This study aimed to investigate inter-/intra-observer delineation variability in GTVs of primary esophageal carcinomas (ECs) based on planning CT with reference to different combinations of diagnostic multimodal images from endoscopy/EUS, esophagography and FDG-PET/CT.C), CT combined with endoscopy/EUS (GTVCE), CT combined with endoscopy/EUS and esophagography (X-ray) (GTVCEX), and CT combined with endoscopy/EUS, esophagography, and FDG-PET/CT (GTVCEXP). The intra-/inter-observer variability in the volume, longitudinal length, generalized CI (CIgen), and position of the GTVs were assessed.Fifty patients with pathologically proven thoracic EC who underwent diagnostic multimodal images before concurrent chemoradiotherapy were enrolled. Five radiation oncologist independently delineated the GTVs based on planning CT only (GTVp>0.05). The mean intra-observer CIgen values for all observers was 0.73 ± 0.15. The mean inter-observer CIgen values for the four multimodal image combinations was 0.67 ± 0.11. The inter-observer CIgen for the four combined images was the largest, showing significant differences with those for the other three combinations. The intra-observer CIgen among different observers and inter-observer CIgen among different combinations of multimodal images showed significant differences (p<0.001). The intra-observer CIgen for the senior radiotherapists was larger than that for the junior radiotherapists (p<0.001).The intra-/inter-observer variability in the volume and longitudinal length of the GTVs showed no significant differences (For radiation oncologists with advanced medical imaging training and clinical experience, using diagnostic multimodal images from endoscopy/EUS, esophagography, and FDG-PET/CT could reduce the intra-/inter-observer variability and increase the accuracy of target delineation in primary esophageal carcinomas. There is large variability in target volume delineation for esophageal carcinoma.Evaluation of inter-/intra-observer delineation variability based on diagnostic multimodal imaging.Multimodal diagnostic image combinations can reduce the intra-/inter-observer variability and increase delineation accuracy.Esophageal carcinoma is the seventh most commonly diagnosed cancer and the third leading cause of cancer deaths worldwide in 2018 . The proConventional three-dimensional CT (3DCT) has been the workhorse modality used to delineate the esophageal tumor target volume. However, it is difficult to determine the proximal and distal extension of tumors and differentiate the layers of the esophageal wall –16. An eIn general, patients scheduled to receive radiotherapy or chemoradiotherapy undergo diagnostic multimodal imaging including enhanced CT, endoscopy/EUS, esophagography, or FDG-PET/CT. In clinical practice, radiation oncologists generally delineate the target volumes based on the planning CT images, with reference to various preexisting diagnostic images. However, the outcome of using different combinations of diagnostic multimodal images on the inter-observer and intra-observer delineation variability remains unclear. The purpose of this study was to investigate the inter-observer and intra-observer delineation variability in the GTVs of primary esophageal tumors with reference to different combinations of multimodal images from endoscopy/EUS, esophagography, and FDG-PET/CT. This study indicated the influence of the addition of different multimodal images on the GTVs delineation variability, which may contribute to making clinical decision on acquire different multimodal images.This study was approved by the institutional research ethics board and informed consent has been obtained from the participants involved. Fifty-one patients with pathologically proven thoracic EC who had undergone preoperative or definitive concurrent chemoradiotherapy between May 2015 and June 2017 at the institutional hospital were enrolled. Among the selected patients, there were seventeen cases each of upper, middle, and lower EC. One patient with lower EC was excluded due to the lack of PET-CT imaging data. All patients underwent a diagnostic imaging examination that included an endoscopy/EUS, esophagography, and FDG-PET/CT before receiving chemoradiotherapy. The average time for acquiring the diagnostic images was within the two-week period before chemoradiotherapy. Endoscopy/EUS examination: All patients underwent diagnostic endoscopy examinations using an electronic gastroscope (Olympus GIF-Q260J) before treatment. Seven patients did not undergo EUS examinations due to esophageal stenosis. The ultrasonic probe (Olympus EVIS EUS EU-ME2) was inserted into the patient’s esophagus along the track of the biopsy forceps to detect the depth of tumor infiltration in the esophageal wall and the extent of proximal and distal tumor infiltration. The distances from the proximal and distal ends of the tumor to the incisors were recorded.Esophagography (X-ray) image acquisition: Esophagography was performed before treatment using a digital radiography machine (Siemens Luminos dRT Max). All barium examinations were performed under fasting conditions, followed by a standard protocol .PET/CT image acquisition: The PET-CT scan was performed within the two-week period prior to the planning CT scan as a part of the routine diagnostic management for EC. An 18F-FDG PET/CT scan of the chest was performed with an integrated PET/CT system (Philips Gemini TF Big Bore). The PET images were reconstructed with the CT-derived attenuation correction using an ordered subset expectation maximization algorithm with post-reconstruction Gaussian filtering, with a full width at half maximum of 5 mm.Planning CT image acquisition: During the simulation, all patients were immobilized using a thermoplastic mask in the supine position with the arms placed along the side of the body. Each patient underwent an enhanced planning CT scan of the thoracic region on a 16-slice CT scanner (Philips Brilliance Bores CT) under free-breathing conditions. The planning CT images were reconstructed using a thickness of 3 mm and subsequently transferred to an Eclipse treatment planning system (Varian Eclipse 11).A treatment planning system  was used to contour the GTVs of the primary EC. The visualization parameter for delineation included the mediastinal window set to +40/400 HU. Before contouring, some clinical information such as the physical examination, pathological findings, and diagnostic CT image data were made available to the observers, while they were blind to the diagnostic endoscopy/EUS, esophagography, and FDG-PET/CT data. If the positive lymph nodes could not be separated from the primary tumor visually, they were delineated together with the primary tumor.C), CT combined with endoscopy/EUS (GTVCE), CT combined with endoscopy/EUS and esophagogram (X-ray) (GTVCEX), and CT combined with endoscopy/EUS, esophagogram, and FDG-PET/CT (GTVCEXP) (Five radiation oncologists (observers), who were blind to the diagnostic endoscopy/EUS, esophagography, and FDG-PET/CT patient data, were asked to independently delineate the GTVs with reference to different combinations of the multimodal images, including planning CT only (GTVGTVCEXP) Figure 1gen), and position of the GTVs was assessed. The intra-observer variability can be generally regarded as the variability of the same observer when re-contouring a single case. However, in this study, it is defined as the variability of the contours on the four multimodal imaging/image combinations for one observer , esophagography, and FDG-PET/CT, with the difference between the tumor length and corresponding longitudinal length of the GTVs subsequently evaluated.gen) was used to assess the overall consistency of all volume combinations delineated by different observers on the same imaging-modality combination, and that delineated by the same observer on different imaging-modality combinations. The formula is given by (Conformity index (CI) was defined as the ratio of the common volume to encompassing volume , 24. Thegiven by , 25:gen is a good parameter for revealing the difference in the volumes delineated based on the size, shape, and location , y (anterior-posterior), and z (superior-inferior) axes of the center of mass (COM) of the volume were measured. The centroid shifts between the different volumes were then obtained. Finally, the three dimensional (3D) centroid shifts were calculated using the followed equation , 26:gen, and position of the GTVs among different observers and different multimodal imaging combinations. The paired t-test was used to compare the volume, longitudinal length, CIgen, and position of the GTVs between two observers or two multimodal imaging combinations. A P<0.05 was considered significant.Statistical analysis was performed using the SPSS software package (SPSS 25.0). All the data had an approximately normal distribution. The one-way ANOVA test was applied to detect the inter-/intra-observer variability in the volume, longitudinal length, CIC, GTVCE, GTVCEX, or GTVCEXP . The intra-observer variability in the volume of the GTVs derived from four different multimodal imaging combinations for observers 1–5 also showed no significant differences . However, the paired comparisons indicated significant differences in the GTV volume between observers 1 and 2, observers 1 and 4, and observers 3 and 4 . Approximate statistical differences in the GTV volume were found between observers 1 and 3, and observers 2 and 4 .C, GTVCE, GTVCEX, and GTVCEXP. The mean longitudinal length for GTVCEXP was larger than the tumor length measured by FDG-PET/CT (p=0.0035). The intra-observer variability in the longitudinal length of the GTVs based on four multimodal imaging combinations for observers 1–5 showed no significant differences . C, GTVCE, GTVCEX, and GTVCEXP . The two-related-samples tests indicated significant differences in the longitudinal lengths of the four GTVs between observers 1 and 2 , observers 1 and 5 , observers 3 and 2 , and observers 3 and 5 .gen values for the four GTVs derived from different multimodal imaging combinations (mean intra-observer CIgen) for each observer. The mean intra-observer CIgen values for all observers was 0.73 ± 0.15. The mean intra-observer CIgen was the largest for observer 4, exhibiting significant differences with that for the other observers. The mean intra-observer CIgen for observer 1 was the lowest, exhibiting significant differences with that for observers 3, 4, and 5. The mean intra-observer CIgen among different observers was statistically significant . gen values for the five GTVs derived from different observers (mean inter-observer CIgen) for each multimodal imaging combination. The mean inter-observer CIgen values for the four multimodal imaging combinations was 0.67 ± 0.11. The mean inter-observer CIgen was the largest for the fourth multimodal imaging combination, which exhibited significant differences with that for the other three combinations. The mean inter-observer CIgen among the different multimodal imaging combinations showed a significant difference .F=3.898, p=0.004). F=0.327, p=0.806).Uncertainties in volume delineation for esophageal carcinomas is a well-recognized potential cause of treatment failure in radiotherapy , 28. MinAccurate target delineation for esophageal cancer is often restricted by the poor discriminative value of current imaging modalities , particuThe results of this study showed no statistically significant inter-observer differences in the esophageal volume estimation based on different combinations of the CT, endoscopy/EUS, esophagography, and FDG-PET/CT data Table 2.CEXP was significantly larger than the tumor length measured by FDG-PET/CT. Therefore, the use of the multimodal images to determine the target length contributes to reducing the limitation of a single image, and improving the accuracy of target delineation; however, this is based on the precondition that the observers develop a good knowledge of the features of the multimodal images via unified training.Similar to the observed variability in the volumes of the GTVs, the inter-observer and intra-observer variability in the longitudinal length showed no statistically significant differences Table 3.gen values for GTVC, GTVCE, GTVCEX, and GTVCEXP for each observer represent the intra-observer variations, which include the random and inherent variations derived from different multimodal imaging combinations for the same observer. Here, the mean CIgen for intra-observer variability (0.73) was larger than that for inter-observer variability (0.67). This indicates that the intra-observer variability in delineating esophageal tumors was lower than the inter-observer variability, which shows agreement with the results reported in other studies -MRI. Compared with the above