Effects of ambient temperature and humidity on COPD mortality in Ganzhou city, China.

This study used the time series data of Ganzhou city to explore the individual and interaction effects of temperature and humidity on COPD death, and identify vulnerable subgroups of the population. We collected daily COPD mortality and meteorological data in Ganzhou from 2016 to 2019. The nonlinear distribution lag model was used to examine the associations and interaction between daily mean temperature and humidity and COPD mortality. For the total population, male and 65 years old or above, the relative risk (RR) for COPD mortality could be significant at extremely low temperature (3.3 ℃), reaching 1.799 (95% confidence interval [CI]: 1.216, 2.662), 1.894 (95% CI: 1.164, 3.084) and 1.779 (95% CI:1.185, 2.670). Also, at extremely low humidity (47.8%), the risk reached 1.888 (95% CI: 1.217, 2.930), 1.837 (95% CI: 1.066, 3.165) and 2.166 (95% CI: 1.375, 3.414). The cumulative COPD death risk for females was 3.524 (95% CI: 1.340, 9.267) at high temperature (30.7 ℃), 1.953(95% CI: 1.036, 3.683) at low humidity (47.8%) and 1.726 (95% CI: 1.048, 2.845) at high humidity (96.7%). For the total COPD deaths and subgroups, the interaction effects between daily temperature and humidity were not significant (p > 0.05). Both extremely low temperature and low humidity increased the risk of COPD death in Ganzhou city, especially for males and people over 65 years old. Females were more sensitive to extremely high temperature and humidity. Patients with COPD should pay attention to self-protection under extreme temperature and humidity weather conditions.

CXCR4 blockade in macrophage promotes angiogenesis in ischemic hindlimb by modulating autophagy.

Chemokine receptor CXCR4 plays a crucial role in leukocyte recruitment and inflammation regulation to influence tissue repair in ischemic diseases. Here we assessed the effect of CXCR4 expression in macrophages on angiogenesis in the ischemic hindlimb of a mouse. Inflammatory cells were increased in the ischemic muscles of hindlimb, and CXCR4 was highly expressed in the infiltrated macrophages but not in neutrophils. Myeloid-specific CXCR4 knockout attenuated macrophage infiltration and subsequent reduced inflammatory response in the ischemic hindlimb, accompanied with better blood reperfusion and higher capillary density as compared with that in LysM Cre+/- (Cre) mice. Similar outcomes were also observed in CRE mice whose bone marrow cells were replaced with those from CXCR4-deficient mice. Gene ontology cluster analysis reviewed that Decorin, a negative regulator of angiogenesis, was reduced in CXCR4-deficient macrophages. CXCR4-deficient macrophages were less inducible into M1 phase by lipopolysaccharide and more favorable for M2 polarization under oxygen/glucose deprivation condition. Enhanced autophagy was detected in CXCR4-deficient macrophages, which was associated with less expression of both Decorin and the inflammatory cytokines. In summary, myeloid-specific CXCR4 deficiency reduced monocyte infiltration and the secretion of inflammatory cytokines and Decorin from macrophages, thus blunting inflammation response and promoting angiogenesis in the ischemic hindlimb.

Rediscovering the value of exercise in patients with hypertrophic cardiomyopathy.

It was previously thought that hypertrophic cardiomyopathy is the leading cause of sudden cardiac death in athletes. This was also extrapolated to the general population. Thereby, exercise was restrained in patients with hypertrophic cardiomyopathy. However, recent studies have shown that hypertrophic cardiomyopathy is not the main cause of sudden cardiac death, and moderate exercise is not only safe but beneficial for patients with hypertrophic cardiomyopathy. With the accumulation of evidence, relevant guidelines recommend low-intensity exercise from the beginning, then gradually recommend moderate-high intensity exercise for patients with hypertrophic cardiomyopathy. This suggests that we should rediscover the value of exercise in patients with hypertrophic cardiomyopathy. It is now widely accepted that patients with hypertrophic cardiomyopathy can benefit from the positive effects of exercise through an individualized exercise prescription based on a comprehensive assessment. This review summarizes the evidence showing patients with hypertrophic cardiomyopathy can exercise safely, and the methods to formulate related exercise prescriptions.

