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.

CXCR4-dependent macrophage-to-fibroblast signaling contributes to cardiac diastolic dysfunction in heart failure with preserved ejection fraction.

Rationale: Heart failure with preserved ejection fraction (HFpEF) can arise from hypertension-induced cardiac remodeling. Monocyte/macrophage accumulation and inflammation are crucial elements in the pathogenesis of hypertension-induced cardiac remodeling. The C-X-C chemokine receptor 4 (CXCR4) is a critical regulator of the macrophage-mediated immune response. Nevertheless, the contribution of CXCR4 to macrophage phenotype and function during the progression of HFpEF remains unclear. Herein, we aimed to determine the role of macrophagic CXCR4 in heart failure with preserved ejection fraction (HFpEF). Methods: As a HFpEF model, wild type mice and myeloid-specific CXCR4 deficiency mice were subjected to pressure overload for 30 days to assess the function of macrophagic CXCR4 on cardiac function. Medium from macrophages was used to treat cardiac fibroblasts to study macrophage-to-fibroblast signaling. Results: We found circulatory CXCR4+ immune cells, mainly monocytes, markedly increased in HFpEF patients with hypertension. In the experimental HFpEF mice model, macrophages but not neutrophils represent the main infiltrating inflammatory cells in the heart, abundantly expressing CXCR4. Myeloid-specific CXCR4 deficient impeded macrophage infiltration and inflammatory response in the heart of HFpEF mice, thus ameliorating cardiac fibrosis and improving cardiac diastolic function. Furthermore, transcriptomic profiling data revealed that CXCR4 loss in macrophages exhibited a decreased transcriptional signature associated with the regulation of inflammatory response. Notably, CXCR4 significantly augmented chemokine (C­X­C) motif ligand (CXCL3) expression, which at least partly contributed to fibrosis by promoting myofibroblast differentiation. Mechanistically, the increased production of pro-inflammatory cytokines in CXCR4 expressed macrophages could be attributed to the suppression of the peroxisome proliferator-activated receptor γ (PPARγ) activity. Conclusions: Collectively, our data supported that the infiltration of CXCR4+ macrophages in the heart exacerbates hypertension-induced diastolic function by promoting pro-inflammatory cytokines production and thus may serve as a potential therapeutic target for hypertension-induced HFpEF.

Ginsenoside Rg3 Prolongs Survival of the Orthotopic Hepatocellular Carcinoma Model by Inducing Apoptosis and Inhibiting Angiogenesis.

AIM: Microvessel density is a marker of tumor angiogenesis activity for development and metastasis. Our preliminary study showed that ginsenoside Rg3 (Rg3) induces apoptosis in hepatocellular carcinoma (HCC) in vitro. The aim of this study was to investigate the cross-link for apoptosis induction and antiangiogenesis effect of Rg3 on orthotopic HCC in vivo. METHODS: The murine HCC cells Hep1-6 were implanted in the liver of mouse. With oral feeding of Rg3 (10 mg/kg once a day for 30 days), the quantitative analysis of apoptosis was performed by using pathology and a transmission electron microscope and microvessel density was quantitatively measured by immunohistochemical staining of the CD105 antibody. The mice treated with Rg3 (n = 10) were compared with the control (n = 10) using Kaplan-Meier analysis. Animal weight and tumor weight were measured to determine the toxicity of Rg3 and antitumor effect on an orthotopic HCC tumor model. RESULTS: With oral feeding of Rg3 daily in the first 30 days on tumor implantation, Rg3 significantly decreased the orthotopic tumor growth and increased the survival of animals (P < 0.05). Rg3-treated mice showed a longer survival than the control (P < 0.05). Rg3 treatment induced apoptosis and inhibited angiogenesis. They contributed to the tumor shrinkage. Rg3 initialized the tumor apoptotic progress, which then weakened the tumor volume and its capability to produce the vascularized network for further growth of the tumor and remote metastasis. CONCLUSION: Rg3 inhibited the activation of microtumor vessel formation in vivo besides its apoptosis induction. Rg3 may be used as an adjuvant agent in the clinical HCC treatment regimen.

Growth Hormone-Releasing Hormone and Its Analogues: Significance for MSCs-Mediated Angiogenesis.

