Citations

AbstractBackgroundPulseless ventricular tachycardia/ventricular fibrillation (VT/VF) is the initial rhythm in a third of in‐hospital cardiac arrest patients. Mechanical circulatory support (MCS) device use remains poorly understood in this population.MethodsWe conducted an observational analysis of temporal trends in the utilization of MCS in VT/VF IHCA between January 2008 and December 2014 utilizing the Nationwide Inpatient Sample (NIS) database. Using multivariable analysis, we assessed factors associated with MCS use and survival to discharge.ResultsAmong 151,628 hospitalizations with VT/VF IHCA, 14,981 (9.9%) received MCS. Intra‐aortic balloon pump (IABP) was the most commonly used MCS (9.1%). From 2008 to 2014, there was significant increase in the utilization of MCS (8.7–11%; ptrend < 0.0001). On multivariable analysis, there was 12‐fold increase and three‐fold increase in the utilization of PVAD and ECMO respectively; however, there was no significant change in the use of IABP. Over the seven‐year sample period, there was significant increase in the overall survival to hospital discharge (35.4–43.5%; ptrend < 0.0001). Survival to hospital discharge increased in both MCS and non‐MCS groups.ConclusionThere was significant increase in utilization of MCS after VT/VF IHCA during the study period. IABP was the most commonly utilized MCS. The survival to hospital discharge increased in the overall study population including both MCS and non‐MCS groups. Future studies are needed to identify patient population most likely to benefit from the use of MCS after VT/VF IHCA.

Abstract Mesenchymal stem/stromal cells (MSCs) release extracellular vesicles (EVs), which shuttle proteins to recipient cells, promoting cellular repair. We hypothesized that cardiovascular risk factors may alter the pattern of proteins packed within MSC-derived EVs. To test this, we compared the protein cargo of EVs to their parent MSCs in pigs with metabolic syndrome (MetS) and Lean controls. Porcine MSCs were harvested from abdominal fat after 16 weeks of Lean- or MetS-diet (n = 5 each), and their EVs isolated. Following liquid chromatography mass spectrometry proteomic analysis, proteins were classified based on cellular component, molecular function, and protein class. Five candidate proteins were validated by Western blot. Clustering analysis was performed to identify primary functional categories of proteins enriched in or excluded from EVs. Proteomics analysis identified 6,690 and 6,790 distinct proteins in Lean- and MetS-EVs, respectively. Differential expression analysis revealed that 146 proteins were upregulated and 273 downregulated in Lean-EVs versus Lean-MSCs, whereas 787 proteins were upregulated and 185 downregulated in MetS-EVs versus MetS-MSCs. Proteins enriched in both Lean- and MetS-EVs participate in vesicle-mediated transport and cell-to-cell communication. Proteins enriched exclusively in Lean-EVs modulate pathways related to the MSC reparative capacity, including cell proliferation, differentiation, and activation, as well as transforming growth factor-β signaling. Contrarily, proteins enriched only in MetS-EVs are linked to proinflammatory pathways, including acute inflammatory response, leukocyte transendothelial migration, and cytokine production. Coculture with MetS-EVs increased renal tubular cell inflammation. MetS alters the protein cargo of porcine MSC-derived EVs, selectively packaging specific proinflammatory signatures that may impair their ability to repair damaged tissues. Stem Cells Translational Medicine 2019;8:430–440

Background: Fifty percent of patients with autosomal dominant polycystic kidney disease (ADPKD) present hypertension (HTN) early on, which increases to nearly 100% at end-stage, and is associated with faster renal functional decline. Endothelial dysfunction (ED) accompanied by oxidative stress (OS) precedes the development of HTN, but the mechanisms responsible remain unknown. The aim of this study was to determine whether NADPH oxidase (NOX4) and mitochondrial dysfunction contribute to OS and ED preceding HTN in early ADPKD. Methods: We prospectively measured plasma levels of homocysteine (Hcy), 8-isoprostane, NOX4 and the mtDNA genes COX3 and ND1 in young normotensive (without BP medication) ADPKD patients, and age-matched healthy volunteers (HV) (n=10, each). Total kidney volume (TKV) and Renal Blood Flow (RBF) were evaluated by MRI. Results: BP levels were higher in ADPKD, and HtTKV was twofold higher in ADPKD vs. controls. eGFR and RBF were similar between the groups (Table). Plasma Hcy, 8-isoprostanes and NOX4 were higher in ADPKD, and correlated directly with HtTKV (p<0.05, Figure), but the correlation with RBF was not significant. Plasma mtDNA copy number were lower in ADPKD compared to controls, and correlated inversely with HtTKV(R 2 0.397 and 0.392 respectively). Conclusion: Early ADPKD is associated with elevation in Hcy, 8-isoprostane, and NOX4 levels, and decreased mtDNA copy numbers, which precede the reduction in RBF and the development of HTN, and are associated with disease severity. NOX4 and mitochondrial abnormalities may contribute to oxidative stress, endothelial dysfunction, and possibly the development of HTN and disease progression in ADPKD.

