Honokiol Inhibits Atrial Metabolic Remodeling in Atrial Fibrillation Through Sirt3 Pathway.

Background and Purpose: Atrial metabolic remodeling plays a critical role in the pathogenesis of atrial fibrillation (AF). Sirtuin3 (Sirt3) plays an important role in energy homeostasis. However, the effect of Sirt3 agonist Honokiol (HL) on AF is unclear. Therefore, the aim of this study is to determine the effect of HL on atrial metabolic remodeling in AF and to explore possible mechanisms. Experimental Approach: irt3 and glycogen deposition in left atria of AF patients were examined. Twenty-one rabbits were divided into sham, P (pacing for 3 weeks), P + H treatment (honokiol injected with pacing for 3 weeks). The HL-1 cells were subjected to rapid pacing at 5 Hz for 24 h, in the presence or absence of HL and overexpression or siRNA of Sirt3 by transfection. Metabolic factors, circulating metabolites, atrial electrophysiology, ATP level, and glycogens deposition were detected. Acetylated protein and activity of its enzymes were detected. Key Results: Sirt3 was significantly down-regulated in AF patients and rabbit/HL-1cell model, resulting in the abnormal expression of its downstream metabolic key factors, which were significantly restored by HL. Meanwhile, AF induced an increase of the acetylation level in long-chain acyl-CoA dehydrogenase (LCAD), AceCS2 and GDH, following decreasing of activity of it enzymes, resulting in abnormal alterations of metabolites and reducing of ATP, which was inhibited by HL. The Sirt3 could regulate acetylated modification of key metabolic enzymes, and the increase of Sirt3 rescued AF induced atrial metabolic remodeling. Conclusion and Implications: HL inhibited atrial metabolic remodeling in AF via the Sirt3 pathway. The present study may provide a novel therapeutical strategy for 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.

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.

Women Are at a Higher Risk of Chronic Metabolic Diseases Compared to Men With Increasing Body Mass Index in China.

Background: Chronic non-communicable diseases are the major causes of mortality in the world. However, few studies have investigated the association between multi-categories BMI and chronic diseases from perspective of sex stratification. This study aimed to investigate the risk of chronic diseases at different BMI levels, and to further explore whether BMI-health risk associations differ by sex. Methods: In total, 21,134 participants aged 19-65 years (60.4% men) from the Tianjin People's Hospital, Tianjin Union Medical Center-Health Management Center were recruited for this cross-sectional study. Sex-specific percentiles of BMI were calculated and divided into 11 categories according to the 2000 CDC growth charts. Health-related indicators, such as hyperglycemia, hypertension, non-alcoholic fatty liver diseases (NAFLD), hyperuricemia, etc., were used as dependent variables in this study. Statistical differences were tested by unpaired Mann-Whitney U-test and chi-squared test. Logistic regression models were used to examine the associations between BMI and health-related indicators. Results: The risk of hyperglycemia (OR: 1.67, 95%CI: 1.23-2.29), NAFLD (OR: 2.22, 95%CI: 1.74-2.85), hypertriglyceridemia (OR: 1.65, 95%CI: 1.28-2.12), and hyperuricemia (OR: 1.39, 95%CI: 1.12-1.72) in men began to increase significantly when BMI was in the range of 22.59-23.89 kg/m2. However, in women, the risk of hyperglycemia (OR: 3.02, 95%CI: 1.25-8.98) and hyperuricemia (OR: 1.94, 95%CI: 1.26-3.05) began to increase significantly when BMI was in the range of 22.76-23.62 kg/m2, and the risk of NAFLD (OR: 5.48, 95%CI: 2.49-14.47) began to increase significantly when BMI was in the range of 21.08-21.97 kg/m2. Besides, at the same BMI level, the risk of diseases in women were significantly higher than that in men, especially when BMI > 25 kg/m2. Conclusion: In the Chinese population, the risk of chronic diseases in women were significantly higher than that in men at the same BMI level, especially when BMI was >25 kg/m2. In addition, the risk of chronic diseases began to increase significantly when BMI was >21.97 kg/m2 in women and 23.89 kg/m2 in men. The results indicated that women should be more alert to the risk of chronic diseases caused by the increase of BMI than men.

Half-dose ticagrelor versus high-dose clopidogrel in reducing platelet reactivity in acute coronary syndrome patients with high on-clopidogrel platelet reactivity (divide study).

