Modern neurosurgery is a relatively young discipline characterized by finesse and complexity. In recent years, neurosurgery in China has made continuous developments, with long-term progress and outstanding discoveries in many aspects of the field.This scientometric investigation aimed to comprehensively provide insight into the development trends of neurosurgery in China, to demonstrate how the field has evolved.PubMed database was searched to retrieve relevant papers published between 1988 and 2018 from neurosurgery institutions in China. The database of the National Natural Science Foundation of China was also retrieved for funding information. Information  and keywords were collected from each paper after removing duplicates and filtering unintentional words. Co-word analysis was performed on the papers’ keywords, and a time distribution matrix of coexisting keywords in a given paper  was established. Co-words were clustered according to their growth rate within years and visually presented with a mountain plot and a heatmap. Trends and potential subspecialties were identified, and each topic, represented either by a co-word from publications or funding from the National Natural Science Foundation of China during the period from 2011 to 2018, was collected and analyzed.Within 15,972 publications on neurosurgery from institutions in China, diagnostic image was found to coexist the most with other keywords. Cluster 0, represented by diagnostic image with retrospective study, contained emerging topics with great developmental potential and demonstrated high growth rates in recent years. This finding suggests that the topics represented in Cluster 0 may represent future areas of important neurosurgical research. We also found that the developmental trend of China’s neurosurgical research is highly correlated with National Natural Science Foundation of China funding acquisition.Co-word analysis and visualization results provided insight into the emerging research topics that are of vital importance, which can be used as a reference by neurosurgeons and researchers for future investigations. In this study, our analysis strategy based on co-word biclustering was able to clearly demonstrate current academic subject development; therefore, co-word biclustering is a reliable bibliometric analysis strategy. Modern neurosurgery, with a history of only 100 years, has been developing rapidly since its birth in the late 19th century. In past decades, modern neurosurgery has experienced three stages of development: classical neurosurgery, microneurosurgery, and minimally invasive neurosurgery . After 1For decades, the most common way for researchers to become familiar with the state of the art and development trends in research has been to read published reviews. However, the large amount of literature that can be found for a single topic makes it increasingly difficult for researchers to quickly find the areas of research they are interested in. In recent years, bibliometric analysis has become increasingly popular. It uses bibliometric characteristics, such as country, institution, journal, or author, to measure the contribution of a research field and to predict, in detail, the research trends or hotspots in a certain field ,5.co-words) during a period of time or if the number of published papers has increased over time, it can represent an emerging area of interest that is currently, or will be in the future, highly important ) AND neurosurgery [Affiliation]) AND (“1988” [Date - Publication]: “2018” [Date - Publication]). We performed the search on September 8, 2019, which yielded a total of 22,056 papers. Search results were screened to removed duplicates. We excluded articles about other subjects of study by title, abstract, and keywords . ArticleWe imported bibliography data and keywords from the papers using NoteExpress , and Excel  was used to establish a database containing bibliography information, such as the year of publication, influencing factors, and journals, and perform descriptive statistical analysis. The main premise of bibliometric analysis based on keywords is that keywords selected by paper authors fully and accurately describe the main content of the paper . If a paAfter processing, there was a total of 15,972 keywords. Because there were relatively few papers published before 2010, the period from 1988 to 2018 was divided into 11 stages . Distribution features of all keywords for every stage were quantitatively assessed for co-word analysis. We used data-mining software  and OpenGL-based mountain visualization were used for biclustering analysis of co-words. We imported the binary matrix data of the 430 co-words into gCLUTO, which uses a clustering algorithm based on partitional clustering, to determine the best number of subgroups The co-words were divided into 3 clusters, and co-word matrix data were shown by a peak plot and a heat map, which visually display distribution characteristics. Word cloud plots for the 3 clusters co-words were created, in which the size of each co-word was determined by its cumulative frequency. We also imported the co-word matrix into Cytoscape  to more intuitively reflect the relationships among 430 co-words with a circular layout.The National Natural Science Foundation of China is the most important funding source in China; therefore, to provide insight into the role played by funding in development trends, funding amounts from 2011 to 2018 for each subdiscipline represented by co-words were collected, and Pearson correlations were calculated.Changes in the number of publications in a certain discipline can be examined, not only to reflect development, but also, to predict future developmental trends. To understand the development of neurosurgery in China in recent years, 15,972 papers from 1988 to 2018 were statistically analyzed year by year . The resWorld Neurosurgery featured the most papers , followed by the Chinese Medical Journal  and PLOS One . Of the top 10 journals, 5 were included in the SCI, among which PLOS One had the highest impact factor (2.776). In total, 2906 papers were published in journals in the SCI , including those in the top 10 journals.Papers published by neurosurgical researchers in China appeared in 1420 journals, of which 802 are included in the SCI. The average number of papers published in the top 10 journals  was 498,Of scientific research institutions affiliated with the first author, 25.35%  were from the top 10 institutions: Beijing Tiantan Hospital was the most prolific institution, with 985 papers .A total of 24,469 keywords were extracted from the papers in the field of neurosurgery published by researchers in China from 1988 to 2018; 430 co-words had growth rates greater than 0 for 2015 to 2016, 2016 to 2017, and 2017 to 2018 . This fidiagnostic image coexisted the most with other keywords , (2) long noncoding with RNA (208 papers), and (3) long noncoding with human (184 papers), respectively. These findings suggest that retrospective analyses of the imaging diagnosis of neurosurgical diseases and studies on human long noncoding RNA are leading areas in Cluster 0.The peak of Cluster 0 was the highest  has a large volume, which indicates that it contains a large number of co-words. The amount of papers containing the co-words in this cluster was low before 2015 . Clustersurgery with human (2357 papers), (2) human with retrospective study (1752 papers), and (3) surgery with female (1615 papers). These results suggest that literature on neurosurgical treatment, retrospective analysis, and surgical treatment of neurosurgical diseases of female patients occupy the main positions in Cluster 1.The peak of Cluster 1 was the lowest  and had the largest volume, with 152 co-words. Cluster 1 contained a large number of papers containing these co-words in this cluster published since 2001 . The most frequent co-words in Cluster 1 were (1) metabolism with signaling (1425 papers), (2) drug effects with pharmacology (1225 papers), and (3) diagnostic imaging with male (1093 papers). We concluded that, in Cluster 2, literature related to metabolic signaling pathways, pharmacology, and papers about neurosurgical imaging diagnosis of male patients were ranked in the leading position.The peak of Cluster 2 was medium height , indicating great similarities among co-words in this category, and of medium volume, with 147 co-words . The number of papers in this cluster has grown rapidly since 2014 and continues to increase rapidly. The top most frequent co-words in this cluster were (1) microRNA was associated with the most papers funded by the National Natural Science Foundation of China (r=0.988), followed by gene expression with RNA (r=0.986) and autophagy with metabolism (r=0.980).The distribution of National Natural Science Foundation of China funding for each topic of neurosurgical research represented by 430 co-words yearly (2011-2018) . The topIn this study, a bibliometric method, with keywords representing neurosurgery research papers from institutions in China published from 1988 to 2018 in the PubMed database, was used to analyze information on emerging topics. Quantitative analysis based on co-word and biclustering analyses of keywords in papers revealed development trends for each cluster of co-words and provides prospects for future research directions.The bibliometric approach can help researchers address enormous amounts information when carrying out scientific investigations. The identification of potential research topics can promote academic advances in certain specialties and can help researchers grasp which emerging themes may become future directions of vital importance in certain disciplines .In China, compared with the development of other fields, neurosurgery developed relatively late. Our study demonstrated a fluctuating and gradual increase in the amount of papers from China’s neurosurgical institutions over time. The amount of publications showed a noticeable increase in recent years, with an explosive increment in 2014 that accounted for 23%  of the total number of papers published from 1988 to 2018. While the number of publications showed an overall upward trend, the period from 1988 to 2006 exhibited steady growth, and the period from 2007 to 2018 exhibited rapid growth; the number of published papers in the latter period was 19 times higher than that in the former. The amount of papers from journals in the SCI increased over time, accounting for 61.00%  of the total number of papers, which indicates development of the research and the influence of the field of neurosurgery in China.The keywords of papers are representative . To a laThe biclustering approach, in contrast to traditional clustering approaches, can simultaneously cluster year of publication and co-words into matrix columns and rows, respectively. Cluster 0, which contains topics that began to gradually develop in recent years, contained the least co-words. This finding reveals that topics represented by co-words included in Cluster 0 as emerging themes may grow in importance in the future, given that they appeared with increasing frequency in recent years. Retrospective analyses of diagnostic imaging data can, not only assist in clinical decision making, but also, improve the accuracy of neurosurgical disease diagnosis and predict response to disease treatment ,24. LongCo-words contained in Cluster 1 and Cluster 2 exhibited large cumulative frequency counts, representing topics that have been studied much in the past, and the amounts have shown growth in recent years. As evidenced by Cluster 1, surgery is still the first choice for neurosurgery-related diseases, such as gliomas. However, traditional craniotomy is dependent on operator experience and visual judgment, and its application is limited because of the inevitable damage to normal tissue and blood vessels . With thAlthough the cumulative frequency counts of co-words in Cluster 0 were low, they increased from 2015 to 2018, which shows great potential for development; therefore, to a large extent, the topics in this cluster may become the future hotspots to which researchers should pay attention.micro-RNA and RNA, the co-word pair gene expression regulation and RNA, and the co-word pair autophagy and metabolism was proportional to the number of papers with National Natural Science Foundation in China funding, which may indicate that funding on these topics has accelerated research progress and literature output. Consistent co-word and biclustering analyses results suggest that research on the function of gene expression regulation of RNA, especially noncoding RNA such as micro-RNAs and long noncoding RNA, is of considerable importance and provide insight into future potential research directions.In general, funding facilitates scientific research. As the largest funding agency of natural science of China, the National Natural Science Foundation has made great efforts in encouraging the development of neurosurgical research over the past years. This study identified that the number of papers represented by the co-word pair Scientometric analysis can provide insight into the development of a research field, highlight research trends over time, and help identify valuable future directions. This study used bibliometric analysis to count and analyze the literature published by Chinese neurosurgical research institutions in the PubMed database from 1988 to 2018. Co-words were divided into 3 clusters that reveal current and future trends for neurosurgery research in China.This study has some limitations. First, we focused only on papers that were indexed in PubMed (a freely available database). Although we believe that PubMed is a sufficiently large database for publications from neurosurgical institutions in China, other databases, such as Web of Science, should be used in future research to obtain more information such as number of citations. Second, the search string was relatively general and may not be able to identify all papers on neurosurgery in China. In addition, because the number of studies has increased over time, the numbers of papers published in recent years may have had an effect on our results to some extent. Future investigations should be performed to provide a more comprehensive evaluation of papers on neurosurgery in China.We applied bibliometric methods  to examine research progression, emerging topics, and future potential research directions in the field of neurosurgery research in China. These findings can be used by neurosurgery researchers as a reference for choosing scientific research projects.


