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Background: Helicobacter pylori (H. pylori) infection is prevalent and associated with the development of various gastric diseases. On the other hand, inflammatory bowel disease (IBD) is an immune-related intestinal disorder influenced by factors like gut microbiota imbalance, genetic predisposition, and environmental influences. Despite extensive research on the H. pylori-IBD relationship, a comprehensive bibliometric analysis in this area is lacking. Therefore, this study aims to use bibliometric methods to explore research trends, hotspots, and frontiers in H. pylori and IBD-related research, offering valuable insights for future research and clinical practice. Methods: We retrieved relevant literature on H. pylori and IBD from the Web of Science Core Collection (WoSCC) and Scopus databases covering 2007 to 2024. We perform a comprehensive analysis within the WoSCC literature. We compare these findings with relevant results from Scopus. Results: Research on H. pylori and IBD has remained prominent in recent years. The United States leads in output, with strong contributions from authors, institutions, and journals. China, despite being a developing country, shows rapid article growth, signaling growing research potential. Key topics include Crohn's disease, gut microbiota, H. pylori infection, and ulcerative colitis. Newer interests include health, cancer prevention, and chronic gastritis. Conclusion: Over the past, research on H. pylori and IBD has primarily centered around epidemiology and clinical studies. The question of whether H. pylori definitively offers protective effects against IBD remains unresolved. Therefore, further investigation could explore the underlying mechanisms of their relationship or initiate long-term prospective cohort studies to gather more compelling evidence.
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BACKGROUND: Pulmonary arterial hypertension (PAH) is a complex and progressive illness that has a multifaceted origin, significant fatality rates, and profound effects on health. The pathogenesis of PAH is poorly defined due to the insufficient understanding of the combined impact of endoplasmic reticulum (ER) stress and immune infiltration, both of which play vital roles in PAH development. This study aims to identify potential ER stress-related biomarkers in PAH and investigate their involvement in immune infiltration. METHODS: The GEO database was used to download gene expression profiles. Genes associated with ER stress were obtained from the MSigDB database. Weighted gene co-expression network analysis (WGCNA), GO, KEGG, and protein-protein interaction (PPI) were utilized to conduct screening of hub genes and explore potential molecular mechanisms. Furthermore, the investigation also delved into the presence of immune cells in PAH tissues and the correlation between hub genes and the immune system. Finally, we validated the diagnostic value and expression levels of the hub genes in PAH using subject-workup characterization curves and real-time quantitative PCR. RESULTS: In the PAH and control groups, a total of 31 genes related to ER stress were found to be differentially expressed. The enrichment analysis revealed that these genes were primarily enriched in reacting to stress in the endoplasmic reticulum, dealing with unfolded proteins, transporting proteins, and processing proteins within the endoplasmic reticulum. EIF2S1, NPLOC4, SEC61B, SYVN1, and DERL1 were identified as the top 5 hub genes in the PPI network. Immune infiltration analysis revealed that these hub genes were closely related to immune cells. The receiver operating characteristic (ROC) curves revealed that the hub genes exhibited excellent diagnostic efficacy for PAH. The levels of SEC61B, NPLOC4, and EIF2S1 expression were in agreement with the findings of bioinformatics analysis in the PAH group. CONCLUSIONS: Potential biomarkers that could be utilized are SEC61B, NPLOC4, and EIF2S1, as identified in this study. The infiltration of immune cells was crucial to the development and advancement of PAH. This study provided new potential therapeutic targets for PAH.