Background: We have previously shown in patients with renovascular hypertension (RVH) that elevated urinary mtDNA copy numbers represent surrogate markers of renal mitochondrial injury. Revascularization with percutaneous transluminal renal angioplasty (PTRA) can lead to acute renal reperfusion injury. However, whether PTRA induces renal mitochondrial injury remains unknown. Methods: We prospectively measured urinary copy number of the mtDNA genes cytochrome-c oxidase-3 (COX3) and NADH dehydrogenase subunit-1 (ND1) by qPCR in 5 RVH patients before and 24hrs after PTRA. Five additional patients were treated before and during PTRA with the mitoprotective drug elamipretide (ELAM, 0.05 mg/kg/hr IV infusion). Healthy volunteers (HV) served as controls (n=5). Results: Baseline blood pressure was similarly elevated in both RVH groups, and eGFR lower than HV (Table). Baseline urinary COX3 and ND1 levels were similarly higher in both RVH groups compared with HV (Fig. A), and directly correlated with serum creatinine levels (R 2 =0.74, p=0.001 and R 2 =0.45, p=0.033, respectively). Over 3 months, eGFR increased only in ELAM-treated patients (Fig. B). Furthermore, the rise in urinary mtDNA 24hrs after PTRA was blunted in PTRA+ELAM versus PTRA+Placebo, and inversely correlated with the change in eGFR of 3 months after PTRA (Fig. C). Conclusion: PTRA induces an acute rise in urinary mtDNA levels, likely reflecting renal mitochondrial injury due to reperfusion injury that inhibits renal recovery. Mitoprotection in this cohort limited PTRA-associated mitochondrial injury and improved renal outcomes after revascularization.

Hypertension, an important cause of chronic kidney disease, is characterized by peritubular capillary (PTC) loss. Circulating levels of endothelial microparticles (EMPs) reflect systemic endothelial injury. We hypothesized that systemic and urinary PTC-EMPs levels would reflect renal microvascular injury in hypertensive patients. We prospectively measured by flow cytometry renal vein, inferior vena cava, and urinary levels of EMPs in essential (n=14) and renovascular (RVH; n=24) hypertensive patients and compared them with peripheral blood and urinary levels in healthy volunteers (n=14). PTC-EMPs were identified as urinary exosomes positive for the PTC marker plasmalemmal-vesicle–associated protein. In 7 RVH patients, PTC and fibrosis were also quantified in renal biopsy, and in 18 RVH patients, PTC-EMPs were measured again 3 months after continued medical therapy with or without stenting (n=9 each). Renal vein and systemic PTC-EMPs levels were not different among the groups, whereas their urinary levels were elevated in both RVH and essential hypertension versus healthy volunteers (56.8%±12.7% and 62.8%±10.7% versus 34.0%±17.8%; both P ≤0.001). Urinary PTC-EMPs levels correlated directly with blood pressure and inversely with estimated glomerular filtration rate. Furthermore, in RVH, urinary PTC-EMPs levels correlated directly with stenotic kidney hypoxia, histological PTC count, and fibrosis and inversely with cortical perfusion. Three months after treatment, the change in urinary PTC-EMPs levels correlated inversely with a change in renal function ( r =−0.582; P =0.011). Therefore, urinary PTC-EMPs levels are increased in hypertensive patients and may reflect renal microcirculation injury, whereas systemic PTC-EMPs levels are unchanged. Urinary PTC-EMPs may be useful as novel biomarkers of intrarenal capillary loss.

Tissue autofluorescence provides fluorescence lifetime contrast between acellular tissue and that containing newly seeded cells. Fiber‐based fluorescence lifetime imaging (FLIm) can be used for tracking recellularization of engineered vascular grafts and potential matrix remodeling at large scale, without compromising sample integrity. FLIm cellular contrast was verified in a subset of samples seeded with eGFP‐labelled cells. Results suggests fiberbased FLIm is a suitable tool for monitoring recellularization of engineered tissue nondestructively.Further details can be found in the article by Alba Alfonso‐Garcia, Jeny Shklover, Benjamin E. Sherlock, et al. (e201700391). image

Mesenchymal stem cells (MSCs) constitute an important repair system, but may be impaired by exposure to cardiovascular risk factors. Consequently, adipose tissue-derived MSCs from pigs with the metabolic syndrome (MetS) show decreased vitality. A growing number of microRNAs (miRNAs) are recognized as key modulators of senescence, but their role in regulating senescence in MSC in MetS is unclear. We tested the hypothesis that MetS upregulates in MSC expression of miRNAs that can serve as post-transcriptional regulators of senescence-associated (SA) genes. MSCs were collected from swine abdominal adipose tissue after 16 weeks of Lean or Obese diet ( n = 6 each). Next-generation miRNA sequencing (miRNA-seq) was performed to identify miRNAs up-or down-regulated in MetS-MSCs compared with Lean-MSCs. Functional pathways of SA genes targeted by miRNAs were analyzed using gene ontology. MSC senescence was evaluated by p16 and p21 immunoreactivity, H2AX protein expression, and SA-β-Galactosidase activity. In addition, gene expression of p16, p21, MAPK3 (ERK1) and MAPK14, and MSC migration were studied after inhibition of SA-miR-27b. Senescence biomarkers were significantly elevated in MetS-MSCs. We found seven upregulated miRNAs, including miR-27b, and three downregulated miRNAs in MetS-MSCs, which regulate 35 SA genes, particularly MAPK signaling. Inhibition of miR-27b in cultured MSCs downregulated p16 and MARP3 genes, and increased MSC migration. MetS modulates MSC expression of SA-miRNAs that may regulate their senescence, and the p16 pathway seems to play an important role in MetS-induced MSC senescence.