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 (C-X-C) 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.

BackgroundGlobal and national estimates on the epidemiology of aortic aneurysms are prerequisites for disease management and policymaking. Based on the Global Burden of Disease (GBD) 2019, this study aimed to discern the global aortic aneurysm burden by systematically analyzing demographic data on mortality and exploring the attributable risks and relevant factors.MethodsThe data analyzed in this study were available in the Global Health Data Exchange (GHDx) online query tool. The population in our study comprised individuals from 204 countries and territories from 1990 to 2019. The estimated annual percentage changes (EAPCs) were performed to assess the temporal trends of aortic aneurysms and their attributable risks. Spearman correlation analysis was performed to explore the relationship between the burden of aortic aneurysm and covariates.ResultsAlthough aortic aneurysm-related deaths (82.1%) and disability-adjusted life years (DALYs) (67%) increased from 1990 to 2019, the global trend of age-standardized rate of death (ASRD) (EAPC: −1.34, 95% CI = −1.46 to −1.22, P < 0.001) and age-standardized rate of DALY (ASDALYR) (EAPC: −1.06, 95% CI = −1.17 to −0.95, P < 0.001) decreased, both of which presented age dependence and gender differences. Smoking and high systolic blood pressure (SBP) were the main attributable risks of disease burden and tend to decease globally (EAPC: −1.89, 95% CI = −2.03 to −1.89, P < 0.001; −1.31 95% CI = −1.43 to −1.19, P < 0.001, respectively). Alcohol abstinence (male: R = −0.71, P < 0.001; female: R = −0.73, P < 0.001), smoking age of initiation (male: R = −0.32, P < 0.001; female: R = −0.50, P < 0.001), physical activity (male: R = −0.50, P < 0.001; female: R = −0.55, P < 0.001), and mean temperature (R = −0.62, P < 0.001) had negative correlation with ASRD. However, cholesterol level (male: R = 0.62, P < 0.001; female: R = 0.39, P < 0.001), body mass index (BMI) (male: R = 0.30, P < 0.001; female R = −0.01, P > 0.05), and alcohol consumption (male: R = 0.46, P < 0.001; female: R = 0.42, P < 0.001) had a positive correlation with ASRM. Besides, standard of living and medical resources positively related to burden of aortic aneurysm.ConclusionIn this study, a decreasing trend of aortic aneurysm burden was found globally, especially in advanced regions. Aged men who smoke and women who have hypertension should pay close attention to, particularly in deprived economic groups, and many approaches can be performed to reduce the burden of aortic aneurysms.

Cardiac dysfunction is a common complication of sepsis with high mortality. The present study was designed to identify the effect of neutrophil-derived lipocalin-2 (LCN2) in septic cardiac dysfunction (SCD) and its potential mechanism. Wild-type (WT) and LCN2-knockout (LCN2 KO) mice were peritoneally injected with lipopolysaccharide (LPS) to induce SCD. The cardiac function was assessed 12 h after LPS injection by echocardiography. Cardiac tissue was harvested for the evaluation of malonaldehyde (MDA) and prostaglandin E synthase 2 (PTGS2) mRNA levels. LPS induced ferroptosis and SCD in mice. LCN2 deficiency attenuated cardiac injury post-LPS administration. In vitro, LCN2 expression in neutrophils increased in response to LPS. Ferroptosis of cardiomyocytes induced by conditioned medium (CM) from LPS-induced neutrophils of WT mice could be attenuated in CM from LPS-induced neutrophils of LCN2 KO mice. Exogenous LCN2 induced H9C2 cell ferroptosis via increasing labile iron pool (LIP). In conclusion, our results showed that LCN2 deficiency prevented heart dysfunction and ferroptosis in SCD mice and suggested that neutrophil-derived LCN2 might be a promising therapeutic target for SCD.

