Sex-dependent association between inflammation, neural stress responses, and impaired myocardial function.

PURPOSE: Evidence to date has failed to reveal unique female determinants of cardiovascular disease. However, a strong association was recently observed between increased metabolic activity in the amygdala, a neural centre involved in the processing of emotions, and impaired myocardial function in women, but not in men. Given the stronger immune responses in females, we sought to retrospectively investigate the interaction between inflammation, perceived stress, and myocardial injury. METHODS: Overall, 294 patients (mean age 66.9 ± 10.0 years, 28.6% women) underwent both, 99mTc-tetrofosmin single-photon emission computed tomography myocardial perfusion imaging and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography for the assessment of cardiac function, bone marrow metabolism (surrogate marker of inflammation), and resting amygdalar activity. RESULTS: A positive association was found between amygdalar metabolism and 18F-FDG bone marrow uptake in women (r = 0.238, p = 0.029), but not in men (r = 0.060, p = 0.385). Linear regression models selected both, abnormal left ventricular ejection fraction (LVEF) and abnormal myocardial perfusion, as significant indicators of an increased amygdalar activity in women (B-coefficient LVEF, - 0.096; p = 0.021; abnormal myocardial perfusion, 3.227; p = 0.043), but not in men (bone marrow p = 0.076; abnormal myocardial perfusion p = 0.420). Accordingly, an interaction term consisting of sex and LVEF/abnormal myocardial perfusion was significant (p = 0.043 and p = 0.015, respectively). CONCLUSIONS: Upregulated amygdalar metabolism is associated with an enhanced inflammatory state in female patients with impaired cardiac function. Given that enhanced activity of the limbic system is associated with worse cardiovascular outcomes, our study suggests that a focus on inflammatory markers and indicators of distress might help to tailor cardiovascular risk assessment and therapy towards the female cardiovascular phenotype.

Microvascular dysfunction and sympathetic hyperactivity in women with supra-normal left ventricular ejection fraction (snLVEF).

BACKGROUND: Recently, a new disease phenotype characterized by supra-normal left ventricular ejection fraction (snLVEF) has been suggested, based on large datasets demonstrating an increased all-cause mortality in individuals with an LVEF > 65%. The underlying mechanisms of this association are currently unknown. METHODS: A total of 1367 patients (352 women, mean age 63.1 ± 11.6 years) underwent clinically indicated rest/adenosine stress ECG-gated 13N-ammonia positron emission tomography (PET) between 1995 and 2017 at our institution. All patients were categorized according to LVEF. A subcohort of 698 patients (150 women) were followed for major adverse cardiac events (MACEs), a composite of cardiac death, non-fatal myocardial infarction, cardiac-related hospitalization, and revascularization. RESULTS: The prevalence of a snLVEF (≥ 65%) was higher in women as compared to that in men (31.3% vs 18.8%, p < 0.001). In women, a significant reduction in coronary flow reserve (CFR, p < 0.001 vs normal LVEF) and a blunted heart rate reserve (% HRR, p = 0.004 vs normal LVEF) during pharmacological stress testing-a surrogate marker for autonomic dysregulation-were associated with snLVEF. Accordingly, reduced CFR and HRR were identified as strong and independent predictors for snLVEF in women in a fully adjusted multinomial regression analysis. After a median follow-up time of 5.6 years, women with snLVEF experienced more often a MACE than women with normal (55-65%) LVEF (log rank p < 0.001), while such correlation was absent in men (log rank p = 0.76). CONCLUSION: snLVEF is associated with an increased risk of MACE in women, but not in men. Microvascular dysfunction and an increased sympathetic tone in women may account for this association.

Association between vertebral bone mineral density, myocardial perfusion, and long-term cardiovascular outcomes: A sex-specific analysis.