In this work, we developed a systematic map to identify and catalogue the literature pertaining to disease modelling for agricultural crops worldwide. Searches were performed in 2021 in the Web of Science and Scopus for papers reporting any type of disease model for 103 crops. In total, 768 papers were retrieved, and their descriptive metadata were extracted. The number of papers found increased from the mid-1900s to 2020, and most of the studies were from North America and Europe. More disease models were retrieved for wheat, potatoes, grapes, and apples than for other crops; the number of papers was more affected by the crop’s economic value than by its cultivated area. The systematic map revealed an underrepresentation of disease models for maize and rice, which is not justified by either the crop economic value or by disease impact. Most of the models were developed to understand the pathosystem, and fewer were developed for tactical disease management, strategic planning, or scenario analysis. The systematic map highlights a variety of knowledge gaps and suggests questions that warrant further research. If not managed, diseases of agricultural crops cause substantial economic losses and reduce food security at household, national, and global levels . New plaWith an increasing world population, a major challenge is how to increase food production . Crop paIn the context of crop protection, a plant disease model is a simplified representation of the relationships between pathogens, crops, and environment (the pathosystem) that cause the development of epidemics; these relationships involve a large number of interactions at different levels of hierarchy over time and/or space ,8. ModelUnfortunately, few plant disease models have been applied for practical disease control ,16,20. RIn the current study, we developed a systematic map of the current status of the research on plant disease models worldwide, as deduced from the published literature. Systematic mapping is a recently developed method ,22 for eThe main objective of our study was to identify and to systematically map scientific literature pertaining to disease modelling for agricultural crops worldwide. We focused on the literature regarding disease prediction models for any crop worldwide.The database resulting from the literature search has four main uses. First, it can be used to determine how the research on plant disease models has varied over the years and among countries, and to identify the most studied crop systems and disease-causing organisms. Second, the database provides a catalogue of models for researchers and stakeholders; this catalog can be used as a resource for the development of new plant disease models, or as a guide for policymakers to decide where resources should be allocated. Third, the database provides a foundation for future systematic reviews and meta-analyses. Fourth, and perhaps most importantly, the database can be used to identify knowledge gaps and to thereby inform future research.The methods used in the development of our systematic map were adapted from existing systematic map reports ,22,23. Thttp://webofknowledge.com/WOS, (accessed on 26 August 2021)) and (ii) Scopus (https://www.scopus.com/ (accessed on 26 August 2021)). Database searches were conducted in English, however the search was not restricted to papers written in English .In 2021, we conducted a search of the two most relevant online bibliographic databases: (i) Web of Science Core Collection (Search terms relevant for the systematic map were identified and combined into search strings using wildcards (*) and connectors (AND and OR). The wildcard (*) enables the search to detect multiple word endings . Search terms were combined using the operator AND (both terms must be present somewhere in the search field) and OR (at least one of the terms must be present in the search field). This allows the search terms to be structured according to four thematic blocks: “Crop”; “Modelling”; “Plant disease”; and “Topic to exclude”.The thematic block “Crop”, which consists of the common name of the crop  or crop groups , was combined with the search strings of the other thematic blocks with the operator AND in the final searches: (crop (block) AND modelling (block) AND plant disease (block)) AND NOT topic to exclude (block)). The full search strings of the three thematic blocks  are presented in The full search was separately performed in the databases for each of the crops. The investigated crops were selected based on FAO data  about thThe papers obtained from the first search in each of the selected databases were imported, and a separate file (library) was created for each crop. When the search was completed, all of the database libraries were incorporated into one new library, and duplicates were removed.consider at least one of the selected crops;report about any type of model ;concern any type of model purpose ;consider any step of model development ;focus on plant diseases, their causal agents , or their vectors.The titles of all of the papers in the library were independently screened by each of us (authors) to remove those papers that failed to do the following:If there was disagreement among the authors on the inclusion of a paper, the authors considered whether the inclusion/exclusion criteria required redefining.Bibliographic information: Authors, title, year of publication, journal, publisher, reference type, language, number of citations, URL or DOI, affiliations of the corresponding author;Crop: Common name, code for crop groups. According to the Indicative Crop Classification (ICC) codes , crops wLocation of study: Country. The affiliation of the corresponding author was used to define the location of the study. The countries were listed as indicated by the FAO based on the ISO 3166 international standard ;Disease-causing organism: Scientific name of the causal agent, vector, or disease when specified in the title, and kingdom of the causal agent. Papers in which the disease-causing organism was not specified in the title were coded as “generic”;Study scope: Based on the title of the model, each model was assigned to the following categories according to its scope and purpose: (i) model for system representation and understanding; (ii) model for tactical disease management; (iii) model for strategic planning; and (iv) model for scenario analysis. The main characteristics and examples of papers for each category are listed in Standardized descriptive metadata from all papers meeting the inclusion criteria were stored in a csv file, which formed the database for the systematic map. Data from each paper was coded as follows:n = 242) were published between 2010 and 2020 , followed by Brazil (n = 40) and Canada (n = 27). Most of the studies conducted in Europe originated from the UK (n = 60), France (n = 47), Germany (n = 34), Italy (n = 33), and Spain (n = 16). Among the Asian countries, most of the studies originated from India (n = 60), China (n = 38), and South Korea (n = 13). Australia and New Zealand contributed 32 and 16 papers, respectively. For Africa, studies have been conducted in Egypt (n = 1), Ethiopia (n = 1), Ivory Coast (n = 1), Kenya (n = 1), South-Africa (n = 2). As indicated by the addresses of the corresponding authors, 59 countries have published papers concerning plant disease models . For Norn = 214 and 210, respectively); although the number of papers was similar for cereal and fruits, the number of ha cultivated was much greater for cereals (36.82 billion) than fruits (1.72 billion) , which are cultivated on > 1 billion ha, than for sugar (n = 23) and beverage/spice crops (n = 13), which are cultivated on only 0.23 and 0.11 billion ha, respectively.Papers on disease models have been published for a wide range of crops . The maibillion) . In the d melons . The numn = 143) and potatoes (n = 80), which differ more in the cultivated area  than in produce value . Grapes (n = 51) and apples (n = 44) were also highly represented, and have little cultivated area  yet high produce value (each with > 90 billion $). For soybean and rice, with 120 and 162 million of cultivated ha, respectively, and 310 and 100 billion $ of produce value, respectively, there were only 38 and 30 papers, respectively. More papers were published for rapeseed (n = 33) than for rice, although the area cultivated (16 million ha) and produce value (36 billion $) were lower. A similar number of papers were published for citrus fruits (n = 28), which are cultivated on only 8 million ha, although with a similar produce value of 39 billion $.The crops represented by the largest number of papers were wheat (n = 20) and the produce value was not very different , however, the area cultivated was substantially greater for nuts than for berries . Few papers were also published concerning tomatoes (n = 19), onion (n = 18), sugar beet (n = 17), and barley (n = 17), which are grown on 5 million ha , and with values ranging from 92 billion $ for barley to 10.6 billion $ for sugar beet .For nuts and berries, the number of papers published was similar (n = 101). Forty-eight papers were published concerning viruses, and 17 papers for their vectors. A total of 44 papers were published for Bacteria, three of which focused on bacterial vectors. Animalia and Protista were considered in two and four papers, respectively. In total, 51 papers were classified as generic as the kingdom of the harmful organism (s) was not mentioned in the title, or as the models were not parametrized for specific pathosystems.The number of papers per pathogen kingdom are listed in n = 680), i.e., models that considered the effect of environment and/or agronomic variables on pathogen/disease development, or that determined the validity of models under epidemiological or cropping conditions different from those under which the models had been developed. Forty papers concerned the use of disease models for tactical management  and 38 concerned strategic planning ; only nine papers concerned the use of disease models as simulators and for scenario analysis  [The numbers of papers addressing disease management  is consistent with the observation of past reviews of plant disease models, which indicates that far more models are developed than are applied for practical disease management ,20,53,54em (DSS) .Venturia inaequalis primary infections on apples; although we classified the scope of both papers as system understanding (as they consider the effect of environment on disease development), Rossi et al. [A limitation of the current study is that in the development of the systematic map, we classified papers according to model, scope, and purpose based only on paper titles; it is therefore possible that some papers included additional scopes or purposes that were not indicated in their titles. For example, Rossi et al. ,61 deal In summary, our systematic map has identified a variety of areas for which there are knowledge gaps and has suggested questions that warrant further research. In particular, our systematic map has provided data that support two commonly made inferences: first, additional attention should be paid to the application of models for practical disease management; and second, increased efforts should be directed at development of disease models for essential crops . Moreover, our systematic map will help researchers identify cropping systems and locations that are sufficiently represented in the literature database to enable systematic review.