A Large-Scale Investigation of Hypoxia-Preconditioned Allogeneic Mesenchymal Stem Cells for Myocardial Repair in Nonhuman Primates: Paracrine Activity Without Remuscularization.

RATIONALE: The effectiveness of transplanted bone marrow mesenchymal stem cells (MSCs) for cardiac repair has been limited; thus, strategies for optimizing stem-cell-based myocardial therapy are needed. OBJECTIVE: The present study was designed to test our central hypothesis that hypoxia-preconditioned MSCs (HP-MSCs) are more effective than MSCs cultured under ambient oxygen levels for the treatment of myocardial injury in a large-scale (N=49), long-term (9 months), nonhuman primate (Cynomolgous monkeys) investigation. METHODS AND RESULTS: MSCs were engineered to express green fluorescent protein, cultured under ambient oxygen or 0.5% oxygen (HP-MSCs) for 24 hours and then tested in the infarcted hearts of Cynomolgus monkeys (1×10(7) cells per heart). Hypoxia preconditioning increased the expression of several prosurvival/proangiogenic factors in cultured MSCs, and measurements of infarct size and left-ventricular function at day 90 after myocardial infarction were significantly more improved in monkeys treated with HP-MSCs than in monkeys treated with the control vehicle; functional improvements in normal cultured bone marrow mesenchymal stem cells-treated monkeys were not significant. HP-MSCs transplantation was also associated with increases in cardiomyocyte proliferation, vascular density, myocardial glucose uptake, and engraftment of the transplanted cells and with declines in endogenous cell apoptosis, but did not increase the occurrence of arrhythmogenic complications. CONCLUSIONS: Hypoxia preconditioning improved the effectiveness of MSCs transplantation for the treatment of myocardial infarction in nonhuman primates without increasing the occurrence of arrhythmogenic complications, which suggests that future clinical trials of HP-MSCs transplantation are warranted.

Stem cell therapy for ischemic heart diseases.

Introduction: Ischemic heart diseases, especially the myocardial infarction, is a major hazard problem to human health. Despite substantial advances in control of risk factors and therapies with drugs and interventions including bypass surgery and stent placement, the ischemic heart diseases usually result in heart failure (HF), which could aggravate social burden and increase the mortality rate. The current therapeutic methods to treat HF stay at delaying the disease progression without repair and regeneration of the damaged myocardium. While heart transplantation is the only effective therapy for end-stage patients, limited supply of donor heart makes it impossible to meet the substantial demand from patients with HF. Stem cell-based transplantation is one of the most promising treatment for the damaged myocardial tissue. Sources of data: Key recent published literatures and ClinicalTrials.gov. Areas of agreement: Stem cell-based therapy is a promising strategy for the damaged myocardial tissue. Different kinds of stem cells have their advantages for treatment of Ischemic heart diseases. Areas of controversy: The efficacy and potency of cell therapies vary significantly from trial to trial; some clinical trials did not show benefit. Diverged effects of cell therapy could be affected by cell types, sources, delivery methods, dose and their mechanisms by which delivered cells exert their effects. Growing points: Understanding the origin of the regenerated cardiomyocytes, exploring the therapeutic effects of stem cell-derived exosomes and using the cell reprogram technology to improve the efficacy of cell therapy for cardiovascular diseases. Areas timely for developing research: Recently, stem cell-derived exosomes emerge as a critical player in paracrine mechanism of stem cell-based therapy. It is promising to exploit exosomes-based cell-free therapy for ischemic heart diseases in the future.

Global burden of atrial fibrillation/flutter: Trends from 1990 to 2019 and projections until 2044.