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Estrés del Retículo Endoplásmico , Humanos , Estrés del Retículo Endoplásmico/genética , Estrés del Retículo Endoplásmico/fisiología , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/diagnóstico , Hipertensión Arterial Pulmonar/metabolismo , Masculino , Femenino , Perfilación de la Expresión Génica/métodos , Persona de Mediana Edad , Bases de Datos Genéticas , Mapas de Interacción de Proteínas/genética , Redes Reguladoras de Genes , Regulación de la Expresión GénicaRESUMEN
Vascular diseases are the leading cause of ischemic necrosis in tissues and organs, necessitating using vascular grafts to restore blood supply. Currently, small vessels for coronary artery bypass grafts are unavailable in clinical settings. Decellularized small-diameter tissue-engineered vessel grafts (SD-TEVGs) hold significant potential. However, they face challenges, as simple implantation of decellularized SD-TEVGs in animals leads to thrombosis and calcification due to incomplete endothelialization. Consequently, research and development focus has shifted toward enhancing the endothelialization process of decellularized SD-TEVGs. This paper reviews preclinical studies involving decellularized SD-TEVGs, highlighting different strategies and their advantages and disadvantages for achieving rapid endothelialization of these vascular grafts. Methods are analyzed to improve the process while addressing potential shortcomings. This paper aims to contribute to the future commercial viability of decellularized SD-TEVGs.
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Prótesis Vascular , Ingeniería de Tejidos , Ingeniería de Tejidos/métodos , Humanos , Animales , Matriz Extracelular Descelularizada/química , Andamios del Tejido/químicaRESUMEN
The ISL LIM homeobox 1 (ISL1) gene belongs to the LIM/homeodomain transcription factor family and plays a pivotal role in conveying multipotent and proliferative properties of cardiac precursor cells. Mutations in ISL1 are linked to congenital heart disease. To further explore ISL1's role in the human heart, we have created a homozygous ISL1 knockout (ISL1-KO) human embryonic stem cell line using the CRISPR/Cas9 system. Notably, this ISL1-KO cell line retains normal morphology, pluripotency, and karyotype. This resource serves as a valuable tool for investigating ISL1's function in cardiomyocyte differentiation.
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Sistemas CRISPR-Cas , Células Madre Embrionarias Humanas , Humanos , Sistemas CRISPR-Cas/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Línea Celular , Corazón , Células Madre Embrionarias/metabolismo , Células Madre Embrionarias Humanas/metabolismo , Proteínas con Homeodominio LIM/genéticaRESUMEN
Sestrins are a type of highly conserved stress-inducing protein that has antioxidant and mTORC1 inhibitory functions. Metabolic dysfunction and aging are the main risk factors for development of human diseases, such as diabetes, neurodegenerative diseases, and cancer. Sestrins have important roles in regulating glucose and lipid metabolism, anti-tumor functions, and aging by inhibiting the reactive oxygen species and mechanistic target of rapamycin complex 1 pathways. In this review, the structure and biological functions of sestrins are summarized, and how sestrins are activated and contribute to regulation of the downstream signal pathways of metabolic and aging-related diseases are discussed in detail with the goal of providing new ideas and therapeutic targets for the treatment of related diseases.
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Neoplasias , Sestrinas , Humanos , Sestrinas/metabolismo , Proteínas Nucleares/metabolismo , Estrés Oxidativo/fisiología , Transducción de Señal/fisiología , Envejecimiento , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas de Choque Térmico/metabolismoRESUMEN
In the clinic, atrial fibrillation (AF) is a common arrhythmia. Despite constant innovation in treatments for AF, they remain limited by a lack of knowledge of the underlying mechanism responsible for AF. In this study, we examined the molecular mechanisms associated with primary mitral regurgitation (MR) in AF using several bioinformatics techniques. Limma was used to identify differentially expressed genes (DEGs) associated with AF using microarray data from the GSE115574 dataset. WGCNA was used to identify significant module genes. A functional enrichment analysis for overlapping genes between the DEGs and module genes was done and several AF hub genes were identified from a protein-protein interaction (PPI) network. Receiver operating characteristic (ROC) curves were generated to evaluate the validity of the hub genes. We examined 306 DEGs and 147 were upregulated and 159 were downregulated. WGCNA analysis revealed black and ivory modules that contained genes associated with AF. Functional enrichment analysis revealed various biological process terms related to AF. The AUCs for the 8 hub genes screened by the PPI network analysis wereâ >â 0.7, indicating satisfactory diagnostic accuracy. The 8 AF-related hub genes included SYT13, VSNL1, GNAO1, RGS4, RALYL, CPLX1, CHGB, and CPLX3. Our findings provide novel insight into the molecular mechanisms of AF and may lead to the development of new treatments.
