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Aims The aim of our study was to assess the clinical significance of the exercise stress testing endpoints, namely 85% of maximal theoretical heart rate (MTHR), metabolic equivalent of task, and rating of perceived exertion (RPE), and their relation to electrocardiographic (ECG) changes in a healthy adult population.Methods A cross-sectional study was conducted on 408 males and 52 females (mean age 39.4 ± 8.6 years) who performed the maximal cycle ergometer exercise stress test until volitional exhaustion, reporting the RPE score at 85% of MTHR and at peak exercise. Metabolic equivalents of task were indirectly calculated from the maximum workload and compared with the predicted values. Sitting torso-lead ECG and blood pressure were recorded at rest, during exercise and during recovery.Results Of 460 participants, 73% exceeded 85% of MTHR. The RPE score represented the overall most significant endpoint of exercise stress testing, with the median value of 17 at peak exercise. ECG events were detected in 23/124 (18.5%) who reached ≤ 85% of MTHR and in 61/336 (18.2%) who achieved >85% of MTHR (p= 0.92). In the latter group, 54% of ECG changes occurred at < 85% of MTHR and 46% at > 85% of MTHR (p= 0.51). If the exercise stress testing had been interrupted at ≤ 85% of MTHR, almost half of the ECG events would have remained undetected and 35% of the cardiovascular abnormalities observed at the diagnostic follow-up would have remained undiagnosed.Conclusion Terminating exercise stress testing before volitional exhaustion and an RPE score of 17 limits the test accuracy and reduces the possibility to detect cardiovascular abnormalities in apparently healthy adult populations.

Components of the cardiac extracellular matrix (ECM) are synthesized by residing cells and are continuously remodeled by them. Conversely, residing cells (including primitive cells) receive constant biochemical and mechanical signals from the ECM that modulate their biology. The pathological progression of heart failure affects all residing cells, inevitably causing profound changes in ECM composition and architecture that, in turn, impact on cell phenotypes. Any regenerative medicine approach must aim at sustaining microenvironment conditions that favor cardiogenic commitment of therapeutic cells and minimize pro‐fibrotic signals, while conversely boosting the capacity of therapeutic cells to counteract adverse remodeling of the ECM. In this Perspective article, we discuss multiple issues about the features of an optimal scaffold for supporting cardiac tissue engineering strategies with cardiac progenitor cells, and, conversely, about the possible antifibrotic mechanisms induced by cell therapy. StemCellsTranslationalMedicine2018;7:506–510

AbstractBackground:New findings on adipose tissue physiology and obesity-associated inflammation status suggest that modification of the adipokine level can be relevant for the long-term prevention of obesity-associated chronic disease.Objectives:The scope of the present study was to investigate the effectiveness of physical exercise in reducing the systemic inflammation related to obesity in children.Methods:We conducted a systematic review with meta-analysis of controlled randomized trials, identified through electronic database search, which investigated the effect of physical exercise, without concomitant dietary intervention, on adiponectin, leptin, and/or other inflammatory markers in children up to age 18 years with a body mass index greater than the 95th percentile for age and sex.Results:Seven trials were included in the meta-analysis, with a total of 250 participants. Compared with the control group without any lifestyle modification, the physical exercise resulted in a reduction in leptin [standardized mean difference (SMD) −1.13; 95% confidence interval (95%CI): −1.89 to −0.37; I2= 79.9%] and interleukin-6 (SMD −0.84; 95%CI: −1.45 to −0.23, I2= 0.9%) and an increase in adiponectin plasma concentration (SMD 0.69; 95%CI: 0.02–1.35; I2= 74.3%).Conclusions:These results indicate that physical exercise improved the inflammatory state in children with obesity. It is unclear whether this effect can reduce the risk of cardiovascular and metabolic disease in adulthood. Clinical trials with a uniform intervention protocol and outcome measurements are required to put our knowledge on adipose tissue biology into a clinical perspective.

Cardiac tissue engineering by means of synthetic or natural scaffolds combined with stem/progenitor cells is emerging as the response to the unsatisfactory outcome of approaches based solely on the injection of cells. Parenchymal and supporting cells are surrounded, in vivo, by a specialized and tissue-specific microenvironment, consisting mainly of extracellular matrix (ECM) and soluble factors incorporated in the ECM. Since the naturally occurring ECM is the ideal platform for ensuring cell engraftment, survival, proliferation, and differentiation, the acellular native ECM appears by far the most promising and appealing substrate among all biomaterials tested so far. To obtain intact scaffold of human native cardiac ECM while preserving its composition, we compared the decellularized ECM (d-ECM) produced through five different protocols of decellularization (named Pr1, Pr2, Pr3, Pr4, and Pr5) in terms of efficiency of decellularization, composition, and three-dimensional architecture of d-ECM scaffolds and of their suitability for cell repopulation. The decellularization procedures proved substantially different. Specifically, only three, of the five protocols tested, proved effective in producing thoroughly acellular d-ECM. In addition, the d-ECM delivered differed in architecture and composition and, more importantly, in its ability to support engraftment, survival, and differentiation of cardiac primitive cells in vitro.