studies, fifty patients with upper, middle, and lower thoracic esophageal carcinoma were enrolled in this study. Moreover, different multimodal imaging combinations, including CT, endoscopy/EUS, esophagography, and FDG-PET/CT, were employed to eliminate any bias from a single imaging technique.The CI studies , 34. Mac studies  reportedC). CT combined with endoscopy/EUS is a simple combination(GTVCE), while CT combined with endoscopy/EUS, esophagography, and FDG-PET/CT (GTVCEXP) is regarded as an effective alternative method to define the GTV accurately , which suggested that a comprehensive combination of multimodal images was more conducive to influence the target delineation compared a simple combination.In addition, the CT is a basic image . The intra-observer CIgen for the senior radiation oncologists  was larger than that for the junior radiation oncologists (observers 1 and 2). An optimum intra-observer CIgen was obtained for the senior radiotherapist who spent minimal time delineating the GTVs (observer 4)  Table 4.erver 4) , 38. In gen calculated for the different multimodal imaging combinations did not increase for the combined CT and endoscopy/EUS data, as compared with CT only, CIgen tended to increase for the combined CT and endoscopy/EUS and esophagography information (p=0.088). Furthermore, the addition of FDG-PET/CT to the endoscopy/EUS, and esophagography data significantly improved the inter-observer CIgen. The use of multimodal imaging, including CT, endoscopy/EUS, esophagography, and FDG-PET/CT, for target delineation reduced the inter-observer variability. CEXP) by five oncologists, and the volume and longitudinal length of GTVCEXP exhibited a good consistency. The effect of FDG-PET/CT on the intra- and inter-observer variability of target volume delineation in patients with gastro-esophageal cancer remains controversial. Vesprini et al.  is mainly influenced by positional and morphological difference of targets. Here, the intra-observer variability in the 3D centroid shifts of the GTVs among different observers showed a significant difference. In the case of no significant variability in the volume of the GTVs, the intra-observer variability in the position could have mainly contributed to the statistical significance in the CIIn conclusion, for radiation oncologists with advanced medical imaging training and clinical experience, the use of diagnostic multimodal images from endoscopy/EUS, esophagography, and FDG-PET/CT for target delineation based on planning CT reduced the intra- and inter-observer variability and increased the accuracy of target delineation in primary thoracic esophageal carcinomas. The use of the combination of multimodal images would reduce uncertainties in volume delineation for esophageal carcinomas, and potentially increase the success rate of radiotherapy. We also found the inter/intra observer variability in the 3D centroid shifts of GTVs were about 3-4mm, whether it is necessary to expand an extra margin to include this error deserves further thinking.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by Shandong Cancer Hospital and Institute. The patients/participants provided their written informed consent to participate in this study.FL and YL contributed to the study design, the patient enrollment, the data statistics and analysis, and writing the manuscript. JL participated in the study design. XW contributed to the patient enrollment. YZ, XL, SL, JW, and MX contributed to the delineation. WW and YG made important contributions in collecting the data and revising the content. All authors contributed to the article and approved the submitted version.This work was supported by Shandong Cancer Hospital and Institute, China. National Natural Science Foundation of China (817732870); Beijing Medical Award Foundation (YXJL-2020-0785-0616); Taishan Scholars Program of Shandong Province (NO.ts 20190982); Wu Jieping Medical Foundation (320.6750.2021-02-79).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. 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P=0.17; I2 = 62%) or overall survival  of NSCLC patients receiving ICIs. Subgroup analyses showed consistent results in studies with univariate or multivariate analytic models . In conclusion, concomitant use of statin seemed to have no significant influence on the survival of patients with NSCLC who were treated with ICIs.Statins are suggested to improve cancer survival by possible anti-inflammatory effect. However, it remains unclear if concomitant use of statins could improve the efficacy of immune checkpoint inhibitors (ICIs) in patients with non-small-cell lung cancer (NSCLC). Accordingly, a meta-analysis was performed to systematically evaluate the effect of concomitant statins in NSCLC patients receiving ICIs. Relevant studies were obtained by literature search in PubMed, Embase, and Web of Science databases. A conservative random-effect model was used to combine the results. Eight cohorts including 2382 patients were included. The programmed death-1/ligand-1 inhibitors were used in seven studies; while the cytotoxic T-lymphocyte-associated protein 4 inhibitors were used in the other study. It was shown that concomitant use of statin did not significantly affect the progression-free survival : 0.86, 95% confidence interval (CI): 0.70 to 1.07,  Immune checkpoint inhibitors (ICIs) are a group of novel anticancer agents which showed substantial therapeutic efficacy in patients with various solid cancers, including patients with non-small-cell lung cancer (NSCLC) –3. CurreThe 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, also named as statins, are well-applied lipid-lowering medications . StatinsThe Meta-Analysis of Observational Studies in Epidemiology (MOOSE)  statemenStudies fitting to the aim of the meta-analysis were retrieved by electronic database search of PubMed, Embase, and Web of Science from the inception of the databases to May 11, 2022. A combined search term was used, which is shown in Supplementary Materials. Filters of human studies, full-length articles, and publication in English were applied in the database search. As a supplementation, we manually checked the citations of the relevant original and reviewed articles for possible studies of interest.The PICOS criteria were used for study inclusion.P (patients) denotes adult patient with NSCLC receiving ICIs, including PD-1/PD-L1 inhibitors, CTLA4 inhibitors, or their combination. No restriction was applied to the pathological types of NSCLC .I (exposure) denotes patients with concomitant use of statins as evidenced by the medical charts or other medical records with no restrictions to the category, dosages, or durations of statin use.C (control) denotes patients without concomitant use of statins which were also evidenced by the medical charts or other medical records.O (outcomes) denotes progression-free survival (PFS) and/or overall survival (OS) between users and nonusers of statins, reported as relative risk. We defined OS as the time elapsed from treatment and to the date of death from any cause and PFS as the interval between initiation of the treatment and the first recurrence or progression event.S (study design) denotes cohort studies published as full-length articles.Reviews, preclinical studies, studies with non-NSCLC patients, studies with no treatment of ICIs, or studies that did not report the outcomes of interest were removed. Moreover, grey literature studies such as conferences, abstracts, or unpublished data were also not considered. These materials were generally not peer-reviewed, and inclusion of these data into the meta-analysis may confound the results.Two independent authors conducted literature search and analysis, data collection, and study quality assessment separately. If discrepancies were encountered, the corresponding author joined the discussion for final judgement. Data of study information, patient demographic factors, types of ICIs, definition of concurrent statin application, outcomes reported, and analytic methods were collected. Study quality assessment was achieved via the Newcastle–Ottawa Scale , with scP values, data of RRs and the standard errors (SEs) could be calculated, and a subsequent logarithmical transformation was conducted to keep stabilized variance and normalized distribution [Q test and the I2 statistic [I2 > 50% reflecting the significant heterogeneity. A random-effect model was applied to combine the results by incorporating the influence of heterogeneity [The main objective was to determine the influence of concomitant statin on survival of patients with NSCLC on treatment of ICIs, which was presented with hazard ratios (HRs) as well as their confidence intervals (CIs). Using the 95% CIs or ribution . Betweentatistic , with I2ogeneity . We obseogeneity . Subgrouogeneity . The RevAs shown in P=0.17; P for Cochrane's Q test = 0.009, I2 = 62%). Sensitivity analysis by excluding one study at a time showed consistent result . Specifically, sensitivity analysis limited to studies of patients taking PD-1/PD-L1 only showed consistent result . Subgroup analyses also showed consistent results in univariate  and multivariate studies . Sensitivity analysis by excluding one study at a time showed consistent results . Specifically, sensitivity analysis limited to studies of patients taking PD-1/PD-L1 only showed consistent results . Subgroup analyses also showed consistent results in univariate  and multivariate studies .Figures In this meta-analysis, we pooled the results of eight cohort studies and showed that concomitant use of statins in NSCLC patients receiving ICIs treatment was not associated with significantly improved survival outcomes, including PFS and OS. Further sensitivity analyses by excluding one study at a time did not significantly affect the results. Moreover, sensitivity analysis limited to studies including NSCLC patients receiving PD-1/PD-1L inhibitors also showed similar results. Finally, subgroup analyses showed that concomitant use of statins in NSCLC patients was not associated with a significantly improved PFS or OS in univariate or multivariate studies. Taken together, current evidence primarily based on retrospective studies in NSCLC patients taking PD-1/PD-1L inhibitors did not show that concurrent use of statins was associated with a significantly improved survival in these patients. Although these results should be further confirmed in large-scale prospective studies, these results did not support the previous hypothesis that concomitant statins may improve the anticancer efficacy of ICIs in patients with NSCLC.To the best of our knowledge, this is the first meta-analysis which summarized the current evidence regarding the influence of concomitant statins in patients with NSCLC receiving ICIs treatment. During the preparation of the manuscript, a meta-analysis was published to evaluate the possible influence of concomitant medications, including statins, on the survival in patients with advanced cancer who were treated with ICIs . HoweverTwo early meta-analyses have suggested the possible benefit of statin use on survival of patients with lung cancer , 19. HowThis meta-analysis also has some limitations. Firstly, most of the studies were retrospective and of limited sample sizes, results of which may be affected by possible recall and selection biases. Accordingly, large-scale prospective cohort studies are needed to validate the findings. Secondly, we could not determine whether difference in the individual category of statins may affect the association of interest since related data were rarely reported among the included studies. Studies are warranted in the future for investigation. Besides, most of the included patients received PD-1/PD-L1 inhibitors rather than CTLA-4 inhibitors. The possible influence of concomitant statin use on survival in NSCLC patients receiving CTLA-4 inhibitors is still to be determined. Finally, although subgroup analysis of multivariate analysis showed consistent results, it remained unknown whether age, sex, ethnicity, comorbidities, and other concurrent medications may significantly affect the association between concomitant statin and survival of these patients, which may be the source of heterogeneity among the included studies. Meta-analysis based on individual-patient data should be performed for further evaluation.To sum up, current evidence from observational studies did not show that concurrent use of statins was associated with a significantly improved survival in NSCLC patients receiving ICIs. Although these results should be further confirmed in large-scale prospective studies, in view of the possible increased risk of adverse events such as skeletal myopathies, concomitant use of statins in NSCLC patients receiving ICIs should be cautious.


