Vericiguat reduces electrical and structural remodeling in a rabbit model of atrial fibrillation.

Purpose: The molecular etiology of atrial fibrillation (AF) and its treatment are poorly understood. AF involves both electrical and structural features. Vericiguat can ameliorate cardiac remodeling in heart failure. The effects of vericiguat on AF, however, are unclear. Here, the actions of vericiguat on atrial structural and electrical remodeling in AF and its possible mechanisms were investigated. Methods and Results: Thirty-six rabbits were randomly allocated to four groups, namely, sham, RAP (pacing with 600 beats/min over three weeks), vericiguat-treated (three weeks' pacing plus daily oral dose of 1.5 mg/kg of vericiguat), and vericiguat-treated only. HL-1 cells received rapid pacing with or without vericiguat. Parameters including electrophysiology, echocardiography, histology, Ca2+ levels, and ICaL density, as well as levels of TRPC6, CaN, NFAT4, p-NFAT4, Cav1.2, collagen I, collagen III, and ST2 were measured. Significant changes of above proteins expression level, circulating biochemical indices, Ca2+ concentrations, and ICaL density in both animals and cell models, these effects were significantly restored by vericiguat. Vericiguat also reversed the enlarged atrium and significantly reduced myocardial fibrosis, together with preventing reduced atrial effective refractory periods (AERPs) and AF induction rate. Conclusion: Vericiguat thus ameliorated AF-associated structural and electrical remodeling. These findings suggest the potential of vericiguat for treating AF.

Effects of Sacubitril/Valsartan on the Expression of CaMKII/Cav1.2 in Atrial Fibrillation Stimulation Rabbit Model.

Methods: Overall, 18 rabbits were randomly divided into control, pacing (600 beats/min), and pacing+sac/val groups. The rabbits in the pacing+sac/val cohort received oral sac/val (10 mg/kg twice daily) across the 21-day investigation period. After three weeks, the atrial effective refractory period (AERP) and AF induction rate were compared. HL-1 cultures were exposed to fast pacing (24 h) with and without LBQ657 (active sacubitril form)/valsartan. Western blots were used for detecting Cav1.2 and CaMKII expression within atrial muscles of the rabbits and HL-1 cultures of AF model. Results: In comparison to the sham cohort, the AF induction rate was markedly increased together with AERP reduction within pacing cohort. Such changes were markedly rescued through sac/val treatment in pacing+sac/val cohort. The proteomic expression profiles of CaMKII and Cav1.2 showed that the CaMKII expression was markedly upregulated, while Cav1.2 expression was downregulated in the pacing cohort. Importantly, these effects were absent in pacing+sac/val cohort. Conclusion: Results of this study show that sac/val treatment regulates the expression of CaMKII/Cav1.2 and could alter this pathway in atrial rapid electrical stimulation models. Therefore, this investigation could contribute to a novel strategy in AF therapeutics in clinical settings.

Detection of circRNA Biomarker for Acute Myocardial Infarction Based on System Biological Analysis of RNA Expression.

Acute myocardial infarction (AMI) is myocardial necrosis caused by the persistent interruption of myocardial blood supply, which has high incidence rate and high mortality in middle-aged and elderly people in the worldwide. Biomarkers play an important role in the early diagnosis and treatment of AMI. Recently, more and more researches confirmed that circRNA may be a potential diagnostic biomarker and therapeutic target for cardiovascular diseases. In this paper, a series of biological analyses were performed to find new effective circRNA biomarkers for AMI. Firstly, the expression levels of circRNAs in blood samples of patients with AMI and those with mild coronary stenosis were compared to reveal circRNAs which were involved in AMI. Then, circRNAs which were significant expressed abnormally in the blood samples of patients with AMI were selected from those circRNAs. Next, a ceRNA network was constructed based on interactions of circRNA, miRNA and mRNA through biological analyses to detect crucial circRNA associated with AMI. Finally, one circRNA was selected as candidate biomarker for AMI. To validate effectivity and efficiency of the candidate biomarker, fluorescence in situ hybridization, hypoxia model of human cardiomyocytes, and knockdown and overexpression analyses were performed on candidate circRNA biomarker. In conclusion, experimental results demonstrated that the candidate circRNA was an effective biomarker for diagnosis and therapy of AMI.

Hydroxychloroquine use and progression or prognosis of COVID-19: a systematic review and meta-analysis.