Worldwide parasites pose a serious threat to the health of both humans and animals, leading to large economic losses. Currently, the treatment of parasitic diseases mainly relies on chemotherapy, and antiparasitic drugs represent the second largest segment of the global animal health market with 23% of the market share . During in vivo and in vitro, especially for ectoparasites. After searching the web of science database, 284 papers related to anti-ectoparasite agents were published by Veterinary Parasitology, Frontiers in Veterinary Sciences, and other international journals worldwide from January 2015 to June 2020, and 204 papers (71.83%) aimed to find the active natural products or extracts from plants, 74 papers (26.06%) focused on essential oils  were derived from natural products . Notably5% were dAdonis coerulea in terms of its acaricidal activity using proteomics and surface plasmon resonance technology, which also is a sensitive and environmentally friendly analytical method  and Diospyros anisandra  are explained respectively, and the leishmanicidal activity of licochalcone A in vitro and in an experimental model of Leishmania (Leishmania) infantum was also proven . S-Methylcysteine (SMC) presented the ameliorate the intestinal damage Induced by Eimeria tenella Infection  and silver nanoparticles biosynthesized with Salvia officinalis leaf performed a protective effect on the hepatic tissue injury induced by Plasmodium chabaudi . Silva Bello et al. proved the prophylactic effects of ivermectin and closantel on Oestrus ovis infestation in sheep. Arfuso et al. and Li et al. also made contributions to this Research Topic. We are aware that the selection of papers is incomplete and does not do justice to the importance of the research field “Antiparasitic Activity and the Modes of Action of Natural Products and Traditional Medicines”. However, it does reflect to some extent where we currently are knowledge-wise, and the topic should receive more attention and be discussed by people.Our group established this Research Topic to present the development of antiparasitic activity and the modes of action of natural products and traditional medicines. Nine papers by 73 authors from nine different countries were published to perform the latest progress in their field, which will help us find more interesting topics. The anthelmintic activity against Currently, the development of new veterinary drugs is slow worldwide. It is important to explore new ways of finding more rational and effective strategies to screen novel active compounds: a crucial but not easy task. The discovery of new and promising antiparasitic agents from natural products and traditional medicines will be important for controlling parasites in the future.XS wrote the manuscript. AP and GI revised the manuscript. JZ supervised the manuscript. All authors contributed to the article and approved the submitted version.This work was financed by the National Natural Science Foundation of China (31772790) and the Innovation Project of the Chinese Academy of Agricultural Sciences (No. CAAS-ASTIP-2015-LIHPS).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


O-β-d-glucopyranosyl-4,6-dihydroxybenzaldehyde (GDHBA) was isolated from the Morus alba (mulberry) fruits and its inhibitory effect on MMP-1 secretion was revealed. In this study, we focused on the effect of GDHBA on TNF-α-induced human dermal fibroblasts (HDFs). GDHBA (50 μM) inhibited ROS generation (18.8%) and decreased NO (58.4%) and PGE2 levels (53.8%), significantly. Moreover, it decreased MMP-1 secretion (55.3%) and increased pro-collagen type I secretion (207.7%). GDHBA (50 μM) decreased the expression of different MAPKs as per western blotting; p-38: 35.9%; ERK: 47.9%; JNK: 49.5%; c-Jun: 32.1%; NF-κB: 55.9%; and cyclooxygenase-2 (COX-2): 31%. This study elucidated a novel role of GDHBA in protecting against skin inflammation and damage through external stimuli, such as UV radiation.Human skin is composed of three layers, of which the dermis is composed of an extracellular matrix (ECM) comprising collagen, elastin, and other proteins. These proteins are reduced due to skin aging caused by intrinsic and extrinsic factors. Among various internal and external factors related to aging, ultraviolet (UV) radiation is the main cause of photoaging of the skin. UV radiation stimulates DNA damage, reactive oxygen species (ROS) generation, and pro-inflammatory cytokine production such as tumor necrosis factor-alpha (TNF-α), and promotes ECM degradation. Stimulation with ROS and TNF-α upregulates mitogen-activated protein kinases (MAPKs), nuclear factor kappa B (NF-κB), and activator protein 1 (AP-1) transcription factors that induce the expression of the collagenase matrix metalloproteinase-1 (MMP-1). Moreover, TNF-α induces intracellular ROS production and several molecular pathways. Skin aging progresses through various processes and can be prevented through ROS generation and TNF-α inhibition. In our previous study, 2- The skin is the outermost organ and makes up approximately 10% of the human body. It is divided into three layers: epidermal, dermal, and subcutaneous tissues , with eaUV radiation is a major external factor causing photoaging of the skin; it induces DNA damage, denaturation of proteins, and production of reactive oxygen species (ROS) in the skin and triggers the degradation of the ECM . ROS plaUV radiation stimulates pro-inflammatory factors, such as tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), and interleukin 1 (IL-1) . TNF-α iO-β-d-glucopyranosyl-4,6-dihydroxybenzaldehyde (GDHBA) was isolated from maqui berry (Aristotelia chilensis) as a novel natural product, but the oxidative and inflammatory responses of this compound in human dermal fibroblasts (HDFs) damaged by UV radiation and TNF-α have not been elucidated [Morus alba fruits significantly inhibited MMP-1 secretion in TNF-α-stimulated HDFs [M. alba fruits, GDHBA exhibited an inhibitory effect on MMP-1 secretion and structural specificity. Therefore, the effects of GDHBA on oxidative and inflammatory responses in TNF-α-treated HDFs were evaluated in this study.In a previous study, 2-ucidated ,18,19. Ited HDFs . Furtherted HDFs . TherefoM. alba fruits inhibited MMP-1 secretion in TNF-α-induced HDFs [2 to investigate the possible suppression of GDHBA oxidation in HDFs.In our previous study, GDHBA  isolatedced HDFs , suggestFirst, HDFs were treated with TNF-α, which is both an oxidative stress stimulator and an inflammatory response inducer. The number of intracellular free radicals produced was measured to determine the level of oxidative stress. Dichlorofluorescein diacetate (DCFDA) was used as the probe. DCFDA, a non-fluorescent material, exhibits high fluorescence when de-esterified and oxidized in cells.p < 0.001) in TNF-α-induced HDFs compared to that in the normal control cells. Meanwhile, ROS production significantly decreased in the GDHBA treatment group compared to that in the TNF-α treatment group . These results indicate that GDHBA has ROS-scavenging activity.As shown in p < 0.01). NO production decreased in a concentration-dependent manner upon treatment with GDHBA compared to that in the TNF-α treatment group  (ROS-induced NO is an inflammatory mediator produced by nitric oxide synthase (NOS) and is associated with innate immunity . We asse: 58.4%) C.2 levels. TNF-α treatment increased the PGE2 level compared to that in the control group . PGE2 levels decreased in a concentration-dependent manner upon treatment with GDHBA compared to that of the TNF-α treatment group  (Prostaglandins (PGs) are involved in the inflammatory response; among them, PGE2 is synthesized by COX-2 . We exam; 53.8%) D.p < 0.001) compared to that in the normal control. GDHBA (50 μM) inhibited the TNF-α-induced increase in MMP-1 expression. MMP-1 secretion decreased upon treatment with GDHBA compared to that in the TNF-α stimulated group . We evaluated the effect of GDHBA treatment on COLIA1 and observed that TNF-α treatment decreased its secretion  compared to that of the normal control cells. Decreased COLIA1 concentration tended to increase by 207.7% after 50 μM GDHBA treatment compared to that of the TNF-α-stimulated group.Collagen is broken down by the collagenase MMP-1; thus, MMP-1 inhibitors may decrease collagen breakdown during skin damage. Therefore, we investigated whether GDHBA could prevent skin aging in TNF-α-stimulated HDFs. MMP-1 secretion increased by 1.70 ± 0.02-fold . However, phosphorylation levels of p38, ERK, and JNK decreased by GDHBA treatment in a concentration-dependent manner. 50 µM GDHBA significantly suppressed the phosphorylation of all MAPKs compared to that in the TNF-α-stimulated group . GDHBA (50 µM) suppressed p-p38 phosphorylation level by 35.9%. Moreover, p-ERK and p-JNK levels decreased in a concentration-dependent manner  .MAPK phosphorylated by UV radiation and TNF-α upregulates the expression of MMP-1 ,23; therp < 0.001; NF-κB: 10.01 ± 0.12-fold, p < 0.01; COX-2: 5.81 ± 0.03-fold, p < 0.001). However, phosphorylation of c-Jun, NF-κB and the expression of COX-2 decreased in the 50 µM GDHBA-treated group . Moreover, p-c-Jun and p-NF-κB levels decreased by GDHBA in a concentration-dependent manner   .TNF-α-induced excessive ROS expression increases the phosphorylation of c-Jun and NF-kB and the expression of COX-2 ,25,26. TM. alba fruits that inhibit collagenase expression.Humans experience intrinsic aging through hormonal changes or extrinsic aging through UV radiation, smoking, and chemicals. The skin is directly exposed to external environmental factors and undergoes aging . UV radiFibroblasts, which are mostly found in the dermal layer of the skin and produce ECM components, endure severe damage during the skin aging process . In agedM. alba fruit and the compounds isolated from the extract exhibited a protective effect against skin damage [A. chilensis); however, its biological and pharmacological effects have not been reported, except for its hydroxyl radical scavenging effect [In our previous study, the extract of n damage . As a fog effect . TherefoROS are formed as a result of normal cellular activity and participate in cell signaling . Cellula2, are stimulated. NO is an important regulatory and effector molecule with diverse biological functions [Inflammatory responses occur when inflammatory mediators, including