Cyclosporine A (CsA) is effective in treating moderate-to-severe atopic dermatitis (AD). This systematic review and meta-analysis aimed to summarize the effectiveness and safety of low-dose (<4 mg/kg) versus high-dose (≥4 mg/kg) CsA and other systemic immunomodulatory agents in patients with AD. Five randomized controlled trials met the inclusion criteria. The meta-analysis included 159 patients with moderate-to-severe AD who were randomized to receive low-dose CsA, and 165 patients randomized to receive high-dose CsA and other systemic immunomodulatory agents. We found that low-dose CsA was not inferior to high-dose CsA and other systemic immunomodulatory agents in reducing AD symptoms . High-dose CsA and other systemic immunomodulatory agents showed a significantly lower incidence of adverse events , however, after sensitivity analysis, there was no difference between the two groups except for one study . Regarding serious adverse events requiring discontinuation of treatment, we observed no significant differences between low-dose CsA and other systemic immunomodulatory agents . Our study may justify the use of low-dose CsA rather than high-dose CsA and other systemic immunomodulatory agents in moderate-to-severe AD. Atopic dermatitis (AD) is the most common, chronic inflammatory skin condition, affecting 5–8% of adults and 11–20% of children . PatientSystemic immunomodulatory agents used to treat AD include cyclosporine A (CsA), methotrexate (MTX), azathioprine, mycophenolate mofetil (MMF), and monoclonal antibodies, such as dupilumab and Janus kinase inhibitors ,6,7. SpeThe aim of this systematic review and meta-analysis of randomized clinical trials (RCTs) is to analyze the efficacy and safety according to the dose of CsA in moderate-to-severe AD.We performed a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines . The popWe performed a systematic search using a protocol with five electronic databases, namely PubMed, Embase, Cochrane Library, Clinical Trial Registry, and the World Health Organization International Clinical Trials Registry Platform. Here, RCTs comparing CsA with other interventions in patients with AD were eligible for inclusion. We used the search terms listed in the Two reviewers (K.K. and H.S.K.) independently evaluated the titles and abstracts obtained from the first screening. Articles that did not focus on CsA use in AD as well as review articles were excluded from this initial screening. After this, the reviewers independently reviewed the full texts of the remaining articles to determine whether they met the following eligibility criteria: (1) RCT comparing the efficacy and safety of CsA in patients with AD and (2) comparisons of outcome measures, including clinical severity, quality of life, and AEs. The primary outcome was the relief of AD symptoms, quantitatively measured using validated scoring systems. The secondary outcome was the occurrence of AEs. Review articles, abstracts without full-text publications, and case study reports were excluded. Disagreements between the reviewers in the selection of particular studies were resolved after discussion with a third reviewer (H.J.Y.).Cochrane Handbook for Systematic Reviews of Interventions [Both reviewers (K.K. and H.S.K.) extracted the data from each eligible study using a structured procedure. Data could be classified by the sample characteristics, the intervention details, and the measurement of outcomes. Outcome measures were divided into primary outcomes, which assessed the efficacy of CsA, and secondary outcomes, assessing the safety of CsA. The reviewers independently assessed the risk of bias for each study using the criteria outlined in the ventions . Disagrep-value < 0.05 was deemed statistically significant. We used the I² statistic to assess heterogeneity in the results of individual studies (I2 >50% was used as a threshold to indicate significant heterogeneity).Statistical analyses were performed using R software  version 4.2.0, “meta” package. To identify differences in treatment effects and AEs between groups, the pooled estimates used standard mean difference (SMD) and incidence relative risk (IRR), respectively, and a random effect model was used with the DerSimonian–Laird method. All tests were two-tailed, and a In the treatment effect analysis, the mean difference between baseline and the last follow-up time point for each group in the study was calculated using descriptive statistics for meta-analysis, and measurement bias between studies was corrected using SMD as summary statistics. Concerning the analysis of AEs, the formula for incidence rate  for each group was calculated as follows:In this study, low-dose CsA (<4 mg/kg) was used as the control group, and high-dose CsA (≥4 mg/kg), MTX, MMF, and prednisolone (PRD) were used as the experimental groups. A total of 255 citations were initially screened on the databases, and 146 individual publications were identified. Of these, 120 studies were excluded after reviewing the titles and abstracts, leaving 26 articles for full-text review. Finally, five articles were selected for eligibility and were included in our final meta-analysis  13,14,1,16,17.Overall, 324 patients were included in our meta-analysis. Of this number, 159 patients were administered low-dose CsA (control group), and 165 patients were administered high-dose CsA and other systemic immunomodulatory agents . The CsA treatment was initiated at 2.5–4 mg/kg/day in the control group ,16,17. IA summary of the data from the studies included in the meta-analysis is presented in The overall incidence rate ratio (IRR) of AEs and 95% CI are shown in Using this systematic review and meta-analytical approach, we compared the efficacy and AEs of low-dose CsA with high-dose CsA and various systemic immunomodulators in AD. This meta-analysis comprised 5 RCTs, which included a total of 324 patients. Analyses of outcomes in patients receiving various systemic immunomodulators showed no significant differences in severity score improvement compared to patients receiving low-dose CsA. Low-dose CsA showed a higher incidence of AEs than other systemic immunomodulators. However, after sensitivity analysis, there was no difference between the low-dose CsA and other systemic immunomodulators in the occurrence of AEs. Furthermore, there was no difference between low-dose CsA and other systemic immunomodulators in the occurrence of serious AEs requiring discontinuation of the clinical trial.Typically, CsA is considered to be the first-line option for patients with severe AD who require systemic immunosuppressive treatment . A previWe found no significant differences between the efficacies of low-dose CsA and MTX. Two previous trials compared MTX and CsA treatments, one in children and one in adults ,16. The We found a significant improvement in the severity of AD, with a lower incidence of AEs after treatment with MMF compared with low-dose CsA. The incidence of serious AEs did not differ significantly between the groups. One trial with a high risk of bias showed equal efficacy of CsA and MMF in adults with SCORAD at 12 weeks, but MMF showed a more delayed response . Nausea No significant differences were observed between the efficacy of low-dose CsA and PRD. A previous study demonstrated that CsA was superior to oral PRD in achieving stable remission, with no relapse within the 12-week follow-up . HoweverThis study had some limitations. There was some heterogeneity in the design of the included trials. In particular, the use of background therapy  varied between studies. Second, this meta-analysis included a few RCTs with a small number of patients with a large variation in dosage of drugs and treatment duration, which should be interpreted with care. Thirdly, CsA is licensed to be used in children over 24 months of age in Korea. Since this study included children over 8 years of age, our recommendations may not be applicable in children between 24 months and 8 years of age. Moreover, there are no comprehensive long-term safety trials for more than 1 year for any treatment. In conclusion, low-dose CsA showed non-inferior efficacy compared to high-dose CsA and various systemic immunomodulators. Further studies, including planned RCTs, will help to confirm and improve the accuracy of our obtained results and provide estimates for children in terms of long-term outcomes and side effects.