Hydroxychloroquine (HCQ) has been implicated in antiviral activity in vitro against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there is still controversy about whether HCQ should be used for coronavirus disease 2019 (COVID-19) patients due to the conflicting results in different clinical trials. To systematically assess the benefits and harms of HCQ for the treatment of COVID-19. Data sources were systematically searched from Pubmed, Biorxiv, ChiCTR, Clinicalrials.gov , and the Cochrane library of RCTs for studies published from inception to June 1, 2020, to obtain any possible inclusion. This meta-analysis of inclusion criteria was directed on the basis of the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P). Pooled studies by the title and abstract were screened and removed in the light of meta-analysis by two reviewers. Seven studies involving 851 participants with COVID-19 were eligible for analysis. There was no significant difference in RT-PCR negative conversion between HCQ group and standard treatment (ST) group (RR = 1.11, 95% CI = 0.77-1.59, P = 0.591). The rate of exacerbated pneumonia on chest CT in HCQ group was lower than that in ST group (RR = 0.44, 95% CI = 0.20-0.94, P = 0.035). There was no statistical difference in progressed illness between the HCQ group and the ST group (RR = 0.66, 95% CI = 0.18-2.43, P = 0.530). Death (RR = 1.92, 95% CI = 1.26-2.93, P = 0.003) was distinctly different in HCQ group compared with ST group in the treatment of COVID-19. Our meta-analysis demonstrated that there was no robust evidence to support prescribing HCQ as a treatment for COVID-19.

Sacubitril/valsartan attenuates atrial electrical and structural remodelling in a rabbit model of atrial fibrillation.

Atrial structural and electrical remodelling play important roles in atrial fibrillation (AF). Sacubitril/valsartan attenuates cardiac remodelling in heart failure. However, the effect of sacubitril/valsartan on AF is unclear. The aim of this study was to evaluate the effect of sacubitril/valsartan on atrial electrical and structural remodelling in AF and investigate the underlying mechanism of action. Thirty-three rabbits were randomized into sham, RAP, and sac/val groups. HL-1 cells were subjected to control treatment or rapid pacing with or without LBQ657 and valsartan. Echocardiography, atrial electrophysiology, and histological examination were performed. The concentration of Ca2+ and expression levels of calcineurin, NFAT, p-NFAT, Cav1.2, collagen Ⅰ and Ⅲ, ANP, BNP, CNP, NT-proBNP, and ST2 in HL-1 cells, and IcaL in left atrial cells, were determined. We observed that compared to that in the sham group, the atrium and right ventricle were enlarged, myocardial fibrosis was markedly higher, AF inducibility was significantly elevated, and atrial effective refractory periods were shortened in the RAP group. These effects were significantly reversed by sacubitril/valsartan. Compared to that in the sham group, collagen Ⅰ and Ⅲ, NT-proBNP, ST2, calcineurin, and NFAT were significantly up-regulated, while p-NFAT and Cav1.2 were down-regulated in the RAP group, and sacubitril/valsartan inhibited these changes. Ca2+ concentration increased and ICaL density decreased in in vivo and in vitro AF models, reversed by sacubitril/valsartan. Sacubitril/valsartan attenuates atrial electrical remodelling and ameliorates structure remodelling in AF. This study paves the way for the possibility of clinical use of sacubitril/valsartan in AF patients.

Chronic B-Type Natriuretic Peptide Therapy Prevents Atrial Electrical Remodeling in a Rabbit Model of Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is an important and growing clinical problem. Current pharmacological treatments are unsatisfactory. Electrical remodeling has been identified as one of the principal pathophysiological mechanisms that promote AF, but there are no effective therapies to prevent or correct electrical remodeling in patients with AF. In AF, cardiac production and circulating levels of B-type natriuretic peptide (BNP) are increased. However, its functional significance in AF remains to be determined. We assessed the hypotheses that chronic BNP treatment may prevent the altered electrophysiology in AF, and preventing AF-induced activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) may play a role. METHODS AND RESULTS: Forty-four rabbits were randomly divided into sham, rapid atrial pacing (RAP at 600 beats/min for 3 weeks), RAP/BNP, and sham/BNP groups. Rabbits in the RAP/BNP and sham/BNP groups received subcutaneous BNP (20 µg/kg twice daily) during the 3-week study period. HL-1 cells were subjected to rapid field stimulation for 24 hours in the presence or absence of BNP, KN-93 (a CaMKII inhibitor), or KN-92 (a nonactive analog of KN-93). We compared atrial electrical remodeling-related alterations in the ion channel/function/expression of these animals. We found that only in the RAP group, AF inducibility was significantly increased, atrial effective refractory periods and action potential duration were reduced, and the density of ICa, L and Ito decreased, while IK1 increased. The changes in the expressions of Cav1.2, Kv4.3, and Kir2.1 and currents showed a similar trend. In addition, in the RAP group, the activation of CaMKIIδ and phosphorylation of ryanodine receptor 2 and phospholamban significantly increased. Importantly, these changes were prevented in the RAP/BNP group, which were further validated by in vitro studies. CONCLUSIONS: Chronic BNP therapy prevents atrial electrical remodeling in AF. Inhibition of CaMKII activation plays an important role to its anti-AF efficacy in this model.