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Catheter ablation (CA) is an essential method for the interventional treatment of atrial fibrillation (AF), and it is very important to reduce long-term recurrence after CA. The mechanism of recurrence after CA is still unclear. We established a long-term model of beagle canines after circumferential pulmonary vein ablation (CPVA). The transcriptome and proteome were obtained using high-throughput sequencing and TMT-tagged LC-MS/LC analysis, respectively. Differentially expressed genes and proteins were screened and enriched, and the effect of fibrosis was found and verified in tissues. A downregulated protein, neuropeptide Y (NPY), was selected for validation and the results suggest that NPY may play a role in the long-term reinduction of AF after CPVA. Then, the molecular mechanism of NPY was further investigated. The results showed that the atrial effective refractory period (AERP) was shortened and fibrosis was increased after CPVA. Atrial myocyte apoptosis was alleviated by NPY intervention, and Akt activation was inhibited in cardiac fibroblasts. These results suggest that long-term suppression of NPY after CPVA may lead to induction of AF through promoting cardiomyocyte apoptosis and activating the Akt pathway in cardiac fibroblasts, which may make AF more likely to reinduce.
Subject(s)
Apoptosis , Atrial Fibrillation , Catheter Ablation , Myocardium , Neuropeptide Y , Pulmonary Veins , Animals , Dogs , Apoptosis/drug effects , Atrial Fibrillation/metabolism , Atrial Fibrillation/surgery , Atrial Fibrillation/pathology , Catheter Ablation/methods , Disease Models, Animal , Fibrosis , Heart Atria/metabolism , Heart Atria/pathology , Multiomics , Myocardium/metabolism , Myocardium/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Neuropeptide Y/metabolism , Proteome/metabolism , Proteomics/methods , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary Veins/metabolism , Pulmonary Veins/surgery , TranscriptomeABSTRACT
OBJECTIVE: The purpose of this study was to assess the utility of information generated by ChatGPT for residency education in China. METHODS: We designed a three-step survey to evaluate the performance of ChatGPT in China's residency training education including residency final examination questions, patient cases, and resident satisfaction scores. First, 204 questions from the residency final exam were input into ChatGPT's interface to obtain the percentage of correct answers. Next, ChatGPT was asked to generate 20 clinical cases, which were subsequently evaluated by three instructors using a pre-designed Likert scale with 5 points. The quality of the cases was assessed based on criteria including clarity, relevance, logicality, credibility, and comprehensiveness. Finally, interaction sessions between 31 third-year residents and ChatGPT were conducted. Residents' perceptions of ChatGPT's feedback were assessed using a Likert scale, focusing on aspects such as ease of use, accuracy and completeness of responses, and its effectiveness in enhancing understanding of medical knowledge. RESULTS: Our results showed ChatGPT-3.5 correctly answered 45.1% of exam questions. In the virtual patient cases, ChatGPT received mean ratings of 4.57 ± 0.50, 4.68 ± 0.47, 4.77 ± 0.46, 4.60 ± 0.53, and 3.95 ± 0.59 points for clarity, relevance, logicality, credibility, and comprehensiveness from clinical instructors, respectively. Among training residents, ChatGPT scored 4.48 ± 0.70, 4.00 ± 0.82 and 4.61 ± 0.50 points for ease of use, accuracy and completeness, and usefulness, respectively. CONCLUSION: Our findings demonstrate ChatGPT's immense potential for personalized Chinese medical education.
