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ABSTRACTIntroductionSodium Glucose co-Transporter 2 (SGLT2) inhibitors (also known as ‘gliflozins’) represent a cornerstone to treat diabetes mellitus. Moreover, recent randomized clinical trials have demonstrated important cardioprotective effects of gliflozins, independent of the presence of diabetes. Herein, we summarize the recent therapeutic progress in the cardiovascular field obtained with SGLT2 inhibitors.Area coveredWe critically examine the rationale and results of recent clinical studies examining the effects of SGLT2 inhibitors on cardiovascular outcomes, along with a brief overview of the main ongoing trials that have been designed in order to answer the many pending questions in the field of gliflozins and cardiovascular disease.Expert opinionThe favorable results of several clinical trials have broadened the therapeutic scenario for SGLT2 inhibitors, opening, at the same time, new challenges. Additionally, recent preclinical findings have evidenced off-target effects of SGLT2 inhibitors.

In this study, we demonstrate that insulin resistance correlates with cognitive impairment in a population of frail hypertensive older adults with pre-diabetes.• We successfully studied 141 patients with hypertension, pre-diabetes, and frailty.• We observed a correlation between two parameters used to assess cognitive decline and insulin resistance.

ABSTRACTIntroduction: Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular calcium (Ca2+) release channels located on the endoplasmic/sarcoplasmic reticulum. The availability of the structure of the ligand-binding domain of IP3Rs has enabled the design of compatible ligands, but the limiting step remains their actual effectiveness in a biological context.Areas covered: This article summarizes the compelling literature on both agonists and antagonists targeting IP3Rs, emphasizing their strengths and limitations. The main challenges toward the discovery and development of IP3 receptor modulators are also described.Expert opinion: Despite significant progress in recent years, the pharmacology of IP3R still has major drawbacks, especially concerning the availability of specific antag onists. Moreover, drugs specifically targeting the three different subtypes of IP3R are especially needed.

Background: To the best of our knowledge, the association of physical impairment and cognitive decline has never been investigated in frail patients with acute myocardial infarction. Aim: The aim of our study is to assess the correlation between physical and cognitive dysfunction in frail patients with ST-elevation myocardial infarction (STEMI). Methods: We examined consecutive frail patients with first STEMI treated with primary percutaneous coronary intervention (PPCI). All patients were evaluated via Mini Mental State Examination (MMSE) and 5-m gait speed test after PPCI. Results: A total of 871 frail patients with suspected STEMI were admitted and 301 patients successfully completed the study. We found that the gait speed significantly correlated with the MMSE score (r: 0.771; p: < 0.001). The independent effects on MMSE score were confirmed in a linear multivariate analysis. Conclusions: Taken together, our findings indicate that an assessment of both cognitive and physical conditions should be included in the comprehensive geriatric evaluation of hospitalized older STEMI patients.

Background: Despite primary percutaneous coronary intervention (PPCI) is generally considered the best therapy in older frail adults with ST-segment elevation myocardial infarction (STEMI), the incidence of re-hospitalization for cardiovascular diseases remains significant in these patients. Aims: We hypothesized that thrombus aspiration (TA) before PPCI could be a useful treatment for reducing mortality and rehospitalizations in frail patients undergoing PPCI for STEMI. Methods: We conducted a study comparing PPCI alone vsTA + PPCI in frail STEMI patients. We examined a cohort of consecutive frail patients aged ≥ 65 years with first STEMI treated with PPCI between February 2008 and July 2015 at the Department of Cardiology of the “Cardarelli” Hospital in Naples, Italy. Results: The study was completed by 389 patients (PPCI: 195, TA + PPCI: 194). At 1-month follow-up, the rate of death from any cause was 7.0% in patients treated with PPCI alone vs 3.0% in patients treated with TA + PPCI (p0.036), whereas death from cardiovascular causes was 6.0% in the PPCI group vs3.0% in the TA + PPCI group (p0.028). Equally important, the rate of re-hospitalization due to heart failure was 7.5% in the PPCI group vs 4.0% in TA + PPCI group (p0.025) and the rate of re-hospitalization due to acute coronary syndrome was 10.0% in the PPCI group vs 4.5% in the TA + PPCI group (p0.016). Conclusion: These results indicate the importance of TA in the treatment of STEMI in a group of high-risk patients such as elderly with frailty.