Mesenchymal stromal cells (MSCs) are promising candidates for regenerative medicine because of their multipotency, immune-privilege, and paracrine properties including the potential to promote angiogenesis. Accumulating evidence suggests that the inherent properties of cytoprotection and tissue repair by native MSCs can be enhanced by various preconditioning stimuli implemented prior to cell transplantation. Growth hormone-releasing hormone (GHRH), a stimulator in extrahypothalamus systems including tumors, has attracted great attentions in recent years because GHRH and its agonists could promote angiogenesis in various tissues. GHRH and its agonists are proangiogenic in responsive tissues including tumors, and GHRH antagonists have been tested as antitumor agents through their ability to suppress angiogenesis and cell growth. GHRH-R is expressed by MSCs and evolving work from our laboratory indicates that treatment of MSCs with GHRH agonists prior to cell transplantation markedly enhanced the angiogenic potential and tissue reparative properties of MSCs through a STAT3 signaling pathway. In this review we summarized the possible effects of GHRH analogues on cell growth and development, as well as on the proangiogenic properties of MSCs. We also discussed the relationship between GHRH analogues and MSC-mediated angiogenesis. The analyses provide new insights into molecular pathways of MSCs-based therapies and their augmentation by GHRH analogues.

Profound Actions of an Agonist of Growth Hormone-Releasing Hormone on Angiogenic Therapy by Mesenchymal Stem Cells.

OBJECTIVE: The efficiency of cell therapy is limited by poor cell survival and engraftment. Here, we studied the effect of the growth hormone-releasing hormone agonist, JI-34, on mesenchymal stem cell (MSC) survival and angiogenic therapy in a mouse model of critical limb ischemia. APPROACH AND RESULTS: Mouse bone marrow-derived MSCs were incubated with or without 10(-8) mol/L JI-34 for 24 hours. MSCs were then exposed to hypoxia and serum deprivation to detect the effect of preconditioning on cell apoptosis, migration, and tube formation. For in vivo tests, critical limb ischemia was induced by femoral artery ligation. After surgery, mice received 50 µL phosphate-buffered saline or with 1×10(6) MSCs or with 1×10(6) JI-34-reconditioned MSCs. Treatment of MSCs with JI-34 improved MSC viability and mobility and markedly enhanced their capability to promote endothelial tube formation in vitro. These effects were paralleled by an increased phosphorylation and nuclear translocation of signal transducer and activator of transcription 3. In vivo, JI-34 pretreatment enhanced the engraftment of MSCs into ischemic hindlimb muscles and augmented reperfusion and limb salvage compared with untreated MSCs. Significantly more vasculature and proliferating CD31(+) and CD34(+) cells were detected in ischemic muscles that received MSCs treated with JI-34. CONCLUSIONS: Our studies demonstrate a novel role for JI-34 to markedly improve therapeutic angiogenesis in hindlimb ischemia by increasing the viability and mobility of MSCs. These findings support additional studies to explore the full potential of growth hormone-releasing hormone agonists to augment cell therapy in the management of ischemia.

[Effect of poly(ADP-ribose)polymerase inhibitor combined with carbo on apoptosis of human breast cancer cells].

OBJECTIVE: To investigate the effect of poly(ADP-ribose)polymerase(PARP)inhibitor ABT888 combined with carbo on apoptosis of human breast cancer cells. METHODS: MTT was used to detect the cell viability of MDA-MB-435s cells after treatment of carbo and ABT888 with different concentration. FACS and Western-blotting were used to detect the cell apoptosis rate and apoptosis-related protein expression, respectively. RESULTS: Combined application of carbo and ABT888 significantly inhibited the proliferation of MDA-MB-435s cells, and the inhibition rates were significantly higher than that of carbo or ABT888 alone. The combination of carbo and ABT888 markedly induced cell apoptosis(26.3%±1.5%) more than carbo(18.6%±1.6%, P<0.01) and ABT888(14.7%±2.3%, P<0.01) alone. Combination of carbo and ABT888 significantly down-regulated the expression of anti-apoptosis factors Bcl-2 and up-regulated the pro-apoptosis proteins Bax and cleaved caspase-3. CONCLUSION: The combination of carbo and ABT888 can suppress the proliferation and induce apoptosis of human breast cancer DA-MB-435s cells.