BACKGROUND: Sexual dimorphism in the manifestation of coronary artery disease (CAD) has unleashed a call to reconsider cardiovascular risk assessment. Alterations of bone mineral density (BMD) have been associated with congestive heart failure and appear to be modified by sex. However, the sex-specific association between BMD, myocardial perfusion, and cardiovascular outcomes is currently unknown. METHODS: A total number of 491 patients (65.9 ± 10.7 years, 32.4% women) underwent 13N-ammonia positron emission tomography/computed tomography for evaluation of CAD, and were tracked for major adverse cardiac events (MACEs). RESULTS: Event-free survival (median follow-up time of 4.3 ± 2.0 years) was significantly reduced in patients with low (≤ 100 Hounsfield units) compared to those with higher BMD (log-rank P = .037). Accordingly, reduced BMD was chosen as significant predictor of MACE in a fully adjusted proportional hazards regression model (P = .015). Further, a first-order interaction term consisting of sex and BMD was statistically significant (P = .007). BMD was significantly lower in patients with abnormal myocardial perfusion or impaired left ventricular ejection fraction (P < .05). This difference, however, was noticed in men, but not in women. CONCLUSIONS: The association between low BMD and cardiovascular disease is sex dependent. Our data suggest that quantification of BMD during myocardial perfusion imaging for evaluation of CAD may be particularly useful in men.

Heart rate reserve during pharmacological stress is a significant negative predictor of impaired coronary flow reserve in women.

PURPOSE: Evidence to date has failed to adequately explore determinants of cardiovascular risk in women with coronary microvascular dysfunction (CMVD). Heart rate responses to adenosine mirror autonomic activity and may carry important prognostic information for the diagnosis of CMVD. METHODS: Hemodynamic changes during adenosine stress were analyzed in a propensity-matched cohort of 404 patients (202 women, mean age 65.9 ± 11.0) who underwent clinically indicated myocardial perfusion 13N-ammonia Positron-Emission-Tomography (PET) at our institution between September 2013 and May 2017. RESULTS: Baseline heart rate (HR) was significantly higher in patients with abnormal coronary flow reserve (CFR, p < 0.001 vs normal CFR). Accordingly, a blunted HR response to adenosine (=reduced heart rate reserve, %HRR) was seen in patients with abnormal CFR, with a most pronounced effect being observed in female patients free of myocardial ischemia (45.9 ± 34.9 vs 26.5 ± 18.0, p < 0.001 in women and 29.1 ± 16.9 vs 24.3 ± 21.7, p = 0.15 in men). Hence, a fully-adjusted multivariate logistic regression model identified HRR as the strongest negative predictor of reduced CFR in women free of myocardial ischemia, but not in men. Accordingly, receiver operating characteristics (ROC) curves for the presence of reduced CFR revealed that a %HRR <35 was a powerful predictor for abnormal CFR with a sensitivity of 81% and a specificity of 60% in women. CONCLUSION: A blunted HRR <35% is associated with abnormal CFR in women. Taking into account HR responses during stress test in women may help to risk stratify the heterogeneous female population of patients with non-obstructive coronary artery disease (CAD).

Heart rate reserve is a long-term risk predictor in women undergoing myocardial perfusion imaging.

BACKGROUND: Although women with cardiovascular disease experience relatively worse outcomes as compared to men, substantial knowledge gaps remain regarding the unique female determinants of cardiovascular risk. Heart rate (HR) responses to vasodilator stress mirror autonomic activity and may carry important long-term prognostic information in women. METHODS AND RESULTS: Hemodynamic changes during adenosine stress were recorded in a total of 508 consecutive patients (104 women) undergoing clinically indicated 13N-ammonia Positron-Emission-Tomography (PET) at our institution. Following propensity matching, 202 patients (101 women, mean age 61.3 ± 12.6 years) were analyzed. During a median follow-up of 5.6 years, 97 patients had at least one cardiac event, including 17 cardiac deaths. Heart rate reserve (% HRR) during adenosine infusion was significantly higher in women as compared to men (23.8 ± 19.5 vs 17.3 ± 15.3, p = 0.009). A strong association between 10-year cardiovascular endpoints and a blunted HRR was observed in women, while this association was less pronounced in men. Accordingly, in women, but not in men, reduced HRR was selected as a strong predictor for adverse cardiovascular events in a Cox regression model fully adjusted for imaging findings and traditional risk factors (HR 2.41, 95% CI 1.23-4.75, p = 0.011). Receiver operating characteristics (ROC) curves revealed that a blunted HRR <21% was a powerful predictor for MACE in women with a sensitivity of 77% and a specificity of 68%. CONCLUSION: Blunted HRR to adenosine stress adds incremental prognostic value for long-term cardiovascular outcomes in women beyond that provided by traditional risk factors and imaging findings.

The effects of the DNA methyltranfserases inhibitor 5-Azacitidine on ageing, oxidative stress and DNA methylation of adipose derived stem cells.

