Systemic Mesenchymal Stem Cell-Derived Exosomes Reduce Myocardial Infarct Size: Characterization With MRI in a Porcine Model.

The observations that mesenchymal stem cells (MSCs) exert cardiac protection and repair via their secretome with the active component(s) identified as exosomes underpinned our test of the efficacy of MSC exosomes in a porcine model of myocardial infarction (MI) when administered systemically by the convenient method of intravenous (IV) bolus injection. Results show that 7 days of IV exosomes results in clear reduction (30-40%) of infarct size measured at both 7 and 28 days post-MI, despite near identical release of hs Troponin T. Together with reduced infarct size, exosome treatment reduced transmurality and lessened wall thinning in the infarct zone. Exosome treated pigs showed relative preservation of LV function with significant amelioration of falls in fractional wall thickening compared with control. However, global measures of LV function were less protected by exosome treatment. It is possible that greater preservation of global LV function may have been attenuated by increased cardiac fibrosis, as T1 values showed significant increase in the exosome pigs compared to control particularly in the infarct related segments. Taken together, these results show clear effects of IV exosomes administered over 7 days to reduce infarct size with relatively preserved cardiac function compared to control treated infarct pigs.

A porcine model of heart failure with preserved ejection fraction: magnetic resonance imaging and metabolic energetics.

AIMS: A significant proportion of heart failure (HF) patients have HF preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF remains a critical unmet need. A key obstacle to therapeutic innovation in HFpEF is the paucity of pre-clinical models. Although several large animal models have been reported, few demonstrate progression to decompensated HF. We have established a model of HFpEF by enhancing a porcine model of progressive left ventricular (LV) pressure overload and characterized HF in this model including advanced cardiometabolic imaging using cardiac magnetic resonance imaging and hyperpolarized carbon-13 magnetic resonance spectroscopy. METHODS AND RESULTS: Pigs underwent progressive LV pressure overload by means of an inflatable aortic cuff. Pigs developed LV hypertrophy (50% increase in wall thickness, P < 0.001, and two-fold increase in mass compared to sham control, P < 0.001) with no evidence of LV dilatation but a significant increase in left atrial volume (P = 0.013). Cardiac magnetic resonance imaging demonstrated T1 modified Look-Locker inversion recovery values increased in 16/17 segments compared to sham pigs (P < 0.05-P < 0.001) indicating global ventricular fibrosis. Mean LV end-diastolic (P = 0.047) and pulmonary capillary wedge pressures (P = 0.008) were elevated compared with sham control. One-third of the pigs demonstrated clinical signs of frank decompensated HF, and mean plasma BNP concentrations were raised compared with sham control (P = 0.008). Cardiometabolic imaging with hyperpolarized carbon-13 magnetic resonance spectroscopy agreed with known metabolic changes in the failing heart with a switch from fatty acid towards glucose substrate utilization. CONCLUSIONS: Progressive aortic constriction in growing pigs induces significant LV hypertrophy with cardiac fibrosis associated with left atrial dilation, raised filling pressures, and an ability to transition to overt HF with raised BNP without reduction in LVEF. This model replicates many aspects of clinical HFpEF with a predominant background of hypertension and can be used to advance understanding of underlying pathology and for necessary pre-clinical testing of novel candidate therapies.

The parmodulin NRD-21 is an allosteric inhibitor of PAR1 Gq signaling with improved anti-inflammatory activity and stability.

Novel analogs of the allosteric, biased PAR1 ligand ML161 (parmodulin 2, PM2) were prepared in order to identify potential anti-thrombotic and anti-inflammatory compounds of the parmodulin class with improved properties. Investigations of structure-activity relationships of the western portion of the 1,3-diaminobenzene scaffold were performed using an intracellular calcium mobilization assay with endothelial cells, and several heterocycles were identified that inhibited PAR1 at sub-micromolar concentrations. The oxazole NRD-21 was profiled in additional detail, and it was confirmed to act as a selective, reversible, negative allosteric modulator of PAR1. In addition to inhibiting human platelet aggregation, it showed superior anti-inflammatory activity to ML161 in a qPCR assay measuring the expression of tissue factor in response to the cytokine TNF-alpha in endothelial cells. Additionally, NRD-21 is much more plasma stable than ML161, and is a promising lead compound for the parmodulin class for anti-thrombotic and anti-inflammatory indications.

Reliability, validity, and responsiveness of the lower extremity functional scale for inpatients of an orthopaedic rehabilitation ward.

STUDY DESIGN: Single-group, repeated-measures study. OBJECTIVE: To estimate the test-retest reliability, construct validity, and responsiveness of the Lower Extremity Functional Scale (LEFS) on inpatients attending an orthopaedic rehabilitation ward. BACKGROUND: The LEFS has acceptable validity on outpatients in assessing functional mobility, but it has not been tested for use on an inpatient orthopaedic ward. METHODS AND MEASURES: Inpatients in an orthopaedic ward (n = 142) completed the 20-item, self-report LEFS on admission, 7 to 10 days after admission, and on discharge. To test reliability, 24 patients had the LEFS repeated 1 day after the admission test, and the intraclass correlation (ICC) and the standard error of measurement (SEM) were calculated. Change scores of the LEFS were evaluated against patients' and therapists' rating of improvement, and change scores of comparison measures that included pain, functional performance, and the composite index created from scores of these comparison measures. The standardized response mean (SRM) of the LEFS was also computed. RESULTS: The ICC of the LEFS was 0.88, and the SEM was 4 LEFS points (LEFS score range, 0-80). The change in LEFS correlated with changes of comparison measures in the same direction of improvement. Patients rated as improved by both themselves and their therapists had significantly larger change in LEFS scores than subjects rated as no change. The SRM of the LEFS from admission to discharge was 1.76 on patients rated as improved. CONCLUSION: The LEFS is reliable and valid to assess group and individual change, and has large responsiveness. The LEFS and the comparison measures likely assess different constructs.

The timed up and go test for use on an inpatient orthopaedic rehabilitation ward.

STUDY DESIGN: Single-group repeated-measures study. OBJECTIVE: To examine the test-retest reliability of the timed up and go (TUG) test and its validity for measuring change and predicting length of stay (LOS) on an inpatient orthopaedic rehabilitation ward. BACKGROUND: The TUG test is used to measure functional mobility of persons with musculoskeletal conditions but it has not been thoroughly tested for use in an inpatient orthopaedic rehabilitation ward. METHODS AND MEASURES: The TUG test was administered to 142 patients on admission to an orthopaedic rehabilitation ward 7 to 10 days after admission and on discharge. To test reliability, 24 subjects had these tests repeated 1 day after admission, and the intraclass correlation (ICC) and standard error of measurement (SEM) were calculated. Change scores of the TUG test were evaluated against change scores in pain and function, and the rating of improvement of the patient and therapist. The standardized response mean (SRM) was also calculated. A regression analysis was performed to determine whether the admission TUG test score could predict LOS. RESULTS: The ICC of the TUG test was 0.80 and the SEM was 10.2 seconds. The change in TUG test scores correlated with the changes in pain (r = 0.21, P<.01) and function (r = -0.23, P<.01), and resulted in an SRM of 0.89 for subjects rated as improved. The admission TUG test scores accounted for only 3.4% of the variance in inpatient LOS. CONCLUSION: The TUG test is reliable and valid to assess group change of inpatients on an orthopaedic rehabilitation ward but is not a good predictor of LOS. LEVEL OF EVIDENCE: Prognosis, level 1b.