OBJECTIVE:. To investigate the in vitro effect of granulocyte macrophage-colony stimulating factor (GM-CSF) on the deposition of extracellular matrix (ECM) in fibroblasts obtained from the skin of patients with systemic sclerosis (Ssc), compared to healthy controls. Methods. Dermal fibroblasts obtained from 14 patients with SSc (7 with the diffuse form and 7 with CREST syndrome) and from 7 controls were studied. Both SSc and normal skin fibroblast cultures were stimulated for 4 and 8 days with 100 ng/ml GM-CFS. GM-CSF receptor (GM-CSFR) expression was determined by Western blot of cell lysates. Immunofluorescence was used to determine GM-CSFR expression and to investigate the deposition of ECM (type I collagen, fibronectin, and tenascin). Quantitative analysis of ECM was performed by ELISA. Expression of type I collagen and metalloproteinase 1 (MMP-1) mRNA was determined by real-time quantitative PCR. Results. Deposition of ECM by normal fibroblasts appeared not to be influenced by stimulation with GM-CSF; in contrast, after stimulation with GM-CSF SSc fibroblasts showed increased deposition of fibronectin and tenascin, while type I collagen production was decreased; these results were found with both immunofluorescence and ELISA. Quantitative PCR revealed that GM-CSF inhibited the expression of mRNA type I collagen in SSc fibroblasts but not in normal fibroblasts, whereas levels of the main collagenolytic enzyme, MMP-1, were not affected. Conclusion. These results suggest that in SSc fibroblasts GM-CSF exerts a blocking effect on the deposition of type I collagen, through an inhibitory action on mRNA, while the production of other components of ECM such as fibronectin and tenascin is increased by stimulation with this cytokine.

OBJECTIVE: To elucidate events that initiate the involvement and stimulation of fibroblasts in systemic sclerosis (SSc). METHODS: We examined 15 patients with SSc diffuse form, 15 with CREST syndrome, and 5 healthy subjects. Cultured fibroblasts obtained from skin biopsies in SSc involved and non-involved areas and norrmal skin fibroblasts were cultured with different doses of granulocyte macrophage colony stimulating factor (GM-CSF) to study the effects of this factor on the expression of GM-CSF receptor (GM-CSFR) on fibroblast proliferation and cellular adhesion structures. RESULTS: Cultured fibroblasts obtained from biopsies of normal and SSc skin areas express GM-CSFR and such expression is increased in SSc fibroblasts. GM-CSF stimulation in vitro did not increase SSc fibroblast growth, in spite of a strongly increased expression of the GM-CSFR. The adhesion structures are always more abundant in SSc fibroblasts as compared to healthy cells and GM-CSF seems able to increase cell adhesion plaques. CONCLUSION: We suggest that shift of fibroblasts toward a more adhesive differentiated pattern, due to or accompanied by an increased expression of GM-CSFR, may be an important event in the pathogenesis of SSc.

Bi-layered scaffolds with a 0°/90° lay-down pattern were prepared by melt-extrusion additive manufacturing (AM) using a poly(ester urethane) (PU) synthesized from poly(ε-caprolactone) diol, 1,4-butandiisocyanate and l-lysine ethyl ester dihydrochloride chain extender. Rheological analysis and differential scanning calorimetry of the starting material showed that compression moulded PU films were in the molten state at a higher temperature than 155°C. The AM processing temperature was set at 155°C after verifying the absence of PU thermal degradation phenomena by isothermal thermogravimetry analysis and rheological characterization performed at 165°C. Scaffolds highly reproduced computer-aided design geometry and showed an elastomeric-like behaviour which is promising for applications in myocardial regeneration. PU scaffolds supported the adhesion and spreading of human cardiac progenitor cells (CPCs), whereas they did not stimulate CPC proliferation after 1–14 days culture time. In the future, scaffold surface functionalization with bioactive peptides/proteins will be performed to specifically guide CPC behaviour.