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BACKGROUND: Surprisingly, despite the high prevalence of metformin use in type 2 diabetes (T2D) patients with heart disease, limited safety data is available regarding metformin use in patients with acute and critical heart disease. METHODS: In this single-center retrospective study, patients admitted to the cardiology department for heart failure (HF) or acute coronary syndrome (ACS) between December 2013 and December 2021 and who underwent arterial blood gas analysis at admission with an estimated glomerular clearance rate of ≥45 ml/min/1.73 m2 were identified. The incidences of hyperlactatemia, acidosis, and 30-day in-hospital mortality were compared between preadmission metformin users and nonusers. RESULTS: Of 526 admissions, 193/193 metformin users/nonusers were selected in a propensity score-matched model. Metformin users had greater lactate levels (2.55 ± 2.07 mmol/l vs. 2.00 ± 1.80 mmol/l P < 0.01), a greater incidence of hyperlactatemia [odds ratio (OR) = 2.55; 95% confidence interval (CI), 1.63-3.98; P < 0.01] and acidosis (OR = 1.78; 95% CI, 1.00-3.16; P < 0.05) at admission and a greater incidence of in-hospital mortality (OR = 3.83; 95% CI, 1.05-13.94; P < 0.05), especially those with HF/acute myocardial infarction, elderly age, or without preadmission insulin use. CONCLUSIONS: Our results suggest that, compared to metformin nonusers, preadmission use of metformin may be associated with a greater incidence of hyperlactatemia and acidosis at admission and greater 30-day in-hospital mortality among T2D patients with HF or ACS at high risk of hypoxia, particularly those without preadmission insulin use. The safety of metformin in this population needs to be confirmed in prospective controlled trials.
Subject(s)
Diabetes Mellitus, Type 2 , Hospital Mortality , Hyperlactatemia , Hypoglycemic Agents , Metformin , Humans , Metformin/therapeutic use , Metformin/adverse effects , Male , Female , Hospital Mortality/trends , Retrospective Studies , Aged , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/mortality , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/epidemiology , Hyperlactatemia/epidemiology , Hyperlactatemia/blood , Hyperlactatemia/chemically induced , Incidence , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/adverse effects , Middle Aged , Hypoxia/epidemiology , Hypoxia/mortality , Hypoxia/blood , Patient Admission/trends , Heart Diseases/epidemiology , Heart Diseases/mortality , Heart Diseases/blood , Aged, 80 and over , Risk FactorsABSTRACT
Landscapes evolution have significantly altered the Earth's energy balance and biogeochemical cycles, thereby exacerbating climate change. This, in turn, affects surface characteristics and the provision of ecosystem services, especially carbon storage. While recent centuries have witnessed unprecedented landscape changes, limited long-term studies have offered insights into the comparison between present-day features and historical conditions. This study utilized historical reconstruction data and remote sensing imagery to assess landscape evolution and its consequences for carbon stocks over 300 years. Employing multiple regression and random forest models were selected to quantify the influence of key landscape metrics on carbon stocks in the Dongting Lake basin, allowing for a thorough analysis across different sub-basins and land types. The results revealed that intensified human disturbances led to increased landscape fragmentation (+82%), regularity (+56%), and diversity (+37%) within the basin. Moreover, carbon stocks decreased from 4.13 Gt to 3.66 Gt, representing an 11.4% loss, with soil carbon stock experiencing the most considerable reduction (0.24 Gt, 51%). These changes in carbon stock metrics corresponded to shifts in landscape patterns, both undergoing significant transitions at the turn of the 21st century. Meanwhile, fragmentation and regularity played a vital role in explaining carbon stock changes, as their increase contributes to greater carbon losses. Likewise, an increase in landscape diversity correlated with decreased carbon stocks, challenging the prevailing notion that enhanced diversity promotes carbon stocks. The influence of landscape patterns on carbon stocks varies notably across distinct land types. An increase in the dominance of farmland and built-up land led to decreased carbon stocks, while the opposite holds true for forestland. Similarly, a decrease in regularity for farmland, forestland, and built-up land benefits carbon storage, while grassland demonstrates the opposite trend. These findings offer insights for countries and regions in the early stages of development or approaching development, suggesting improvements in land use practices and strategies to address climate change. This involves offsetting land-based carbon emissions through changes in landscape spatial configuration.