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Fibrilación Atrial , Insuficiencia de la Válvula Mitral , Humanos , Fibrilación Atrial/genética , Instituciones de Atención Ambulatoria , Área Bajo la Curva , Biología Computacional , Redes Reguladoras de Genes , Sinaptotagminas , Subunidades alfa de la Proteína de Unión al GTP Gi-GoRESUMEN
Ca2+-activated K+ channels are critical to cellular Ca2+ homeostasis and excitability; they couple intracellular Ca2+ and membrane voltage change. Of these, the small, 4-14 pS, conductance SK channels include three, KCNN1-3 encoded, SK1/KCa2.1, SK2/KCa2.2 and SK3/KCa2.3, channel subtypes with characteristic, EC50 â¼ 10 nM, 40 pM, 1 nM, apamin sensitivities. All SK channels, particularly SK2 channels, are expressed in atrial, ventricular and conducting system cardiomyocytes. Pharmacological and genetic modification results have suggested that SK channel block or knockout prolonged action potential durations (APDs) and effective refractory periods (ERPs) particularly in atrial, but also in ventricular, and sinoatrial, atrioventricular node and Purkinje myocytes, correspondingly affect arrhythmic tendency. Additionally, mitochondrial SK channels may decrease mitochondrial Ca2+ overload and reactive oxygen species generation. SK channels show low voltage but marked Ca2+ dependences (EC50 â¼ 300-500 nM) reflecting their α-subunit calmodulin (CaM) binding domains, through which they may be activated by voltage-gated or ryanodine-receptor Ca2+ channel activity. SK function also depends upon complex trafficking and expression processes and associations with other ion channels or subunits from different SK subtypes. Atrial and ventricular clinical arrhythmogenesis may follow both increased or decreased SK expression through decreased or increased APD correspondingly accelerating and stabilizing re-entrant rotors or increasing incidences of triggered activity. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.
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Fibrilación Atrial , Canales de Potasio de Pequeña Conductancia Activados por el Calcio , Humanos , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/genética , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Fibrilación Atrial/metabolismo , Atrios Cardíacos/metabolismo , Potenciales de Acción/fisiología , Miocitos Cardíacos/metabolismoRESUMEN
The primary pacemaking activity of the heart is determined by a spontaneous action potential (AP) within sinoatrial node (SAN) cells. This unique AP generation relies on two mechanisms: membrane clocks and calcium clocks. Nonhomologous arrhythmias are caused by several functional and structural changes in the myocardium. MicroRNAs (miRNAs) are essential regulators of gene expression in cardiomyocytes. These miRNAs play a vital role in regulating the stability of cardiac conduction and in the remodeling process that leads to arrhythmias. Although it remains unclear how miRNAs regulate the expression and function of ion channels in the heart, these regulatory mechanisms may support the development of emerging therapies. This study discusses the spread and generation of AP in the SAN as well as the regulation of miRNAs and individual ion channels. Arrhythmogenicity studies on ion channels will provide a research basis for miRNA modulation as a new therapeutic target.
