Lerman, Amir

AbstractAutologous transplantation of mesenchymal stem cells (MSCs) is a viable option for the treatment of several diseases. Evidence indicates that MSCs release extracellular vesicles (EVs) and that EVs shuttle miRNAs to damaged parenchymal cells to activate an endogenous repair program. We hypothesize that comorbidities may interfere with the packaging of cargo in MSC‐derived EVs. Therefore, we examined whether metabolic syndrome (MetS) modulates the miRNA content packed within MSC‐derived EVs. MSCs were collected from swine abdominal adipose tissue after 16 weeks of lean or obese diet (n = 7 each). Next‐generation RNA sequencing of miRNAs (miRNA‐seq) was performed to identify miRNAs enriched in MSC‐derived EVs and their predicted target genes. Functional pathway analysis of the top 50 target genes of the top 4 miRNAs enriched in each group was performed using gene ontology analysis. Lean‐ and MetS‐EVs were enriched in, respectively, 14 and 8 distinct miRNAs. Target genes of miRNAs enriched in MetS‐EVs were implicated in the development of MetS and its complications, including diabetes‐related pathways, validated transcriptional targets of AP1 family members Fra1 and Fra2, Class A/1 (Rhodopsin‐like receptors), and Peptide ligand‐binding receptors. In contrast, miRNAs enriched in Lean EVs target primarily EphrinA‐EPHA and the Rho family of GTPases. MetS alters the miRNA content of EVs derived from porcine adipose tissue MSCs. These alterations could impair the efficacy and limit the therapeutic use of autologous MSCs in subjects with MetS. Our findings may assist in developing adequate regenerative strategies to preserve the reparative potency of MSCs in individuals with MetS. © 2017 International Society for Advancement of Cytometry

Background Adenosine‐assisted transthoracic Doppler‐derived coronary flow reserve ( TDE ‐ CFR ) reflects coronary vascular function. The prognostic and incremental value of left anterior descending coronary artery TDE ‐ CFR above myocardial perfusion scintigraphy in patients with suspected myocardial ischemia has not yet been studied. Methods and Results Three hundred seventy‐one patients (mean age, 62.3±8.7 years; 46.8% males) referred to myocardial perfusion scintigraphy attributed to suspected myocardial ischemia were included in the study. The TDE ‐ CFR result was blinded to the referring physician. Patients were followed up regarding major cardiovascular events, defined as cardiovascular death, myocardial infarction, or acute revascularization during a median follow‐up time of 4.5 years. A TDE ‐ CFR value of ≤2.0 was considered reduced. Major cardiovascular events occurred during follow‐up in 60 patients (16.2%). A reduced TDE ‐ CFR was detected in 76 patients (20.5%). Patients with reduced TDE ‐ CFR had an event rate of 36.8% compared to 10.8% in patients with normal TDE ‐ CFR (unadjusted hazard ratio, 4.63; 95% CI, 2.78–7.69; P <0.001). In a multivariate model, TDE ‐ CFR remained a significant independent predictor of major cardiovascular events. The major cardiovascular events rate was 7.5% in patients without myocardial perfusion scintigraphy‐detected myocardial ischemia and normal TDE ‐ CFR (n=200), 24.2% in patients without ischemia but with reduced TDE ‐ CFR (n=33), and 46.5% in patients with both myocardial perfusion scintigraphy–detected myocardial ischemia and a reduced TDE ‐ CFR (n=43; P <0.001). Conclusions Coronary microvascular dysfunction, as determined by TDE ‐ CFR, is a strong independent predictor of cardiovascular events and adds incremental prognostic value compared with myocardial perfusion scintigraphy. The current study supports routine assessment of CFR in patients with suspected ischemic heart disease.

Uric acid is a risk factor for coronary artery disease in postmenopausal women, but the association with inflammation and coronary endothelial dysfunction (CED) is not well defined. The aim of this study was to determine the relationship of serum uric acid (SUA), inflammatory markers, and CED. In this prospective cohort study, SUA, high-sensitivity C-reactive protein levels, and neutrophil count were measured in 229 postmenopausal women who underwent diagnostic catheterization, were found to have no obstructive coronary artery disease, and underwent coronary microvascular function testing, to measure coronary blood flow response to intracoronary acetylcholine. The average age was 58 years (interquartile range, 52–66 years). Hypertension was present in 48%, type 2 diabetes mellitus in 5.6%, and hyperlipidemia in 61.8%. CED was diagnosed in 59% of postmenopausal women. Mean uric acid level was 4.7±1.3 mg/dL. Postmenopausal women with CED had significantly higher SUA compared with patients without CED (4.9±1.3 versus 4.4±1.3 mg/dL; P =0.02). There was a significant correlation between SUA and percent change in coronary blood flow to acetylcholine ( P =0.009), and this correlation persisted in multivariable analysis. SUA levels were significantly associated with increased neutrophil count ( P =0.02) and high-sensitivity C-reactive protein levels ( P =0.006) among patients with CED, but not among those without CED. SUA is associated with CED in postmenopausal women and may be related to inflammation. These findings link SUA levels to early coronary atherosclerosis in postmenopausal women.

Valvular interstitial cells from diseased aortic valve leaflets show their ability to regenerate–to proliferate and grow, to express appropriate genes and to deposit suitable proteins–in a non-degenerative nanofibrous substrate.