TNF-α, NO, and PGEunctions . Low conunctions ,42. NO p2, one of the PGs, increases with aging and skin inflammation [2 synthesis, is upregulated by ROS and TNF-α [2 production to measure the anti-inflammatory response capacity of GDHBA treatment and found that GDHBA was effective in suppressing the TNF-α-induced increase in PGE2 levels  as previously described [GDHBA was isolated from escribed . BrieflyGDHBA was dissolved in 10 mM dimethyl sulfoxide . TNF-α  was dissolved in 1% bovine serum albumin fraction V  solution and stored at −20 °C.2 and 37 °C.HDFs were obtained from PromoCell GmbH . The cells were cultured in DMEM containing 10% fetal bovine serum  and 1% antibiotics. Subculturing was performed till the cells reached 80–90% confluency in 100 mm dishes. Cell culture was performed in an incubator maintained at 5% CO4 cells/well) and incubated for 24 h; the culture medium was changed to serum-free medium (DMEM without FBS) and incubated for 24 h. Then, the cells were treated with a specific concentration (μM) of GDHBA and incubated for 24 h. To evaluate the cytotoxicity of GDHBA, the supernatant was discarded, 10% EZ-Cytox solution in serum-free medium  was added, and the plate was incubated for 1 h. Absorbance was measured using a SPARK 10M microplate reader  at 450 nm.HDFs were plated in clear bottom 48-well cell culture plates (2 × 104 cells/well) and incubated for 24 h; the culture medium was changed to serum-free medium (DMEM without FBS) and incubated for 24 h. The cells were treated with 5, 10, and 50 μM GDHBA for 1 h before exposure to 20 ng/mL TNF-α for 24 h. Absorbance was measured using a SPARK 10M microplate reader at 450 nm.HDFs were plated in clear bottom 48-well cell culture plates (2 × 104 cells/well) and incubated for 24 h; the culture medium was changed to serum-free medium (DMEM without FBS) and incubated for 24 h. Then, the cells were treated with 5, 10, and 50 μM GDHBA for 1 h before exposure to 20 ng/mL TNF-α and 10 μM DCFDA (Sigma-Aldrich) for 15 min. Fluorescence was measured using a SPARK 10M microplate reader at 485/535 nm.HDFs were plated in 96-well black plates (1 × 104 cells/well) and incubated for 24 h; the culture medium was changed to serum-free medium (DMEM without FBS) and incubated for 24 h. The cells were treated with 5, 10, and 50 μM GDHBA for 1 h before exposure to 20 ng/mL TNF-α for 24 h. Griess assay was performed to measure the concentration of nitrite in the supernatant. The supernatants were incubated with 1% sulfanilamide, 0.1% N-(1-naphthyl)-ethylenediamine, and 5% phosphoric acid for 10 min at room temperature. Nitrite content was measured using a SPARK 10M microplate reader at 540 nm. The level of NO produced in each sample was determined using a standard sodium nitrite (NaNO2) curve.HDFs were plated in 96-well black plates (1 × 105 cells/well) and incubated for 24 h; the culture medium was changed to serum-free medium (DMEM without FBS) and incubated for 24 h. The cells were treated with 5, 10, and 50 μM GDHBA for 1 h before exposure to 20 ng/mL TNF-α for 15 min or 6 h. Cell samples for the investigation of MAPK, c-Jun, and NF-κB expression were exposed to TNF-α for 15 min, and the samples for the investigation of COX-2 expression were exposed to TNF-α for 6 h. After washing with DPBS, the cells were lysed using 1× radioimmunoprecipitation assay (RIPA) buffer . The protein concentration was quantified using a BCA Protein Assay Kit . Equal amounts of protein were loaded onto polyacrylamide gels and separated by electrophoresis. The proteins were then transferred onto polyvinylidene difluoride (PVDF) membranes. The membrane was placed in TBS-Tween20  containing 5% skim milk and allowed to react for 1 h. Primary and secondary antibodies were incubated overnight at 4 °C and room temperature, respectively, for 2 h.HDFs were plated in clear bottom 6-well cell culture plates (3 × 10® West Femto Maximum Sensitivity Chemiluminescent Substrate (Thermo Fisher Scientific) and a Fusion Solo Chemiluminescence System . Protein bands were quantified using the ImageJ program .Finally, protein bands were observed using Super Signalp < 0.05.GraphPad Prism version 8.0.1 , a statistical program, was used to analyze the experimental results. Data are expressed as mean ± standard error of the mean (SEM). After analysis by one-way ANOVA, statistical significance was confirmed by Tukey’s test at M. alba fruit, on damage to TNF-α-induced HDFs. GDHBA decreased oxidative stress-induced ROS levels in TNF-α-stimulated HDFs and decreased the expression of the inflammatory mediators NO and PGE2. It also inhibited MMP-1 expression and increased COLIA1 secretion. GDHBA suppressed the phosphorylation of p38, ERK, JNK, c-Jun, and NF-κB and the expression of COX-2. Thus, GDHBA suppressed the damage in HDFs by regulating oxidative and inflammatory responses under TNF-α-stimulated conditions. Although additional experiments are needed to understand the effects of GDHBA on skin damage, it is a potential agent that can ameliorate skin damage and prevent anti-inflammatory effects.We investigated the effect of GDHBA, isolated from


Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome frequently seen in elderly patients, the incidence of which is steadily increasing due to an ageing population and the increasing incidence of diseases, such as diabetes, hypertension, obesity, chronic renal failure, and so on. It is a multifactorial disease with different phenotypic aspects that share left ventricular diastolic dysfunction, and is the cause of about 50% of hospitalizations for heart failure in the Western world. Due to the complexity of the disease, no specific therapies have been identified for a long time. Sodium-Glucose Co-Transporter 2 Inhibitors (SGLT2-Is) and Glucagon-Like Peptide Receptor Agonists (GLP-1 RAs) are antidiabetic drugs that have been shown to positively affect heart and kidney diseases. For SGLT2-Is, there are precise data on their potential benefits in heart failure with reduced ejection fraction (HFrEF) as well as in HFpEF; however, insufficient evidence is available for GLP-1 RAs. This review addresses the current knowledge on the cardiac effects and potential benefits of combined therapy with SGLT2-Is and GLP-1RAs in patients with HFpEF. HFpEF is not a well-defined clinical entity, but a multifactorial disease. It is an amalgam of cardiovascular (CV), metabolic, renal, and geriatric conditions ,2, with Type 2 diabetes mellitus (T2DM) and heart failure (HF) frequently occur together ,5. The pThe pathophysiology of HF in diabetic patients is complex. “Diabetic cardiomyopathy”, defined as ventricular systolic or diastolic dysfunction in the absence of other causes , is an increasingly recognized entity . SeveralEspecially in view of the emerging cardiometabolic phenotypes , GLP-1RA and SGLT2-Is are receiving increasing attention as potential therapeutic strategies in HFpEF because of their glucose-lowering, anti-inflammatory, and anti-remodeling effects. Indeed, GLP-1RAs and SGLT2-Is have been shown to reduce the risk of CV events in T2DM patients because of several proposed protective mechanisms . TherefoIn this review, we summarise the current evidence on the potential benefit of GLP-1 RAs and SGLT2-Is in patients with HFpEF, especially in those with high cardio-nephro-metabolic risk.Multiple mechanisms lead to HFpEF, including dysfunction in atrial and ventricular active relaxation, increased passive stiffness, and reduction in arterial compliance. Moreover, the presence of endothelial oxidative stress is associated with a decreased nitric oxide (NO) bioavailability, which causes vasoconstriction and enhances a pro-inflammatory and pro-thrombotic state. The cardiac remodeling is affected by changes in the composition and structure of the extracellular matrix with fibrillar collagen deposition. In such a scenario, the LV diastolic dysfunction is the final disease expression of heterogeneous phenotypes and clinical presentations .Hypertension is the steadfast underpinning of HFpEF. Ageing, obesity, pulmonary hypertension (PH), and coronary artery disease affect HFpEF presentation and progression ,22. TheiAgeing Phenotype: Age is a major risk factor for HFpEF [or HFpEF ,25. Manyor HFpEF ,27. Ageior HFpEF ,29. Clinor HFpEF .Obesity Phenotype: Obesity, defined as an elevated body mass index  >30, is a recognized risk factor for new onset of HFpEF [2) [of HFpEF ,32 sinceof HFpEF , and LV of HFpEF . In addiof HFpEF . About 6FpEF [2) . It has FpEF [2) ,38. T2DM is strictly linked to obesity and to the development of HFpEF. The 49% of 5988 patients constituting the study sample of the EMPEROR-Preserved trial was affected by diabetes . This grPulmonary Hypertension Phenotype: The main leading cause of pulmonary venous hypertension (type 2) is increased pressure in the left atrial. In HFpEF, the right ventricular structure and function deteriorate over time; such deterioration is associated with coronary heart disease, obesity, atrial fibrillation, increased pressure pulmonary venous, and increased left heart filling pressures. When the left ventricular filling pressures increase, there is an increased afterload of the right ventricle, resulting in a remodelling of the pulmonary vascular system. Therefore, it becomes essential to carefully evaluate diuretic therapy in patients with HFpEF in an attempt to normalize pressures at the level of the left heart [ft heart . Ischemic Heart Disease Phenotype: In contrast to HFrEF, where obstructive coronary artery disease (CAD) is a significant illness determinant and needs specific management, ischemic myocardial injury does not play an essential role in the pathophysiology of HFpEF [of HFpEF ,45. Thouof HFpEF ,47, acutof HFpEF . Althougof HFpEF . In a reof HFpEF . It is, The integration of clinical data, biomarkers, and electrocardiographic and echocardiographic parameters is necessary to set up a correct therapeutic strategy for the whole spectrum of patients with HFpEF. Such integration is very complex; therefore, ways of phenotyping guided by mathematical/statistical algorithms, the so-called “machine learning”, of which a “cluster” analysis was first proposed by Shah et al. in 2015, represent the first example for outlining pheno-groups that may be a therapeutic target for randomized clinical trials in the future . For exaThe identification of glucagon-like