Routine coronary artery disease (CAD) secondary prevention strategies target standard modifiable cardiovascular risk factors (SMuRFs), which include: diabetes mellitus, dyslipidemia, hypertension, and smoking. However, a significant proportion of patients with acute coronary syndrome (ACS) present without any SMuRFs. The angiographic severity of disease in this population has not yet been investigated.After propensity score matching of patients without SMuRFs and patients with ≥1 SMuRFs (ratio 1:3), we used zero-inflated negative binomial regression modeling to investigate the relationship of SMuRF-less status with the angiographic severity of CAD, as measured by the SYNTAX score. Survival analysis was performed to investigate differences in all-cause mortality at 30 days and at the end of follow-up period.p = 0.26). The 30-day risk for all-cause mortality was higher for SMuRF-less patients compared to patients with ≥1 SMuRFs ; however, the all-cause mortality risk was not different between the two groups over a median 1.7-year follow-up .We analyzed 534 patients presenting with ACS who underwent coronary angiography. Of them, 56 (10.5%) presented without any SMuRF. After propensity score matching, the median SYNTAX score was 13.8 (IQR 0–22.1) in 56 SMuRF-less patients and 14 (IQR 5–25) in 166 patients with ≥1 SMuRFs. SMuRF-less status was associated with increased odds of zero SYNTAX score , but not with decreased SYNTAX score among patients with non-zero SYNTAX score ; the overall distribution of the SYNTAX score was similar between the two groups (Among patients with ACS, the absence of SMuRFs is associated with increased odds for non-obstructive CAD and with increased short-term mortality rates. Annually, millions of people suffer an acute coronary syndrome (ACS) driven by an atherosclerosis-related coronary artery narrowing or occlusion . The majHowever, a growing body of research now recognizes a significant proportion of patients presenting with ACS without having any SMuRF (SMuRF-less status) –8. The pTo that end, our study aims to investigate associations of the SMuRF-less status with CAD angiographic severity, as assessed with the SYNTAX score, and evaluate the association of the SMuRF-less status with short- and long-term mortality rates in a cohort of well-characterized ACS patients.post hoc analysis conducted among patients with ACS, enrolled in the Correlation of the severity of Coronary Artery Disease with patients’ metabolic profile (CorLipid) trial . In brief, the CorLipid trial aimed: (1) to investigate the metabolic fingerprint of patients undergoing coronary angiography in AHEPA University Hospital of Thessaloniki, Greece, and (2) to develop metabolomics-based predictive models for the prediction of CAD severity. The protocol and main outcomes of the trial have been already published  to May 2021 (last patient enrollment). The database included variables describing medical history, baseline clinical, laboratory, and angiographic characteristics.The SMuRFs  were all defined as binary variables, recorded at patient enrollment. Patients with DM, dyslipidemia and hypertension were defined as those meeting at least one of the following criteria: (a) administration of anti-diabetic, anti-hyperlipidemic or anti-hypertensive medication, respectively; (b) diagnostic code of DM, dyslipidemia or hypertension  in at least one hospital admission; or (c) history of medical illnesses as provided by the patients. Smoking history was defined as current self-reported use of tobacco products.Coronary angiographic images of every patient were independently evaluated by two experienced interventional cardiologists (GSi and GSo), blinded to patient clinical characteristics and outcomes, who calculated the SYNTAX score. SYNTAX score constitutes an angiographic grading tool to determine CAD complexity. It is derived from summarizing the points assigned to each individual lesion identified in the coronary arterial tree with at least 50% diameter narrowing in vessels of more than 1.5 mm diameter .Follow-up data were acquired until November 2021 through telephonic or in-person interviews with study participants. The vital status of all patients was additionally verified through the Greek Civil Registration System.The primary study outcome was the association of the SMuRF-less status with the angiographic severity of CAD, as assessed with the SYNTAX score. A secondary study outcome was to compare the risk of all-cause mortality in patients with and without SMuRFs according to both short- and long-term patients’ follow-up .Categorical variables are summarized as frequencies with percentages, and continuous variables as medians with interquartile ranges (IQR = Q3 − Q1). The Pearson Chi-square or Fisher’s exact test were used for comparison between categorical variables, whereas continuous variables were compared using the Wilcoxon rank-sum test.Missing observations were regarded as missing at random and were dealt with the use of multiple imputation; a predictive mean matching method with 50 iterations was used to create 5 complete imputation datasets.We used propensity score matching without replacement to adjust for confounding. Patients without any SMuRFs were matched with patients with ≥1 SMuRFs on a 1:3 ratio. We used greedy nearest neighbor propensity score matching without replacement with a propensity score generated by logistic regression with the use of age, sex, family history of CAD, body mass index (BMI), estimated glomerular filtration rate (eGFR), and ST-elevation myocardial infarction (STEMI) occurrence at the index event as covariates. Covariate balance was assessed with the use of a Love plot, and standardized mean differences below 0.1 for all covariates indicated adequate balance.zero-part model); and (b) a second part to predict the SYNTAX score in patients with a non-zero SYNTAX score (count-part model). Odds ratios (ORs) and incidence rate ratios (IRRs) with corresponding 95% confidence intervals (CIs) are reported to summarize the effect of the SMuRF-less status on the SYNTAX score in the two parts, respectively.Aiming to avoid assessing the SYNTAX score as an arbitrarily defined categorical variable, we assessed its distribution as a continuous variable in our analysis. Specifically, because of the excessive presence of zero values in the SYNTAX score distribution, a zero-inflated binomial regression model was utilized to associate the SMuRF-less status with the SYNTAX score in the matched population. This model separated the regression into two distinct parts: (a) a first part to predict whether a patient is more likely to present with a zero or non-zero SYNTAX score . A Cox regression analysis was performed in the matched population to report hazard ratios (HRs) with corresponding 95% CIs for the risk of early- and long-term all-cause mortality in patients without SMuRFs.tidyverse, mice, matchIt, pscl, and survival packages. A two-sided p-value of less than 0.05 was considered statistically significant.All analyses were conducted in R  with the use of Of the 958 patients enrolled in the CorLipid study, a total of 534 (55.7%) presented with ACS and their data were utilized for the current analysis with a median follow-up of 1.7 years ; the baseline covariates had a minimal proportion of missing values  and werep = 0.26).Among the SMuRF-less patients, the median SYNTAX score was 13.8 (IQR = 0–22.1), whereas in patients with ≥1 SMuRFs the median SYNTAX score was 14  in ACS patients presenting without SMuRFs, the severity of CAD did not differ in patients who presented with positive SYNTAX score. This could introduce the notion that SMuRF-less patients represent a heterogeneous population who exhibit larger variation in the severity of CAD , 23. AnoMoreover, our study adds to the growing body of literature that SMuRF-less patients with ACS suffer from excess early all-cause mortality risk  –7, 21; yAccording to Figtree et al., a major part of observed excess early mortality in SMuRF-less patients could be attributed to arrhythmic causes, since early deaths of STEMI patients were not associated with re-infarctions, strokes, recurrent revascularization procedures, and heart failure-related hospitalizations . Hence, Our findings should be interpreted in the context of several limitations. Firstly, this is an observational analysis, prone to bias due to undiscovered confounding, despite the propensity-score-matching approach. Secondly, our data derive from a relatively limited sample of Greek patients presenting with ACS in a PCI-referral hospital and, hence, our analyses – yielding wide CIs of the effect measures – may not apply to other (multi-ethnic) populations. Thirdly, there were no available data on the cause of patients’ death (cardiac or non-cardiac) and, hence, we could not associate the progressively increasing death rate or any death etiology with the SMuRF-less status Furthermore, SMuRFs were defined as binary variables based on clinical diagnoses and accepted cut-off values; yet, DM, dyslipidemia and hypertension might have been also defined as continuous ones to assess the potential gradient of the relative risk. With regard to smoking status, data on previous (ex-) smoking status or the number of pack-years were not available. Data regarding patients’ diet and physical activity were also not available. Lastly, this study did not assess novel known markers of cardiovascular disease such as high-sensitivity C-reactive protein, triglyceride and lipoprotein(a) levels along with novel gene scores.Nevertheless, this study adds to the existing literature about SMuRF-less status and triggers future efforts for the discovery and further investigation of novel biomarkers  and post hoc analyses of existing trials and patient-level meta-analyses, could raise hypotheses and provide significant insights directing clinical pathways for this group of patients. Future larger studies should first validate our findings, before making any implications for different therapeutic management of some SMuRF-less patients with ACS with angiographically less severe CAD disease (zero SYNTAX score) and until then society guidelines should be followed for all patients with ACS, regardless of the SMuRF status.Current guidelines do not specifically address the management of CAD in patients without SMuRFs . EnhanceIn conclusion, SMuRF-less status may be associated with increased odds for non-obstructive CAD, although the overall distribution of SYNTAX score did not differ substantially between patients with and without SMuRFs. Our survival analysis suggests that absence of SMuRFs is significantly linked with increased risk of 30-day all-cause mortality, whereas long-term mortality rates were similar. These findings highlight the need for further research into SMuRF-less status in ACS patients and potential implications on the efficacy of guideline-recommended management, especially during the immediate post-ACS period.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Scientific Committee of AHEPA University Hospital (reference number 12/13-06-2019) and by the Directory Board of AHEPA University Hospital (reference number: 17/29-08-2019). The patients/participants provided their written informed consent to participate in this study.GSo, GGP, and IF contributed to the conception or design of the work. AP, IF, SZ, EK, NS, DM, and AK contributed to the acquisition, analysis, or interpretation of data for the work. AP, IF, and SZ drafted the manuscript. EK, NS, DM, AK, ID, GGK, and GSi critically revised the manuscript. All authors gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy.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.


