American journal of physiology. Heart and circulatory physiology最新文献

{"title":"The Role of Mechanosignaling in the Control of Myocardial Mass.","authors":"Maicon Landim-Vieira, Paula Nieto Morales, Summer ElSafty, Aida Rahimi Kahmini, Mark J Ranek, Christopher Solís","doi":"10.1152/ajpheart.00277.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00277.2024","url":null,"abstract":"<p><p>Regulation of myocardial mass is key for maintaining cardiovascular health. This review highlights the complex and regulatory relationship between mechanosignaling and myocardial mass, influenced by many internal and external factors including hemodynamic and microgravity, respectively. The heart is a dynamic organ constantly adapting to changes in workload (preload and afterload) and mechanical stress exerted on the myocardium, influencing both physiological adaptations and pathological remodeling. Mechanosignaling pathways such as the mitogen-activated protein kinases (MAPK) and the phosphoinositide 3-kinases and serine/threonine kinase (PI3K/Akt) pathways, mediate downstream effects on gene expression and play key roles in transducing mechanical cues into biochemical signals, thereby modulating cellular processes, including control of myocardial mass. Dysregulation of these processes can lead to pathological cardiac remodeling, such as hypertrophic cardiomyopathy. Furthermore, recent studies have highlighted the importance of protein quality control mechanisms, such as the ubiquitin-proteasome system, in settings of extreme physiological conditions that alter the heart workload such as pregnancy and microgravity. Overall, this review provides a thorough insight into how mechanical signals are converted into chemical signals to regulate myocardial mass in both healthy and diseased conditions.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted Circulating Lipid Mediators and Immune Cell Gene Transcripts After ST-Elevation Myocardial Infarction.","authors":"Dae Hyun Lee, Gunjan Upadhyay, Siddabasave Gowda B Gowda, Vasundhara Kain, Md Abdul Malek, Nicholas Carris, Samip Vasaiwala, Timothy Yeatman, Guilherme Oliveira, Shu-Ping Hui, Ganesh V Halade","doi":"10.1152/ajpheart.00494.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00494.2024","url":null,"abstract":"<p><p>Residual inflammation drives atherogenesis to atherosclerosis and myocardial infarction, which triggers acute inflammation. In preclinical studies, polyunsaturated fatty acids-derived specialized pro-resolving mediators (SPMs) have been shown to promote recovery after MI, in contrast to pro-inflammatory lipid mediators (PIMs). However, the dynamic changes of lipid mediators after ST-elevation myocardial infarction (STEMI), particularly after percutaneous coronary intervention (PCI) and respective gene transcripts, are poorly understood. Therefore, the study aimed to assess the early dynamic changes in circulating lipid mediators and lipid pathway transcripts in STEMI patients who undergo PCI. In this prospective observational clinical study, patients with STEMI (n=10) and control subjects (n=6) were included. Plasma samples for lipid mediator profiling (targeted oxylipids) and whole blood for inflammation-related transcript expression were collected at baseline before PCI, 2 hours, and 24 hours post-PCI. A total of 10 STEMI patients received PCI with a mean age of 53.3 years, 90% male. Linoleic acid and DPA levels were higher in STEMI patients. A subset of PIM levels (HETEs, PGE₂) were elevated at the baseline, with a subsequent decrease in circulating levels at 2 hours after PCI (TXB₂, LTB₄, 20-OH-LTB₄). A subset of SPM levels (HEPEs) were elevated at the baseline of STEMI suggestive overlap of inflammation-resolution signaling. The temporal kinetics of LMs showed that both the initiation of inflammation and the resolution process start simultaneously and continue as an endogenous repair mechanism during STEMI. Therefore, approaches to increase these endogenous bioactive resolution mediators content and/or efficacy before PCI should be considered in treating MI patients.