Human adipose tissue is a great source of adult mesenchymal stem cells (MSCs) which are recognized from their ability to self-renew and differentiation into multiple lineages. MSCs have promised a vast therapeutic potential in treatment many diseases including tissue injury and immune disorders. However, their regenerative potential profoundly depends on patients' age. Age-related deterioration of MSC is associated with cellular senescence mainly caused by increased DNA methylation status, accumulation of oxidative stress factors and mitochondria dysfunction. We found that DNA methyltransferase (DNMT) inhibitor i.e. 5-Azacytidine (5-AZA) reversed the aged phenotype of MSCs. Proliferation rate of cells cultured with 5-AZA was increased while the accumulation of oxidative stress factors and DNA methylation status were decreased. Simultaneously the mRNA levels of TET proteins involved in demethylation process were elevated in those cells. Moreover, cells treated with 5-AZA displayed reduced reactive oxygen species (ROS) accumulation, ameliorated superoxide dismutase activity and increased BCL-2/BAX ratio in comparison to control group. Our results indicates that, treating MSCs with 5-AZA can be justified therapeutic intervention, that can slow-down and even reverse aged- related degenerative changes in those cells.

The Cladophora glomerata Enriched by Biosorption Process in Cr(III) Improves Viability, and Reduces Oxidative Stress and Apoptosis in Equine Metabolic Syndrome Derived Adipose Mesenchymal Stromal Stem Cells (ASCs) and Their Extracellular Vesicles (MV's).

This study investigated in vitro effects of freshwater alga Cladophora glomerata water extract enriched during a biosorption process in Cr(III) trivalent chromium and chromium picolinate on adipose-derived mesenchymal stromal stem cells (ASCs) and extracellular microvesicles (MVs) in equine metabolic syndrome-affected horses. Chemical characterisation of natural Cladophora glomerata was performed with special emphasis on: vitamin C, vitamin E, total phenols, fatty acids, free and protein-bound amino acids as well as measured Cr in algal biomass. To examine the influence of Cladophora glomerata water extracts, in vitro viability, oxidative stress factor accumulation, apoptosis, inflammatory response, biogenesis of mitochondria, autophagy in ASCs of EMS and secretory activity manifested by MV release were investigated. For this purpose, various methods of molecular biology and microscopic observations (i.e., immunofluorescence staining, SEM, TEM, FIB observations, mRNA and microRNA expression by RT-qPCR) were applied. The extract of Cladophora glomerata enriched with Cr(III) ions reduced apoptosis and inflammation in ASCs of EMS horses through improvement of mitochondrial dynamics, decreasing of PDK4 expression and reduction of endoplastic reticulum stress. Moreover, it was found, that Cladophora glomerata and Cr(III) induce antioxidative protection coming from enhanced SOD activity Therefore, Cladophora glomerata enriched with Cr(III) ions might become an interesting future therapeutic agent in the pharmacological treatment of EMS horses.

Cytotoxicity, Bactericidal, and Antioxidant Activity of Sodium Alginate Hydrosols Treated with Direct Electric Current.

The aim of the study was to investigate the effect of using direct electric current (DC) of 0, 200, and 400 mA for five minutes on the physiochemical properties, cytotoxicity, antibacterial, and antioxidant activity of sodium alginate hydrosols with different sodium chloride concentrations. The pH, oxidation-reduction potential (ORP), electrical conductivity (EC), and available chlorine concentration (ACC) were measured. The effect of sodium alginate hydrosols treated with DC on Staphylococcus aureus, Listeria monocytogenes, Bacillus cereus, Micrococcus luteus, Escherichia coli, Salmonella enteritidis, Yersinia enterocolitica, Pseudomonas fluorescence, and RAW 264.7 and L929 cells was investigated. Subsequently, the antioxidant properties of hydrosols were evaluated by determining the scavenging ability of 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH) and ferric reducing antioxidant power (FRAP). The results have shown that after applying 400 mA in hydrosol samples with 0.1% and 0.2% NaCl all tested bacteria were inactivated. The ACC concentration of C400 samples with NaCl was equal to 13.95 and 19.71 mg/L, respectively. The cytotoxicity analysis revealed that optimized electric field conditions and the addition of sodium chloride allow for the avoidance of toxicity effects on normal cells without disturbing the antibacterial effects. Due to the presence of oxidizing substances, the DPPH of variants treated with DC was lower than the DPPH of control samples.

