patients, 225 (52.8%) were diagnosed with plaque rupture (PR), 161 (37.8%) with plaque erosion (PE), and 25 (5.9%) with calcified nodules (CN). Impaired FMD was found to be associated with plaque rupture (odds ratio [OR] = 4.22, 95% confidence interval [CI]: 2.07-6.72, p = 0.012) after adjusting for potential confounding factors. Furthermore, impaired FMD was linked to an increased incidence of MACEs (hazard ratio [HR] = 3.12, 95% CI: 1.27-6.58, p = 0.039). Conclusions:Impaired FMD was observed in three quarters of ACS patients and can serve as a noninvasive predictor of plaque rupture and risk for future adverse cardiac outcomes.

Myocardial infarction (MI) is one of the leading causes of death worldwide. Danlou tablet (Dan) is an effective traditional Chinese medicine for cardiac protection, although the underlying mechanism was not fully understood. In this study, we used a murine MI model and demonstrated that Dan administration effectively attenuated myocardial apoptosis, cardiac remodeling, and heart failure post MI. Dan increased CD31-positive capillaries in MI hearts, and reduced the apoptosis and oxidative stress in human umbilical vein endothelial cells after oxygen–glucose deprivation stress, simultaneously with the activated HIF-1α/VEGFA/eNOS signaling. Moreover, inhibition of eNOS by L-NAME attenuated Dan-induced protection against MI, and abolished its effect in promoting angiogenesis and reducing endothelial apoptosis and oxidative stress. Collectively, Dan is beneficial to promote eNOS-dependent endothelial protection and angiogenesis thus protecting against MI. A deep understanding of Dan-induced protection might help promote clinical usage of Dan in MI treatment.

Immunoglobulin A nephropathy (IgAN), the most common primary renal disease, is characterized by abnormal IgA1 deposition. IgAN is caused by NOD-like receptor pyrin domain-containing-3 (NLRP3), which regulates innate immunity. Gubentongluo (GB) decoction, a traditional Chinese medicine, is an effective clinical treatment for IgAN in China. However, little is known about the underlying mechanisms. In this study, IgA1, which is separated from patients with IgAN, together with GB decoction was applied to treat human mesangial cells (HMCs). CCK-8 and the enzyme-linked immunosorbent assay were used to assess cell proliferation and the production of interleukin-1β (IL-1β), respectively. qPCR and Western blot were applied to detect the expression levels of NLRP3, IL-1β, and caspase-1. Our results showed that GB decoction inhibited IgA1-induced cell proliferation and IL-1β production. Furthermore, IgA1-induced upregulation of IL-1β, NLRP3, and caspase-1 was reduced after treatment with GB. Interestingly, MCC950, an NLRP3 inhibitor, showed similar effect as GB decoction. Additionally, NLRP3 overexpression stimulated cell proliferation, IL-1β secretion, and the expressions of IL-1β and caspase-1 in HMCs. But these effects could be alleviated by GB decoction. In conclusion, GB may play a protective role in IgAN cell model by inhibiting NLRP3.

Myocardial ischemia/reperfusion injury (I/RI) may potentiate cardiac remodeling and heart failure, while effective therapies for I/RI remain lacking. Circulating human plasma-derived extracellular vesicles (hEV) have great potential to protect against I/RI. However, the effective delivery of hEV in vivo remains a limiting factor for clinical application. The present study constructs a biomimetic delivery system of platelet membrane-fused hEV (P-hEV), utilizing the natural affinity of platelets for hEV delivery to the injured vascular and myocardial sites. The results show that platelet membrane and hEV membrane fusion can be achieved through repeated extrusion. Compared to non-modified hEV, P-hEV uptake is greatly enhanced in human umbilical vein endothelial cells (HUVECs) stressed by oxygen-glucose deprivation/reperfusion (OGD/R). Functionally, P-hEV inhibits HUVEC and neonatal rat cardiomyocyte (NRCM) apoptosis and promotes HUVECs migration and tube formation under OGD/R stress in vitro. Intravenous delivery of P-hEV more effectively targets and accumulates at injury sites in the heart. Furthermore, P-hEV significantly enhances protection against acute I/RI and attenuates cardiac remodeling at three weeks post-I/RI. In conclusion, the platelet membrane-fused hEV delivery system enhances the target delivery of EV to protect against myocardial I/RI, presenting a novel drug delivery system for ischemic heart diseases.