Subject(s)
Carbon , Climate Change , Ecosystem , Carbon/analysis , Soil/chemistry , Conservation of Natural Resources , Lakes/chemistry , Carbon SequestrationABSTRACT
Background: Strain analysis of cardiac magnetic resonance imaging (CMR) is important for the prognosis of heart failure (HF). Herein, we aimed to identify the characteristics and prognostic value of strain analysis revealed by CMR in different HF phenotypes. Methods: Participants with HF, including HF with reduced ejection fraction, HF with mildly reduced ejection fraction, and HF with preserved ejection fraction, and controls were enrolled. The baseline information and clinical parameters of participants were collected, and echocardiography and CMR examination were performed. Three-dimensional strain analysis was performed in the left ventricle, right ventricle, left atrium, and right atrium using CMR. A multifactor Cox risk proportional model was established to assess the influencing factors of cardiovascular adverse events in patients with HF. Results: During a median follow-up of 999 days (range: 616-1334), 20.6% of participants (73/354) experienced adverse events (HF readmission and/or cardiovascular death). Univariable Cox regression revealed that a 1% increase in left atrial global longitudinal strain (LAGLS) was associated with a hazard ratio (HR) of 1.21 [95% confidence interval (CI):1.15-1.28; P < 0.001]. Left ventricular global circumferential strain (LVGCS) (HR, 1.18; 95% CI: 1.12-1.24; P < 0.001), and left ventricular global longitudinal strain (LVGLS) (HR, 1.27; 95% CI: 1.20-1.36; P < 0.001) were also associated with HF hospitalizations and cardiovascular deaths. Among clinical variables, hypertension (HR, 2.11; 95% CI: 1.33-13.36; P = 0.002), cardiomyopathy (HR, 2.26; 95% CI: 1.42-3.60; P < 0.001) were associated with outcomes in univariable analysis. Multivariable analyses revealed that LAGLS (95% CI: 1.08-1.29; P < 0.001), LVGLS (95% CI:1.08-1.29; P < 0.001) and LVGCS (95% CI: 1.19-1.51; P < 0.001) were significantly associated with outcomes. Among clinical variables, hypertension (95% CI: 1.09-3.73; P < 0.025) remained a risk factor. Conclusion: CMR plays an obvious role in phenotyping HF. Strain analysis, particularly left atrial and left ventricular strain analysis (LAGLS, LVGLS, and LVGCS) has good value in predicting adverse outcome events.
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BACKGROUND: Cardiac intrinsic autonomic nerve remodelling has been reported to play an important role in the recurrence of atrial fibrillation after radiofrequency ablation, which significantly affects the long-term efficacy of this procedure. lncRNAs have been shown to interact in the pathological processes underlying heart diseases. However, the roles and mechanisms of lncRNAs in cardiac intrinsic autonomic nerve remodelling during atrial fibrillation reduction after ganglionated plexus ablation remain unknown. OBJECTIVES: The aim of this study was to investigate the mechanism by which lncRNA- 056298 modulates GAP43 to affect cardiac intrinsic autonomic nerve remodelling and facilitate the induction of atrial fibrillation after ganglionated plexus ablation. METHODS: A canine model of right atrial ganglionated plexus ablation was established. The atrial electrophysiological characteristics and neural markers were detected before and after 6 months of ganglionated plexus ablation. High-throughput sequencing was used to screen differentially expressed lncRNAs in target atrial tissues, and lncRNA- 056298 was selected to further explore its effects and mechanisms on cardiac intrinsic autonomic nerve remodelling. RESULTS: The induction rate of atrial fibrillation increased in dogs after ganglionated plexus ablation. Overexpression of lncRNA-056298 by lentivirus can shorten the atrial effective refractory period and increase the induction of atrial fibrillation. lncRNA- 056298 promoted cardiac intrinsic autonomic nerve remodelling via endogenous competition with cfa-miR-185 to induce transcription of its target gene GAP43, thereby affecting the induction of atrial fibrillation. CONCLUSIONS: lncRNA-056298 regulates GAP43 by sponging miR-185, which affects cardiac intrinsic autonomic nerve remodelling and mediates atrial fibrillation induction after ganglionated plexus ablation.