Static magnetic field enhances the viability and proliferation rate of adipose tissue-derived mesenchymal stem cells potentially through activation of the phosphoinositide 3-kinase/Akt (PI3K/Akt) pathway.

The aim of this work was to investigate the effects of 0.5T static magnetic field (sMF) on the viability and proliferation rate of human adipose-derived mesenchymal stromal stem cells (hASCs) via activation of the phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathway. In a 7-d culture we examined cell growth kinetic and population doubling time (PDT). We also examined cell morphology and the cellular senescence markers level. Exposure to sMF enhanced the viability of these cells. However, the effect was blocked by treating the cells with LY294002, a P13K inhibitor. We compared this effect by Western Blot analysis of Akt protein expression. We also examined whether the cell response on sMF stimulation is dependent on integrin engagement and we measured integrin gene expression. Our results suggest that stimulation using sMF is a viable method to improve hASC viability. sMF is involved in mechanisms associated with controlling cell proliferative potential signaling events.

Equine metabolic syndrome impairs adipose stem cells osteogenic differentiation by predominance of autophagy over selective mitophagy.

Adipose-derived mesenchymal stem cells (ASC) hold great promise in the treatment of many disorders including musculoskeletal system, cardiovascular and/or endocrine diseases. However, the cytophysiological condition of cells, used for engraftment seems to be fundamental factor that might determine the effectiveness of clinical therapy. In this study we investigated growth kinetics, senescence, accumulation of oxidative stress factors, mitochondrial biogenesis, autophagy and osteogenic differentiation potential of ASC isolated from horses suffered from equine metabolic syndrome (EMS). We demonstrated that EMS condition impairs multipotency/pluripotency in ASCs causes accumulation of reactive oxygen species and mitochondria deterioration. We found that, cytochrome c is released from mitochondria to the cytoplasm suggesting activation of intrinsic apoptotic pathway in those cells. Moreover, we observed up-regulation of p21 and decreased ratio of Bcl-2/BAX. Deteriorations in mitochondria structure caused alternations in osteogenic differentiation of ASCEMS resulting in their decreased proliferation rate and reduced expression of osteogenic markers BMP-2 and collagen type I. During osteogenic differentiation of ASCEMS , we observed autophagic turnover as probably, an alternative way to generate adenosine triphosphate and amino acids required to increased protein synthesis during differentiation. Downregulation of PGC1α, PARKIN and PDK4 in differentiated ASCEMS confirmed impairments in mitochondrial biogenesis and function. Hence, application of ASCEMS into endocrinological or ortophedical practice requires further investigation and analysis in the context of safeness of their application.

Multifunctional Properties of Binary Polyrhodanine Manganese Ferrite Nanohybrids-From the Energy Converters to Biological Activity.

The PRHD@MnFe2O4 binary hybrids have shown a potential for applications in the biomedical field. The polymer cover/shell provides sufficient surface protection of magnetic nanoparticles against adverse effects on the biological systems, e.g., it protects against Fenton's reactions and the generation of highly toxic radicals. The heating ability of the PRHD@MnFe2O4 was measured as a laser optical density (LOD) dependence either for powders as well as nanohybrid dispersions. Dry hybrids exposed to the action of NIR radiation (808 nm) can effectively convert energy into heat that led to the enormous temperature increase ΔT 170 °C (>190 °C). High concentrated colloidal suspensions (5 mg/mL) can generate ΔT of 42 °C (65 °C). Further optimization of the nanohybrids amount and laser parameters provides the possibility of temperature control within a biologically relevant range. Biological interactions of PRHD@MnFe2O4 hybrids were tested using three specific cell lines: macrophages (RAW 264.7), osteosarcoma cells line (UMR-106), and stromal progenitor cells of adipose tissue (ASCs). It was shown that the cell response was strongly dependent on hybrid concentration. Antimicrobial activity of the proposed composites against Escherichia coli and Staphylococcus aureus was confirmed, showing potential in the exploitation of the fabricated materials in this field.

Increased long-term mortality in women with high left ventricular ejection fraction: data from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) long-term registry.