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MicroARNs , Nodo Sinoatrial , Humanos , Nodo Sinoatrial/fisiología , MicroARNs/genética , MicroARNs/metabolismo , Arritmias Cardíacas/metabolismo , Canales Iónicos/metabolismo , Frecuencia Cardíaca , Potenciales de Acción/fisiologíaRESUMEN
Normal cardiac automaticity is dependent on the pacemaker cells of the sinoatrial node (SAN). Insufficient cardiac pacemaking leads to the development of sick sinus syndrome (SSS). Since currently available pharmaceutical drugs and implantable pacemakers are only partially effective in managing SSS, there is a critical need for developing targeted mechanism-based therapies to treat SSS. SAN-like pacemaker cells (SANLPCs) are difficult to regenerate in vivo or in vitro because the genes and signaling pathways that regulate SAN development and function have not been fully elucidated. The development of more effective treatments for SSS, including biological pacemakers, requires further understanding of these genes and signaling pathways. Compared with genetic models and bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq) technology promises to advance our understanding of cellular phenotype heterogeneity and molecular regulation during SAN development. This review outlines the key transcriptional networks that control the structure, development, and function of the SAN, with particular attention to SAN markers and signaling pathways detected via scRNA-seq. This review offers insights into the process and transcriptional network of SAN morphogenesis at a single-cell level and discusses current challenges and potential future directions for generating SANLPCs for biological pacemakers.
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BACKGROUND: Existing methods for in vitro differentiation of human pluripotent stem cells (hPSCs) into sinoatrial node-like cells (SANLCs) require complex and undefined medium constituents. This might hinder the elucidation of the molecular mechanisms involved in cardiac subtype specification and prevent translational application. In our study, we aimed to establish a chemically defined differentiation methods to generate SANLCs effectively and stably. METHODS: We induced human embryonic stem cells (hESCs)/induced PSCs (hiPSCs) to pan-cardiomyocytes by temporal modulation of the WNT/ß-catenin (WNT) signaling pathway with GSK3 inhibitor and WNT inhibitor. During cardiac mesoderm stage of the differentiation process, signaling of WNT, retinoid acid (RA), and fibroblast growth factor (FGF) was manipulated by three specific molecules. Moreover, metabolic selection was designed to improve the enrichment of SANLCs. Finally, RT-PCR, immunofluorescence, flow cytometry, and whole cell patch clamp were used to identify the SANLCs. RESULTS: WNT, RA, and FGF signaling promote the differentiation of hPSCs into SANLCs in a concentration- and time window-sensitive manner, respectively. Synergetic modulation of WNT, FGF, and RA signaling pathways enhance the pacemaker phenotype and improve the differentiation efficiency of SANLCs (up to 45%). Moreover, the purification based on lactate metabolism and glucose starvation further reached approximately 50% of SANLCs. Finally, the electrophysiological data demonstrate that cells differentiated with the proposed protocol produce a considerable number of SANLCs that display typical electrophysiological characteristics of pacemaker cells in vitro. CONCLUSION: We provide an optimized and chemically defined protocol to generate SANLCs by combined modulation of WNT, RA, and FGF signaling pathways and metabolic selection by lactate enrichment and glucose starvation. This chemically defined method for generating SANLCs might provide a platform for disease modeling, drug discovery, predictive toxicology, and biological pacemaker construction.
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Células Madre Pluripotentes Inducidas , Nodo Sinoatrial , Diferenciación Celular , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/farmacología , Glucosa/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Ácido Láctico , Miocitos Cardíacos/metabolismo , Nodo Sinoatrial/metabolismo , Vía de Señalización WntRESUMEN
Primary right ventricular vascular malformation is a rare primary benign anomaly in heart in nature. Due to the extremely low incidence and the progress on the classification of vascular malformation, a few cases were reported in the literatures. In the current case study, a 55-year-old women presented with a cardiac mass that was identified in right ventricle during a routine medical checkup. Magnetic resonance imaging demonstrated a well-circumscribed mass attached to the interventricular septum. Median sternotomy for the surgical resection of the mass and a cardiopulmonary bypass were performed. The intraoperative transesophageal echocardiogram showed that the mass had been successfully removed. The patient recovered well and was discharged from hospital 9 days after the surgery. The pathological diagnosis was primary cardiac arteriovenous malformation. No mass recurrence was shown by echocardiography during the 13 months' follow-up.