There are limited data regarding the clinical impact of diabetes duration for patients with heavy calcified coronary lesions. We sought to determine the clinical impact of diabetes duration on clinical outcomes in patients with heavily calcified lesions who required rotational atherectomy during percutaneous coronary intervention (PCI). A total of 540 diabetic patients (583 lesions) were enrolled between January 2010 and October 2019. Patients were classified into three subgroups: patients with no diabetes mellitus (non-DM), shorter duration (S-DM), and longer duration (L-DM), of which duration was divided at 10 years. During 18 months of follow-up-duration, diabetes duration was significantly associated with the primary outcome. The incidence rate of target-vessel failure (TVF), the primary outcome, was significantly higher in the L-DM group compared with non-DM or S-DM. Among secondary outcomes, any repeat revascularization (RR) was frequently observed in the L-DM compared with other groups. In multivariate analysis, the risk of TVF and any RR was 1.9 times and 2.4 times higher in L-DM than in non-DM, respectively. This study firstly demonstrated that there is an association between a longer DM duration and poor clinical outcomes in patients with severe calcified CAD after PCI. More careful monitoring for recurrence is needed during follow-up in those patients. Diabetes mellitus (DM) is a well-known risk factor for coronary artery disease (CAD)  and is aSince DM is a chronic, progressive disease leading to micro- or macrovessel damage , the durBased on the 10-year prevalence period, we compared the clinical outcome and procedure details during RA.The study population consisted of 540 patients (583 lesions) with heavily calcified CAD who received PCI using RA from January 2010 to October 2019 at 9 tertiary centers in Korea within the ROCK registry approved by the institutional review board of each hospital. Data were collected at enrolled centers using a standardized case report form to record clinical characteristics, demographic characteristics, procedural data, and follow-up data. Follow-up data were collected up to 18 months based on clinical records and on physician or patient interviews at the time of registry enrollment. This study was approved by the regional ethics committee for each participating hospital, and all patients provided their written informed consent to the use of medical data for the registry study.To determine the presence and duration of diabetes, we reviewed the medical records; otherwise, they were self-reported. DM duration was calculated as the difference between age and age of onset of diabetes. Patients whose duration of diabetes was not investigated were excluded from the studyPatients divided into three subgroups based on 10 years duration. The reason for dividing the groups at 10 years is that a type 2 DM duration of 10 years is known to be the point at which beta cell loss becomes irreversible and cannot be restored through the achievement of glycemic control . This prProcedure details including RA standard technique, RA system, and treatment strategy were same as previously published report . During The primary endpoint was the composite rate of target-vessel failure (TVF), defined as target-vessel revascularization (TVR), target-vessel spontaneous myocardial infarction (TVMI), or cardiac death. The secondary endpoints included all-cause death, cardiac death, TVMI, any MI, any revascularization, and TVR. Technical/procedural success, in-hospital events, or peri-procedural complication were also investigated. The definition of outcomes was the same as in the previously published report mentioned above .2 by the Modification of Renal Diet (MDRD) equation from baseline serum creatinine  vs. 5 [7.7%] vs. 20 [14.9%], p = 0.012). Moreover, the level of lipid profile was different between non-DM versus S-DM or L-DM, which showed significantly lower in the diabetic groups than in the non-DM group. The level of HbA1c level increased gradually according to the DM duration . MVD was lower in the no DM group than in the diabetic group, but there was no difference between the S-DM and L-DM groups . Among secondary outcomes, any repeat revascularization was frequently observed in the L-DM compared with other groups , while S-DM group did not show statistical significance   .interaction = 0.033). However, there was no risk difference in the subgroups with CKD, dialysis, or lesions of chronic total occlusion  patients with longer DM duration, especially more than 10 years, showed poorer clinical outcomes in terms of TVF and RR than non-diabetic patients or those with shorter DM duration even after revascularization; (2) a long DM duration did not affect the procedural details, in-hospital and procedural outcomes except for CIN during PCI using RA.This is the first study to examine the associations between DM duration and clinical outcomes in a Korean population with CAD. Our registry is the largest, all-comer, multi-center registry, including CAD patients with advanced atherosclerosis in Korea. All patients received PCI with drug-eluting stents (DESs), especially second-generation DES, except for one patient with a first-generation DES, which reflect the current revascularization strategy for significant CAD ,19.Additionally, all patients underwent RA during PCI, which meant that the majority of patients in this study population might have significant CAD lesions with severe calcification. Using this registry, our study showed the novel results that demonstrated the clinical impact of DM duration on clinical outcomes in advanced CAD after revascularization. Indeed, there have been several studies demonstrating poor clinical outcomes of DM duration in CAD patients ,20. HoweIt is well-known that DM is an independent predictor of adverse clinical outcome in CAD patients after revascularization ,6. Our sHowever, the incidence rate of clinical outcomes in the shorter DM duration group was numerically higher but did not achieve statistical significance compared to the non-DM group in this study. In our registry, the duration of S-DM group was relatively short (median 5 [IQR 0.17–7.33] years), including 20 30.8%) patients who were diagnosed as DM within 1 year. Therefore, the S-DM group may include diabetic patients without complications. Even though the presence of DM itself is associated with poor clinical outcomes as mentioned above , adverse.8% patieOur study showed similar results regarding the procedural details as well as in-hospital and procedural outcomes, except for CIN. CIN occurred more frequently in the longer DM duration group. Prolonged DM is associated with microvascular complication including microalbuminuria ,32,33. IOperators are usually more careful with patients with diffuse narrowing CAD during RA and worry about distal embolization, leading to flow compromising and peri-procedure MI. Since DM may affect the coronary vessel more diffusely narrowing including capillaries  and longIn subgroup analysis, the present study was in agreement with several previous studies that showed that the relative risk of vascular disease associated with DM was substantially higher in women than men ,37. AlthThis study was based on a nonrandomized registry with inherent methodological limitations. Thus, there is a possibility of selection bias. Second, the number of study participants and events was relatively small, limiting the statistical power of our multivariate analysis. Third, the proportion of the S-DM group was relatively small (14%). Therefore, caution is necessary when interpretating our results.This study firstly demonstrated that there is an association between a longer DM duration (≥10 years) and poor clinical outcomes in patients with severe calcified CAD lesions after PCI, especially in terms of TVF and RR. We should be more careful about recurrence during follow-up in those patients.


Despite continuous advancement in the field, heart failure (HF) remains the leading cause of hospitalization among the elderly and the overall first cause of hospital readmission in developed countries. Implantable hemodynamic monitoring is being tested to anticipate the clinical exacerbation onset, potentially preventing an emergent acute decompensation. To date, only pulmonary artery pressure (PAP) sensor received the approval to be implanted in symptomatic heart failure patients with reduced ejection fraction. However, PAP's indirect estimation of left ventricular filling pressure can be inaccurate in some contexts.The VECTOR-HF study (NCT03775161) is examining the safety, usability and performance of the V-LAP system, a latest-generation device capable of continuously monitoring left atrial pressure (LAP). In our center, five advanced HF patients have been enrolled. After confirmation of the transmitted data reliability, LAP trends and waveforms have guided therapy optimization. The aim of this work is to share clinical insights from our center preliminary experience with V-LAP application.Over a median follow-up time of 18 months, LAP–based therapy optimization managed to reduce intracardiac pressure over time and no hospital readmission occurred. This result was paralleled by an improvement in both functional capacity (6MWT distance 352.5 ± 86.2 meters at baseline to 441.2 ± 125.2 meters at last follow-up) and quality of life indicators .Preliminary evidence from V-LAP application at our institution support a promising efficacy. However, further study is needed to confirm the technical reliability of the device and to exploit the clinical benefit of left-sided hemodynamic remote monitoring. Heart failure (HF) is a complex clinical syndrome, affecting millions of patients worldwide . DespiteIn this scenario, facilitating the journey of a patient through remote monitoring could be intended as a significant step forward. Whether non-invasive monitoring is still lacking conclusive evidence of benefit, the efficacy of implantable hemodynamic monitoring is currently being tested.Fluid overload represents a key driver for worsening HF and hospitalizations. Its detection and assessment at an early stage is the main task for good management of HF, but it is currently done sub-optimally. The rationale beneath the application of wireless hemodynamic monitoring lies in the pathophysiological demonstration that clinical manifestations of congestive HF appear late in the progression to acute decompensation, whereas intracardiac pressures rise gradually and can anticipate, even by weeks, the onset of the symptoms, offering the opportunity to provide an accurate assessment of incipient pulmonary congestion –5. The tTM System  is the only one approved by the regulatory agencies , may overcome these limitations . In our via a secured cloud-based system. The safety, usability, and performance of this new technology are currently being tested in the V-LAP™ Left Atrium Monitoring system for Patients with Chronic systolic and Diastolic Congestive Heart Failure (VECTOR-HF) trial . After 3 months of the implantation, the pulmonary capillary wedge pressure (PCWP), measured during an RHC procedure, was compared with the LAP, and assessed by V-LAP, according to the study design.The V-LAP™ system  is the latest-generation device, capable of monitoring the LAP directly with an intracardiac leadless sensor and transmitting data  wirelessly to an external reader . Once itIn our center, as part of the VECTOR-HF trial, V-LAP™ was implanted in five patients suffering from HF and in the NYHA III class. LAP trends have been remotely monitored over time to guide the optimization of therapy . The preThis is the case of a 75 year-old male, suffering from HF with reduced ejection fraction (HFrEF) (LVEF 25%). The patient reported no history of coronary artery disease (CAD) and remained symptomatic for dyspnea on mild exertion (NYHA class III) despite optimal medical therapy (OMT) with beta-blockers, angiotensin receptor-neprilysin inhibitor (ARNi), mineralocorticoid receptor antagonist (MRA), loop diuretics plus device therapy with implantable cardioverter-defibrillator (ICD), and cardiac resynchronization therapy (CRT). His cardiovascular history started in 2015 when he was diagnosed with severe mitral regurgitation (MR), surgically treated with valve replacement. After V-LAP implantation and reliability confirmation, LAP measurements were analyzed. The patient reported high compliance (> 95%) with the measurements. In the first 12 months, a progressive increase