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Essential hypertension is a notable threat for the older (age, ≥65 years) population. However, to the best of our knowledge, a real-world study assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablets in older Chinese patients with essential hypertension has not been performed. Therefore, the present study aimed to evaluate the efficacy and safety of OM-AML tablets in these patients. A total of 463 older Chinese patients with essential hypertension treated with OM-AML (20/5 mg) tablets (Sevikar®) were analyzed in a prospective, single-arm, multi-center, real-world study. Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, and at week (W)4 and W8 after OM-AML tablet administration were measured. The mean ± standard error change of SeSBP/SeDBP was -10.3±0.8/-4.6±0.5 and -12.5±0.8/-5.6±0.5 mmHg at W4 and W8, respectively. At W4, 74.1 and 26.8% of patients achieved BP target according to the China and American Heart Association (AHA) criteria, while at W8, 78.0 and 38.7% of patients reached these BP targets accordingly. Finally, 76.5 and 80.5% of patients achieved BP response at W4 and W8, respectively. Furthermore, home-measured SeSBP and SeDBP were significantly decreased from W1 to W8 (both P<0.001). Additionally, the satisfaction of both patients and physicians was elevated at W8 compared with at W0 (both P<0.001). The medication possession rate from baseline to W4 and W8 was 95.5 and 92.5%. The most common drug-associated adverse events by system organ classes were nervous system disorder (4.5%), vascular disorder (2.8%), and general disorder and administration site conditions (2.6%), which were generally mild. In conclusion, OM-AML tablets may be considered effective and safe in lowering BP, enabling the achievement of guideline-recommended BP targets in older Chinese patients with essential hypertension.
ABSTRACT
There lacks real-world study with a large sample size assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM-AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM-AML (20/5 mg) tablet were analyzed in the current prospective, single-arm, multi-center, real-world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was -10.8 ± 0.4/-6.6 ± 0.3 mmHg at W4 and -12.7 ± 0.5/-7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home-measured SeSBP and SeDBP decreased from W1 to W8 (both p < .001). Besides, patients' and physicians' satisfaction were elevated at W8 compared with W0 (both p < .001). The medication possession rate was 94.8% from baseline to W4 and 91.3% from baseline to W8. The most common drug-related adverse events were nervous system disorders (4.6%), vascular disorders (2.6%), and general disorders and administration site conditions (2.3%) by system organ class, which were generally mild and manageable. In conclusion, OM-AML tablet is one of the best antihypertensive agents in patients with essential hypertension.
Subject(s)
Amlodipine Besylate, Olmesartan Medoxomil Drug Combination , Hypertension , Leukemia, Myeloid, Acute , Sulfonamides , Humans , Hypertension/drug therapy , Hypertension/epidemiology , Hypertension/chemically induced , Olmesartan Medoxomil/pharmacology , Amlodipine/adverse effects , Hydrochlorothiazide/therapeutic use , Tetrazoles/pharmacology , Imidazoles/adverse effects , Drug Therapy, Combination , Double-Blind Method , Antihypertensive Agents/adverse effects , Blood Pressure/physiology , Essential Hypertension/drug therapy , Leukemia, Myeloid, Acute/chemically induced , Leukemia, Myeloid, Acute/drug therapyABSTRACT
Background: Non-melanoma skin cancer (NMSC) is a prevalent skin malignancy. It has been indicated in many studies that trihalomethanes (THMs) exposure has a strong association with tumors but has not been associated with NMSC. Our investigation aims to explore the association between THMs exposure and NMSC. Methods: Cross-sectional data from the 2011 to 2020 National Health and Nutrition Examination Survey (NHANES) was collected. Poisson regression and subgroup analyses were performed to evaluate the association between individual THMs components and NMSC. Fitted smoothing curves and generalized additive models were also used. Results: This study involved 5,715 individuals, 98 (1.7%) of whom self-reported NMSC. After adjusting for covariates, Poisson regression showed that higher blood TBM levels were associated with an increased likelihood of NMSC (OR = 1.03; 95% CI: 1.01-1.05, p = 0.002). However, the correlation between the blood levels of TCM, DBCM, and BDCM and the likelihood of NMSC was not statistically significant (all p > 0.05). Subgroup analysis and interaction tests showed no significant differences between blood TBM concentration and the likelihood of NMSC, indicating that age, gender, and race were significantly independent of this positive association (all p < 0.05). Conclusions: Our results implied that among adults older than 65 years old in the U.S., elevated blood TBM concentrations were positively associated with NMSC. More prospective investigations are required to validate this relationship with the early prevention of NMSC.