AIMS: There are significant sex-specific differences in left ventricular ejection fraction (LVEF), with a higher LVEF being observed in women. We sought to assess the clinical relevance of an increased LVEF in women and men. METHODS AND RESULTS: A total of 4632 patients from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry (44.8% women; mean age 58.7 ± 13.2 years in men and 59.5 ± 13.3 years in women, P = 0.05), in whom LVEF was measured by cardiac computed tomography, were categorized according to LVEF (low <55%, normal 55-65%, and high >65%). The prevalence of high LVEF was similar in both sexes (33.5% in women and 32.5% in men, P = 0.46). After 6 years of follow-up, no difference in mortality was observed in patients with high LVEF in the overall cohort (P = 0.41). When data were stratified by sex, women with high LVEF died more often from any cause as compared to women with normal LVEF (8.6% vs. 7.1%, log rank P = 0.032), while an opposite trend was observed in men (5.8% vs. 6.8% in normal LVEF, log rank P = 0.89). Accordingly, a first order interaction term of male sex and high LVEF was significant (hazard ratios 0.63, 95% confidence intervals 0.41-0.98, P = 0.043) in a Cox regression model of all-cause mortality adjusted for age, cardiovascular risk factors, and severity of coronary artery disease (CAD). CONCLUSION: Increased LVEF is highly prevalent in patients referred for evaluation of CAD and is associated with an increased risk of death in women, but not in men. Differentiating between normal and hyperdynamic left ventricles might improve risk stratification in women with CAD. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01443637.

Impact of summer season on pre-hospital time delays in women and men undergoing primary percutaneous coronary intervention.

BACKGROUND: Pre-hospital delays have been associated with poor outcomes in patients with acute ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). It is currently unknown how environmental variables affect treatment delays in these patients. METHODS AND RESULTS: The association between environmental variables, time to treatment including transportation times and adverse in-hospital events was assessed in 1828 consecutive patients with STEMI undergoing primary PCI between 2010 and 2014 in the Montreal metropolitan area. Median[Q1;Q3] total ischemia time was significantly longer during summer season (April-September) as compared to winter season (October-March, 201[140;305] min vs 187[126;266] min, p = 0.022). This difference between seasons was due to a significant increase in median decision time to seek treatment for symptoms during summer (90[46;185] min vs 78[40;156], p = 0.004). The former peaked during July and August and was most pronounced in men. Hence, outside temperature and summer season were identified as strong predictors of prolonged decision time in patients with STEMI (p < 0.001 and p = 0.002, respectively). Transportation times slightly increased during winter season and snow fall, this difference, however, was not significant (p = 0.46). A significant increase in in-hospital adverse outcomes following primary PCI was observed during summer season as compared to winter season (7.2% vs 4.8%, p = 0.032). Accordingly, multivariate logistic regression models adjusted for baseline variables identified summer season as a strong predictor of periprocedural adverse events (OR 1.83, 95% CI 1.2-3.11, p = 0.037). CONCLUSION: Contrary to our initial hypothesis, pre-hospital delays in patients with STEMI are considerably longer and associated with adverse in-hospital outcomes during summer season. Considering the consequences of global warming, it is imperative that educational efforts targeting patients' perception are implemented to counter treatment delays.

Association between beta-adrenoceptor antagonist-induced sympathicolysis and severity of coronary artery disease as assessed by coronary computed tomography angiography (CCTA).

Enhanced sympathetic nervous system activity is associated with increased mortality in many cardiac conditions including heart failure and coronary artery disease (CAD). To ensure adequate image quality of coronary CT angiography (CCTA), pre-scan ß-adrenergic blockers (BB) are routinely administered. It is currently unknown whether sensitivity to sympathicolytic compounds is associated with severity of CAD. A total of 2633 consecutive patients (1733 [65.8%] men and 900 [34.2%] women, mean age 56.7 ± 11.5 years) undergoing CCTA for exclusion of significant CAD at our department between 06/2013 and 12/2016 were evaluated. Acute heart rate (HR) responses to BB administration were recorded in all patients. Coronary plaque burden as indicated by segment severity score (SSS), segment involvement score (SIS), and significant CAD (i.e. > 50% luminal narrowing) was higher in weak responders to BB as compared to strong responders to BB (p = 0.001 for SSS and SIS, and p = 0.021 for significant CAD). Accordingly, in a multiple linear regression model adjusted for known risk factors of CAD such as smoking, hypertension, diabetes and dyslipidaemia, as well as age, sex, body mass index (BMI), glomerular filtration rate, and HR during CCTA scan, a strong response to BB was selected as a significant independent negative predictor of coronary plaque burden (beta coefficient - 0.08, p = 0.001). We demonstrate that individuals with a weak acute response to BB administration encounter an increased risk of severe CAD. Taking into account sensitivity to sympatho-inhibition may add complementary information in patients undergoing CCTA for evaluation of CAD.