peptide-1 (GLP-1), belonging to the family of gut-derived incretin hormones, paved the way years ago to the development of GLP-1 RAs, with the intention of enlarging the armamentarium of therapeutic options for T2DM. This new class of drugs, which is initially made up of short-acting compounds  and subsequently includes new second-generation molecules that are administered once weekly , has shortly been demonstrated to have several vascular actions going beyond the mere anti-hyperglycemic effects. Consequently, a number of experimental and clinical studies have been conducted over time, aiming at better understanding the pathophysiological mechanisms underlying the beneficial CV effects (mainly on atherosclerotic CV disease) observed in some dedicated CV outcomes trials with GLP-1 RAs ,54,55,56At the pathophysiological level, since GLP-1 RAs are expressed in endothelial cells, as well as in monocytes, macrophages, and vascular smooth muscle cells, native GLP-1 exerts a number of diverse actions on the vasculature . As a maAccordingly, animal models of accelerated atherosclerosis have confirmed the diverse beneficial effects of GLP-1 RAs on plaque progression, including reducing plaque hemorrhage, preserving the integrity of the fibrous cap, and preventing plaque rupture . NoteworTaken together, all this evidence supporting the significant role of GLP-1 receptor stimulation against the atherosclerotic process provides solid grounds for the preferential use of GLP-1 RAs in diabetic patients with or at high risk of atherosclerotic CV diseases. New research is on the way to explore the potential synergistic (additive?) effects of GLP-1 RAs with other classes of drugs with proven CV benefits, such as SGLT-2 Is, in an attempt to further improve CV protection in patients with T2DM .Sodium-glucose cotransporter 2 belongs to a family of glucose transporter proteins localized in the first segment of the proximal renal tubule and responsible for the majority of filtered glucose and sodium reabsorption. SGLT2-Is are a novel class of drugs for the treatment of T2DM and HF ,81,82.Maximal glucose tubular transport (TmG) in healthy adult men is approximately 375 mg/min, which corresponds to 300 mg of glucose per day ,84,85. BIn patients with T2DM, the expression of SGLT2 receptors in the proximal tubule is higher than healthy individuals . During CV beneficial effects of SGLT2-Is include positive hemodynamic effects with a reduction in preload and afterload and improved cardiac contractility, related not only to the increased diuresis and natriuresis, but also to nephron remodeling, endothelial function improvement and, through glycosuria, also loss of body weight and adipose tissue with reduced insulin resistance ,97,98. ACurrent clinical practice guidelines strongly recommend the use of SGLT2-Is in the treatment of patients with HFrEF (Class I). However, these guidelines still make a weaker recommendation for their use in HF with mildly reduced or preserved ejection fraction, based on the data of the DELIVER that have been published recently . A recen2. Reno-protection was also consistent across studies, irrespective of baseline albuminuria and use of RAS blockade [In clinical trials, SGLT2-Is reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with T2DM and also provided protection against acute kidney injury with consistent benefits across studies. These data provide substantive evidence supporting the use of SGLT2-Is to prevent major kidney outcomes in people with T2DM. The trials that determined these conclusions included the EMPA-REG OUTCOME for Empagliflozin, the CANVAS Program and CREDENCE for Canagliflozin, and the DECLARE–TIMI 58 for Dapagliflozin. Although there was evidence that the proportional effect of SGLT2-Is might attenuate with declining kidney function, there was clear, separate evidence of benefit for all estimated glomerular filtration rate (eGFR) subgroups, including in participants with a baseline eGFR 30–45 mL/min per 1.73 mblockade . As it hblockade . Canagliblockade . Ertugliblockade . The exablockade   [Verma et al. reported the effects of a 3-month Empagliflozin (10 mg/day) treatment in terms of heart function. In 10 patients with T2DM and established CV disease, treatment with Empagliflozin was associated with a significant reduction in LV mass index and improved LV diastolic function, as assessed in terms of lateral e′  . HoweverA small study that evaluated the effect of Canagliflozin on LV remodeling in DM patients with HF showed that LV filling pressure, as assessed using a tissue Doppler, decreased significantly after 6 months of treatment, and the effect was maintained even after 12 months of therapy. Many other mechanisms may be responsible for the improvement of LV diastolic function. From those, the reduction of preload, the improvement of endothelial dysfunction and aortic stability, the reduction of epicardial fat accumulation, and the hypertrophy of visceral adipocytes are very important ,120,121.GLP-1 RAs also have positive effects on LV diastolic function. Bizino et al. demonstrated that the administration of liraglutide reduced early LV diastolic filling and LV filling pressure . GLP-1 RCoenraad Withaar et al., in a multi-hit mouse model of HFpEF showed that treatment with liraglutide reduces cardiometabolic dysregulation; improves cardiac function; reduces myocardial hypertrophy and fibrosis; and reduces atrial volume, natriuretic peptide levels, and pulmonary congestion. Although it is not yet clear what is the true cardioprotective mechanism of GLP-1 RAs in diabetic patients with HFpEF or in diabetic patients at high risk of HFpEF, the authors are in agreement with the hypotheses that have been previously formulated in other experimental and clinical studies: the beneficial effects on the heart arise not only from a reduction in body weight, LV mass, and cardiac stiffness; but they also come from the direct effects of GLP-1 RAs on the CV system deriving from natriuresis, the central and peripheral vasodilation, and a reduction in both blood pressure and cardiac fibrosis. GLP-1 RA may postpone the onset of HFpEF as it may delay the onset of diabetic cardiomyopathy .HFpEF is a multifactorial disease with different phenotypic aspects; therefore, due to the high complexity of this syndrome, therapies targeting the sympathetic and RAA system activation have not shown mortality benefit in HFpEF. The pharmacological treatment of HFpEF represents the biggest ‘unmet medical need’ in the scientific community, and not only in the CV community. In recent years, various consensus documents have outlined the different modalities applicable to the phenotyping of patients with HFpHF. This underscores how the “one size fits all” is not suitable for patients with HFpEF, and it is necessary for therapeutic strategies to be individualized through the identification of the clinical phenotypes of the disease. Currently, therapies for HFpEF are often limited to something to improve the symptoms.People affected by diabetes have a high risk of developing HFpEF and vice versa, suggesting shared pathophysiological mechanisms exist; this, in turn, engenders the potential for common treatments. In fact, T2DM is closely associated with microvascular complications and microvascular dysfunctions, and plays an important role in the onset of HFpEF.SGLT2-Is, which started as antidiabetic drugs, have become one of the key pillars of HFrEF therapy due to their positive pleiotropic effects on the kidney, liver, pancreas, blood vessels, and adipose tissue. The EMPA-REG OUTCOME showed that Empagliflozin treatment of DM patients had no significant effect on hemodynamic parameters during the three months of therapy, but induced rapid and sustained improvement in LV diastolic function (E/e′) . ProscriThe use of Dapagliflozin resulted in a significant reduction in LV filling pressure as estimated by E/e′ during exercise in patients with type 2 DM.The EMPEROR-Preserved was the first study on HFpEF that compared Empaglifozin vs. placebo in patients with EF > 40%, regardless of the presence of diabetes, and demonstrated a reduction in the risk of HF-related hospitalizations and CV mortality and an improvement in renal outcomes. In fact, previous studies, such as the CHARM-Preserved (with candesartan), the TOPCAT (with spironolactone), and the PARAGON HF , did not document a significant treatment benefit over placebo in this clinical setting. The EMPEROR-Preserved trial is a real revolution in the treatment of HFpEF because, after years of inconclusive studies of drugs used in such condition, its results offer for the first time the potential benefit of improving outcomes and quality of life in HFpEF patients .The recent DELIVER trial demonstrated that Dapagliflozin is effective compared to placebo in reducing CV death and HF hospitalizations in patients with mildly reduced or preserved ejection fraction, and in patients with previous <40% EF which subsequently increased above 40% , openingOther antidiabetic drugs that have demonstrated positive CV effects are GLP-1 RAs. In previous randomized controlled trials with patients with T2DM, liraglutide, semaglutide, and duraglutide have been shown to reduce CV mortality, but not the incidence of HF or hospitalization for HF. A growing body of evidence shows a significant beneficial effect of GLP-1 RAs on LV diastolic function in patients with T2DM. Studies that examined patients with T2DM and without CV disease demonstrated that liraglutide reduces LV filling pressure  and imprSGLT2-Is and GLP-1 RAs could be important weapons in the therapy of HFpEF, but to date, the data are poor because there is still a lack of studies evaluating the effects of their combined treatment. The goal should be to provide unambiguous clinical evidence in order to improve the effectiveness of the therapeutic armamentarium for the prevention and treatment of CV and renal diseases in cardio-metabolic high-risk patient, in order to improve organ damage and reduce CV morbidity and mortality. Therefore, what is the optimal therapy for HFpEF? Certainly, it is crucial to treat the cause of HFpEF and control all comorbidities, not only with medical therapy but also with changes in lifestyle habits. A future challenge will be to try to tailor an appropriate treatment strategy specific to the phenotype-dominant disease in individual patients.