in LAP was observed. Accordingly, the medical therapy was tailored, increasing the titration of furosemide and spironolactone, ranging from an initial daily dosage of furosemide of 12.5 mg every day (QD) to the current dose of furosemide/spironolactone 25/37 mg QD plus furosemide 25 mg every other day (EOD). The patient was remotely instructed to perform the proposed therapy adjustments and a stable LAP reduction was finally achieved . Over a A 71 year-old male patient suffering from ischemic chronic HFrEF (LVEF 34%), yet in OMT, experienced worsening dyspnea (NYHA III) and was hospitalized for decompensation. After discharge, the patient still reported mild exertion dyspnea and he was enrolled in the VECTOR-HF trial. Medical therapy has been consistently potentiated, according to the LAP trends recorded. The patient's tolerance to increased diuretic regimens was low, reporting hypotensive events and needing several furosemide daily dose adjustments over time. Guideline-oriented medical therapies (beta-blocker and ARNi) were further up-titrated. Although a clear LAP reduction was not observed, the slope of the rising trend was notably blunted, and the patient experienced no acute decompensation during follow-up. When the patient was solicited to double his daily LAP measurements, a constant discrepancy in LAP values throughout the day was revealed, with higher pressure being recorded in the evening hours. This trend was not explained by the normal hemodynamic circadian rhythm, featured by inverse diurnal rise. Diuretic dosage over the 24 h was recalibrated and these variations were flattened . To dateA 67 year-old man with a long history of hypertrophic cardiomyopathy, with impaired systolic function (LVEF 28%), experienced multiple episodes of HF decompensation, despite OMT. Due to his advanced age, he was denied a heart transplant. After enrollment, we observed substantial LAP fluctuations in day-to-day measurements, hindering our aim to identify any gradual trend and estimate the risk of decompensation. Among our cohort, he is the only one with permanent atrial fibrillation, and the irregularity in his LAP trends should be, at least in part, explained by this condition. To overcome this disadvantage, we asked the patient to perform the measurements two times a day. He showed high compliance to daily LAP assessments, amounting to 99% at 18 months. Over almost a year, only two hot phases of sustained increasing LAP were noticed and treated with ambulatory intravenous diuretic therapy (up to furosemide 80 mg) plus the increase of the oral diuretic daily dosage. A LAP reduction was obtained, and no further decompensation was reported . During A 72 year-old man with HFrEF (LVEF 36%) and non-ischemic dilated cardiomyopathy (LVEF 36%) was evaluated by our HF unit for dyspnea on mild exertion, peripheral edema, and increased NT-proBNP levels. Being ineligible for a heart transplant and unwilling to implant a left ventricular assist device, in November 2020, the choice was made to employ V-LAP remote monitoring. The adherence to daily LAP measurements was lower than other patients (65–70% at 15 months), impairing our ability to provide a personalized treatment. To date, he still complains of shortness of breath during daily activities (NYHA III), and an episode of sustained ventricular arrhythmia was recorded and treated by ICD with an appropriate shock. The available LAP measures did not display any reliable steady progression nor clear pathological elevation, but due to limited data, in-person assessments were scheduled every 2 months. Based on clinical findings, intravenous furosemide was administered during these appointments. A LAP reduction was observed and no hospitalization occurred. NT-proBNP levels increased from 1,932 pg/ml (prior implantation) to 2,711 pg/ml (at 12 months). As shown by KCCQ values, quality of life perception remained almost unchanged: the overall summary score ranged from 59.79 at baseline to 67.71 at 12 months, whereas the clinical summary score passed from 65.42 at baseline to 60.41 at 12 months. Comorbidities, such as chronic obstructive pulmonary disease and severe polyarticular osteoarthrosis could have affected his quality of life and physical capability, evaluated by the 6MWT, which reported poor performance (280 m without significant variation observed during the follow-up).A 76 year-old female patient, suffering from HFrEF (LVEF 30%) and non-ischemic dilated cardiomyopathy, experienced three hospitalizations for acute HF over 2021. She reported a very active lifestyle until a few months before, but in November 2021, the symptoms burden forced her home. Despite a complete up-titration of all guidelines-indicated medical therapies and CRT-D implantation, dyspnea on mild exertion persisted and the recurrence of peripheral edema required frequent diuretic dosage adjustments. In the absence of any feasible end-stage therapeutic option for this patient, she was implanted with the V-LAP monitoring system. At the end of February 2022, the calculated LAP was compared with the pulmonary capillary wedge pressure measured through right heart catheterization. Since then, LAP data have been visible to the clinical team. The extreme adherence (96%) to daily measurements over the first 3 months since implantation will help us to interpret future LAP trends and to avoid further HF exacerbations.The V-LAP system represents an innovative implantable device for patients with advanced chronic HF aiming to reduce HF-related hospitalizations. A rise in LVEDP can be observed since the earliest phases of HF subclinical progression, offering a sweet spot to reduce intracardiac pressures and, in turn, prevent hospital readmission. The PAP monitoring system has not demonstrated a clear benefit on HF prognosis , 7. The The multicenter VECTOR-HF first-in-man trial is evaluating the safety, usability, and performance of the V-LAP™ system in those individuals who cannot benefit from the guidelines-indicated end-stage solution, being not eligible for heart transplant nor, in turn, for mechanical circulatory support.In the present issue, we report our initial 3-year-experience with five patients with advanced HF, with a history of frequent hospital readmission and recurrently increased proBNP levels, showing the feasibility and safety of this approach.Since the first human use of an implanted LAP monitoring system, trans-septal puncture has proved to be mechanically safe without neither cardiovascular nor neurological concerns , 14. HowTM usage that has been highlighted in a preliminary analysis by another center  and was paralleled by an increase in the perceived quality of life, as indicated by the KCCQ, and physical capability assessed by 6MWT  pandemic . Since tThe application of the V-LAP system seems safe and reliable. In addition, preliminary clinical insights from our center's triennial experience support a promising efficacy of V-LAP empowered remote monitoring strategy in patients with advanced HF. However, future large trials will be crucial, both to confirm the clinical value of left-sided hemodynamic monitoring, and to standardize an effective LAP-guided medical management.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Fondazione Policlinico Universitario A. Gemelli IRCCS-Ethics Committee. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.FC, DD'A, and AR conducted the study. DP, FB, CT, GL, NA, GP, and RL supported the realization of the study. AR had a leading role in writing the manuscript. FC and DD'A had a leading role in manuscript revision. DP, LC, MG, and AI had a supporting role in manuscript revision. All authors have read and agreed to the content of the manuscript.Funding for the VECTOR-HF trial was made available by Vectorious Medical Technologies.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.


Hypertriglyceridemia (HTG) is a prevalent medical condition in patients with cardiometabolic risk factors and is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), if left undiagnosed and undertreated. Current guidelines identify HTG as a risk-enhancing factor and, as a result, recommend clinical evaluation and lifestyle-based interventions to address potential secondary causes of elevated triglyceride (TG) levels. For individuals with mild to moderate HTG at risk of ASCVD, statin therapy alone or in combination with other lipid-lowering medications known to decrease ASCVD risk are guideline-endorsed. In addition to lifestyle modifications, patients with severe HTG at risk of acute pancreatitis may benefit from fibrates, mixed formulation omega-3 fatty acids, and niacin; however, evidence does not support their use for ASCVD risk reduction in the contemporary statin era. Novel therapeutics including those that target apoC-III and ANGPTL3 have shown to be safe, well-tolerated, and effective for lowering TG levels. Given the growing burden of cardiometabolic disease and risk factors, public health and health policy strategies are urgently needed to enhance access to effective pharmacotherapies, affordable and nutritious food options, and timely health care services. Normal fasting triglyceride (TG) levels are defined as <150 mg/dL, while mild to moderate hypertriglyceridemia (HTG) is defined as TG levels between 150 to 499 mg/dL and severe HTG as TG levels of ≥500 mg/dL ,3,4. AlmObservational and genetic studies have established HTG as an important contributor to atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis (AP). For this reason, there is a renewed focus on identifying and treating HTG both for primary and secondary prevention. In this review, we discuss the physiology, etiology, and landscape of current and emerging pharmacologic therapies for the treatment of HTG to reduce ASCVD risk.TG has important physiological roles, serving as a fuel source for energy production in skeletal and cardiac muscle and facilitating the storage of excess energy in adipose tissue . TG is tIn the intestine, dietary lipids are packaged into ApoB48-containing chylomicrons. In the liver, hepatic cholesterol and triglycerides are packaged into ApoB100-containing very low-density lipoproteins (VLDL). Several sources contribute to the hepatic lipid pool, including dietary nutrients , circulating free fatty acids, and lipoprotein breakdown.In the circulation, the enzyme lipoprotein lipase (LPL) releases the TG from TRL by catalyzing the hydrolysis of TG to free fatty acids (FFA). FFA then cross the endothelium for oxidation in skeletal and cardiac muscle or for storage in adipose tissue. Successive rounds of metabolism by LPL yield increasingly dense, more cholesterol rich, and less triglyceride rich particles, termed remnant lipoproteins . SpecifiIn the final stage of their lifecycle, particles are taken up by specialized receptors on the surface on hepatocytes, notably the LDL-receptor (LDL-R) and LDL-related receptor 1 (LRP1) among others, which facilitate the recycling of TRL lipid and protein contents. Steady-state TG levels and the abundance of TRL in the circulation are determined by the relative rates of TRL production, metabolism, and clearance. Accordingly, factors which increase production or reduce the clearance of TRL can lead to HTG .HTG promotes atherosclerosis through several mechanisms. First, HTG reflects elevated TRL concentrations in the circulation and TRL, as with other apoB-containing lipoproteins, are directly atherogenic. In fact, research indicates that nearly all apoB-containing lipoproteins  are approximately equal in atherogenicity on a per particle basis . Second,Multiple lines of evidence indicate that elevated TRL levels (defined as elevated TG or elevated remnant cholesterol) are associated with ASCVD risk in both primary and secondary prevention, even among statin-treated patients ,13. In aThe atherosclerotic risk associated with TRL is related to the concentration of these atherogenic apoB-containing particles and enhanced by their TG content. Especially in cases of HTG, calculated LDL-C levels may underestimate an individual’s ASCVD risk when there is significant discordance between LDL-C and apoB or non-HDL-C. Consistent with this, non-HDL-C and apoB levels reflect the full risk due to atherogenic lipoproteins better than LDL-C in observational and interventional clinical trials . TherefoCurrent guidelines for patients with mild to moderate HTG focus on lifestyle modifications and a consideration of statin therapy based on an individual’s cardiovascular risk . For higIn addition to the