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Sepsis-induced myocardial dysfunction (SIMD) is associated with poor prognosis and increased mortality in patients with sepsis. Cytokines are important regulators of both the initiation and progression of sepsis. Interleukin-15 (IL-15), a pro-inflammatory cytokine, has been linked to protective effects against myocardial infarction and myocarditis. However, the role of IL-15 in SIMD remains unclear. We established a mouse model of SIMD via cecal ligation puncture (CLP) surgery and a cell model of myocardial injury via lipopolysaccharide (LPS) stimulation. IL-15 expression was prominently upregulated in septic hearts as well as cardiomyocytes challenged with LPS. IL-15 pretreatment attenuated cardiac inflammation and cell apoptosis and improved cardiac function in the CLP model. Similar cardioprotective effects of IL-15 pretreatment were observed in vitro. As expected, IL-15 knockdown had the opposite effect on LPS-stimulated cardiomyocytes. Mechanistically, we found that IL-15 pretreatment reduced the expression of the pro-apoptotic proteins cleaved caspase-3 and Bax and upregulated the anti-apoptotic protein Bcl-2. RNA sequencing and Western blotting further confirmed that IL-15 pretreatment suppressed the activation of nuclear factor kappa B (NF-κB) signaling in mice with sepsis. Besides, the addition of NF-κB inhibitor can significantly attenuate cardiomyocyte apoptosis compared to the control findings. Our results suggest that IL-15 pretreatment attenuated the cardiac inflammatory responses and reduced cardiomyocyte apoptosis by partially inhibiting NF-κB signaling in vivo and in vitro, thereby improving cardiac function in mice with sepsis. These findings highlight a promising therapeutic strategy for SIMD.

Ventricular arrhythmogenesis is a key cause of sudden cardiac death following myocardial infarction (MI). Accumulating data show that ischemia, sympathetic activation, and inflammation contribute to arrhythmogenesis. However, the role and mechanisms of abnormal mechanical stress in ventricular arrhythmia following MI remain undefined. We aimed to examine the impact of increased mechanical stress and identify the role of the key sensor Piezo1 in ventricular arrhythmogenesis in MI. Concomitant with increased ventricular pressure, Piezo1, as a newly recognized mechano-sensitive cation channel, was the most up-regulated mechanosensor in the myocardium of patients with advanced heart failure. Piezo1 was mainly located at the intercalated discs and T-tubules of cardiomyocytes, which are responsible for intracellular calcium homeostasis and intercellular communication. Cardiomyocyte-conditional Piezo1 knockout mice (Piezo1Cko) exhibited preserved cardiac function after MI. Piezo1Cko mice also displayed a dramatically decreased mortality in response to the programmed electrical stimulation after MI with a markedly reduced incidence of ventricular tachycardia. In contrast, activation of Piezo1 in mouse myocardium increased the electrical instability as indicated by prolonged QT interval and sagging ST segment. Mechanistically, Piezo1 impaired intracellular calcium cycling dynamics by mediating the intracellular Ca2+ overload and increasing the activation of Ca2+-modulated signaling, CaMKII, and calpain, which led to the enhancement of phosphorylation of RyR2 and further increment of Ca2+ leaking, finally provoking cardiac arrhythmias. Furthermore, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Piezo1 activation remarkably triggered cellular arrhythmogenic remodeling by significantly shortening the duration of the action potential, inducing early afterdepolarization, and enhancing triggered activity.This study uncovered a proarrhythmic role of Piezo1 during cardiac remodeling, which is achieved by regulating Ca2+ handling, implying a promising therapeutic target in sudden cardiac death and heart failure.