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular Matrix Instability and Chronic Inflammation Underlie Maladaptive Right Ventricular Pressure Overload Remodeling and Failure in Male Mice.","authors":"Ilaria Russo, Wen Dun, Swasti Mehta, Sowda Ahmed, Christos Tzimas, Nobuaki Fukuma, Emily J Tsai","doi":"10.1152/ajpheart.00331.2024","DOIUrl":"10.1152/ajpheart.00331.2024","url":null,"abstract":"<p><p>Right ventricular dysfunction (RVD) portends increased death risk for heart failure (HF) and pulmonary arterial hypertension (PAH) patients, regardless of left ventricular function or disease etiology. In both, RVD arises from chronic RV pressure overload and represents advanced cardiopulmonary disease. RV remodeling responses and survival rates of patients, however, differ by sex. Men develop more severe RVD and die at younger ages than do women. Mechanistic details of this sexual dimorphism in RV pressure overload remodeling are incompletely understood. We sought to elucidate the cardiac histologic and molecular pathophysiology underlying the sex-specific RV remodeling phenotypes, maladaptive (decompensated RVD with RV failure) versus adaptive (compensated RVD). We subjected male (M-) and female (F-) adult mice to moderate pulmonary artery banding (PAB) for 9wks. Mice underwent serial echocardiography, cardiac MRI, RV pressure-volume loop recordings, histologic and molecular analyses. M-PAB developed severe RVD with RV failure (RVF), increased RV collagen deposition and degradation, extracellular matrix (ECM) instability, and recruitment and activation of macrophages. Despite equal severity and chronicity of RV pressure overload, F-PAB had more stable ECM, lacked chronic inflammation, and developed mild RVD without RVF. ECM destabilization and chronic activation of recruited macrophages are associated with maladaptive RV remodeling and RVF in M-PAB. These two RV remodeling phenotypes suggest that adverse ECM remodeling and chronic inflammation are also sex-dependent, thereby contributing to the sexual dimorphism of RV pressure overload remodeling. Further mechanistic studies are needed to assess their pathogenic roles and potential as targets for RVD therapy and RVF prevention.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is neuropeptide Y really involved with regulating resting blood pressure?","authors":"Heidi A Kluess","doi":"10.1152/ajpheart.00791.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00791.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is HFpEF a chicken or an egg? Utility of models for a clinical syndrom.","authors":"Aram A Babakr, Mariana Angoa-Perez, Charles S Chung","doi":"10.1152/ajpheart.00812.2024","DOIUrl":"https://doi.org/10.1152/ajpheart.00812.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acceleration of age-related impairments in vascular function in women: interrogation of the (un)usual hormonal suspects.","authors":"Kylee S West, Nathaniel D M Jenkins","doi":"10.1152/ajpheart.00730.2024","DOIUrl":"10.1152/ajpheart.00730.2024","url":null,"abstract":"","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1387-H1389"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connecting transcriptomics with computational modeling to reveal developmental adaptations in pediatric human atrial tissue.","authors":"Shatha Salameh, Devon Guerrelli, Jacob A Miller, Manan Desai, Nicolae Moise, Can Yerebakan, Alisa Bruce, Pranava Sinha, Yves d'Udekem, Seth H Weinberg, Nikki Gillum Posnack","doi":"10.1152/ajpheart.00474.2024","DOIUrl":"10.1152/ajpheart.00474.2024","url":null,"abstract":"<p><p>Nearly 1% of babies are born with congenital heart disease-many of whom will require heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate drug therapies, and inform clinical care decisions related to surgical repair and postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is limited. In this study, we collected right atrial tissue samples from pediatric patients (<i>n</i> = 117) undergoing heart surgery. Patients were stratified into five age groups. We measured age-dependent adaptations in cardiac gene expression and used computational modeling to simulate action potential and calcium transients. Enrichment of differentially expressed genes revealed age-dependent changes in several key biological processes (e.g., cell cycle, structural organization), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited age-dependent trends, with changes in calcium handling (<i>I</i>_NCX) and repolarization (<i>I</i>_K1) most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We observed a shift in repolarization reserve, with lower <i>I</i>_Kr expression in younger patients, a finding potentially tied to an increased amplitude of <i>I</i>_Ks that could be triggered by elevated sympathetic activation in pediatric patients. Collectively, this study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology, shedding light on molecular mechanisms underlying cardiac maturation and function throughout development.