increased ASCVD risk associated with mild to moderately elevated TG levels, HTG is also responsible for up to 15% of AP cases, with the risk and severity of AP increasing in a dose-dependent manner with elevations in TG levels ,24. SpecMild to moderate HTG occurs because of inherited and environmental factors. Even in patients with pathologic genetic variants that affect TG metabolism, environmental and modifiable characteristics have an important impact on TG levels and health outcomes . ContempMonogenic disorders that cause HTG are rare; however, they are more likely to be found in individuals with the most severe HTG (TG levels > 1000 mg/dL) . Recent In addition to genetic and lifestyle factors associated with HTG, secondary causes leading to elevated TG levels may include certain classes of medications including beta blockers, corticosteroids, and antipsychotics, as well as medical and metabolic conditions such as chronic kidney disease, uncontrolled hypothyroidism, and psoriasis . CliniciGiven the strong association between lifestyle and behavioral factors with elevated TG levels, as well as significant associations between HTG and metabolic syndrome, many of the same treatment approaches for managing insulin resistance, DM, obesity, cardiovascular disease, and fatty liver can be integrated into the care for those with high TG levels. To address the risk of ASCVD associated with HTG, current guidelines recommend an approach to clinical management based on lifestyle strategies, as well as pharmacotherapies utilized for an LDL-C risk-based approach. For patients with severe HTG, lifestyle modifications and pharmacotherapies that specifically lower TG are recommended to reduce the risk of AP. Lifestyle modifications that may result in TG reductions include weight loss (as much as 70% reduction), dietary modifications  (>70%), and physical activity (≤30%) ,34,35. RThere are different management strategies for optimizing diet, but all should follow healthful approaches that are evidence-based and feasible. Counseling should begin by stressing the elimination or avoidance of caloric-sweetened beverages and ultra-processed foods, along with reviewing what constitutes a heart-healthy diet. Such a diet should be rich in vegetables, fruits, nuts, whole grains, while minimizing simple starches. There should also be a focus on small portions of lean cuts of meat, favoring seafood when possible, and the preference for polyunsaturated (PUFA) or monounsaturated fats as cooking oil in food preparation, as opposed to saturated and trans-fats. Individuals with severe HTG and hyperchylomicronemia , should also reduce total fat from their diet until they have TG levels of <500 mg/dL.In line with the TG-lowering benefit of PUFA, it is recommended for all individuals to consume ≥2 servings of fish or seafood per week (≥8 ounces), which among other benefits, will increase the intake of omega-3 PUFA and take the place of other less healthy food choices. While fatty fish are recommended for individuals with mild to moderate HTG, those with severe HTG may require leaner seafood options.It is also important to note the effect of alcohol consumption on TG levels and related metabolic conditions. It has been shown that consuming one ounce of alcohol per day corresponds with a 5–10% higher concentration of TGs when compared with nondrinkers . For indWhile statins are generally known for their role in decreasing LDL-C levels and reducing individuals’ ASCVD risk, they also provide a 10–30% dose-dependent reduction in TGs in patients with HTG . In patiHowever, among statin-treated patients whose LDL-C levels are controlled, elevated TG levels may account for a significant proportion of their residual risk of a recurrent cardiovascular event. In a pooled analysis of 10 clinical trials (N = 5724) of statin-treated individuals with ASCVD, remnant cholesterol was significantly associated with coronary atheroma progression, which was independent of LDL-C, HDL-C, apoB, C-reactive protein, and other clinical risk factors. Higher concentrations of remnant cholesterol, the cholesterol content present in VLDL, is also associated with increased MACE risk . In addiA study using CANHEART  cohort data from nearly 2.5 million adults in the Ontario population found that nearly one in four statin-treated individuals with ASCVD had HTG and controlled LDL-C levels, and that the risk of ASCVD events increased in a stepwise manner with increasing TG levels . In a poStatins lower LDL-C, but also lower TRL, and higher intensity statins do so more than lower intensity statins. Although statins lower ASCVD risk in patients with HTG, elevated TG levels in statin-treated patients is a marker of residual cardiovascular risk even when the LDL-C is well controlled. Consequently, it is suggested that these individuals may be candidates for interventions such as more intensive lifestyle modifications, high-intensity statins, and high dose icosapent ethyl omega-3 fatty acids, as well as emerging therapies to further reduce their residual cardiovascular risk.Fibric acid derivatives are the most potent TG-lowering pharmacotherapy along with high dose omega 3 fatty acids. They have shown a benefit for ASCVD risk reduction when used as monotherapy, but not when added to statins. Over the past 35 years, there have been a number of key fibrate trials conducted to determine their utility for cardiovascular risk reduction including HHS (Helsinki Heart Study), VA-HIT , ACCORD (Action to Control Cardiovascular Risk in Diabetes), FIELD (Fenofibrate Intervention and Event Lowering in Diabetes), DAIS (Diabetes Atherosclerosis Intervention Study), BIP (Bezafibrate Infarction Prevention), and most recently the PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes) trial . A recenDespite null findings from PROMINENT, there are several key takeaways that can inform clinical practice and future research trials. First, given that several post hoc and secondary analyses of previous fibrate trials suggested the clinical benefits of fibrate therapy among individuals with HTG and low HDL-C levels, the subsequent findings that fibrates do not reduce ASCVD events in statin-treated patients with HTG strengthen the case for conducting rigorous studies assessing the validity of post hoc analyses before implementing them into clinical practice . Second,Omega-3 fatty acids including mixtures of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and purified EPA (icosapent ethyl) have been shown to decrease very high TG levels despite different effects on other physiologic parameters. There have been a number of key studies investigating the role of omega-3 fatty acids for ASCVD risk reduction, including GISSI-P , JELIS (Japan EPA Lipid Intervention Study), ORIGIN , ASCEND (A Study of Cardiovascular Events iN Diabetes), REDUCE-IT , VITAL , STRENGTH , and OMEMI . It is important to note that baseline TG levels were not included as part of the eligibility criteria for several of these large trials . The recThe GISSI-P study was conducted in patients with a recent MI (≤3 months) and found that low doses of EPA+DHA was beneficial; however, only a relatively small subset of participants were on statin therapy . Since tThe REDUCE-IT study sought to confirm the findings of the JELIS study and address its limitations in a double-blinded randomized placebo-controlled clinical trial with a higher dose form of purified EPA. The investigators found that icosapent ethyl significantly lowered the risk of ischemic events including cardiovascular death among statin-treated adults (N = 8179) with ASCVD or DM and other risk factors who had mild to moderate HTG and LDL-C levels of 41–100 mg/dL . AnalysiIn contrast to the findings in REDUCE-IT, the STRENGTH trial found that the addition of a carboxylic acid formulation of EPA and DHA (omega-3 CA) resulted in no significant differences in the composite MACE outcome, when compared with the corn oil placebo among statin-treated patients  with high cardiovascular risk, HTG, and low HDL-C levels . PotentiAPOC3 loss-of-function mutations are associated with a 40% reduction in TG levels and CHD risk ) in humans found that—among three patients with FCS and TG levels between 1406 and 2083 mg/dL—plasma apoC-III levels were reduced by 71% to 90% and TG levels decreased by 56% to 86% [In 2014, results from the first study to inhibit % to 86% . Several% to 86% . To addr% to 86% . Compare% to 86% . It is oIn addition to ApoC-III, emerging TG-lowering therapies are also targeting ANGPTL3, given that previous studies have shown loss-of-function variants to be associated with decreased plasma TG and LDL-C levels, as well as a reduction in CHD risk ,81. SeveIn terms of the former, recent data from the TRANSLATE-TIMI 70 trial (TaRgeting ANGPTL3 with an aNtiSense oLigonucleotide in AdulTs with dyslipidEmia) showed that Vupanorsen significantly reduced non-HDL-C and TG levels, with modest effects on LDL-C and apoB levels among statin-treated adults (N = 286) with non-HDL-C levels of ≥100 mg/dL and TG levels of ≥150–500 mg/dL . InjectiSo far, evinacumab investigation has been focused on LDL-C reduction in patients with homozygous familial hypercholesterolemia for whom the FDA has approved its use. Its potential role in the care of individuals with HTG at risk for ASCVD and/or AP is under investigation. However, it has been reported that evinacumab does not lower TG levels in individuals with FCS who lack LPL activity, but may still have an important role in managing moderate and severe HTG in non-FCS patients .HTG is commonly encountered in the primary and secondary medical care of patients, especially in those with DM and other cardiometabolic conditions, and contributes to a higher risk for ASCVD and AP.National practice guidelines recognize HTG as a risk-enhancing factor and favor an algorithmic stepwise approach to the care of at-risk patients. All individuals with HTG should be evaluated for and address secondary causes, as well as to undergo individualized lifestyle counseling. Individuals with severe HTG should receive TG-lowering pharmacotherapy, along with lifestyle modification, as primary treatment to reduce AP risk. Those at risk for ASCVD should receive statin-based care, with attention to LDL-C (as well as non-HDL-C and/or apoB), with pharmacotherapy known to reduce ASCVD risk including ezetimibe, proprotein convertase subtilisin-kexin 9 monoclonal antibodies (PCSK9 mAb), and/or a high dose icosapent ethyl esters according to the level of risk and lipid/lipoprotein response. Fibrates, over the counter and prescription mixed formulation omega-3 fatty acids, and niacin have no role in treating elevated TG to reduce ASCVD risk in statin-treated patients in contemporary care, though they may be of value in lowering TG levels in patients with severe HTG to reduce their risk of AP. Patients with HTG often have DM and pharmacologic therapies aimed at treating DM, such as glucagon-like peptide-1 receptor agonists (GLP1-RA), sodium glucose transporter-2 inhibitors (SGLT2i), and metformin, can enable weight loss, improve glycemic control, lower TG, and reduce ASCVD risk.Novel therapeutics in development including those that target apoC-III and ANGPTL3 appear to be safe, well-tolerated, and effective for the lowering of TG. They may have differing roles in treating individuals with severe HTG and have the potential to offer additional ASCVD risk reduction for those with mild to moderate HTG as well, depending on the results from clinical trials specifically designed to explore this question.Clinicians must be mindful of the additional burden of pharmacotherapy and the relative powerful impact of lifestyle modifications. The authors acknowledge the important role of personal responsibility for managing lifestyle factors, but stress to our patients and to the readers that we live in a toxic food environment. The current diet in the U.S. has resulted in ~70% of adults with overweight/obesity, ~50% with prediabetes/DM, and ~25% with HTG. Addressing this concern will require a sustained and concerted societal effort beyond what any individual clinician–patient interaction(s) can achieve. However, until that time, clinicians must address care for the patient with HTG with a holistic, empathetic, and individualized approach. In addition to personalized dietary/lifestyle counseling, optimally supported by a registered dietitian nutritionist, appropriate use of evidence-based pharmacotherapies is needed to reduce ASCVD risk.