BackgroundFunctional vitamin B12 deficiency is common in cardiovascular diseases (CVDs), such as heart failure and myocardial infarction. Methylmalonic acid (MMA) is a specific and sensitive marker of vitamin B12 deficiency. However, there are scarce data in regard to the relationship between MMA and CVDs.Materials and methodsIn this cross-sectional study, we analyzed data of 5,313 adult participants of the National Health and Nutrition Examination Survey (NHANES) 2013–2014. Associations between MMA and other variables were assessed with linear regression models. Univariable and multivariable logistic regression models were employed to explore the association between MMA and CVDs.ResultsThe weighted prevalence of CVDs was 8.8% in the general population of the USA. Higher MMA levels were found in participants with CVDs (p < 0.001). Linear regression models revealed positive associations between serum MMA level and age (p < 0.001), glycohemoglobin (p = 0.023), fasting glucose (p = 0.044), mean cell volume (p = 0.038), and hypertension (p = 0.003). In the multivariable logistic model adjusting for age, gender, ethnicity, smoking, hypertension, glycohemoglobin, body mass index (BMI), low-density lipoprotein-cholesterol (LDL-C), renal dysfunction and vitamin B12, serum MMA (adjusted odds ratio, 3.08; 95% confidence interval: 1.63–5.81, p = 0.002, per ln nmol/L increment) was associated with CVDs.ConclusionOur study demonstrated that elevated serum MMA levels were independently associated with the presence of CVDs and may be used to predict the occurrence of CVDs.

Migratory locusts shift between aggregating together during gregarious phases and living individually during solitary phases. Here, the authors find that the D1-like dopamine receptor regulates the olfactory attraction underlying this behavioral switch via microRNA-9a and adenylyl cyclase.

Cardiac calcification is a crucial but underrecognized pathological process, greatly increasing the risk of cardiovascular diseases. Little is known about how cardiac fibroblasts, as a central mediator, facilitate abnormal mineralization. Erythropoietin-producing hepatoma interactor B2 (EphrinB2), previously identified as an angiogenic regulator, is involved in fibroblast activation, while its role in the osteogenic differentiation of cardiac fibroblasts is unknown. Bioinformatics analysis was conducted to characterize the expression of the Ephrin family in human calcified aortic valves and calcific mouse hearts. The effects of EphrinB2 on cardiac fibroblasts to adopt osteogenic fate was determined by gain- and loss-of-function. EphrinB2 mRNA level was downregulated in calcified aortic valves and mouse hearts. Knockdown of EphrinB2 attenuated mineral deposits in adult cardiac fibroblasts, whereas overexpression of EphrinB2 promoted their osteogenic differentiation. RNA sequencing data implied that Ca2+-related S100/receptor for advanced glycation end products (RAGE) signaling may mediate EphrinB2-induced mineralization in cardiac fibroblasts. Moreover, L-type calcium channel blockers inhibited osteogenic differentiation of cardiac fibroblasts, implying a critical role in Ca2+ influx. In conclusion, our data illustrated an unrecognized role of EphrinB2, which functions as a novel osteogenic regulator in the heart through Ca2+ signaling and could be a potential therapeutic target in cardiovascular calcification. [ABSTRACT FROM AUTHOR]

[Figure: see text]. [ABSTRACT FROM AUTHOR]

Background: Valvular heart disease (VHD) is expected to cause an increase in public-health problems in the coming years, especially in elderly populations. We aim to estimate the incidence, mortality, and burden of VHD, by age, from 1990 to 2017 in 195 countries and territories.Methods: We estimated the incidence, mortality, and burden of VHD based on the Global Burden of Disease Study 2017. All metrics are presented with their 95% uncertainty intervals (UIs). The Socio-demographic Index was used to identify whether developmental status correlates with health outcomes.Results: The global incidence of rheumatic heart disease (RHD) decreased by 8.67% between 1990 and 2017, while that of non-rheumatic VHD (NRVHD) increased by 45.10%. There was a 54.00% decrease in age-standardized death rate (ASDR) for RHD, but a small and non-significant decrease (-3.00%) in the ASDR for NRVHD. The global age-standardized disability-adjusted life years (DALY) rate of RHD decreased by 53.52%, while there was a 12.62% reduction in the age-standardized DALY rate of NRVHD.Conclusions: The burden from different VHDs demonstrated a diverse change at a global level between 1990 and 2017. Although RHD burden has an obvious means of mitigation, a substantially high incidence of NRVHD was observed over this time period, especially in the elderly, which may lead to high health care costs and signify the potential for even higher costs in the future. [ABSTRACT FROM AUTHOR]