<b>NEW & NOTEWORTHY</b> To date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is limited. In this study, we demonstrate age-dependent adaptations in the gene expression profile of >100 atrial tissue samples collected from congenital heart disease patients. We coupled transcriptomics datasets with computational modeling to simulate action potentials and calcium transients for different pediatric age groups.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1413-H1430"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in the functional morphology of coronary arteries in embryonic mice.","authors":"Shion Nagasawa, Masami Kodama, Ryu Hagiwara, Kazuho Sakamoto, Koichi Nishiyama, Yuichiro Arima, Hiroki Kurihara, Junko Kurokawa","doi":"10.1152/ajpheart.00186.2024","DOIUrl":"10.1152/ajpheart.00186.2024","url":null,"abstract":"<p><p>Sex differences in the development and progression of cardiovascular disease manifest across multiple life stages. These differences are associated with variations in cardiovascular morphology and function between the sexes. Although estrogens and sex hormones are associated with sex differences in cardiovascular diseases in reproductive adults, the molecular mechanisms of cardiovascular sex differences during development are largely unknown. Thus, we investigated sex differences in cardiovascular development. We used a newly developed coronary arteriogram system to visualize the morphology of the coronary arteries in murine anterior surface ventricles at embryonic day 17.5 by injecting nanoparticle ink at a constant pressure. No sex difference was found in the length of ventricle. Based on the boundary value of the distribution of that length, the hearts were divided into \"long\" and \"short\" groups and the diameters of the left coronary arteries were analyzed. The mean diameter of the coronary arteries was significantly smaller in females than in males only in the group with the longer length of ventricle. This ventricular size-specific sex difference was observed in the presence of vasodilators such as NOC7 (1-Hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene). When NOC7 was perfused into the left coronary arteries of embryonic day 17.5 mice, females with longer ventricles showed larger left coronary arteries than males. These sex differences in vasodilation capacity suggest that factors related to drug reactivity such as signaling pathways are present at a late embryonic stage. These results indicate that sex differences in the functional morphology of the left coronary arteries exist at a late embryonic stage in mice.<b>NEW & NOTEWORTHY</b> This study introduces a novel coronary angiography method for analyzing murine embryonic hearts, revealing sex differences in coronary artery morphology and contractile function in the late stage of the fetal period. By categorizing heart components based on size, we unveil nuanced insights into sexual dimorphism during this critical fetal period. This work contributes insights into the early origins of sexual dimorphism in coronary vessels, laying the foundation for further understanding of cardiovascular development.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1390-H1399"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sertraline-induced 5-HT dysregulation in mouse cardiomyocytes and the impact on calcium handling.","authors":"Yongjun Lu, Elizabeth Kenkel, Kathy Zimmerman, Robert M Weiss, Robert D Roghair, Sarah E Haskell","doi":"10.1152/ajpheart.00692.2023","DOIUrl":"10.1152/ajpheart.00692.2023","url":null,"abstract":"<p><p>Selective serotonin reuptake inhibitors (SSRIs) are prescribed in 15% of pregnancies in the United States for depression. Maternal use of SSRIs has been linked to an increased risk of congenital heart defects, but the exact mechanism of pathogenesis is unknown. SSRIs, including sertraline, are permeable to the placenta and can produce direct fetal exposure. Previously, we have shown decreased cardiomyocyte proliferation, left ventricle size, and cardiac expression of the serotonin receptor 5-HT_2B in the offspring of mice exposed to the SSRI sertraline relative to the offspring of saline-exposed mice. Using a mouse model of in utero plus neonatal sertraline exposure, we observed lengthened peak-to-peak time of calcium oscillation (saline 784 ± 76 ms; sertraline 1,121 ± 130 ms, <i>P</i> < 0.001) and decreased expression of critical genes in calcium regulation. We also observed significant upregulation of specific microRNAs (miRNAs) that