Aims: Atrial fibrillation/atrial flutter (AF/AFL) is a critical public health issue worldwide, and its epidemiological patterns have changed over the decades. This work aimed to assess the global trends of AF/AFL and attributable risks from 1990 to 2019. Methods and results: The present study utilized data from the Global Burden of Disease Study 2019 to examine the temporal trends, attributable risks, and projections of AF/AFL. The estimated annual percentage change (EAPC) and age-standardized rate (ASR) were employed for this purpose. The findings revealed that in 2019, AF/AFL accounted for 4.72 million incident cases, 59.70 million prevalent cases, 0.32 million deaths, and 8.39 million disability-adjusted life years (DALYs). Furthermore, the results indicated that males under 70 years of age had a higher incidence, prevalence, and DALYs than females, while the rates were similar for both genders between 70 and 74 years. However, this pattern was reversed in individuals over the age of 75, with females exhibiting a higher total incidence, prevalence, and DALYs than males. The age-standardized rates (ASRs) of prevalence, incidence, mortality, and DALYs increased with an increase in the socio-demographic index (SDI). The three primary contributors to AF/AFL were high systolic blood pressure, high body-mass index, and smoking. Majority of risk factors exhibited a unimodal distribution, with a peak between the ages of 50 and 70. Conclusions: The disease burden of AF/AFL is still severe worldwide and getting worse. To encourage prevention and treatment, systematic regional surveillance of AF/AFL should be put in place.

Meta-analysis of randomized controlled trials on magnesium in addition to beta-blocker for prevention of postoperative atrial arrhythmias after coronary artery bypass grafting.

BACKGROUND: Atrial arrhythmia (AA) is the most common complication after coronary artery bypass grafting (CABG). Only beta-blockers and amiodarone have been convincingly shown to decrease its incidence. The effectiveness of magnesium on this complication is still controversial. This meta-analysis was performed to evaluate the effect of magnesium as a sole or adjuvant agent in addition to beta-blocker on suppressing postoperative AA after CABG. METHODS: We searched the PubMed, Medline, ISI Web of Knowledge, Cochrane library databases and online clinical trial database up to May 2012. We used random effects model when there was significant heterogeneity between trials and fixed effects model when heterogeneity was negligible. RESULTS: Five randomized controlled trials were identified, enrolling a total of 1251 patients. The combination of magnesium and beta-blocker did not significantly decrease the incidence of postoperative AA after CABG versus beta-blocker alone (odds ratio (OR) 1.12, 95% confidence interval (CI) 0.86-1.47, P = 0.40). Magnesium in addition to beta-blocker did not significantly affect LOS (weighted mean difference -0.14 days of stay, 95% CI -0.58 to 0.29, P = 0.24) or the overall mortality (OR 0.59, 95% CI 0.08-4.56, P = 0.62). However the risk of postoperative adverse events was higher in the combination of magnesium and beta-blocker group than beta-blocker alone (OR 2.80, 95% CI 1.66-4.71, P = 0.0001). CONCLUSIONS: This meta-analysis offers the more definitive evidence against the prophylactic administration of intravenous magnesium for prevention of AA after CABG when beta-blockers are routinely administered, and shows an association with more adverse events in those people who received magnesium.

The impacts of the combination service model of cardiac rehabilitation on patient outcomes: evidence from a hospital experience.

This research is to test whether the combination model (CM) (combining cardiac rehabilitation (CR) with other cardiovascular medical services) impact patients' readmissions, physical and psychological outcomes. We found that CM significantly enhances patients' exercise ability and psychological condition and reduces readmission rates after discharged from the hospital, compared to patients that are admitted to non-CM. Departments' physical resources weaken the impact of CM on patients' physical outcomes and readmission rates while increasing patients' psychological conditions. Human resources strengthen the impact of CM on patients' readmission rates while reducing the impact on patients' physical outcomes. Our results provide empirical evidence for hospital resource constraints puzzle and reallocation. These results provide a possibility of introducing CM as a way to deal with CR implementing challenges.

What we already knowThe impact of service models (such as healthcare integrations) on hospital- and patient-level outcomes has been empirically verified.Scholars demonstrate that cardiac rehabilitation (CR) can improve secondary prevention outcomes with comprehensive risk reduction and long-term care, but there are still barriers and challenges to implement CR.Prior studies show hospital resources have significant impacts on practices implementing, patients' satisfaction and readmission rates.What this article addsWe extend the research on service providing field. Patients choose combination model (CM), which significantly enhances their exercise ability and psychological condition. Their readmission rates are also reduced.Higher departments' physical resources diminish the reduction of patients' admission rates, and human resources strengthen the reduction of patients' readmission rates.These results suggest that CM benefits patients' outcomes, and department resources favor certain outcomes.