ABSTRACTIntroduction: Angiopoietin-like (ANGPTL) proteins belong to a family of eight secreted factors that are structurally related to proteins that modulate angiogenesi, commonly known as angiopoietins. Specifically, ANGPTL3, ANGPTL4, and ANGPTL8 (the ‘ANGPT L3-4-8 triad’), have surfaced as principal regulators of plasma lipid metabolism by functioning as potent inhibitors of lipoprotein lipase. The targeting of these proteins may open up future therapeutic avenues for metabolic and cardiovascular disease.Areas covered: This article systematically summarizes the compelling literature describing the mechanistic roles of ANGPTL3, 4, and 8 in lipid metabolism, emphasizing their importance in determining the risk of cardiovascular disease. We shed light on population-based studies linking loss-of-function variations in ANGPTL3, 4, and 8 with decreased risk of metabolic conditions and cardiovascular disorders. We also discuss how the strategies aiming at targeting the ANGPT L3-4-8 triad could offer therapeutic benefit in the clinical scenario.Expert opinion: Monoclonal antibodies and antisense oligonucleotides that target ANGPTL3, 4, and 8 are potentially an efficient therapeutic strategy for hypertriglyceridemia and cardiovascular risk reduction, especially in patients with limited treatment options. These innovative therapeutical approaches are at an embryonic stage in development and hence further investigations are necessary for eventual use in humans.

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Introduction.L-Arginine (L-Arg) is a semi-essential amino acid involved in a number of biological processes. L-Arg has been recently shown to have beneficial effects on functional capacity in heart failure. However, the molecular mechanism underlying these actions are mostly unknown and a potential direct effect of L-Arg on cardiac fibroblasts has never been investigated hitherto. Transforming growth factor (TGF)-β is one of the main profibrotic cytokines, known to activate fibroblasts into myofibroblasts stimulating the production of extracellular matrix (ECM). In fibrosis condition, excessive ECM alters myocardial structure, eventually impairing cardiac function.Hypothesis.We hypothesized that L-Arg could mitigate TGF-β-dependent phenoconversion of human cardiac fibroblasts (HCFs).Methods.We isolated primary cardiac fibroblasts from human hearts (protocol approved by the Institutional Review Board for protection of human subjects) and tested a model of fibrosis obtained by treatment with TGF-β. Isolated HCFs were characterized by immunostaining. Early passage HCFs were treated with TGF-β or TGF-β + L-Arg at different doses and time points. The mitochondrial generation of reactive oxygen species (ROS) was assessed by MitoSox at the confocal microscopy.Results.TGF-β induced a significant upregulation of established markers of myofibroblast activation and fibrosis (including Fibronectin, Col1A1, Col1A2,and Periostin), which was significantly attenuated by L-Arg, as confirmed by RT-qPCR, immunostaining, and immunoblot. Moreover, we observed that TGF-β treatment significantly increased the mitochondrial generation of ROS, which was again prevented by co-treatment with L-Arg. In addition, L-Arg significantly reduced SMAD-2 protein expression.Conclusions.Our findings demonstrate, for the first time to our knowledge, the anti-fibrotic role of L-Arg in HCFs, mediated via a TGF-β/SMAD-2 signaling pathway.

Introduction:Mounting evidence indicates that endothelial dysfunction and oxidative stress play crucial roles in the pathophysiology of COVID-19 and Long-COVID.Hypothesis:We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have beneficial effects on Long-COVID symptoms.Methods:We designed a nationwide multicenter clinical study, in which a survey assessing several symptoms that have been previously associated with Long-COVID was administered to COVID-19 survivors; the subjective perception of the tolerance to the effort was measured as well, trough the Borg scale. Patients were divided in two groups, with a 2:1 ratio: the first group included patients treated with L-Arginine + Vitamin C, whereas the second group was treated with multivitaminic combinations (alternative treatment). Before administering the survey, patients completed 30 days of treatment.Results:1590 patients were initially enrolled, of which 1390 successfully completed the study. Following a 30-day treatment with L-Arginine + Vitamin C, the survey revealed that patients in this treatment group had significantly lower scores compared to the other group. There were no other significant differences between the two groups. Furthermore, when examining the subjective perception of the tolerance to the effort (modified Borg scale), we observed a significantly lower value (p<0.0001) in the L-Arginine + Vitamin C patients compared to the alternative-treatment arm.Conclusions:Our findings indicate for the first time that the supplementation with L-Arginine + Vitamin C has favorable effects in Long-COVID, in terms of reducing its typical symptoms and improving the perceived tolerance to effort.

