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Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. IL-1[beta], a main effector of NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, is a key modulator of conditions associated with inflammation, such as AF and CKD. Circulating IL-1[beta] levels were elevated patients with CKD who had AF (versus patients with CKD in sinus rhythm). Moreover, NLRP3 activity was enhanced in atria of patients with CKD. To elucidate the role of NLRP3/IL- 1[beta] signaling in the pathogenesis of CKD-induced AF, [Nlrp3.sup.-/-] and WT mice were subjected to a 2-stage subtotal nephrectomy protocol to induce CKD. Four weeks after surgery, IL-1[beta] levels in serum and atrial tissue were increased in WT CKD (WT-CKD) mice versus sham-operated WT (WT-sham) mice. The increased susceptibility to pacing-induced AF and the longer AF duration in WT-CKD mice were associated with an abbreviated atrial effective refractory period, enlarged atria, and atrial fibrosis. Genetic inhibition of NLRP3 in [Nlrp3.sup.-/-] mice or neutralizing anti-IL- 1[beta] antibodies effectively reduced IL- 1[beta] levels, normalized left atrial dimensions, and reduced fibrosis and the incidence of AF. These data suggest that CKD creates a substrate for AF development by activating the NLRP3 inflammasome in atria, which is associated with structural and electrical remodeling. Neutralizing IL-1[beta] antibodies may be beneficial in preventing CKD-induced AF., Introduction Atrial fibrillation (AF) is the most commonly diagnosed cardiac arrhythmia, with a high prevalence worldwide (1, 2). AF significantly affects the quality of life, as it is associated with [...]

Using multigenerational, single-cell tracking we explore the earliest events of biofilm formation by Pseudomonas aeruginosa During initial stages of surface engagement (≤20 h), the surface cell population of this microbe comprises overwhelmingly cells that attach poorly (∼95% stay

Calcium (Ca2+) ions are a key second messenger involved in the rhythmic excitation and contraction of cardiomyocytes throughout the heart. Proper function of Ca2+-handling proteins is required for healthy cardiac function, whereas disruption in any of these can cause cardiac arrhythmias. This comprehensive review provides a broad overview of the roles of Ca2+-handling proteins and their regulators in healthy cardiac function and the mechanisms by which mutations in these proteins contribute to inherited arrhythmias. Major Ca2+ channels and Ca2+-sensitive regulatory proteins involved in cardiac excitation–contraction coupling are discussed, with special emphasis on the function of the RyR2 macromolecular complex. Inherited arrhythmia disorders including catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, Brugada syndrome, short QT syndrome, and arrhythmogenic right-ventricular cardiomyopathy are discussed with particular emphasis on subtypes caused by mutations in Ca2+-handling proteins. [ABSTRACT FROM AUTHOR]

Space medicine is key to the human exploration of outer space and pushes the boundaries of science, technology, and medicine. Because of harsh environmental conditions related to microgravity and other factors and hazards in outer space, astronauts and spaceflight participants face unique health and medical challenges, including those related to the heart. In this review, we summarize the literature regarding the effects of spaceflight on cardiac structure and function. We also provide an in-depth review of the literature regarding the effects of microgravity on cardiac calcium handling. Our review can inform future mechanistic and therapeutic studies and is applicable to other physiological states similar to microgravity such as prolonged horizontal bed rest and immobilization. [ABSTRACT FROM AUTHOR]