The LBBAp was successful in 83% (35/42) of patients, with satisfactory pacing thresholds (0.8 ± 0.2 V at 0.4 ms). In the LBBAp group, the mean paced-QRS duration obtained during RV apical pacing (173 ± 18 ms) was significantly reduced by LBBAp . Compared with the RVp group, the LBBAp group showed more physiological pacing, suggested by a much narrower paced-QRS duration . The pacing threshold was comparable in both groups. The LBBAp group revealed stable pacing thresholds for 6.8 ± 4.8 months post-implant and no serious complications including lead dislodgement or septal perforation. The novel approach of LBBAp using SDES leads and the new dedicated pre-shaped delivery sheaths was effectively and safely performed, even by inexperienced operators with LBBAp procedures.Until recently, left bundle branch area pacing (LBBAp) has mostly been performed using lumen-less fixed screw leads. There are limited data on LBBAp with conventional style-driven extendable screw-in (SDES) leads, particularly data performed by operators with no previous experience with LBBAp procedures. In total, 42 consecutive patients undergoing LBBAp using SDES leads and newly designed delivery sheaths (LBBAp group) were compared with those treated with conventional right ventricular pacing (RVp) for atrioventricular block (RVp group,  Cardiac conduction system pacing such as His-bundle pacing (HBp) and left bundle branch area pacing (LBBAp) is considered a more physiological treatment for patients with symptomatic bradycardia compared with conventional right ventricular pacing (RVp), which is frequently associated with ventricular dyssynchrony, pacing-induced cardiomyopathy, and higher mortality ,2. PriorSince Huang et al.  addresseMost LBBAp procedures have been performed using lumen-less fixed screw (LLFS) pacing leads  delivered through pre-shaped or steerable guiding sheaths  undergoing LBBAp procedures were prospectively enrolled (LBBAp group) for the present study. The LBBAp group was matched to a control group with conventional RVp (RVp group) using a propensity score (PS) at a ratio of 1:2. Patients in the RVp group were selected among those who underwent permanent pacemaker (PPM) implantation for symptomatic bradyarrhythmia from January 2019 to February 2022. To compare the immediate post-implant p-QRSD, only patients with a de novo PPM implant for atrioventricular block (AVB) were included in the control RVp group. We excluded patients with sinus node dysfunction (SND) without AVB or replacement procedures . Leadlesn = 32), targeting of LBBA was performed using the “9-partition method”, without His signal mapping [The thickness of the basal interventricular septum was assessed by echocardiography prior to procedures. LBBAp was performed using SDES pacing leads  and specifically designed, fixed-curve delivery sheaths . The Selectra 3D sheaths with three primary curves  were available. The 12-lead electrocardiograms and the intracardiac electrograms from the pacing lead in a unipolar configuration were continuously recorded. The procedure was performed in a similar way as previously described ,16,17,18 mapping ,15,18. U mapping . Success mapping ,20. ContAfter the LBBAp procedures, p-QRSD was measured at a sweep speed of 100 mm/s by LBBAp and by RV apical pacing (RVAp) with a temporary pacing wire E. In pat2, body surface area, hypertension, diabetes mellitus, heart failure, myocardial infarction, previous heart surgery, atrial fibrillation/flutter, chronic renal failure, LV ejection fraction (LVEF), and LV end-diastolic dimension. The LBBAp and RVp groups were matched in a 1:2 ratio using a nearest-neighbor model based on PS. The Mann–Whitney test was used for comparison of p-QRSD, pacing threshold, or pacing impedance between the LBBAp and RVp groups. Statistical analyses were performed using the statistical package SPSS 25.0 software .Categorical variables are presented as counts with percentages and were compared using Fisher’s exact test. Continuous variables are presented as means with standard deviations. Change in p-QRSD (during RVAp and LBBAp) or pacing threshold (at baseline and during follow-up) in the same patients was tested using the Wilcoxon signed-rank test (only in the LBBAp group). The PS was estimated using a regression model with the following baseline variables: age, sex, heightIn the LBBAp group, LBBAp was attempted as a first-choice pacing strategy in 42 patients . The indn = 224), SND without AVB (n = 324), a leadless pacemaker (n = 28) or a biventricular pacemaker (n = 184) were excluded. Of the remaining 244 patients with de novo PPM implantation for AVB, 84 were selected by PS matching and analyzed as the RVp group. Depending on the location of the RV pacing lead (RV septum or apex), the RVp group was subdivided into RVSp  or RVAp  subgroups. After PS matching, no significant differences in baseline characteristics were observed between the two groups (We selected the RVp (control) group out of 1046 patients who received PPM implantation between January 2019 and February 2022 . First, o groups .p < 0.001) (p < 0.001).Of the 42 patients who underwent LBBAp procedures, 35 (83%) met the criteria of success with satisfactory pacing thresholds (0.8 ± 0.2 V at 0.4 ms pulse width) and impedances (645 ± 103 Ω). The mean p-QRSD by using LBBAp was 116 ± 14 ms, which was significantly reduced, compared with that by using RVAp in the same patients  A. The mep = 0.299). When patients were divided into the first- and second-half groups, the procedure and fluoroscopic times were significantly reduced in the second-half group, compared with the first-half group  in 2 patients, middle-sized (55 mm) in 24 patients, and large-sized (65 mm) in 16 patients. For each patient, 1.5 ± 0.6 delivery sheaths were used.Two leads were damaged during the procedures. In one case, the extension–retraction function was impaired, suggesting inner coil breakage. In the other case, the screw was overstretched during unscrewing for repositioning. In contrast, in a patient who required four cycles of repositioning (screwing/unscrewing), the screw remained intact until the final successful implant.p = 0.132.There was no septal perforation, lead dislodgement, or new-onset pericardial effusion before discharge and during a short-term follow-up of 6.8 ± 4.8 months, except for one case of dislodgement that occurred during sheath slitting. Follow-up pacing threshold was measured in 33 of 42 patients in the LBBAp group and it remained low and stable; baseline vs. follow-up, 0.8 ± 0.2 vs. 0.9 ± 0.2 V at 0.4 ms, n = 84), the LBBAp group (n = 42) showed more physiological ventricular pacing, suggested by a much narrower-paced QRS duration . Even if the RVp group was divided into RVAp (n = 31) and RVSp (n = 53) subgroups, the p-QRSD was significantly shorter in the LBBAp than in either of the RVp subgroups (p = 0.001), suggesting that more physiological ventricular contraction was achieved by using LBBAp.When compared with the RVp group  the success rate of LBBAp using SDES leads and new pre-shaped sheaths was high , with satisfactory pacing thresholds (0.8 ± 0.2 V at 0.4 ms) even by operators who had not performed any LBBAp procedure using LLFS or SDES leads, and the procedure/fluoroscopic times were significantly reduced with repeated procedures; (2) short-term safety of LBBAp with this new approach was demonstrated without significant complications such as septal perforation, lead dislodgement, pericardial effusion, or pneumothorax; and (3) more physiological ventricular pacing suggested by narrower p-QRSDs was achieved by LBBAp, compared with RVp, without compromising pacing threshold or impedance.p = 0.834), without lead revision. Additionally, screwing attempts, screw implant depth, procedural/fluoroscopy times, and bipolar pacing thresholds  were comparable between the two lead systems. In line with the previous studies, our results indicate that LBBAp using SDES leads and new fixed sheaths was effective and safe with implant success rate, p-QRSD, and pacing thresholds or impedances comparable to those of previous reports.Previously, conduction system pacing such as HBp or LBBAp was performed using LLFS leads and Medtronic pre-shaped C315HIS) or steerable guiding sheaths (C304) ,11,12,21HIS or stn = 11, procedural time 55 ± 22 min, and fluoroscopic time 18 ± 10 min). Most of our patients had impaired LBB conduction (AVB or LBBB), and we did not use the “dual lead technique” developed by Huang et al., which probably led to the lower rate of LBB potential recording  in our study than that in the previous report [Our bipolar pacing threshold (0.8 ± 0.2 V) seemed to be slightly higher than the previous data (0.6 ± 0.1 V) . Howevers report . The meaAlthough the SDES lead (5.6 Fr) has a slightly greater diameter than the LLSF lead (4.1 Fr), screwing the SDES leads into the septal myocardium was effective without causing septal perforation. However, there were two cases where the extendable–retractable screw was broken during lead repositioning. Therefore, careful handling of the SDES leads may be needed during repositioning. In addition, simple recommendations to avoid this risk were previously reported by le Polain de Waroux et al. as follows: do not further rotate the lead if no progression is observed, never remove the stylet insertion tool before the lead reaches its final position, and never try to unscrew the helix before repositioning .The RVAp-induced QRS widening is one of the well-known risk factors for LV dyssynchrony, pacing-induced cardiomyopathy, and long-term poor prognosis ,2,24. ThWe acknowledge that the present study has several limitations. First, a small number of patients was analyzed for a short duration. Therefore, we were not able to investigate specific factors to help operators select an optimal-sized primary curve of the Selectra 3D sheaths for each patient. However, our data are one of the largest LBBAp cohorts performed using the new approach. In addition, there was no chance to perform the right-sided subclavian implantation; accordingly, we cannot provide data on the right-sided approach. In a previous study, repetitive lead dislodgment was reported while slitting the right-sided delivery sheath. The authors also experienced the rotation of the lead being hindered by the over-torqued right-sided sheath . TherefoLBBAp using stylet-driven extendable screw-in pacing leads and the new pre-shaped delivery sheaths is feasible and safe without acute, significant complications, even when performed by operators with no previous experience with LBBAp procedures. LBBAp provided more physiological ventricular pacing, compared with conventional RVp, with remarkably narrower p-QRSD without compromising pacing threshold or impedance.