Introduction:Anderson-Fabry disease (AFD) is a systemic disorder caused by impaired alpha-galactosidase (GLA) activity, leading to a progressive cardiomyopathy, with hypertrophy and diastolic dysfunction. However, the molecular mechanisms underlying these features are unknown.Aim:To explore the role of mitochondria as a pathogenic mechanism of cardiac dysfunction in AFD.Methods:We tested a transgenic mouse that lacks endogenous GLA and expresses human R301Q-GLA [Tg/GLA knockout]. We performed serial ecochardiographic, histological, and biochemical analyses on cardiac tissue and single cell contractility on isolated adult cardiomyocytes (CM). Moreover, we assessed mitochondrial morphology/function in mouse embryonic fibroblasts (MEFs).Results:AFD-MEFs display an impaired mitochondrial respiration and reduced ATP synthesis. Increased mitochondrial levels of DRP1, LC3II, and MFN-ubiquitination along with accumulation of fragmented mitochondria and autophagosomes indicate the presence of mitophagy-targeted mitochondria that were not removed. Reduced PGC-1a and mitochondrial-DNA synthesis in AFD-MEFs indicate impaired mitochondrial biogenesis as well. Altogether, our data indicate impaired mitophagy and quality control of AFD-mitochondria. At echocardiography, AFD mice showed diastolic dysfunction and hypertrophy starting from 9 months. Isolated AFD-CMs exhibit reduced inotropic response to isoproterenol. Remarkably, alterations of cardiac mitochondrial function were observed starting from 3 months, including increased levels of MFN2-ubiquitination, DRP1 and LC3II, decreased levels of PGC-1a along with accumulation of disarranged mitochondria and autophagosomes. Frank impairment of mitochondrial respiration in AFD-CMs and reduced myocardial ATP-content was detected from 6 months, together with increased release of Cytochrome-C in the cytosol. Strikingly, mitochondrial dysfunction was also detected in fibroblasts isolated from AFD patients, which have a significantly reduced electron transport chain activity.Conclusions:In AFD, energetic alterations associated with impaired autophagy/mitophagy, are evident at 3 months and progressively lead to cardiac hypertrophy and dysfunction.

Introduction:Ischemia with non-obstructive coronary arteries (INOCA) is a relatively new condition, often observed in patients with angina. However, the exact pathophysiology of INOCA is not fully understood, and its management remains very debated.Hypothesis:We hypothesized that admission hyperglycemia in INOCA patients could be associated with the risk of being re-hospitalized for chest pain.Methods:We evaluated INOCA patients referred to our Institution between 2016 and 2021 for percutaneous coronary intervention (PCI). We divided our population in quintiles according to the values of the stress hyperglycemia ratio (SHR), calculated as the ratio of admission blood glucose (expressed as mmol/L) and HB1Ac (%). We calculated Kaplan-Meier product limits for cumulative ratio of reaching the endpoint and we applied the log-rank test. To further confirm our results, we performed a multivariable analysis in order to adjust for potential confounders.Results:2874 INOCA patients were enrolled in our study. At 1-year follow-up, the risk of hospitalization for chest pain was progressively higher in patients with higher SHR values (p<0.001). To rule out the impact of potential confounders, we performed a multivariable analysis adjusting for potential risk factors for re-hospitalization, including age, BMI, hypertension, dyslipidemia, diabetes, smoking, and creatinine; this analysis confirmed the significant association of admission SHR and re-hospitalization in INOCA patients.Conclusions:To the best of our knowledge, this is the first report showing that admission SHR is an independent risk factor for hospitalization in INOCA patients, with or without diabetes. Our data indicate that hyperglycemia may trigger coronary microvascular dysfunction driving worse outcomes in this class of patients; in this context, glycemic control may be a main goal to be achieved in this population. Further studies in larger populations and with a longer follow-up are warranted to confirm our findings.