DNA methylation (DNAm) and microRNAs (miRNAs) have been implicated in a wide-range of human diseases. While often studied in isolation, DNAm and miRNAs are not independent. We analyzed associations of expression of 283 miRNAs with DNAm at >400K CpG sites in whole blood obtained from 3565 individuals and identified 227 CpGs at which differential methylation was associated with the expression of 40 nearby miRNAs (cis-miR-eQTMs) at FDR<0.01, including 91 independent CpG sites at r2 < 0.2. cis-miR-eQTMs were enriched for CpGs in promoter and polycomb-repressed state regions, and 60% were inversely associated with miRNA expression. Bidirectional Mendelian randomization (MR) analysis further identified 58 cis-miR-eQTMCpG-miRNA pairs where DNAm changes appeared to drive miRNA expression changes and opposite directional effects were unlikely. Integration of genetic variants in joint analyses revealed an average partial between cis-miR-eQTM CpGs and miRNAs of 2% after conditioning on site-specific genetic variation, suggesting that DNAm is an important epigenetic regulator of miRNA expression. Finally, two-step MR analysis was performed to identify putatively causal CpGs driving miRNA expression in relation to human complex traits. We found that an imprinted region on 14q32 that was previously identified in relation to age at menarche is enriched with cis-miR-eQTMs. Nine CpGs and three miRNAs at this locus tested causal for age at menarche, reflecting novel epigenetic-driven molecular pathways underlying this complex trait. Our study sheds light on the joint genetic and epigenetic regulation of miRNA expression and provides insights into the relations of miRNAs to their targets and to complex phenotypes. [ABSTRACT FROM AUTHOR]

Genetic variants at SH2B3 are associated with blood pressure and circulating β2M (β-2 microglobulin), a well-characterized kidney filtration biomarker. We hypothesize that circulating β2M is an independent risk predictor of hypertension and may causally contribute to its development. The study sample consisted of 7 065 Framingham Heart Study participants with measurements of plasma β2M. Generalized estimating equations were used to test the association of β2M with prevalent and new-onset hypertension. There were 2 145 (30%) cases of prevalent hypertension at baseline and 886 (21%) cases of incident hypertension during 6 years of follow-up. A 1-SD increase in baseline plasma β2M was associated with a greater risk of prevalent (odds ratio 1.14, 95% CI 1.05-1.24) and new-onset (odds ratio 1.18, 95% CI 1.07-1.32) hypertension. Individuals within the top β2M quartile had a greater risk than the bottom quartile for prevalent (odds ratio 1.29, 95% CI 1.05-1.57) and new-onset (odds ratio 1.59, 95% CI 1.20-2.11) hypertension. These associations remained essentially unchanged in analyses restricted to participants free of albuminuria and chronic kidney disease. Mendelian randomization demonstrated that lower SH2B3 expression is causal for increased circulating β2M levels, and in a hypertensive mouse model, knockout of Sh2b3 increased β 2 M gene expression. In a community-based study of healthy individuals, higher plasma β2M levels are associated with increased risk of prevalent and incident hypertension independent of chronic kidney disease status. Overlapping genetic signals for hypertension and β2M, in conjunction with mouse knockout experiments, suggest that the SH2B3-β2M axis plays a causal role in hypertension. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) of intermediate phenotypes, such as circulating protein or metabolite levels, can identify genetic associations that may be mechanistic in nature. We therefore postulated that identifying plasma protein-associated genetic variants, known as protein quantitative trait loci (pQTLs), that coincide with previously-identified GWAS loci, and conducting Mendelian Randomization (MR) on these protein-trait associations can identify clinically-useful, causal biomarkers of complex disease phenotypes. For proof-of-concept, we identified the soluble receptor for advanced glycation end-products (sRAGE) as a putatively causal biomarker of pulmonary emphysema. The study sample consisted of Framingham Heart Study (FHS) 2nd (n=3281) and 3rd (n=4017) generation participants with plasma sRAGE measurements and phenotypic characterization of pulmonary function including forced expiration volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC. Chronic obstructive pulmonary disease (COPD) was defined as FEV1/FVC < 0.7. and longitudinal outcomes consisted of ΔFEV1, ΔFVC, Δ(FEV1/FVC), and incident COPD. MR causal testing was conducted using all independent sRAGE cis -pQTLs as instrumental variables for plasma sRAGE levels, and percent emphysema as the outcome. Among FHS participants, plasma sRAGE was cross-sectionally associated with FEV1, FVC, and FEV1/FVC, and longitudinally associated with ΔFEV1, ΔFVC, and Δ(FEV1/FVC). MR analyses demonstrated sRAGE to have a protective causal effect on emphysema (β=-0.108, P =4.5E-04). We demonstrate the efficacy of our proteomics-based approach for biomarker discovery and provide evidence that sRAGE is casual for COPD. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. IL-1β, a main effector of NLR family pyrin domain–containing 3 (NLRP3) inflammasome activation, is a key modulator of conditions associated with inflammation, such as AF and CKD. Circulating IL-1β levels were elevated in patients with CKD who had AF (versus patients with CKD in sinus rhythm). Moreover, NLRP3 activity was enhanced in atria of patients with CKD. To elucidate the role of NLRP3/IL-1β signaling in the pathogenesis of CKD-induced AF, Nlrp3–/– and WT mice were subjected to a 2-stage subtotal nephrectomy protocol to induce CKD. Four weeks after surgery, IL-1β levels in serum and atrial tissue were increased in WT CKD (WT-CKD) mice versus sham-operated WT (WT-sham) mice. The increased susceptibility to pacing-induced AF and the longer AF duration in WT-CKD mice were associated with an abbreviated atrial effective refractory period, enlarged atria, and atrial fibrosis. Genetic inhibition of NLRP3 in Nlrp3–/– mice or neutralizing anti–IL-1β antibodies effectively reduced IL-1β levels, normalized left atrial dimensions, and reduced fibrosis and the incidence of AF. These data suggest that CKD creates a substrate for AF development by activating the NLRP3 inflammasome in atria, which is associated with structural and electrical remodeling. Neutralizing IL-1β antibodies may be beneficial in preventing CKD-induced AF. [ABSTRACT FROM AUTHOR]