Quantification of intrathoracic fat adds prognostic value in women undergoing myocardial perfusion imaging.

AIM: Amongst patients with coronary artery disease (CAD), women experience relatively worse outcomes as compared to men. Evidence to date has failed to explore unique female imaging targets as major determinants of cardiovascular risk. We sought to assess the prognostic value of epicardial (EFV) and intrathoracic fat volume (IFV) quantification in women and men with suspected and known CAD. METHODS AND RESULTS: Intrathoracic fat volume and EFV were calculated from non-contrast CT and analyzed in a propensity-matched cohort of 190 patients (95 women, mean age 62.5 ±â€¯11.3 years) undergoing myocardial perfusion imaging (MPI) and coronary computed tomography angiography (CCTA) for evaluation of CAD. IFV and EFV were significantly lower in women as compared to men (198.2 ±â€¯78.4 vs 293.2 ±â€¯114.7 cm3 and 105.6 ±â€¯48.9 vs 135.8 ±â€¯60.9 cm3, p < 0.001) and showed a strong association with coronary artery calcium score (CACS) and obstructive CAD in women (p < 0.05), but not in men. Fat volumes were not related to abnormal MPI in either population (p = NS). During a median follow-up of 2.8 years, high IFV was associated with reduced event free survival (log rank = 0.019 vs low IFV) in women, but not in men. Accordingly, a multivariate Cox regression model adjusted for cardiovascular risk factors, CACS, CCTA, and MPI findings selected IFV as a significant predictor of major adverse cardiovascular events (MACE) in women (HR 1.32, 95%CI 1.18-1.55, p = 0.001). CONCLUSION: Quantification of IFV provides incremental prognostic value for MACE in women, beyond that provided by traditional risk factors and imaging findings.

Metabolic Activity in Central Neural Structures of Patients With Myocardial Injury.

Background Increasing evidence suggests a psychosomatic link between neural systems and the heart. In light of the growing burden of ischemic cardiovascular disease across the globe, a better understanding of heart-brain interactions and their implications for cardiovascular treatment strategies is needed. Thus, we sought to investigate the interaction between myocardial injury and metabolic alterations in central neural areas in patients with suspected or known coronary artery disease. Methods and Results The association between resting metabolic activity in distinct neural structures and cardiac function was analyzed in 302 patients (aged 66.8±10.2 years; 70.9% men) undergoing fluor-18-deoxyglucose positron emission tomography and 99mTc-tetrofosmin single-photon emission computed tomography myocardial perfusion imaging. There was evidence for reduction of callosal, caudate, and brainstem fluor-18-deoxyglucose uptake in patients with impaired left ventricular ejection fraction (<55% versus ≥55%: P=0.047, P=0.022, and P=0.013, respectively) and/or in the presence of myocardial ischemia (versus normal perfusion: P=0.010, P=0.013, and P=0.016, respectively). In a sex-stratified analysis, these differences were observed in men, but not in women. A first-order interaction term consisting of sex and impaired left ventricular ejection fraction or myocardial ischemia was identified as predictor of metabolic activity in these neural regions (left ventricular ejection fraction: P=0.015 for brainstem; myocardial ischemia: P=0.004, P=0.018, and P=0.003 for callosal, caudate, or brainstem metabolism, respectively). Conclusions Myocardial dysfunction and injury are associated with reduced resting metabolic activity of central neural structures, including the corpus callosum, the caudate nucleus, and the brainstem. These associations differ in women and men, suggesting sex differences in the pathophysiological interplay of the nervous and cardiovascular systems.

Age- and sex-dependent changes in sympathetic activity of the left ventricular apex assessed by 18F-DOPA PET imaging.