Inhibition of pathological cardiac hypertrophy is recognized as an important therapeutic strategy for heart failure, although effective targets are still lacking in clinical practice. Homeodomain interacting protein kinase 1 (HIPK1) is a conserved serine/threonine kinase that can respond to different stress signals, however, whether and how HIPK1 regulates myocardial function is not reported. Here, it is observed that HIPK1 is increased during pathological cardiac hypertrophy. Both genetic ablation and gene therapy targeting HIPK1 are protective against pathological hypertrophy and heart failure in vivo. Hypertrophic stress-induced HIPK1 is present in the nucleus of cardiomyocytes, while HIPK1 inhibition prevents phenylephrine-induced cardiomyocyte hypertrophy through inhibiting cAMP-response element binding protein (CREB) phosphorylation at Ser271 and inactivating CCAAT/enhancer-binding protein β (C/EBPβ)-mediated transcription of pathological response genes. Inhibition of HIPK1 and CREB forms a synergistic pathway in preventing pathological cardiac hypertrophy. In conclusion, HIPK1 inhibition may serve as a promising novel therapeutic strategy to attenuate pathological cardiac hypertrophy and heart failure.

BACKGROUND Myocardial infarction with nonobstructive coronary artery (MINOCA) is a heterogeneous syndrome caused by different pathophysiologic mechanisms. There is limited evidence regarding prognosis of patients with MINOCA caused by different mechanisms.OBJECTIVES The present study aimed to assess the underlying mechanisms of MINOCA by optical coherence to-mography (OCT) and to correlate with clinical outcomes.METHODS Patients with MINOCA were divided into 2 groups based on OCT findings: atherosclerotic MINOCA (Ath-MINOCA) and nonatherosclerotic MINOCA (non-Ath-MINOCA). Major adverse cardiac events (MACE) were defined as cardiac death, nonfatal MI, target lesion revascularization, stroke, and rehospitalization for unstable or progressive angina.RESULTS Among 7,423 patients with a clinical diagnosis of MI who underwent angiography, 190 of 294 MINOCA were studied using OCT. The causes of Ath-MINOCA (n = 99, 52.1%) were plaque erosion (n = 64, 33.7%), plaque rupture (n = 33,17.4%), and calcified nodule (n = 2, 1.1%) whereas the causes of non-Ath-MINOCA (n = 91, 47.9%) were spon-taneous coronary artery dissection (n = 8, 4.2%), coronary spasm (n = 9, 4.7%), and unclassified cause (n = 74, 38.9%). The 1-year MACE was 15.3% for Ath-MINOCA vs 4.5% for non-Ath-MINOCA (P = 0.015). An atherosclerotic cause was an independent predictor of MACE (HR: 5.36 [95% CI: 1.08-26.55]; P = 0.040), mainly driven by target lesion revasculari-zation and rehospitalization, despite the composite endpoint including cardiac death and MI showing no difference.CONCLUSIONS OCT identified a cause in 61.1% of MINOCA, in which Ath-MINOCA represents an important and distinct MINOCA subset. Ath-MINOCA were more common and associated with worse outcomes. (Incidence Rate of Heart Failure After Acute Myocardial Infarction With Optimal Treatment; NCT03297164; Paradigm Shift in the Treatment of Patients With ACS; NCT02041650) (J Am Coll Cardiol Img 2023;16:521-532 ) (c) 2023 by the American College of Cardiology Foundation.

Myocardial ischemia/reperfusion injury (I/RI) and ventricular remodeling are the critical pathological basis of heart failure. Danlou tablet (Dan) is a kind of Chinese patent medicine used in angina pectoris treatment in China. However, it remains unclear whether and how Dan could protect against cardiac remodeling after myocardial I/RI. In this study, both preventive and therapeutic administration of Dan attenuated ventricular remodeling and cardiac dysfunction at 3 weeks after myocardial I/RI. Dan inhibited Bax/Bcl2 ratio and Caspase3 cleavage in heart tissues and also inhibited apoptosis of human AC16 cells and neonatal rat cardiomyocytes stressed by oxygen and glucose deprivation/reperfusion. Mechanistically, Dan inhibited myocardial apoptosis through phosphorylating AKT and FoxO3a, thereby inhibiting downstream BIM and PUMA expressions. Collectively, these results demonstrate that Dan treatment is effective to protect against cardiac remodeling and dysfunction after myocardial I/RI and provide theoretical basis for its cardioprotection and clinical application in treating ischemic cardiac diseases.