Intracardiac biopsy of cardiac tumors with echocardiographic guidance: Case report.

Background: Primary cardiac tumors are very rare, and about 20-30% of them are malignant tumors. Since early signs of cardiac tumors are non-specific, diagnosis can be challenging. There is a lack of the recommended guidelines or standardized strategies for diagnosis and optimal treatment for this disease. As the definite diagnoses of most tumors are made by pathologic confirmation, biopsied tissue is essential in determining the treatment for patients with cardiac tumors. Recently, intracardiac echocardiography (ICE) has been introduced to assist biopsy procedures of cardiac tumors and it provides high-quality imaging. Case Description: Due to its low prevalence and variable presentation, cardiac malignant tumors usually are easily missed. Hereby, we report three cases of patients who presented with non-specific signs of cardiac disorder and was initially suspended diagnosis as lung infection or cancer. Under the guidance of ICE, cardiac biopsies were successfully on cardiac masses, giving critical data for diagnosis and treatment planning. No procedural complications were obtained in our cases. These cases are intended to highlight the clinical value and importance of ICE-guided biopsy of intracardiac mass. Conclusions: The diagnosis of primary cardiac tumors relies on the histopathological results. In our experience, using ICE for biopsy of an intracardiac mass is an attractive tool to increase diagnostic results and reduce the risk of cardiac complications associated with inadequate targeting of the biopsy catheters.

Deficiency of GDF-11 Accelerates TAC-Induced Heart Failure by Impairing Cardiac Angiogenesis.

The role of growth differentiation factor (GDF)-11 in cardiac diseases has not been fully determined. Our study revealed that GDF-11 is not essential for myocardial development and physiological growth, whereas its absence exacerbates heart failure under pressure overload condition via impairing the responsive angiogenesis. GDF-11 induced VEGF expression in CMs by activating the Akt/mTOR pathway. The effect of endogenous GDF-11 on the heart belongs to local self-regulation of myocardial tissue, rather than a way of systemic regulation.

Nano-hydroxyapatite accelerates vascular calcification via lysosome impairment and autophagy dysfunction in smooth muscle cells.

Vascular calcification (VC) is a common characteristic of aging, diabetes, chronic renal failure, and atherosclerosis. The basic component of VC is hydroxyapatite (HAp). Nano-sized HAp (nHAp) has been identified to play an essential role in the development of pathological calcification of vasculature. However, whether nHAp can induce calcification in vivo and the mechanism of nHAp in the progression of VC remains unclear. We discovered that nHAp existed both in vascular smooth muscle cells (VSMCs) and their extracellular matrix (ECM) in the calcified arteries from patients. Synthetic nHAp had similar morphological and chemical properties as natural nHAp recovered from calcified artery. nHAp stimulated osteogenic differentiation and accelerated mineralization of VSMCs in vitro. Synthetic nHAp could also directly induce VC in vivo. Mechanistically, nHAp was internalized into lysosome, which impaired lysosome vacuolar H+-ATPase for its acidification, therefore blocked autophagic flux in VSMCs. Lysosomal re-acidification by cyclic-3',5'-adenosine monophosphate (cAMP) significantly enhanced autophagic degradation and attenuated nHAp-induced calcification. The accumulated autophagosomes and autolysosomes were converted into calcium-containing exosomes which were secreted into ECM and accelerated vascular calcium deposit. Inhibition of exosome release in VSMCs decreased calcium deposition. Altogether, our results demonstrated a repressive effect of nHAp on lysosomal acidification, which inhibited autophagic degradation and promoted a conversion of the accumulated autophagic vacuoles into exosomes that were loaded with undissolved nHAp, Ca2+, Pi and ALP. These exosomes bud off the plasma membrane, deposit within ECM, and form calcium nodules. Vascular calcification was thus accelerated by nHAP through blockage of autophagic flux in VSMCs.

Nano-Sized Hydroxyapatite Induces Apoptosis and Osteogenic Differentiation of Vascular Smooth Muscle Cells via JNK/c-JUN Pathway.