Subject(s)
Skin Neoplasms , Trihalomethanes , Adult , Humans , Aged , Nutrition Surveys , Cross-Sectional Studies , Prospective Studies , Skin Neoplasms/epidemiologyABSTRACT
BACKGROUND: Autonomic remodeling of the atria plays a pivotal role in the development of atrial fibrillation (AF) and exerts a substantial influence on the progression of this condition. Hyperlipidemia is a predisposing factor for AF, but its effect on atrial nerve remodeling is unclear. The primary goal of this study was to explore the possible mechanisms through which the consumption of a high-fat diet (HFD) induces remodeling of atrial nerves, and to identify novel targets for clinical intervention. METHODS: Cell models were created in vitro by subjecting cells to palmitic acid (PA), while rat models were established by feeding them a high-fat diet. To investigate the interplay between cardiomyocytes and nerve cells in a co-culture system, we utilized Transwell cell culture plates featuring a pore size of 0.4 µm. The CCK-8 assay was employed to determine cell viability, fluorescent probe DCFH-DA and flow cytometry were utilized for measuring ROS levels, JC-1 was used to assess the mitochondrial membrane potential, the Griess method was employed to measure the nitric oxide (NO) level in the supernatant, a fluorescence-based method was used to measure ATP levels, and MitoTracker was utilized for assessing mitochondrial morphology. The expression of pertinent proteins was evaluated using western blotting (WB) and immunohistochemistry techniques. SNAP was used to treat nerve cells in order to replicate a high-NO atmosphere, and the level of nitroso was assessed using the iodoTMT reagent labeling method. RESULTS: The study found that cardiomyocytes' mitochondrial morphology and function were impaired under high-fat stimulation, affecting nitric oxide (NO) production through the CRIF1/SIRT1/eNOS axis. In a coculture model, overexpression of eNOS in cardiomyocytes increased NO expression. Moreover, the increased Keap1 nitrosylation within neuronal cells facilitated the entry of Nrf2 into the nucleus, resulting in an augmentation of P21 transcription and a suppression of proliferation. Atrial neural remodeling occurred in the HFD rat model and was ameliorated by increasing myocardial tissue eNOS protein expression with trimetazidine (TMZ). CONCLUSIONS: Neural remodeling is triggered by high-fat stimulation, which decreases the production of NO through the CRIF1/eNOS/P21 axis. Additionally, TMZ prevents neural remodeling and reduces the occurrence of AF by enhancing eNOS expression.
Subject(s)
Atrial Fibrillation , Rats , Animals , Nitric Oxide , Kelch-Like ECH-Associated Protein 1/metabolism , NF-E2-Related Factor 2/metabolism , Heart Atria/metabolismABSTRACT
The case report shares evidence for a better understanding of atrial standstill. This being a rare arrhythmogenic condition. This is a 46-year-old woman presented with multiple sites of arterial embolism, including lower extremity arteries, coronary artery, and cerebral artery. Unexpectedly, multiple arterial embolization in the patient was due to atrial standstill by transthoracic echocardiography and cardiac electrophysiological study. An additional family investigation revealed that the patient's brother and sister also suffered from this disease. In search of further understanding the case, we carried out the genetic testing of the family and a frame shift double-G insertion mutation at c.1567 in the LMNA gene was found in all the three individuals. The patient recovered well after anticoagulation therapy and left bundle branch area pacing. This report remarks on the importance of multiple sites of arterial embolism which should be wary of family atrial standstill.
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The abandonment of rice terraces in hilly agroecosystems in recent decades has caused substantial changes in microbial characteristics and their impact on microbial necromass carbon (MNC) and soil organic carbon (SOC). Nevertheless, the regulatory mechanisms and impact pathways of MNC remain unclear. Here, soil samples were collected from 0 to 120 cm soil profiles in rice terraces, dry land (DL), and forest land (FL) for analysis. After converting rice terraces to DL and FL, MNC decreased significantly by 31.12% and 38.33%, while SOC decreased significantly by 51.26% and 29.87% respectively. These reductions are due to the loss of terrace management practices and associated functions. There were no significant changes in bacterial necromass carbon (BNC), whereas fungal necromass carbon (FNC) experienced a significant decrease. As a result, the decline in SOC may be primarily attributed to the reduction in FNC. BNC and FNC were regulated by bacterial life history strategies and fungal biomass, respectively. However, bacterial copiotrophs experienced a significant reduction after rice terrace abandonment. The regulation of BNC may be influenced by other factors, potentially offsetting the negative impact of abandonment. Dissolved organic carbon and bulk density were the primary control factors for bacterial community composition and fungal biomass, respectively. Additionally, the impact of soil layers on the alterations in MNC and SOC was more significant compared to the abandonment of rice terraces. These findings indicate that short-term abandonment of rice terraces results in a decrease in SOC, potentially compromising the ecological service function of the hilly agroecosystems. In the face of rapid population growth and global warming, it is crucial to minimize terrace abandonment and enhance utilization rates. This approach will effectively support sustainable terrace management and ecological services.