Introduction:Neuropilin-1 has been recently identified as a co-factor needed for the entry of SARS-CoV-2 in host cells and has been linked to neurologic symptoms of COVID-19 (Science 2020). Emerging evidence indicates that exosomal microRNAs (miRNAs) are involved in a number of physiologic and pathologic processes. However, to our knowledge, exosomal miRNAs have not been hitherto investigated in COVID-19.Hypothesis:Since we have recently demonstrated that miR-24 targets the 3’UTR of the gene encoding for Neuropilin-1 and this miRNA is expressed in human brain endothelial cells, we hypothesized an association between plasma levels of CD31+extracellular vesicles (EVs) enriched in miR-24 and the risk of cerebrovascular manifestations in patients hospitalized for COVID-19.Methods and Results:We obtained plasma from >300 COVID-19 patients; as control COVID-19 negative populations, we obtained plasma from healthy donors and patients hospitalized for cerebrovascular disorders. CD31+EVs were isolated from plasma on hospital admission, and miR-24 levels were quantified. When comparing patients with vswithout cerebrovascular disorders, we found that plasma levels of CD31+EV miR-24 were significantly different between these populations. We did not find any significant difference among groups when assessing circulating free levels of miR-24. Using a multiple regression analysis, adjusting for age, hypertension, and diabetes, the association between EV miR-24 and cerebrovascular complications in COVID-19 patients was confirmed (P<0.05).Conclusions:This is the first study showing a significant association between EV non-coding RNAs and clinical outcome in COVID-19 patients. Our results are relevant for basic researchers, because we identified an unprecedented significant association between EV miR-24 and cerebrovascular disorders, which could be helpful to better understand the molecular mechanisms underlying the pathophysiology of cerebrovascular events in COVID-19, as well as for clinicians, inasmuch as this association may help healthcare professionals in identifying COVID-19 patients who are at high risk of developing cerebrovascular disease.

Introduction:Hyperglycemia (HG) has been shown to adversely affect the outcome of ST-elevation myocardial infarction (STEMI).Hypothesis:We hypothesized that HG at hospital admission could increase the risk of in-stent restenosis after primary percutaneous coronary intervention (PCI) for STEMI.Methods:We enrolled consecutive STEMI patients referred to the division of Cardiology of "Antonio Cardarelli" Hospital in Naples, comparing normoglycemic subjects (NG), patients without diabetes mellitus but with HG (HG-non-DM), and patients with both HG and DM (HG-DM).Results:A total of 336 propensity score matched patients were included in the study: 112 NG, 112 HG-non-DM, and 112 HG-DM. At 1-year follow-up, 6.5% of NG patients, 14.0% of HG-non-DM, and 18.5% of HG-DM had been re-hospitalized for restenosis; Kaplan-Meier curves (p: 0.009) are depicted in the Figure.We then examined these findings applying a multivariate analysis with Cox regression in HG-non-DM patients, observing a significant association with restenosis for glycemia at hospital admission, total and LDL-cholesterol.Conclusions:The present study is the first to evaluate the effects of HG on the risk of restenosis in STEMI patients without DM, comparing the results to both HG-DM and NG subjects. Taken together, our data indicate that HG is associated with adverse outcomes in STEMI patients independently of DM. These findings emphasize the importance of glycemic control in all STEMI patients in order to reduce the risk of complications.

Introduction:Following an ischemic injury, the persistence of cardiac myofibroblast (myo-FBs) contributes to fibrosis and adverse myocardial remodeling, especially if myoFBs remain active in otherwise healthy areas of the heart, away from the site of injury. The exact mechanisms underlying myo-FB activation and persistence remain unknown.Hypothesis:Since recent genome-wide association (GWA) studies have identified a significant association between gain-of-function mutations in genes encoding for inositol 1,4,5-trisphosphate receptors (IP3Rs) and ischemic heart disease, we hypothesized that IP3Rs could be involved in post-ischemic cardiac fibrosis.Methods:We applied an established model of ischemia/reperfusion (I/R) to a newly generated triple KO mouse specifically lacking all isoforms of IP3Rs in cardiac myo-FBs, in order to avoid compensatory responses.Results:After I/R, IP3Rs level is not changed in the scar area, whereas it is markedly upregulated in the remote regions. Compared to control littermates, KO mice display a reduced interstitial fibrosis and an attenuated myocardial dysfunction following I/R.Mechanistically, we show for the first time that IP3Rs modulate apoptosis in myo-FBs following ischemic injury in a calcium-independent manner, i.e.by directly sequestrating the pro-apoptotic factor PUMA (p53 upregulated modulator of apoptosis), thereby favoring the detrimental myoFBs persistence in the remote areas. Strikingly, these results were confirmed in human cardiac specimens from patients with heart failure, as well as in vitroin human FBs, in which IP3Rs are shown to regulate cell proliferation and migration.Conclusions:Our findings indicate that the IP3R-PUMA interaction selectively regulate the activation of cardiac myo-FBs located in the regions remote from the ischemic injury.

The platelet GPIIIa plays a pivotal role in platelet aggregation. Previous studies showed an association between the GPIIIa PlA1/A2polymorphism and coronary thrombosis, while there is only contrasting evidence about its role in stroke. We explored the possibility that this polymorphism represents a risk factor for stroke in hypertensive patients.