BACKGROUND: Sexual dimorphism in cardiac sympathetic outflow has recently gained attention in the context of Takotsubo cardiomyopathy. Previous studies suggest that there are sex- and age-dependent differences in peripheral autonomic control, however, data on cardiac-specific sympathetic activation in aged women and men are lacking. METHODS AND RESULTS: Regional quantitative analysis of cardiac fluorine-18 (18F)- Dihydroxyphenylalanine (DOPA) uptake was retrospectively performed in 133 patients (69 females, mean age 52.4±17.7 years) referred for assessment of neuroendocrine tumours (NET) by Positron-Emission-Tomography. Cardiac 18F-DOPA uptake was significantly higher in women as compared to men (1.33±0.21 vs. 1.18±0.24, p<0.001). This sex-difference was most pronounced in the apical region of the left ventricle (LV, 1.30±0.24 in women vs. 1.13±0.25 in men, p<0.001) and in individuals >55 years of age (1.39±0.25 in women vs. 1.09±0.24 in men, p<0.001). Women showed a prominent increase in myocardial 18F-DOPA uptake with age with the strongest increase seen in the LV apical region (r = 0.34, p = 0.004). Accordingly, sex and age were selected as significant predictors of LV apical 18F-DOPA uptake in a stepwise linear regression model. No age-dependent changes of cardiac 18F-DOPA uptake were observed in men or in the right ventricular region. CONCLUSION: Our study suggests that aging is related to sex-specific changes in regional cardiac sympathetic activity. Future studies will have to assess whether the increase in LV apical 18F-DOPA uptake with age in women is of pathogenic relevance for the higher susceptibility of postmenopausal women to conditions associated with increased sympathetic activity.

The Effect of Low-Magnitude Low-Frequency Vibrations (LMLF) on Osteogenic Differentiation Potential of Human Adipose Derived Mesenchymal Stem Cells.

INTRODUCTION: In the current study, we investigated the effect of low magnitude, low frequency (LMLF) mechanical vibrations on the osteogenic differentiation potential of human adipose derived mesenchymal stem cells (hASC), taken from elderly patients. METHODS: During 21 days in osteogenic culture medium, cells were periodically exposed to three different frequencies (25, 35 and 45 Hz) of continuous sinusoidal oscillation, using a vibration generator. We measured cell proliferation, cell morphology, calcium and phosphorus deposition using Almar Blue assay, fluorescence microscopy, scanning electron microscopy, and a EDX detector, respectively. Osteogenic differentiation was measured by assessing protein and mRNA levels. Osteogenesis was confirmed by detection of specific markers with alkaline phosphatase and enzyme-linked immunosorbent assays for: bone morphogenetic protein 2 (BMP-2), osteocalcin (OCL) and osteopontin (OPN). RESULTS: We found that 25 Hz vibrations had the greatest impact on hASC morphology, ultrastructure, and proliferation. We observed the formation of osteocyte- and hydroxyapatite-like structures, an increased quantity of calcium and phosphorus deposits, and increased differentiation in the stimulated groups. CONCLUSIONS: Our findings suggest that LMLF vibrations could be used to enhance cell-based therapies for treatment of bone deficits, particularly in elderly patients, where the need is greatest.

Corrigendum to "Metformin Decreases Reactive Oxygen Species, Enhances Osteogenic Properties of Adipose-Derived Multipotent Mesenchymal Stem Cells In Vitro, and Increases Bone Density In Vivo".

[This corrects the article DOI: 10.1155/2016/9785890.].

Li+ activated nanohydroxyapatite doped with Eu3+ ions enhances proliferative activity and viability of human stem progenitor cells of adipose tissue and olfactory ensheathing cells. Further perspective of nHAP:Li+, Eu3+ application in theranostics.

Spinal cord injuries (SCI) often require simultaneous regeneration of nerve tissue and bone. Hydroxyapatites are described as bioresorbable materials with proper biocompatibility and osteoconductivity, therefore its application for spinal surgery is considered. In this paper, we present repeatable method for developing nanocrystalline calcium hydroxyapatites structurally modified with Li+ ions (nHAP:Li+). Obtained biomaterials were profoundly characterized in terms of their physicochemical properties. Moreover, we have shown that nHAP:Li+ doped with europium (Eu3+) may serve as a theranostic agent, what additionally extend its potential usage for SCI treatment. The biocompatibility of nHAP:Li+ was determined using human olfactory ensheathing cells (hOECs) and adipose tissue-derived multipotent stromal cells (hASCs). Both population of cells are eagerly applied for cell-based therapies in SCI, mainly due to their paracrine activity. The extensive in vitro studies showed that nHAP:Li+ promotes the cells proliferation, viability and cell-cell interactions. Obtained results provides encouraging approach that may have potential application in regenerative medicine and that could fulfil the promise of personalized medicine - important in SCI treatment.