BackgroundCalcific aortic valve disease (CAVD) was highly prevalent among developed countries and caused numerous deaths. Based on the Global Burden of Disease 2019, this study was designed to present comprehensive epidemiological information, attributable risks, and relevant factors.MethodsAll data were available online via the Global Health Data Exchange (GHDx). In this study, we analyzed the global incidence, prevalence, deaths, and disability-adjusted life years (DALYs) of CAVD across different regions from 1990 to 2019. We applied the estimated annual percentage changes (EAPCs) to evaluate the change trends and their attributable risks. In addition, we explored several relevant factors.ResultsFrom 1990 to 2019, the incidence cases, prevalence cases, CAVD-related deaths, and DALYs of CAVD gradually increased globally. However, the age-standardized death rate (ASDR) was relatively stable, and the age-standardized DALYs rate gradually declined during the past 30 years. Males and elderly individuals were more likely to suffer from CAVD. High systolic blood pressure (SBP) was the predominant attributable risk of disease burden that presented a global downward trend (death: EAPC = −0.68, 95% CI −0.77~−0.59, P < 0.001; DALYs: EAPC = −0.99, 95% CI −1.09 to −0.89, P < 0.001). Alcohol consumption (R = 0.79, P < 0.001), smoking prevalence (R = 0.75, P < 0.001), and calcium (R = 0.72, P < 0.001) showed a positive correlation with the age-standardized incidence rate (ASIR), whereas classic monsoon region (R = −0.68, P < 0.001) and mean temperature (R = −0.7, P < 0.001) showed a negative correlation with age-standardized incidence rate (ASIR). Besides, medical and healthcare resources presented a positive correlation with ASIR. Meanwhile, similar relationships were found in age-standardized prevalence rate (ASPR), ASDR, and age-standardized DALY rate (ASDALYR).ConclusionCAVD displays widely varied spatial distribution around the world, of which high SDI regions have the highest burdens. Age is a powerful factor and hypertension a predominant attributable risk factor. Moreover, controlling blood pressure, avoiding smoking, reducing alcohol consumption, and so on, could effectively reduce the burden of CAVD.

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Abdominal aortic aneurysms (AAAs) are a chronic vascular disease characterized by pathological luminal dilation. Aortic rupture is the fatal consequence of AAAs. Ginkgo biloba extracts (GBEs), a natural herb extract widely used as food supplements, drugs, and cosmetics, has been reported to suppress development of calcium chloride-induced AAAs in mice. Calcium chloride-induced AAAs do not rupture, while angiotensin II (AngII)-induced AAAs in mice have high rate of aortic rupture, implicating potentially different mechanisms from calcium chloride-induced AAAs. This study aimed to determine whether GBE would improve aortic dilation and rupture rate of AngII-induced AAAs. Male apolipoprotein E (apoE) -/- mice were infused with AngII and administered either GBE or its major active ingredients, flavonoids and ginkgolides, individually or in combination. To determine the effects of GBE in mice with established AAAs, male apoE-/- mice were firstly infused with AngII for 28 days to develop AAAs, and then administered either GBE or vehicle in mice with established AAAs, which were continuously infused with AngII for another 56 days. GBE, but not the two major active components separately or synergistically, prevented aortic rupture, but not aortic dilation. The protection of GBE from aortic rupture was independent of systolic blood pressure, lipid, and inflammation. GBE also did not attenuate either aortic rupture or progressive aortic dilation in mice with established AAAs. GBE did not reduce the atherosclerotic lesion areas, either. In conclusion, GBE prevents aortic rupture in AngII-infused hypercholesterolemic mice, but only in the early phase of the disease development.

Exercise-based cardiac rehabilitation is safe and effective for chronic heart failure (CHF) patients. The present study aimed to investigate the effects of traditional Chinese exercise (TCE) on patients with CHF and the impact of exercise types and duration. Evaluation of randomized controlled trials (RCTs) of TCE in patients with CHF published since 1997 from PubMed, Embase, Web of Science, the Cochrane Library, Chongqing VIP, Wanfang Databases, and the China National Knowledge was performed. A total of 41 RCTs, including 3209 patients with CHF, were included. It showed that TCE significantly increased 6-min walk distance (6MWD) [mean difference (MD) = 72.82 m, p < 0.001] and left ventricular ejection fraction (MD = 5.09%, p < 0.001), whereas reduced B-type natriuretic peptide (BNP) (MD = −56.80 pg/mL, p < 0.001), N-terminal pro-BNP (MD = −174.94 pg/mL, p < 0.05), and Minnesota Living with Heart Failure Questionnaire scores (MD = −11.31, p < 0.001). However, no significant difference was found in the effects of TCE on peak oxygen consumption. The increase in TCE weekly duration and program duration significantly improved 6MWD (MD = 71.91 m, p < 0.001; MD = 74.11 m, p < 0.001). The combination of TCE and conventional aerobic exercise significantly improved 6MWD (MD = 19.86 m, p < 0.005). TCE improves exercise capacity, cardiac function, and quality of life in patients with CHF, which might be an optimal and available pattern of exercise-based cardiac rehabilitation.