PURPOSE: The deposition of hydroxyapatite (HAp) crystals plays an important role in the development of vascular calcification (VC). This study aimed to demonstrate the effects of nanosized HAp (nHAp) on vascular smooth muscle cells (VSMCs) and VC progression. METHODS: Transmission electron microscopy (TEM) was used to examine cellular uptake of nHAp. Cell viability was determined using CCK-8 assay kit. Mitochondrial impairment and reactive oxygen species were detected by TEM and fluorescence dye staining, respectively. Cell apoptosis was detected by Western blot analysis and Annexin V staining. Mouse model of VC was built via applying nHAp on the surface of abdominal aorta. Calcification was visualized by Alizarin red and von Kossa staining. RESULTS: We found that nHAp could promote osteogenic transformation of VSMCs by elevating expression of runt-related factor 2 (Runx2), osteopontin (OPN) and alkaline phosphatase (ALP), impairing function and morphology of mitochondria and inducing apoptosis of VSMCs. More phosphorylation of c-Jun N-terminal protein kinase/c-JUN (JNK/c-JUN) in VSMCs was detected after mixing nHAp with VSMCs. HAp-induced osteogenic transformation of VSMCs was blocked by JNK inhibitor SP600125, resulted in decreased ALP activity, less Runx2 and OPN expressions. SP600125 also inhibited apoptosis of VSMCs. Application of nHAp to outside of aorta induced osteogenic transformation and apoptosis of VSMCs, and significant deposition of calcium on the vessel walls of mice, which can be effectively attenuated by SP600125. CONCLUSION: JNK/c-JUN signaling pathway is critical for nHAp-induced calcification, which could be a potential therapeutic target for controlling the progression of VC.

Small extracellular vesicles containing miR-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates.

Stem cell-derived small extracellular vesicles (sEVs) promote angiogenesis after myocardial infarction (MI). However, the components of sEVs that contribute to these effects and the safety and efficiency of engineered sEV treatment for MI remain unresolved. Here, we observed improved cardiac function, enhanced vascular density, and smaller infarct size in mice treated with the sEVs from hypoxia-preconditioned (HP) mesenchymal stem cells (MSCs) (HP-sEVs) than in mice treated with normoxia-preconditioned (N) MSCs (N-sEVs). MicroRNA profiling revealed a higher abundance of miR-486-5p in HP-sEVs than in N-sEVs, and miR-486-5p inactivation abolished the benefit of HP-sEV treatment, whereas miR-486-5p up-regulation enhanced the benefit of N-sEV treatment. Matrix metalloproteinase 19 (MMP19) abundance was lower in HP-sEV-treated than N-sEV-treated mouse hearts but was enriched in cardiac fibroblasts (CFs), and Mmp19 was identified as one of the target genes of miR-486-5p. Conditioned medium from CFs that overexpressed miR-486-5p or silenced MMP19 increased the angiogenic activity of endothelial cells; however, medium from CFs that simultaneously overexpressed Mmp19 and miR-486-5p abolished this effect. Mmp19 silencing in CFs reduced the cleavage of extracellular vascular endothelial growth factor (VEGF). Furthermore, miR-486-5p-overexpressing N-sEV treatment promoted angiogenesis and cardiac recovery without increasing arrhythmia complications in a nonhuman primate (NHP) MI model. Collectively, this study highlights the key role of sEV miR-486-5p in promoting cardiac angiogenesis via fibroblastic MMP19-VEGFA cleavage signaling. Delivery of miR-486-5p-engineered sEVs safely enhanced angiogenesis and cardiac function in an NHP MI model and may promote cardiac repair.

GDF11 enhances therapeutic efficacy of mesenchymal stem cells for myocardial infarction via YME1L-mediated OPA1 processing.