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Pulmonary hypertension (PH) associated with congenital heart disease is a progressive hemodynamic disease that can lead to increased pulmonary vascular resistance, vascular remodeling, and even right heart failure and death. LF3 is a novel inhibitor of the reporter gene activity of ß-catenin/TCF4 interaction in the Wnt/ß-catenin signal pathway. However, whether this action of LF3 can prevent PH development remains unclear. In this study, we investigated the therapeutic effect of LF3 in rat primary pulmonary artery smooth muscle cells (PASMCs) of the PH model. We found that LF3 inhibited the decrease in pulmonary artery acceleration time and ejection time by ultra-high-resolution ultrasound imaging and blocked the increase of pulmonary artery systolic pressure by using the BL420 biological function experimental system and right ventricular hypertrophy index by the electronic scales. Simultaneously, it prevented the increase of α-smooth muscle actin and fibronectin and the decrease of elastin in pulmonary arteries of rats in the PH group, as revealed by an immunohistochemical analysis. Moreover, cell proliferation and migration assays showed that LF3 significantly reduced the proliferation and migration of PASMCs. Western blotting and quantitative real-time polymerase chain reaction analyses revealed that LF3 suppressed the expression of proliferating cell nuclear antigens and Bcl-2 and increased the expression of Bax but did not alter the expressions of ß-catenin and TCF4. Taken together, LF3 can reduce the migration and proliferation of PASMCs and induce their apoptosis to prevent the development of PH. It would be worthwhile to explore the potential use of LF3 in the treatment of PH.
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Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Sulfonamidas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/metabolismo , Actinas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Elastina/metabolismo , Fibronectinas/metabolismo , Hemodinámica/efectos de los fármacos , Hipertensión Pulmonar/patología , Masculino , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Antígeno Nuclear de Célula en Proliferación/genética , Antígeno Nuclear de Célula en Proliferación/metabolismo , Arteria Pulmonar/citología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/patología , Ratas Sprague-Dawley , Sulfonamidas/química , Factor de Transcripción 4/genética , Factor de Transcripción 4/metabolismo , Remodelación Vascular/efectos de los fármacos , beta Catenina/antagonistas & inhibidores , beta Catenina/genética , BencenosulfonamidasRESUMEN
BACKGROUND: Extended-duration work shifts (EDWSs) might affect the health of physician residents, causing autonomic alteration. Skin sympathetic nerve activity (SKNA) recorded by noninvasive neuro-electrocardiography (neuECG) is used to estimate cardiac sympathetic tone. In this study, we aim to evaluate the impact of EDWSs on nocturnal SKNA assessed in resident doctors. METHODS: Twenty-four residents working EDWSs and 12 PhD students not working nightshift schedules were prospectively recruited. The neuECG was performed between 12 am and 6 am for 5 consecutive nights. SKNA was filtered from neuECG recorded signals. The questionnaires regarding work stress and sleep quality, blood pressure, and salivary alpha-amylase and cortisol levels were administered. RESULTS: The hours of weekly working and sleep opportunities were similar between residents and students, while residents reported more work stress and worse sleep quality. In residents, SKNA at 6 am (SKNA6am) was significantly higher than SKNA2am during the precall night, revealing a dipping pattern. However, the SKNA dipping disappeared during the on-call night and prominently flattened during the first postcall night, the full recovery of which was delayed until the second postcall nights. The morning blood pressure and salivary alpha-amylase and cortisol levels were similar between the precall and postcall days. In contrast, SKNA in students exhibited a constant dipping profile for all recorded nights. CONCLUSIONS: In healthy young adults, SKNA presents a dip night. The SKNA dip is impaired by working a nightshift, with a delayed recovery. The neuECG might serve as a useful tool to detect subclinical autonomic disturbances in shiftworkers.