Introduction:Recent genome-wide association studies have evidenced a significant association between gain-of-function mutations in genes encoding for Inositol 1,4,5-trisphosphate receptors(IP3Rs) and ischemic heart disease. Three isoforms of IP3Rs have been identified in mammals (IP3R1-3) and their expression pattern is overlapping and redundant. To our knowledge, functional studies examining the exact role of IP3Rs in post-ischemic cardiac remodeling are missing.Hypothesis:We hypothesize that IP3Rs play a key role in the activation of cardiac myo-fibroblasts (myo-FBs) in myocardial infarction (MI).Methods and Results:We performed an integrated set of in vivo, ex vivo, and in vitroexperiments aiming at identifying the role of myo-FB IP3Rs in post-ischemic cardiac remodeling. We generated cardiac myo-FB-specific triple IP3R knock-out (IP3RTKO) mice (Cre/loxrecombination; Promoter: Periostin,an established marker labeling activated FBs following cardiac injury, selectively upregulated in activated myo-FBs but not in quiescent FBs), allowing us to overcome the difficulties encountered following the KO or KD of a single IP3R, a strategy that has been shown to induce compensatory upregulation of the other isoforms. IP3RTKOmice exhibit a significantly (p<0.001) reduced interstitial cardiac fibrosis and chronic inflammation, and attenuated myocardial dysfunction following MI compared with control IP3Rfloxor PeriostinCrelittermates. IP3R ablation also reduced the expression of pro-inflammatory interleukins and chemokine ligands. Moreover, FBs lacking IP3Rs display significantly reduced migratory and secretory capacities, a finding confirmed both in murine and human FBs. Mechanistically, we show that IP3Rs regulate inter-organelle calcium fluxes between endoplasmic reticulum (ER) and mitochondria, autophagy/mitophagy, mitochondrial unfolded protein response (UPR), oxidative stress, and ER stress in primary isolated myo-FBs following ischemic injury.Conclusions:Our results indicate for the first time that IP3Rs are essential for the regulation of activation and persistence of myo-FBs, playing a crucial role in cardiac fibrosis post-MI through a mechanism that involves UPR and autophagy.

Introduction:Substantial evidence has shown that Mediterranean diet can reduce the risk of metabolic syndrome (MS). However, the development of retail distribution has radically changed food supply worldwide. For instance, in the Mediterranean area, industrial retail favors shipments of groceries from regions that are intensive producers of mass food, generating the long supply chain (LSC) of food; on the other hand, short supply chains (SSCs) typically involve local self-producers promoting local markets. To our knowledge, the role of food retail and distribution in the determination of the risk of developing MS has not been studied hitherto.Hypothesis:We hypothesized that food chain length could affect the risk of developing metabolic alterations such as MS in a population accustomed to Mediterranean diet.Methods:We compared the SSC of food, in which aliments are mainly produced in loco, usually with traditional and low-technology methodologies, to the LSC of food. MS was defined using the latest ?Harmonized Criteria? to diagnose MS [CirculationVol.120 (16), Pg.1640]. The study was registered in the ClincalTrial.govdatabase (NCT03305276).Results:We recruited 407 subjects (average age: 56 years; 59% males), all adhering to Mediterranean diet, living in rural or urbanized areas of Southern Italy. The most important source of food in rural areas is represented by locally grown vegetables and meat of courtyard animals (SSC), whereas in metropolitan areas people mainly eat retail food (LSC). The actual dietary habits were confirmed through a validate questionnaire, designed to distinguish SSC and LSC viaa specific score. No significant differences were observed between SSC and LSC groups in terms of common demographic and metabolic parameters. Intriguingly, we found that being on Mediterranean diet with a SSC significantly (p=0.007) reduced the prevalence of MS compared with LSC, a result that was confirmed after correcting for confounding variables.Conclusions:Taken together, our findings show for the first time that the length of food supply chain is an independent predictor of the risk of MS in a population accustomed to Mediterranean diet, supporting the importance of local food environments in the determination of cardiovascular risk.