Background: Coronavirus-2019 (COVID-19) is known to affect the heart and is associated with a pro-inflammatory state. Most studies to date have focused on clinically sick subjects. Here, we report cardiac and proinflammatory biomarkers levels in ambulatory young adults with asymptomatic or mild COVID-19 infection compared to those without infection 4-8 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) testing., Methods: 131 asymptomatic or mildly symptomatic subjects were enrolled following testing for SARS-COV-2. Fifty subjects tested negative, and 81 subjects tested positive. Serum samples were collected for measurement of C-reactive protein, ferritin, interleukin-6, NT-pro-B-type natriuretic peptide, and cardiac troponin 28-55 days after SARS-COV-2 RT-PCR testing., Results: Biomarker levels trended higher in SARS-COV-2-positive vs negative subjects, but differences in biomarker levels or proportion of subjects with elevated biomarkers were not statistically significant with respect to SARS-COV-2 status. Among individuals with ≥ 1 comorbidity, odds of elevated CRP were greater compared to individuals without any comorbidities (odds ratio [OR] = 2.90); this effect size was increased 1.4-fold among SARS-COV-2-positive subjects (OR = 4.03). Similarly, NT-pro-BNP was associated with CVD, with the strongest association in COVID-positive individuals (OR = 16.9)., Conclusions: In a relatively young, healthy adult population, mild COVID-19 infection was associated with mild elevations in cardiac and proinflammatory biomarkers within 4-8 weeks of mild or asymptomatic COVID-19 infection in individuals with preexisting comorbidities, but not among individuals without comorbidities. For the general population of young adults, we did not find evidence of elevation of cardiac or proinflammatory biomarkers 4-8 weeks after COVID-19 infection. Clinical Perspective : This is a characterization of cardiac and proinflammatory biomarkers in ambulatory subjects following asymptomatic or mild COVID-19 infection. Young, ambulatory individuals did not have cardiac and proinflammatory biomarker elevation 4-8 weeks after mild COVID-19 infection. However, COVID-19 infection was associated with biomarker elevations in select individuals with comorbidities. Clinical study number: H-47423., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)