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Calidad del Sueño , Sistema Nervioso Simpático , Electrocardiografía , Frecuencia Cardíaca , Humanos , Piel , Adulto JovenRESUMEN
Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased risk of all-cause mortality and complications. The autonomic nervous system (ANS) plays a central role in AF, with the heart regulated by both extrinsic and intrinsic properties. In the extrinsic ANS, the sympathetic fibers are derived from the major paravertebral ganglia, especially the stellate ganglion (SG), which is a source of cardiac sympathetic innervation since it connects with multiple intrathoracic nerves and structures. The major intrinsic ANS is a network of axons and ganglionated plexi that contains a variety of sympathetic and parasympathetic neurons, which communicate with the extrinsic ANS. Simultaneous sympathovagal activation contributes to the development of AF because it increases calcium entry and shortens the atrial action potential duration. In animal and human studies, neuromodulation methods such as electrical stimulation and renal denervation have indicated potential benefits in controlling AF in patients as they cause SG remodeling and reduce sympathetic outflow. This review focuses on the neural mechanisms relevant to AF and the recent developments of neuromodulation methods for AF control.
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Fibrilación Atrial/fisiopatología , Sistema Nervioso Autónomo/fisiopatología , Atrios Cardíacos/inervación , Frecuencia Cardíaca , Técnicas de Ablación , Potenciales de Acción , Animales , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/terapia , Sistema Nervioso Autónomo/cirugía , Señalización del Calcio , Terapia por Estimulación Eléctrica , Humanos , Simpatectomía , Resultado del TratamientoRESUMEN
OBJECTIVES: To investigate the effects of cytotoxin-associated gene A- (CagA-) positive Helicobacter pylori on proliferation, invasion, autophagy, and expression of miR-125b-5p in colon cancer cells. METHODS: Colon cancer cells were cocultured with H. pylori (CagA+) to analyze the effects of H. pylori on miR-125b-5p and autophagy. Colon cancer cells infected with H. pylori (CagA+) were mimicked by transfection of CagA plasmid. The effects of CagA on the proliferation, invasion, and autophagy of colon cancer cells were analyzed. Cell counting kit-8 (CCK-8), clone formation, and Transwell assays were used to detect cell viability, proliferation, and invasion ability, respectively. Proteins and miRNAs were detected by western blotting and qPCR, respectively. RESULTS: H. pylori (CagA+) inhibited expression of miR-125b-5p and promoted autophagy in colon cancer cells. MiR-125 b-5p was underexpressed in colon cancer cells after CagA overexpression. CagA promoted colon cancer cell proliferation, invasion, and autophagy. Overexpression of miR-125b-5p inhibited the proliferation, invasion, and autophagy of colon cancer cells and reversed the effects of CagA. CONCLUSION: H. pylori (CagA+) infection may promote the development and invasion of colon cancer by inhibiting miR-125b-5p.
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To prepare a tissue-engineered pulmonary valved conduit (PVC) with good tensile strength and biocompatibility. Sixty adult porcine PVCs were used to determine the optimal decellularization time. Five juvenile porcine decellularized PVCs and five juvenile porcine crosslinked PVCs were subsequently prepared according to the optimized decellularization and crosslinking methods. All PVCs were implanted into juvenile sheep for 8 months and then were harvested for staining. With a low concentration of detergent (0.25% Triton X-100+0.25% sodium deoxycholate), the decellularization effect on porcine PVCs was complete by 24 hours, and there was minimal damage to the matrix. Gelatin embedding and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) crosslinking improved the biomechanical properties of decellularized PVCs and reduced their immunogenicity. After implantation, the diameter and thickness of the PVCs in the decellularized and crosslinked groups increased significantly. In both groups, the conduits were unobstructed, with soft and smooth inner walls and without thrombosis, ulceration or neoplasia. The valves slightly degenerated with mild to moderate regurgitation. CD31-positive endothelial cells were visible on the inner surface of the conduits and valves. Scattered smooth muscle actin-positive cells were found in the middle layer of the conduit. The percentage of CD4- and CD68-positive cells and the calcium content were highest in decellularized porcine PVCs and lowest in ovine PVCs. The percentage of the matrix that was laminin-positive in decellularized and crosslinked porcine PVCs was lower than it was in ovine PVCs. Gelatin-embedded and EDC-crosslinked porcine PVCs can be "hosted" in sheep, with good biocompatibility, growth potential, and reduced calcification.