Subject(s)
Carbon , Oryza , Carbon/analysis , Soil , Biomass , Forests , Bacteria , Soil MicrobiologyABSTRACT
[This corrects the article DOI: 10.3389/fped.2022.1065758.].
ABSTRACT
Background and aims: Studies showed that elevated preoperative serum uric acid(SUA) levels are associated with recurrence of atrial fibrillation(AF) after catheter ablation. UA:creatinine ratio(UCR - UA normalised for renal function) has appeared as a new biomarker and is considered to reflect endogenous UA levels preferably because it eliminates the influence of renal function. This study aimed to investigate the correlation between UCR and recurrence of AF after catheter ablation. Methods and results: A total of 233 consecutive patients with symptomatic, drug-refractory AF underwent catheter ablation. All participants underwent history-taking, physical examination and blood biochemistry analysis at baseline. After a mean follow-up of 23.99 ± 0.76 months, recurrence ratios for each UCR quartile (from lowest quartile to highest) were 10.9%, 23.6%, 23.6%, and 41.8%, respectively (P = 0.005). Multivariate Cox regression analysis revealed that UCR was an independent predictor of AF recurrence (HR 1.217, 95%CI 1.008-1.468; P = 0.041). Subgroup analysis showed that UCR was associated with AF recurrence in paroxysmal AF (HR 1.426, 95% CI 1.092-1.8608; P = 0.009) and in male patients (HR 1.407, 95% CI 1.015-1.950; P = 0.04). A cut-off point of 4.475 for the UCR had sensitivity of 65.5% and specificity of 59.6% in predicting AF recurrence (P = 0.001). Conclusion: Our results demonstrate that elevated preoperative UCR is associated with recurrence of AF after catheter ablation, and it indicate UCR maybe a predictive factor for the recurrence of AF.
Subject(s)
Atrial Fibrillation , Catheter Ablation , Humans , Male , Atrial Fibrillation/surgery , Uric Acid , Creatinine , Treatment Outcome , Risk Factors , Catheter Ablation/adverse effects , Catheter Ablation/methodsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Inflammatory injury is an important pathological factor for the formation of atherosclerotic plaque. It is well known that Puerarin and Tanshinone IIA (Pue-Tan) can significantly reduce interleukin-1ß (IL-1ß) levels and delay the atherosclerosis (AS) process clinically in China. Previous evidence has shown that the Succinate/HIF-1α/IL-1ß inflammatory signaling axis (Succinate axis) promotes the progression of atherosclerotic inflammatory plaques. It is not clear whether Pue-Tan inhibits inflammatory plaques by reducing the level of IL-1ß through the succinate signaling axis. AIM OF STUDY: Find out the interaction between Pue-Tan targets and the succinate axis by means of network pharmacology and bioinformatics analysis and to further confirm whether Pue-Tan can inhibit vascular inflammation and delay the formation of atherosclerotic inflammatory plaques by targeting the succinate signaling axis. MATERIALS AND METHODS: Firstly, animal experiments were conducted to verify the changing relationship between Succinate and IL-1ß under Pue-Tan intervention. Secondly, network pharmacology approach was employed to uncover the specific targets of Pue-Tan in the intervention of AS from multiple levels of components, proteins, and pathways, and at the same time, the target must be a key factor of the succinate signaling axis. Autodock vina1.5.6 was applied to molecular docking for Pue-Tan and target protein. Subsequently, cells experiment and animal experiment were performed to verify Pue-Tan inhibiting the inflammatory progression of atherosclerosis by targeting succinate signaling axis. RESULTS: Firstly, we first found that the reduction of IL-1ß was positively correlated with succinate in the serum of Pue-Tan-treated mice. Secondly, network pharmacology compared with molecular docking showed that hypoxia-induced factor-1α (HIF-1α) was the key target of Pue-Tan and the key node of succinate singling axis. Finally, in vitro study, Pue-Tan significantly reduced the factors of succinate axis just as HIF-1α siRNA; in vivo study, we confirmed a decreased expression of succinate axis and ICAM-1 in the aorta of ApoE-/- mice under Pue-Tan intervention, which was consistent with the in vitro results. CONCLUSION: This study confirmed that Pue-Tan blocked the succinate axis by targeting HIF-1α to prevent the formation of atherosclerotic inflammatory plaques and delay the pathological process of AS. Network Pharmacology, Bioinformatics of Molecular Docking, and Molecular Biology Validation can be used as a effective way to discover and verify the pharmacological mechanism of TCM.