Growth differentiation factor 11 (GDF11) has been shown to promote stem cell activity, but little is known about the effect of GDF11 on viability and therapeutic efficacy of cardiac mesenchymal stem cells (MSCs) for cardiac injury. To understand the roles of GDF11 in MSCs, mouse heart-derived MSCs were transduced with lentiviral vector carrying genes for both GDF11 and green fluorescent protein (GFP) (MSCsLV-GDF11 ) or cultured with recombinant GDF11 (MSCsrGDF11 ). Either MSCsrGDF11 or MSCs LV-GDF11 displayed less cell apoptosis and better paracrine function, as well as preserved mitochondrial morphology and function under hypoxic condition as compared with control MSCs. GDF11 enhanced phosphorylation of Smad2/3, which upregulated expression of YME1L, a mitochondria protease that balances OPA1 processing. Inhibitors of TGF-ß receptor (SB431542) or Smad2/3 (SIS3) attenuated the effects of GDF11 on cell viability, mitochondrial function, and expression of YME1L. Transplantation of MSCsGDF11 into infarct heart resulted in improved cell survival and retention, leading to more angiogenesis, smaller scar size, and better cardiac function in comparison with control MSCs. GDF11 enhanced viability and therapeutic efficiency of MSCs by promoting mitochondrial fusion through TGF-ß receptor/Smad2/3/YME1L-OPA1 signaling pathway. This novel role of GDF11 may be used for a new approach of stem cell therapy for myocardial infarction.

Exosomes derived from human umbilical cord MSCs rejuvenate aged MSCs and enhance their functions for myocardial repair.

BACKGROUND: Age and other cardiovascular risk factors have been reported to impair the activities of mesenchymal stem cells (MSCs), which will affect the efficacy of stem cell transplantation. The objective of the study is to investigate whether exosomes derived from human umbilical cord MSCs (UMSCs) could enhance the activities of bone marrow MSCs from old person (OMSCs), and improve their capacity for cardiac repair. METHODS: Exosomes extracted from conditioned medium of UMSCs were used to treat OMSCs to generate OMSCsExo. The key molecule in the exosomes that have potential to rejuvenate aged MSCs were screened, and the role of OMSC was tested in the mouse model of mycardial infarction (MI). RESULTS: We found the activity of senescence-associated ß-galactosidase and the expression of aging-related factors such as p53, p21, and p16 were significantly higher in OMSCs than those in UMSCs. After treatment with UMSC exosomes, these senescence phenotypes of OMSCs were remarkably reduced. The proliferation, migration, differentiation, and anti-apoptotic and paracrine effect were increased in OMSCsExo. In vivo study, mice with cardiac infarction had significantly better cardiac function, less fibrosis, and more angiogenesis after they were injected with OMSCsExo as compared with those with OMSC. There was more miR-136 expression in UMSCs and OMSCsExo than in OMSCs. Upregulation of miR-136 by transfection of miR-136 mimic into OMSCs significantly attenuated the apoptosis and senescence of OMSCs. Apoptotic peptidase activating factor (Apaf1) was found to be the downstream gene that is negatively regulated by miR-136 via directly targeting at its 3'UTR. CONCLUSION: Our data suggest that exosomes from young MSCs can improve activities of aged MSCs and enhance their function for myocardial repair by transferring exosomal miR-136 and downregulating Apaf1.

Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way.

Hypoxia treatment enhances paracrine effect of mesenchymal stem cells (MSCs). The aim of this study was to investigate whether exosomes from hypoxia-treated MSCs (ExoH) are superior to those from normoxia-treated MSCs (ExoN) for myocardial repair. Mouse bone marrow-derived MSCs were cultured under hypoxia or normoxia for 24 h, and exosomes from conditioned media were intramyocardially injected into infarcted heart of C57BL/6 mouse. ExoH resulted in significantly higher survival, smaller scar size and better cardiac functions recovery. ExoH conferred increased vascular density, lower cardiomyocytes (CMs) apoptosis, reduced fibrosis and increased recruitment of cardiac progenitor cells in the infarcted heart relative to ExoN. MicroRNA analysis revealed significantly higher levels of microRNA-210 (miR-210) in ExoH compared with ExoN. Transfection of a miR-210 mimic into endothelial cells (ECs) and CMs conferred similar biological effects as ExoH. Hypoxia treatment of MSCs increased the expression of neutral sphingomyelinase 2 (nSMase2) which is crucial for exosome secretion. Blocking the activity of nSMase2 resulted in reduced miR-210 secretion and abrogated the beneficial effects of ExoH. In conclusion, hypoxic culture augments miR-210 and nSMase2 activities in MSCs and their secreted exosomes, and this is responsible at least in part for the enhanced cardioprotective actions of exosomes derived from hypoxia-treated cells.