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Bioprótesis , Prótesis Valvulares Cardíacas , Válvula Pulmonar/trasplante , Animales , Materiales Biocompatibles , Calcinosis/prevención & control , Carbodiimidas , Reactivos de Enlaces Cruzados , Modelos Animales de Enfermedad , Gelatina , Técnicas In Vitro , Ovinos , Porcinos , Resistencia a la Tracción , Ingeniería de TejidosRESUMEN
BACKGROUND: Subcutaneous nerve stimulation (ScNS) delivered directly to large subcutaneous nerves can be either antiarrhythmic or proarrhythmic, depending on the stimulus output. OBJECTIVE: The purpose of this study was to perform a prospective randomized study in a canine model of persistent AF to test the hypothesis that high-output ScNS using blindly inserted subcutaneous electrodes can reduce ventricular rate (VR) during persistent atrial fibrillation (AF) whereas low-output ScNS would have opposite effects. METHODS: We prospectively randomized 16 male and 15 female dogs with sustained AF (>48 hours) induced by rapid atrial pacing into 3 groups (sham, 0.25 mA, 3.5 mA) for 4 weeks of ScNS (10 Hz, alternating 20-seconds ON and 60-seconds OFF). RESULTS: ScNS at 3.5 mA, but not 0.25 mA or sham, significantly reduced VR and stellate ganglion nerve activity (SGNA), leading to improvement of left ventricular ejection fraction (LVEF). No differences were found between the 0.25-mA and sham groups. Histologic studies showed a significant reduction of bilateral atrial fibrosis in the 3.5-mA group compared with sham controls. Only 3.5-mA ScNS had significant fibrosis in bilateral stellate ganglions. The growth-associated protein 43 (GAP43) staining of stellate ganglions indicated the suppression of GAP43 protein expression in the 3.5-mA group. There were no significant differences of nerve sprouting among all groups. There was no interaction between sex and ScNS effects on reduction of VR and SGNA, LVEF improvement, or results of histologic studies. CONCLUSION: We conclude that 3.5-mA ScNS with blindly inserted electrodes can improve VR control, reduce atrial fibrosis, and partially improve LVEF in a canine model of persistent AF.
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Fibrilación Atrial , Atrios Cardíacos , Frecuencia Cardíaca , Función Ventricular Izquierda , Animales , Perros , Femenino , Masculino , Fibrilación Atrial/fisiopatología , Fibrilación Atrial/terapia , Atrios Cardíacos/fisiopatología , Frecuencia Cardíaca/fisiología , Marcapaso Artificial , Ganglio Estrellado , Función Ventricular Izquierda/fisiologíaRESUMEN
BACKGROUND: Premature ventricular complexes (PVCs) exhibit circadian fluctuation. We determine if PVCs of different origin exhibit specific circadian patterns. METHODS: We analyzed Holter recordings from patients with monomorphic PVCs who underwent catheter ablation. PVC circadian patterns were classified as fast-heart rate- (HR-) dependent (F-PVC), slow-HR-dependent (S-PVC), or HR-independent (I-PVC). PVC origins were determined intraprocedurally. RESULTS: In a retrospective cohort of 407 patients, F-PVC and S-PVC typically exhibited diurnal and nocturnal predominance, respectively. Despite decreased circadian fluctuation, I-PVC generally had heavier nocturnal than diurnal burden. PVCs of left anterior fascicle origin were predominantly S-PVC, while those of posterior hemibranch origin were mostly F-PVC. PVCs originating from the aortic sinus of Valsalva (ASV) were predominantly I-PVC, while most PVCs arising from the left ventricular outflow tract (LVOT) were F-PVC. Using a diurnal/nocturnal PVC burden ratio of 0.92 as the cutoff value to distinguish LVOT from ASV origin achieved 97% sensitivity and, as further verification, an accuracy of 89% (16/18) in a prospective cohort of patients with PVCs originating from either ASV or LVOT. In contrast, PVCs originating from right ventricles, such as right ventricular outflow tract, did not show distinct circadian patterns. CONCLUSIONS: The circadian patterns exhibit origin specificity for PVCs arising from left ventricles. An analysis of Holter monitoring provides useful information on PVC localization in ablation procedure planning.