Endothelial inflammation is recognized as a critical condition in the development of cardiovascular diseases. TNF-induced inflammation of endothelial cells is linked to the formation of lipid droplets, augmented cortical stiffness, and nanostructural endothelial plasma membrane remodelling, but the insight into the mechanism linking these responses is missing. In the present work, we determined the formation of lipid droplets (LDs), nanomechanical, and nanostructural responses in the model of TNF-activated vascular inflammation in the isolated murine aorta using Raman spectroscopy, fluorescence imaging, atomic force microscopy (AFM), and scanning electron microscopy (SEM). We analysed the possible role of Rac1, a major regulator of cytoskeletal organization, in TNF-induced vascular inflammation. We demonstrated that the formation of LDs, polymerization of F-actin, alterations in cortical stiffness, and nanostructural protuberances in endothelial plasma membrane were mediated by the Rac1. In particular, we revealed a significant role for Rac1 in the regulation of the formation of highly unsaturated LDs formed in response to TNF. Inhibition of Rac1 also downregulated the overexpression of ICAM-1 induced by TNF, supporting the role of Rac1 in vascular inflammation. Altogether, our results demonstrate that LDs formation, an integral component of vascular inflammation, is activated by Rac1 that also regulates nanomechanical and nanostructural alterations linked to vascular inflammation.The online version contains supplementary material available at 10.1007/s00018-022-04362-7. Mechanistic insight into multiple changes at the biochemical, mechanical, and structural levels that occur inside the endothelium in vascular inflammation is important for understanding the mechanisms of cardiovascular diseases. Inflammation of endothelial cells (ECs) induced for example by a pro-inflammatory cytokine tumour necrosis factor (TNF) results in a broad spectrum of endothelial responses including the activation of the polymerization process of F-actin in ECs , decreasRas homologous (Rho) protein family, belonging to small guanosine–trisphosphate binding proteins (GTPases), are considered to be central regulators of actin reorganization and consequently function in cell migration, adhesion, polarity, membrane trafficking and cytokinesis , 12. IntLDs are defined as spherical cytoplasmic inclusions rich in triacylglycerols and cholesterols, surrounded by a phospholipid monolayer membrane including the proteins . LDs werIn this work, we investigated whether Rac1 activation is involved in LDs biogenesis in endothelial inflammation as well as in mechanism linking LDs formation with nanomechanical and nanostructural alterations of the TNF-induced inflammatory state of ECs inside isolated blood vessels. Using the combination of techniques: Raman spectroscopy, fluorescence imaging, atomic force microscopy (AFM) and scanning electron microscopy (SEM) demonstrated that the formation of LDs, the polymerization of F-actin, changes in cortical stiffness, and nanostructural response to TNF stimulation were Rac1-dependent.Detailed and expanded methods are included in the Supplementary Information.TNF), atglistatin , or Rac1 inhibitor: NSC23766 trichydrochloride .Briefly, the aorta were isolated from C57/BL/6 J mice, cleaned from the surrounding tissue, cut into rings and transferred to medium , 1% non-essential amino acids and 20% fetal bovine serum). The aortic rings were then incubated in the absence or presence of murine TNF-α , AFM, and SEM imaging, while the non-fixed aorta was used for AFM-based nanoindentation measurements. Immunostaining of ICAM-1 expression was performed in cross sections of the aorta.For Raman, fluorescence, AFM, and SEM measurements en face aorta preparations were used as described before , 26. Brica. 30 mW), a laser with the excitation wavelength of 532 nm, and 0.4 s exposure time per spectrum. The nominal minimal horizontal and vertical resolution for our setup is 0.32 and 0.53 μm, respectively, and sampling density of 0.40–0.50 and 1.0 μm in x/y and z direction, respectively, were used. The cortical stiffness of the endothelium was determined using an atomic force microscope  equipped with a feedback-controlled heating device . To exclusively determine the stiffness of the endothelial cell cortex, soft triangular cantilevers  with a nominal spring constant of 0.03 N/m and a polystyrene sphere (10 µm) as a tip were used.Raman and AFM imaging was carried out using a WITec Confocal Raman Imaging system . Raman spectra of tissues were collected with the application of a 63 × water immersive objective , using the maximum laser power at the sample position , or TNF in the presence of atglistatin and NSC23766 (TNF + Atgl + NSC23766). In immunohistochemical staining, PECAM-1 is used primarily to demonstrate the presence of endothelial cells and visualisation of the shape of EC based on endothelial cell intercellular junctions. The images of PECAM-1 staining did not show any visible differences in comparison to control, indicating the preserved integrity of the endothelial layer in the blood vessel in all studied conditions .en face aorta stimulated by TNF + Atgl  confirmed the presence of LDs in the endothelial layer of the aortic wall. This was evidenced by the mutual position of the signals from the LDs and the PECAM-1, indicating endothelial cell intercellular junctions [To confirm that LDs were located in the endothelium, 3D fluorescence and Raman imaging were provided Fig. . Fluoresunctions  3 choline group, respectively [To study the composition of LDs formed in ECs or SMCs in response to TNF, the single Raman spectra were extracted from the core of each LDs and then averaged. Such obtained single spectra , and average Raman spectra (with denoted standard error of mean showing heterogeneity) of LDs localised in ECs or SMCs are presented in Fig. brations  indicateectively .−1, assigned to the in-plane C=C–H bending, C=C stretching and =C–H stretching modes, respectively [2) intensity ratio obtained by integration of the respective Raman bands (1662/1446 cm–1) and fitted to a calibration curve for unsaturated fatty acids  [−1 (S–S stretching vibrations of disulphide bonds in the elastin structure) [ca. 1666 and 2940 cm−1 indicated the presence of protein components. It is presumed that the Raman signal of proteins in the spectra of LDs in SMCs came mainly from elastin fibres, as the basal membrane, composed mostly of elastin, was a border between ECs and SMCs.The representative Raman spectra of LDs localised in SMCs, in comparison to the Raman spectrum of elastin (green spectrum) are presented in Fig. alanine) , 943  , 860  , and 528ructure) , as wellen face aorta stimulated by TNF, the AFM was used. Force–distance curves analysis allowed for studying the effects of structural changes of the sub-membranous F-actin architecture on TNF response, and characterizing the cortical stiffness of ECs. In general, a two-stage response in endothelial cortical stiffness was evoked by TNF stimulation: a short incubation with the cytokine (1–2 h) did not cause changes (1.22 ± 0.07 pN/nm), while longer incubation  resulted in significantly increased cortical stiffness of aortic ECs  in comparison to unstimulated cells (1.21 ± 0.07 pN/nm). However, stiffness after 48 h was reduced in relation to 24 h of incubation , hence, ECs within en face aorta were stained for F-actin fibres and nucleic acids . The images of phalloidin-stained TNF-stimulated ECs confirmed the formation of thicker bundles and induction of F-actin polymerisation, as evidenced by higher phalloidin-specific fluorescence intensity Fig. C. This rTo test whether the Rac1 was involved in alterations in nanomechanical properties of ECs inside isolated blood vessels in response to TNF, we blocked Rac1 activity by NSC23766, which resulted in a significant decrease in cortical stiffness in ECs stimulated with TNF + NSC23766 (1.26 ± 0.03 pN/nm), in comparison to TNF alone . On the surface of TNF-activated ECs inside the blood vessels, we repeatedly observed nanomechanical alterations by AFM imaging, in comparison to the control; however, they were absent in ECs stimulated with TNF in the presence of the Rac1 inhibitor , which represented a small area of interest, in comparison to scanning electron microscopy imaging (SEM). SEM imaging confirmed the existence of nanostructural protuberances in the large region (250 × 250 µm per image) of TNF-activated ECs inside isolated blood vessels, in comparison to the control , were all associated with the ongoing inflammation of ECs within ied Fig. . A repreied Fig. C, and inied Fig. F, in comied Fig. A. Neitheied Fig. B nor atgied Fig. E increasied Fig. D, as welied Fig. G.Fig. 6EIn the present work, we demonstrated that in the isolated murine vessel stimulated with TNF, a reliable model of vascular inflammation, biogenesis of LDs was mediated by Rac1-dependent pathway and was correlated to parallel changes in nanomechanical and nanostructural properties of endothelial cells including augmented cortical stiffness, cytoskeleton remodelling, and protuberances in the nanostructure of endothelial surface. In the present work, we not only underscored the indispensable role of Rac1 in the dynamic formation of LDs in endothelial inflammation but also a tight control of LDs degradation by ATGL. Indeed, the chemical composition of LDs in TNF-induced endothelial inflammation in the aorta could be studied in detail only in the presence of ATGL inhibition to prevent dynamic disappearance of LDs in the stimulated endothelium by a pro-inflammatory cytokine.2 (PLA2) activation in response to a variety of stimuli, including cytokines was reported in the literature [2–AA cascade in the formation of LDs and eicosanoid biosynthesis in the vascular wall. In previous studies, LDs formation was linked to PGI2 generation [The major finding of this work was the demonstration that Rac1 signalling is involved in the formation of LDs , and negligible content of cholesterols and phospholipids Fig.  with LDsAn interesting finding of this work to detect that TNF-induced LDs (in the presence of atglistatin) were formed not only in the endothelium but also in the smooth muscle cells Fig. , indicat+ intake [Increased stiffness of ECs cortex is considered as a hallmark of endothelial dysfunction , 44 and + intake  or infla+ intake . In gene+ intake . Shiftin2 from cell membrane [In fact, both the formation of LDs (via AA release via PLAmembrane ) and incmembrane . Indeed,membrane , especiamembrane .TNF-induced inflammation of endothelial cells is associated with the formation of lipid droplets, augmented cortical stiffness, as well as nanostructural endothelial plasma membrane remodeling. All these phenomena seem to be Rac-1 dependent, but further studies are need to understand in-depth mechanisms linking and explaining these phenomena, on subcellular level, or in vivo .The important limitation of the present work explaining our experimental approach was that in TNF-stimulated aorta en face, newly formed LDs in the endothelial layer were rapidly metabolized in contrast to endothelial cells in culture maintaining LDs for a longer time , 9. ThusIn conclusion, we underscored the central and indispensable role of Rac1 in TNF-induced inflammation of ECs in the isolated murine aorta. Our results indicated that LDs formation was dynamically regulated by both Rac1 and ATGL. Activation of Rac1 was shown to represent a central pathway orchestrating LDs formation with nanomechanical and nanostructural alterations of the TNF-induced inflammation of ECs inside isolated blood vessels and thus may provide a therapeutic target for reducing vascular inflammation.Supplementary file1 (DOCX 3187 KB)Below is the link to the electronic supplementary material.


