regulation of cardiac stem cells by micrornas state of the art

Abstract Stem cells have a therapeutic potential in various medical conditions. In cases without sufficient response to conventional drug treatments, stem cells represent a next generation therapeutic strategy in cardiovascular diseases. Cardiac stem cells (CSCs), among a wide variety of stem cell sources, have been identified as a valid option for stem cell-based therapy in cardiovascular diseases. CSCs mainly act as a cell source to supply the physiological need for cardiovascular cells. However, they have been demonstrated to reproduce the myocardial cells under pathological settings. Despite their roles and functions have somewhat been clarified, molecular pathways underlying the regulatory mechanisms of CSCs are still not fully elucidated. Several studies have recently shown that different microRNAs (miRNAs) play a substantial role in regulating and controlling both the physiological and pathological proliferation and differentiation of stem cells. MiRNAs are small non-coding RNA molecules that regulate gene expression and may undergo aberrant expression levels during pathological conditions. Understanding the way through which miRNAs regulate CSC behavior may open up new horizons in modulating these cells in vitro to devise sophisticated approaches for treating patients with cardiovascular diseases. In this review article, we tried to discuss available evidence about the role of miRNAs in regulating CSCs

A systematic review and meta-analysis on the effects of statins on pregnancy outcomes.

Abstract Background and aims Statins are contraindicated in pregnancy, due to their potential teratogenicity. However, data are still inconsistent and some even suggest a potential benefit of statin use against pregnancy complications. We aimed to investigate the effects of statins on pregnancy outcomes, including stillbirth, fetal abortion, and preterm delivery, through a systematic review of the literature and a meta-analysis of the available clinical studies. Methods A literature search was performed through PubMed, Scopus, and Web of Science up to 16 May 2020. Data were extracted from 18 clinical studies (7 cohort studies, 2 clinical trials, 3 case reports, and 6 case series). Random effect meta-analyses were conducted using the restricted maximum likelihood method. The common effect sizes were calculated as odds ratios (ORs) and their 95% confidence interval (CI) for each main outcome. Results Finally, nine studies were included in the meta-analysis. There was no significant association between statin therapy and stillbirth [OR (95% CI) = 1.30 (0.56, 3.02), p=0.54; I2 = 0%]. While statin exposure was significantly associated with increased rates of spontaneous abortion [OR (95% CI) = 1.36 (1.10–1.68), p=0.004, I2 = 0%], it was non-significantly associated with increased rates of induced abortion [OR (95% CI) = 2.08 (0.81, 5.36), p=0.129, I2 = 17.33%] and elective abortion [OR (95% CI) = 1.37 (0.68, 2.76), p=0.378, I2 = 62.46%]. A non-significant numerically reduced rate of preterm delivery was observed in statin users [OR (95% CI) = 0.47 (0.06, 3.70), p=0.47, I2 = 76.35%]. Conclusions Statin therapy seems to be safe as it was not associated with stillbirth or induced and elective abortion rates. Significant increase after statin therapy was, however, observed for spontaneous abortion. These results need to be confirmed and validated in future studies

The Association between HDL-C and Subclinical Atherosclerosis Depends on CETP Plasma Concentration:Insights from the IMPROVE Study

The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMT(max); cIMT(mean-max) of bifurcations, common and internal carotids; plaque-free common carotid [PF CC]-IMTmean) were available for the full cohort. In drug-free subjects, plasma CETP correlated with HDL-C levels (r = 0.19, p < 0.0001), but not with cIMT variables. When stratified according to HDL-C quartiles, CETP positively correlated with cIMT(max) and cIMT(mean-max), but not with PF CC-IMTmean, in the top HDL-C quartile only. Positive associations between the CETP concentration and cIMT(max) or cIMT(mean-max) were found in the top HDL-C quartile, whereas HDL-C levels were negatively correlated with cIMT(max) and cIMT(mean-max) when the CETP concentration was below the median (HDL-C x CETP interaction, p = 0.001 and p = 0.003 for cIMT(max) and cIMT(mean-max), respectively). In the full cohort, three CETP SNPs (rs34760410, rs12920974, rs12708968) were positively associated with cIMT(max). rs12444708 exhibited a significant interaction with HDL-C levels in the prediction of cIMT(max). In conclusion, a significant interplay was found between plasma CETP and/or CETP genotype and HDL-C in the prediction of carotid plaque thickness, as indexed by cIMT(max). This suggests that the association of HDL-C with carotid atherosclerosis is CETP-dependent

Neutrophil to lymphocyte ratio is not related to carotid atherosclerosis progression and cardiovascular events in the primary prevention of cardiovascular disease: results from the IMPROVE study

Inflammation is a component of the pathogenesis of atherosclerosis and is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). The neutrophil to lymphocyte ratio (NLR) is a possible inflammation metric for the detection of ASCVD risk, although results of prospective studies are highly inconsistent on this topic. We investigated the cross‐sectional relationship between NLR and carotid intima‐media thickness (cIMT) in subjects at moderate‐to‐high ASCVD risk. The prospective association between NLR, cIMT progression, and incident vascular events (VEs) was also explored. In 3341 subjects from the IMT‐Progression as Predictors of VEs (IMPROVE) study, we analyzed the association between NLR, cIMT, and its 15‐month progression. The association between NLR and incident VEs was also investigated. NLR was positively associated with cross‐sectional measures of cIMT, but not with cIMT progression. The association between NLR and cross‐sectional cIMT measures was abolished when adjusted for confounders. No association was found between NRL and incident VEs. Similarly, there were no significant differences in the hazard ratios (HRs) of VEs across NLR quartiles. NLR was neither associated with the presence and progression of carotid atherosclerosis, nor with the risk of VEs. Our findings do not support the role of NLR as a predictor of the risk of atherosclerosis progression and ASCVD events in subjects at moderate‐to‐high ASCVD risk, in primary prevention. However, the usefulness of NLR for patients at a different level of ASCVD risk cannot be inferred from this study

A tryptophan metabolite prevents depletion of circulating endothelial progenitor cells in systemic low-grade inflammation

BackgroundChronic systemic inflammation reduces the bioavailability of circulating endothelial progenitor cells (EPCs). Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme of immune tolerance catalyzing the initial step of tryptophan degradation along the so-called l-kynurenine (l-kyn) pathway, that is induced by inflammatory stimuli and exerts anti-inflammatory effects. A specific relationship between IDO1 activity and circulating EPC numbers has not yet been investigated.MethodsIn this study, circulating EPCs were examined in mice treated with low doses of lipopolysaccharide (LPS) to mimic low-grade inflammation. Moreover, the association between IDO1 activity and circulating EPCs was studied in a cohort of 277 patients with variable systemic low-grade inflammation.ResultsRepeated low doses of LPS caused a decrease in circulating EPCs and l-kyn supplementation, mimicking IDO1 activation, significantly increased EPC numbers under homeostatic conditions preventing EPC decline in low-grade endotoxemia. Accordingly, in patients with variable systemic low-grade inflammation, there was a significant interaction between IDO1 activity and high-sensitivity C-reactive protein (hs-CRP) in predicting circulating EPCs, with high hs-CRP associated with significantly lower EPCs at low IDO1 activity but not at high IDO1 activity.InterpretationOverall, these findings demonstrate that systemic low-grade inflammation reduces circulating EPCs. However, high IDO1 activity and l-kyn supplementation limit circulating EPC loss in low-grade inflammation

Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

: Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups &lt;0.0001); however, subjects with FH/M- and lp(a) score ≥1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level ≥190 mg/dL (or from 68% to 50%, considering a more conservative formula). Conclusions Our study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P &lt; 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population