Subject(s)
Atherosclerosis , Plaque, Atherosclerotic , Mice , Animals , Plaque, Atherosclerotic/drug therapy , Succinic Acid/therapeutic use , Interleukin-1beta , Molecular Docking Simulation , Atherosclerosis/metabolism , Hypoxia , SuccinatesABSTRACT
Atrial structural remodeling takes on a critical significance to the occurrence and maintenance of atrial fibrillation (AF). As revealed by recent data, insulin-like growth factor-1 receptor (IGF-1R) plays a certain role in tissue fibrosis. In this study, the mechanism of IGF-1R in atrial structural remodeling was examined based on in vivo and in vitro experiments. First, cluster analysis of AF hub genes was conducted, and then the molecular mechanism was proposed by which IGF-1R regulates myocardial fibrosis via the PI3K/Akt/FoxO3a pathway. Subsequently, the mentioned mechanism was verified in human cardiac fibroblasts (HCFs) and rats transduced with IGF-1 overexpression type 9 adeno-associated viruses. The results indicated that IGF-1R activation up-regulated collagen â protein expression and Akt phosphorylation in HCFs and rat atrium. The administration of LY294002 reversed the above phenomenon, improved the shortening of atrial effective refractory period, and reduced the increased incidence of AF and atrial fibrosis in rats. The transfection of FoxO3a siRNA reduced the anti-fibrotic effect of LY294002 in HCFs. The above data revealed that activation of IGF-1R takes on a vital significance to atrial structural remodeling by facilitating myocardial fibrosis and expediting the occurrence and maintenance of AF through the regulation of the PI3K/Akt/FoxO3a signaling pathway.
Subject(s)
Atrial Fibrillation , Animals , Humans , Rats , Atrial Fibrillation/genetics , Fibrosis , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptor, IGF Type 1/genetics , Receptor, IGF Type 1/metabolism , Receptor, IGF Type 1/pharmacology , Signal TransductionABSTRACT
OBJECTIVE: New drugs to block the occurrence of atrial fibrillation (AF) based on atrial structural remodeling (ASR) are urgently needed. The purpose of this study was to study the role of intermedin 1-53 (IMD1-53) in ASR and AF formation in rats after myocardial infarction (MI). MATERIAL AND METHODS: Heart failure was induced by MI in rats. Fourteen days after MI surgery, rats with heart failure were randomized into control (untreated MI group, n = 10) and IMD-treated (n = 10) groups. The MI group and sham group received saline injections. The rats in the IMD group received IMD1-53, 10 nmol/kg/day intraperitoneally for 4 weeks. The AF inducibility and atrial effective refractory period (AERP) were assessed with an electrophysiology test. Additionally, the left-atrial diameter was determined, and heart function and hemodynamic tests were performed. We detected the area changes of myocardial fibrosis in the left atrium using Masson staining. To detect the protein expression and mRNA expression of transforming growth factor-ß1 (TGF-ß1), α-SMA, collagen â , collagen III, and NADPH oxidase (Nox4) in the myocardial fibroblasts and left atrium, we used the Western blot method and real-time quantitative polymerase chain reaction (PCR) assays. RESULTS: Compared with the MI group, IMD1-53 treatment decreased the left-atrial diameter and improved cardiac function, while it also improved the left-ventricle end-diastolic pressure (LVEDP). IMD1-53 treatment attenuated AERP prolongation and reduced atrial fibrillation inducibility in the IMD group. In vivo, IMD1-53 reduced the left-atrial fibrosis content in the heart after MI surgery and inhibited the mRNA and protein expression of collagen type â and III. IMD1-53 also inhibited the expression of TGF-ß1, α-SMA, and Nox4 both in mRNA and protein. In vivo, we found that IMD1-53 inhibited the phosphorylation of Smad3. In vitro, we found that the downregulated expression of Nox4 was partly dependent on the TGF-ß1/ALK5 pathway. CONCLUSIONS: IMD1-53 decreased the duration and inducibility of AF and atrial fibrosis in the rats after MI operation. The possible mechanisms are related to the inhibition of TGF-ß1/Smad3-related fibrosis and TGF-ß1/Nox4 activity. Therefore, IMD1-53 may be a promising upstream treatment drug to prevent AF.