modulate serotonin signaling in neonatal cardiac tissues (<i>Slc6a4: miR-223-5p, miR-92a-2-5p, miR-182-5p; Htr2a: miR-34b-5p, miR-182-5p; Htr2b: miR-223-5p, miR-92a-2-5p, miR-337-5p</i>) (<i>P</i> < 0.05) with corresponding levels of the target mRNAs downregulated (<i>Slc6a4</i> 0.73 ± 0.05; <i>Htr2a</i> 0.67 ± 0.04; <i>Htr2b</i> 0.72 ± 0.03; all <i>P</i> < 0.01), resulting in decreased production of the cognate proteins. Adult mice at 10 wk showed altered cardiac parameters including decreased heart rates in males (saline 683 ± 8 vs. sertraline 666 ± 6 beats/min, <i>P</i> < 0.05) and ejection fraction in females (saline 83.9 ± 0.6% vs. sertraline 80.6 ± 1.1%, <i>P</i> < 0.05). These findings raise the question of whether sertraline exposure during development may increase the potential risk for cardiac disease when subjected to stress.<b>NEW & NOTEWORTHY</b> Sertraline exposure during development decreased the expression of critical genes in calcium regulation and lengthened periods in calcium oscillation in neonatal cardiomyocytes. Sertraline upregulated specific microRNAs that may modulate serotonin signaling in neonatal cardiac tissues, which corresponded with a decrease in the levels of the corresponding target mRNAs. Although the echocardiograms in our adult mice suggest a mild phenotype associated with sertraline exposure, these upregulated microRNAs (miRNAs) have been linked to adult cardiovascular disease and heart failure.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1559-H1576"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142456049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y bioavailability.","authors":"Stephen A Klassen, Jacqueline K Limberg, Ronée E Harvey, Chad C Wiggins, Julia E Spafford, Nathaniel J Iannarelli, Jonathon W Senefeld, Wayne T Nicholson, Timothy B Curry, Michael J Joyner, J Kevin Shoemaker, Sarah E Baker","doi":"10.1152/ajpheart.00639.2024","DOIUrl":"10.1152/ajpheart.00639.2024","url":null,"abstract":"<p><p>What is the purpose of sympathetic neuronal action potential (AP) discharge and recruitment patterns for human vascular regulation? This study tested the hypothesis that sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y (NPY) bioavailability. We used microneurography to record muscle sympathetic nerve activity and a continuous wavelet transform to detect sympathetic APs during a baseline condition and intravenous dexmedetomidine infusion (α₂-adrenergic agonist, 10-min loading infusion of 0.225 µg·kg^-1; maintenance infusion of 0.1-0.5 µg·kg·h^-1) in six healthy individuals (5 females, 27 ± 6 yr). Arterial blood samples provided NPY (enzyme-linked immunosorbent assay) and norepinephrine (liquid chromatography-tandem mass spectrometry) levels at baseline and the dexmedetomidine maintenance infusion. Linear mixed-model regressions assessed the relationships between AP discharge, recruitment, and neurotransmitter levels. Across baseline and the dexmedetomidine condition, NPY levels were positively related to mean arterial pressure (β = 1.63 [0.34], <i>P</i> = 0.002), total AP clusters (β = 0.90 [0.22], <i>P</i> = 0.005), and AP frequency (β = 0.11 [0.03], <i>P</i> = 0.003). Norepinephrine levels were not related to mean arterial pressure (β = 0.03 [0.02], <i>P</i> = 0.133) but were positively related to total AP clusters (β = 19.50 [7.07], <i>P</i> = 0.030) and AP frequency (β = 2.66 [0.81], <i>P</i> = 0.014). These data suggest that sympathetic neuronal discharge and recruitment patterns regulate NPY and norepinephrine bioavailability in healthy adults. As such, sympathetic neuronal firing strategies are important for human vascular regulation.<b>NEW & NOTEWORTHY</b> The purpose of sympathetic neuronal discharge and the recruitment of neuronal subpopulations for human circulatory homeostasis remains unknown. This study tested the hypothesis that sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y (NPY) bioavailability. Across baseline and an intravenous dexmedetomidine infusion (α₂-adrenergic agonist) sympathetic action potential (AP) frequency and total sympathetic AP clusters were associated with NPY bioavailability. This is the first study to report that sympathetic neuronal discharge and recruitment patterns regulate NPY bioavailability to support circulatory homeostasis in humans.</p>","PeriodicalId":7692,"journal":{"name":"American journal of physiology. Heart and circulatory physiology","volume":" ","pages":"H1599-H1605"},"PeriodicalIF":4.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}