Introduction:The mitochondrial unfolded protein response (UPRmt) is an evolutionary conserved process evoked when the mitochondrial protein folding environment is compromised. The major regulators of the UPRmtinclude Activating Transcription Factor 5(ATF5) and Lon Peptidase 1(LONP1). UPRmthas been recently shown to be involved in cardiac pressure overload; however, its functional role in post-ischemic heart failure (HF) and its regulation by non-coding RNAs have never been investigated hitherto.Hypothesis:We hypothesize that UPRmtis a key process in the pathophysiology of post-ischemic HF and is regulated by specific microRNAs (miRNAs, miRs).Methods:To test the mechanistic role of miRs in the modulation of UPRmtin HF we combined bioinformatic approaches (to identify miRs targeting the crucial players of UPRmt) with an in vivomurine model of ischemic HF (coronary ligation).Results:We identified and biologically validated in vitrovia luciferase assay two miRs, namely miR-129-5p and miR-489, as specific modulators of the expression of ATF5 and LONP1, respectively. Four weeks after LAD ligation both miRs were significantly (p<0.01) upregulated in the left ventricle compared to sham conditions, whereas their respective targets, ATF5 and LONP1, were markedly downregulated, both at the mRNA and protein level. These alterations were accompanied by perturbations in UPRmtand also in endoplasmic reticulum UPR (UPRER), including upregulation of HSP60, HSP10, and mtDNAj, as well as the three main arms of ER stress. A dual miR in vivotargeting, using miR-129-5p and miR-489 antagomirs, significantly improved the UPRmtresponse and overall cardiac function, whereas single approaches yielded minimal results. Intriguingly, despite having as a main target a mitochondrial protease (LONP1), antagomiR-489 alone had significant effects on the modulation of UPRER. These results were further supported by ex vivoexperiments in primary isolated cardiomyocytes, in terms of contractility and mitochondrial dynamics and function (including fission/fusion and Seahorse assays).Conclusions:Taken together our results indicate that miR-129-5p and miR489 regulate UPRmtin cardiomyocytes in post-ischemic HF via specific targeting of ATF5 and LONP1.

Introduction:Mounting evidence has shown that exosomal non-coding-RNAs play a pivotal role in cell-cell communication. However, their contribution in the phenoconversion of cardiac fibroblasts to active myofibroblasts in myocardial infarction (MI) has not been investigated.Hypothesis:We hypothesize that exosomal microRNAs (miRs) are involved in the activation of myofibroblasts following ischemic injury.Methods:We tested our hypothesis trough means of bioinformatic tools and a murine model of MI, obtained via surgical ligation of the left anterior coronary artery; we measured the expression levels of a set of miRs in fibroblasts and cardiomyocyte-derived exosomes; we used miR inhibitors and mimics to evaluate post-MI myofibroblast phenoconversion.Results:Compared with SHAM conditions, miR-92a was significantly (p<.01) upregulated (absolute values) in cardiomyocyte-derived exosomes as well as in fibroblasts isolated at different time points after MI. This miRs was shown to specifically target SMAD7 (Mothers against decapentaplegic homolog 7), an established inhibitor of ?SMA (?-Smooth muscleactin)expression (a fundamental player in myofibroblast activation); such interaction was predicted using bioinformatic tools and validated via luciferase assays. Furthermore, primary isolated cardiac fibroblasts were activated both when incubated with exosomes derived from ischemic cardiomyocytes and when cultured in conditioned medium of post-MI cardiomyocytes, whereas no significant effects were observed after incubation with exosomes or medium from sham cardiomyocytes. Myofibroblast activation was assessed measuring the expression of ?SMA, periostin, collagen I/III, fibroblast activation protein, and fibronectin ED-A. Additionally, miR-92a regulated the post-MI inflammatory response (also in terms of IL-6 and CXCL1). Inhibiting exosome release (GW4869 10?M 12h) significantly attenuated all these responses. The mechanistic contribution of miR-92a to fibroblast phenoconversion was further confirmed using miR-92a mimics and inhibitors.Conclusions:Taken together, our findings indicate that miR-92a is transferred to fibroblasts in form of exosomal cargo, and is crucial for post-MI activation of myofibroblasts.

Combined inhibition of DYRK1A and TGF-β pathways synergistically enhances proliferation and differentiation of human pancreatic beta cells.

T lymphocytes release exosomes containing specific microRNAs that cause apoptosis of pancreatic β cells in type 1 diabetes.

Adding rivaroxaban to standard therapy in patients with heart failure and no atrial fibrillation did not show any beneficial effect on death risk.

Lymphangiogenesis modulates inflammation by clearing immune cells in the infarcted heart in a lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1)–dependent process to ameliorate cardiac dysfunction.

Activation of autophagy improves post-infarction myocardial function in mice.

Immune-related cardiac adverse events can ensue following immunotherapies.

Neovascularization induced by acute myocardial infarction is mediated by clonal expansion of mature endothelial cells, which is triggered by VEGFR-2 signaling.