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Ablación por Catéter/métodos , Ritmo Circadiano/fisiología , Electrocardiografía Ambulatoria/métodos , Complejos Prematuros Ventriculares , Femenino , Frecuencia Cardíaca , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Planificación de Atención al Paciente , Estudios Retrospectivos , Complejos Prematuros Ventriculares/diagnóstico , Complejos Prematuros Ventriculares/fisiopatología , Complejos Prematuros Ventriculares/cirugíaRESUMEN
OBJECTIVE: To explore the role of joint regulation of Wnt and bone morphogenetic protein (BMP) signaling pathways in the differentiation of human induced pluripotent stem cells (hiPSCs) into cardiomyocytes. METHODS: HiPSCs were cultured and observed under inverted phase contrast microscope. Immunofluorescence staining was used to observe the expressions of hiPSCs pluripotent markers (OCT3/4, NANOG, and TRA-1-60). HiPSCs were passaged which were taken for subsequent experiments within the 35th passage. When the fusion degree of hiPSCs was close to 100%, the CHIR99021 (Wnt pathway activator) was added on the 0th day of differentiation. Different concentrations of IWP4 (inhibitor of Wnt production) were added on the 3rd day of differentiation, and the best concentration of IWP4 was added at different time points. The optimal concentration and the best effective period of IWP4 were obtained by detecting the expression of troponin T (TNNT2) mRNA by real-time fluorescence quantitative PCR. Then, on the basis of adding CHIR99021 and IWP4, different concentrations of BMP-4 were added on the 5th day of differentiation, and the best concentration of BMP-4 was added at different time points. The optimal concentration and best effective period of BMP-4 were obtained by detecting the expression of TNNT2 mRNA. Finally, hiPSCs were divided into three groups: Wnt group, BMP group, and Wnt+BMP group. On the basis of adding CHIR99021 on the 0th day of differentiation, IWP4, BMP-4, and IWP4+BMP-4 were added into Wnt group, BMP group, and Wnt+BMP group respectively according to the screening results. Cells were collected on the 7th and the 15th days of differentiation. The expressions of myocardial precursor cell markers [ISL LIM homeobox 1 (ISL1), NK2 homeobox 5 (NKX2-5)] and cardiomyocyte specific markers [myocyte enhancer factor 2C (MEF2C), myosin light chain 2 (MYL2), MYL7, and TNNT2] were detected by real-time fluorescent quantitative PCR. Cells were collected on the 28th day of differentiation, and the expression of cardiac troponin T (cTnT) was detected by flow cytometry and immunofluorescence staining. RESULTS: The results of cell mophology and immunoflurescence staining showed that the OCT3/4, NANOG, and TRA-1-60 were highly expressed in hiPSCs, which suggested that hiPSCs had characteristics of pluripotency. The optimal concentration of IWP4 was 10.0 µmol/L ( P<0.05) and the best effective period was the 3rd day ( P<0.05) in inducing hiPSCs to differentiate into cardiomyocytes. The optimal concentration of BMP-4 was 20.0 ng/mL ( P<0.05) and the best effective period was the 3rd day ( P<0.05). The relative expressions of ISL1, NKX2-5, MEF2C, MYL2, MYL7, and TNNT2 mRNAs, the positive expression ratio of cTnT detected by flow cytometry, and sarcomere structure detected by immunofluorescence staining of Wnt+BMP group were superior to those of Wnt group ( P<0.05). CONCLUSION: Joint regulation of Wnt and BMP signaling pathways can improve the differentiation efficiency of hiPSCs into cardiomyocytes.