This issue starts with a Letter to the Editor from Prof. Kohler (Free University Berlin) and an interview by Dr. R. van der Boon with Prof. B. Meder who holds professorship of ‘Precision Digital Health’ at the University of Heidelberg . At first glance, one may wonder the alikeness, yet a gentle pause learns that both papers hit the very heart of our journal, thereby substantiating the clinical, scientific, and societal need and hopefully value of our beloved journal. Digital health (DH) reflects a vision and ambition that sails on the waves of incessant technological innovations in the field of data collection, transfer, stockage, and analysis. The vision and ambition are to foster and/or to improve health and well-being via subject-centred prevention and/or treatment of disease and disabilities that—from a broader perspective—must be affordable and accessible to all. As such, it demands a free and plural world in which individual and societal sovereignty are fundamental, which must unconditionally be respected and if not, strongly condemned and overpowered.Accomplishment of the above is not easy. It is complicated by conditions that pointlessly take away human and financial resources needed to build a better world to the benefit of all, more so than a lack of technological ingenuity and solutions. With respect to medicine and all other domains of value to quality of life and survival of flora and fauna that includes humankind, we are dealing with huge volumes of multidimensional data of different physical nature that are collected by on-site or remote tools, their transfer, storage, analysis, and finally proper interpretation and reaction. The first two papers of this issue briefly touch upon this and are a warming up of the subsequent papers in this issue.The implementation of DH  to effective and affordably reduce the burden of disease and/or disabilities is not an easy undertaking. A proper understanding of the intricacies of all constituents of the ‘DH-chain’ is mandatory. To start at the end of the chain, one must understand of how the findings of analyses came about for proper interpretation and ensuing reaction. This is in essence not different when using ‘regular statistics’ or interpreting the findings of randomised clinical trails. Yet, artificial intelligence (AI) for the assessment of associations between data is a bit more esoteric.et al. is in this respect very welcome, and more of those are wanted since DH is complex spanning a vast array of domains that demands quite some Olympic brain gymnastics. As such the paper of Al-Zaiti et al. is tutorial and gaps the bridge between the preclinical  and clinical field. The checklist for the evaluation of the rigour and reproducibility of the four machine learning building blocks—data curation, feature engineering, model development, and clinical deployment—is informative and stimulates further contemplation.The paper of Al-Zaiti et al., Lachmann et al.) are related to valvular heart disease and another six to electrophysiology. Van Dam et al. report on the application of CineECG to the 12-lead surface electrocardiogram (ECG) for the 3D visualization of atrial electrical activity during the PQ-interval, relating atrial electrical activity to the atrial anatomy. Five papers focus on the detection/prediction of atrial fibrillation (Afib) via AI-enabled analysis of the ambulatory ECG by Holter monitoring  and clinical relevance of early detection of Afib .This is followed by a series of 15 original papers that are exemplar of what has been discussed above. Two papers  and patient-specific related features such as gender  and clinical conditions such as hyperthyroidism  and pulmonary hypertension  is presented next. The series of original papers end with two on remote monitoring that may be used for continued care and treatment of the patient in his/her own environment or rehabilitation , emphasizing the significance of telemedicine.The role of AI in finding relationships between features stemming from electromagnetic waves  and two review papers , which focus on specific domains of DH and AI-enabled analysis in specific patient categories and purposes. Notwithstanding their focus, they indirectly deliver a wider awareness of what may be expected of DH in medicine.This issue ends with a short report  all free-men a say in government when tension between factions rose. At roughly the same time the Chinese embraced Kongfuzi, better known as Confucius, when authorities started battling for dominance. Quousque tandem abutere, Catilina, patientia nostra (Cicero)? Cicero will most likely address his discourse today to other people than Catilina.Steven Weinberg  once said ‘there is no limit to the human brain’. He may be right. We can solve whatever problem provided humankind has the will to do so. Yet, one may question who will benefit from DH and technological innovations lessening the burden of disease and/or disabilities given the increasing inequality in the fundamental needs of decent life between populations and regions in the world, so nicely discussed in ‘Doughnut Economics’ by Kate Raworth. So, on a more global scale, there is a lot at stake and, henceforth, to fulfill our dream of a better life and world. As Henry Kissinger said, ‘history of mankind is a succession of war and peace’. This will unfortunately continue as long as we—or some—do not or do not want to learn from history. At the dawn of the 6We may hope that all and good mother earth, which is the cradle and preserve of life, may benefit from the fruits of science(s) that best thrives in the realm of freedom and respect for the pillars of life and society via debate, thesis, and antithesis. Via this journal, we seek to contribute the best we can. Gratitude goes to those who make this happen, especially the authors and reviewers. To give an idea of what it takes, the 15 original papers and two reviews of this issue have been reviewed by an average of three reviewers/paper  during an average of three rounds . We hope for a prosperous journey.


Heart failure (HF) is a complex clinical syndrome that occurs as a consequence of structural or functional impairment of ventricular filling and/or ejection . It is aOver the last 30 years, a plethora of data from animal models have improved our understanding of the pathophysiology of HFrEF at the molecular and cellular levels. Meanwhile, clinicians have developed and used different therapeutic strategies for treating HFrEF. Disappointingly, effective therapies for patients with HFrEF are not adequate, with the notable exception of sodium-glucose cotransporter two inhibitors (SGLT2i); their benefit for these patients was recently demonstrated . AlthougThe mechanisms leading to impaired LV relaxation and filling remain obscure. They involve the consequences of multiple comorbidities and other contributing factors such as aging or lifestyle habits. Recent studies have shown that HFpEF is a heterogeneous syndrome, with dissimilar abnormalities observed at the cellular level in patients. For instance, recent studies have shown that disruption of the t-tubules in HFpEF is not involved, unlike in HFrEF ; the conIn this Research Topic, we present a series of articles from experts in various areas of HF.The Research Topic starts with two articles on cardiorespiratory dysfunction and HFpEF.Toledo et al. discuss the possible effect of the activation of central chemoreflex pathways on autonomic function and its potential role in breathing disorders during HFpEF. By comparing to HFrEF, where most studies have been done , the authors highlight that enhanced central chemoreflex sensitivity, cardiac autonomic imbalance, and breathing disorders are all observed in experimental animal models based on non-ischemic HFpEF. However, the precise mechanism(s) responsible for central chemoreflex sensitization, autonomic imbalance, and respiratory disorders in HFpEF are not yet clearly established.In a review article, Toledo et al. ask for further studies on cardiorespiratory dysfunction, Jones et al. investigate the relation between obstructive sleep apnea and obesity in animal models. They show that caloric restriction can prevent obesity-induced LV hypertrophy. This protects against intermittent hypoxia induced remodeling, independent of leptin signaling. Clinical relevance of these observations needs additional investigations.As Cornuault et al. aims to present and discuss evidence supporting a causal role of endothelial dysfunction in the pathophysiology of HFpEF in patients and animal models. Endothelial cells dysfunction can alter cardiomyocytes functions such as survival, contractility and metabolism. The authors conclude that at molecular and cellular levels, endothelial to cardiomyocyte crosstalk is still poorly understood and new animal models of HFpEF should bring some clues regarding pathophysiology.A second review article focuses on endothelial dysfunction as a critical player of HFpEF development. The review by Lamonzie et al. provides a new aspect on imaging diagnosis. Cardiac magnetic resonance imaging (MRI) is the gold standard for evaluating myocardial function, volumes, and scarring. Currently, gadolinium-based contrast agents are widely used to improve the sensitivity and specificity of imaging. As an extracellular agent, gadolinium is a powerful tool for imaging scarring and highlighting intravascular and extracellular spaces. Manganese-enhanced MRI (MEMRI) has emerged as a complementary approach, enabling intracellular myocardial contrast imaging that can identify functional myocardium through its ability to act as a calcium analog. An important issue is the possible cardiac toxicity of manganese. Lamonzie et al. provide a comprehensive evaluation of its toxicity. At the whole heart level, micromolar concentrations of manganese, up to 25 μM, have no impact on cardiac function. At the cellular level, a small decrease in the calcium transient amplitude and action potential duration are observed, mainly due to a block of L-type Ca2+ channels. MnCl2 at a concentration of 25 µM decreases T1 in MRI experiments, demonstrating that this concentration is sufficient for using manganese as a contrast agent. The authors conclude that as MEMRI has the potential to monitor changes in intracellular Ca2+ homeostasis at the whole heart level, it should optimize patient diagnosis and therapeutic decision-making by providing visualization of potentially arrhythmic locations.In this Research Topic, an article by Jian et al. demonstrate that HF-induced ionic remodeling reduced conduction safety and increased tissue vulnerability to the genesis of unidirectional conduction blocks. The Purkinje fiber-ventricle junction can form a potential substrate for the genesis of conduction failure that leads to re-entry. The study by Jian et al. highlights the utility of single cell and multiscale modeling of cardiac electrophysiology as an important tool to widen the understanding of underlying mechanisms at cellular and tissue levels.The last research article uses numerical modelling to investigate the role of the Purkinje fiber-ventricle junction on pro-arrhythmic events. In conclusion, this Research Topic covers a broad range of HFpEF at different levels. Cleary, more basic, translational, and clinical research is needed to delineate the complexity of the mechanisms involved in HFpEF and their interactions. Given the multidimensionality of the HFpEF syndrome, new experimental models, which represent clinical situations, are required. In terms of patients, in depth imaging as well as genomic, proteomic, and metabolomic analyses will help for a better characterization. Both human and animal models will contribute to identifying potential therapeutic targets. We hope that this Research Topic encourages further investigation of these exciting areas.