Inflammation is an indispensable biological process stimulated by infection and injuries. Inflammatory mechanisms related to extracellular vesicles (EVs), which are small membrane structures carrying various molecules, were summarized in this review. Emerging evidence from animal studies has highlighted the role of EVs in modulating inflammatory responses, by transporting various molecules involved in host defense. In this review, we have discussed the role of EV miRNAs in inflammation. Rodent studies associated with extracellular miRNAs in inflammatory diseases, published from 2012 to 2022, were explored from PUBMED, EMBASE, and MEDLINE. A total of 95 studies were reviewed. In summary, EV-associated miRNAs play a key role in various diseases, including organ injury, immune dysfunction, neurological disease, metabolic syndrome, vesicular disease, arthritis, cancer, and other inflammatory diseases. Diverse EV-associated miRNAs regulate inflammasome activation and pro- and anti-inflammatory cytokine levels by targeting genes. The inflammatory response is a rapid and complex physiological process that involves defense mechanisms acting against infections and injuries ,2. InflaEVs are small vesicles  that can be categorized into the following three types according to their size and biogenesis: exosomes, microvesicles, and apoptotic bodies . EVs areThis report presents an overview of the recent studies on extracellular miRNAs, with a focus on their role in inflammatory diseases in animals.All relevant studies were initially searched on EMBASE, MEDLINE and PUBMED database using the following search keywords: “extracellular vesicles”, “exosome”, “inflammatory diseases”, and “microRNA”. We included rodent studies published from November 2012 to April 2022 and overlapping studies were excluded. Eventually, we identified 320 potentially relevant literatures for further eligibility assessments.n = 100); (2) full text not available (n = 1); (3) not English (n = 1), (4) virus or infection-induced experiment model (n = 14), (5) not a rodent study (n = 92). Title and abstract screening were performed and six studies with no specific microRNA target (n = 12) and five studies with no mention of microRNA mechanism were excluded. As shown in Three authors  independently assessed the 320 literatures and a total of 208 studies were excluded based on the following exclusion criteria: (1) review article  mouse model established by cecal ligation puncture (CLP), miR-125 in exosomes derived from endothelial cells promoted VEGF expression, inflammatory response, improved pathological changes, restrained lung water content, protein content in bronchoalveolar lavage fluid, and cell apoptosis by targeting TOP2A . In an L and Asc . In anot and Asc .snail-1 and reduced inflammation and fibrosis in the infarcted heart in a rat myocardial infarction model [miR-133-MSC transplantation improved cardiac function, and miR-133-overexpressing MSCs repressed cardiac expression of on model . βARKct on model . In a raon model . In a doon model . In an aon model . Using ton model . In a seon model . miR-223on model . In a moon model . In angion model .In a dextran sulfate sodium (DSS)-induced colitis mouse model, miR-378 carried by hucMSC exosomes attenuated colitis by regulating macrophage pyroptosis and inhibiting NLRP3 inflammasome activation . MoreoveIn the ischemia/reperfusion-injured mouse kidney, miR-23a-enriched exosomes from hypoxic tubular epithelial cells promoted tubulointerstitial inflammation in mice by inhibiting A20; hence, miR-23a inhibition suppressed renal tubulointerstitial inflammation . In a leIn a taurocholate-induced acute pancreatitis rat model, pro-inflammatory miR-155 was increased in plasma exosomes, and miR-122 and miR-21 were decreased compared to that in plasma control exosomes. The levels of miRNAs in pancreatitis-associated ascitic fluid exosomes were similar to those in plasma control exosomes. Plasma exosomes had higher pro-inflammatory activity in macrophages . In an aTen articles that we explored were related to the immune dysfunction of miRNAs in exosomes. Immune dysfunction is a disorder of the immune system that includes sepsis and asthma. Recent studies have investigated the roles of miRNAs in immune dysfunction and the associated diseases. We have now organized each miRNA that was introduced as the target of different immune dysfunction studies .For a Rab27KO mouse model that displays a chronic, low-grade inflammatory condition, exosomes carrying miR-155 can rescue LPS responsiveness, and the reduction in miR-155 targeting SHIP1 and IRAK-M is involved in this rescue . In an iOnly 13 articles included in this study were related to neurological diseases of miRNA in exosomes. Neurological diseases are associated with nervous system disorders. Here, we have discussed the roles or attenuation of miRNAs in exosomes in neurological diseases .In a mouse with middle cerebral artery occlusion used for cerebral infarction model, exosome-miR-542 derived from MSCs suppressed cerebral injury and inflammation by inhibiting TLR4 . In a stOnly seven of the ninety-five articles explored were related to metabolic syndromes involving miRNAs of exosomes. Metabolic syndrome increases the risk of heart disease, diabetes, and other health problems. Here, we determined how miRNAs in exosomes play a role in metabolic syndrome .In a streptozotocin (STZ)-induced diabetic rat model, miR-21 exosomes from MSCs promoted ulceration repair, ischemic hindlimb blood perfusion, ischemic repair, and angiogenesis . Using aAmong the 95 articles, only 8 articles were associated with miRNAs exosomes in vesicular disease. Vesicular disease is a kind of blood vessel disorder, which can occur in the location of different types of artery and veins. We organized the relations between miRNA exosomes and versicular diseases .In a mouse model of atherosclerotic diabetes, EPC-derived exosomes and its miRNAs ameliorated diabetic atherosclerotic plaques, endothelial dysfunction, and inflammatory factors . In an aSix of the ninety-five articles studied were related to miRNA exosomes involved in arthritis. Arthritis is a disorder that commonly affects joints. This usually makes it difficult for them to be active. We examined how exosomal miRNAs influence arthritis .In a mouse model of mBSA-induced arthritis, the injection of anti-miR-132 attenuated inflammatory arthritis . In a moOnly five of the ninety-five articles we studied were associated with roles of miRNA exosomes in cancer. Cancer is a type of disease with abnormally increased growth of cells that spreads easily, commonly leading to low survival rates. We discussed the relationships between the different types of cancer and miRNAs in exosomes and determined the underlying mechanism .In a mouse model, tumor growth was decreased by miR-155, whereas miR-205 increased tumor growth. miR-155 and miR-205 play important roles in tumor growth of breast cancer cells in mice . In a brEleven articles were discussed that dealt with other inflammatory diseases. We examined the mechanisms of action of miRNA exosomes in diverse diseases .In a ligature-induced periodontitis and diet-induced obesity mouse model, an miR-25 inhibitor suppressed local inflammation, and exosomes of miR-25 in saliva contributed to the advancement of diabetes-associated periodontitis . Using aExperimental studies of EVs and miRNAs are newly emerging and are in demand. We focused on diverse EV-associated miRNAs that play crucial roles in various inflammatory diseases. In this review, we have discussed the association of miRNAs in EVs with inflammatory diseases in rodent models. EVs have been recognized as the cargo of various molecules transported from origin cells to recipient cells mostly in all organisms. EVs also play complex and important roles in the pathophysiology of several diseases. Moreover, diverse EV-associated miRNAs play crucial roles in various inflammatory diseases. Given the previously suggested functions of EVs and increasing interest in clinical implications of EVs in various diseases, this study focused on miRNA in EVs in inflammatory diseases to further analyze their involvement in inflammatory responses. However, the studies included in this review are insufficient for comprehensive knowledge about the mode of action of extracellular miRNAs in inflammation. In addition, the included studies mostly reported changes in miRNA expression in different disease models, yet there was limited evidence of how the loss or gain of each miRNA function work in disease conditions. Further functional studies on each miRNA in inflammatory disease are needed to confirm the use of extracellular miRNAs as potential biomarkers or as a therapeutic method in which they can be safely and efficiently delivered to the target region. Nevertheless, our understanding suggests an opportunity for further study of extracellular miRNAs as biomarkers and the early diagnosis of inflammatory diseases and disorders. Moreover, the use of EVs might further offer the possibility of gene therapeutic approaches for inflammation.