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Background: Strain analysis of cardiac magnetic resonance (CMR) is critical for the diagnosis and prognosis of heart failure (HF) with preserved ejection fraction (HFpEF). Our study aimed to identify the diagnostic and prognostic value of strain analysis revealed by CMR in HFpEF. Methods: Participants in HFpEF and control were recruited according to the guideline. Baseline information, clinical parameters, blood samples were collected, and echocardiography and CMR examination were performed. Various parameters, including global longitudinal strain, global circumferential strain (GCS) and global radial strain in left ventricle (LV), right ventricle (RV), and left atrium, were measured from CMR. Receiver operator curve (ROC) was established to evaluate the diagnostic and prognostic value of strains in HFpEF. Results: Seven strains, with the exception of RVGCS, were employed to generate ROC curves after t-test. All strains had significant diagnostic value for HFpEF. The area under curve (AUC) of LV strains was greater than 0.7 and the AUC of the combined analysis of LV strains was 0.858 (95% confidence interval (CI): 0.798-0.919, sensitivity: 0.713, specificity: 0.875, P < 0.001), indicating that they had a higher diagnostic value than individual LV strains. However, individual strains had no predictive value in identifying end-point events in HFpEF, the AUC of coanalysis of LV strains was 0.722 (95% CI: 0.573-0.872, sensitivity: 0.500, specificity: 0.959, P = 0.004), indicating its prognostic relevance. Conclusion: Individual strain analysis in CMR may be useful for diagnosing HFpEF, the combination of LV strain analysis had the highest diagnostic value. Moreover, the prognostic value of individual strain analysis in predicting HFpEF outcome was not satisfactory while the combined usage of LV strain analysis was prognostically valuable in HFpEF outcome prediction.
Subject(s)
Heart Failure , Humans , Heart Failure/diagnostic imaging , Stroke Volume , Ventricular Function, Left , Prognosis , Magnetic Resonance SpectroscopyABSTRACT
ABSTRACT: As a first-line therapy, sacubitril/valsartan (S/V) plays a significant role in the treatment of heart failure. However, its effect on renal function is still uncertain. We searched PubMed, EMBASE, the Cochrane Library, and Clinical Trials for randomized controlled trials to evaluate the effect of S/V on renal function in patients. The results are reported as the mean difference, relative ratio, and 95% confidence intervals. A total of 13 randomized controlled trials were included (19,367 patients). Among them, 11 studies focused on patients with heart failure, 1 on patients with acute myocardial infarction, and 1 on patients with chronic kidney disease. We found that fewer worsening renal function events, elevated creatine level events, and severe hyperkalemia events (blood potassium >6.0 mmol/L) occurred in the S/V group than those in the renin-angiotensin-aldosterone system inhibitor (RASi) group. The estimated glomerular filtration rate decreased in both the S/V group and the RASi group, but the change was more obvious in the RASi group. There was no significant difference in hyperkalemia events (blood potassium >5.5 mmol/L) between the 2 groups. Subgroup analysis showed that with the extension of follow-up time (>6 months), worsening renal function events occurred less frequently in the S/V group than in the RASi group. Existing evidence has shown that S/V is superior to RASi in general renal safety. Perhaps with the prolongation of treatment time, the advantages of S/V are more obvious.