PURPOSE: High on-treatment platelet reactivity (HTPR) after clopidogrel administration in patients with acute coronary syndrome (ACS) has been associated with an increased risk of adverse events. Our previous studies reported that half-dose ticagrelor provides a similar inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation as standard-dose ticagrelor, but half-dose of ticagrelor has not been studied in Chinese ACS patients with HTPR. This study aimed to compare the antiplatelet action of half-dose ticagrelor with high-dose clopidogrel in ACS patients with HTPR. METHODS: In this single-center randomized controlled trial, 80 (of 418 screened, 19.13%) ACS patients with HTPR while on clopidogrel were randomized to either half-dose ticagrelor (90 mg LD, then 45 mg twice daily) or high-dose clopidogrel (150 mg once daily). Platelet function was assessed by thromboelastography (TEG) and light transmission aggregometry (LTA), and adverse events were monitored throughout the study for 30 days. RESULTS: The ADP-induced platelet inhibition rate (IR) as measured by TEG was significantly higher for half-dose ticagrelor compared with high-dose clopidogrel (70.40% [61.10%-91.70%] vs. 44.25% [34.67%-79.07%], p = 0.001). The repeated HTPR rate was dramatically higher for high-dose clopidogrel compared with half-dose ticagrelor (6 of 32, 18.75% vs. 1 of 35, 2.85%; p = 0.04). No patients in either treatment group exhibited a major bleeding event or other adverse events. CONCLUSIONS: In ACS patients with HTPR, half-dose ticagrelor is more effective than high-dose clopidogrel in reducing platelet reactivity (NCT03062462).

Aldosterone stimulation mediates cardiac metabolism remodeling via Sirt1/AMPK signaling in canine model.

Aldosterone (Aldo), a pivotal hormone that is ubiquitously expressed in systemic tissues of mammals, is a crucial factor in the pathogenesis of cardiac disease. Accumulating evidence suggests that disturbances in cell energy metabolism are involved in increasing aldosterone levels. However, the precise mechanism underlying the impact of cardiac metabolic remodeling underlying aldosterone stimulation remains limited. In this work, we evaluated the underlying effect of aldosterone on regulating cardiac metabolism remodeling in a canine model. Fifteen beagle dogs were divided into a control group (n = 5), Aldo group (n = 5), and a group treated with spironolactone (SP), a mineralocorticoid receptor antagonist (n = 5), for 4 weeks. Blood pressure, electrocardiogram and respiratory parameters, H&E, Masson staining, ultrastructural changes, the adenosine triphosphate (ATP) and free fatty acid (FFA) levels of ventricular tissues, the level of mRNA, and the protein expression of key metabolic factors and regulators were assessed. The Sirt1/AMPK signaling pathway was significantly inhibited in the canine model of aldosterone stimulation, resulting in a reduction of the key downstream metabolic factors involved in glucose and fatty acid oxidation. The dysregulation of expression of key factors in glycogen metabolism led to glycogen deposition, an increase in FFA levels, a reduction in ATP levels, apoptosis, inflammatory cell infiltration, and mitochondrial damage in the ventricular myocardium. These effects were significantly restored by spironolactone. Aldosterone stimulation induced cardiac metabolic remodeling in ventricular cardiomyocytes possibly through the Sirt1/AMPK signaling pathway, implying that this pathway may provide a novel therapeutic target for cardiac metabolic remodeling.

(-)-Epicatechin Suppresses Angiotensin II-induced Cardiac Hypertrophy via the Activation of the SP1/SIRT1 Signaling Pathway.

BACKGROUND/AIMS: Flavonol (-)-epicatechin (EPI) is present in high amounts in cocoa and tea products, and has been shown to exert beneficial effects on the cardiovascular system. However, the precise mechanism of EPI on cardiomyocyte hypertrophy has not yet been determined. In this study, we examined whether EPI could inhibit cardiac hypertrophy. METHODS: We utilised cultured neonatal mouse cardiomyocytes and mice for immunofluorescence, immunochemistry, qRT-PCR, and western blot analyses. RESULTS: 1µM EPI significantly inhibited 1µM angiotensin II (Ang II)-induced increase of cardiomyocyte size, as well as the mRNA and protein levels of ANP, BNP and ß-MHC in vitro. The effects of EPI were accompanied with an up-regulation of SP1 and SIRT1, and were abolished by SP1 inhibition. Up-regulation of SP1 could block Ang II-induced increase in cardiomyocyte size, as well as the mRNA and protein levels of ANP, BNP and ß-MHC, and increase the protein levels of SIRT1 in vitro. Moreover, 1 mg/kg body weight/day EPI significantly inhibited mouse cardiac hypertrophy induced by Ang II, which could be eliminated by SP1 inhibition in vivo. CONCLUSION: Our data indicated that EPI inhibited AngII-induced cardiac hypertrophy by activating the SP1/SIRT1 signaling pathway.

Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR-α/sirtuin 1/PGC-1α pathway.

BACKGROUND AND PURPOSE: Atrial metabolic remodelling is critical for the process of atrial fibrillation (AF). The PPAR-α/sirtuin 1 /PPAR co-activator α (PGC-1α) pathway plays an important role in maintaining energy metabolism. However, the effect of the PPAR-α agonist fenofibrate on AF is unclear. Therefore, the aim of this study was to determine the effect of fenofibrate on atrial metabolic remodelling in AF and explore its possible mechanisms of action. EXPERIMENTAL APPROACH: The expression of metabolic proteins was examined in the left atria of AF patients. Thirty-two rabbits were divided into sham, AF (pacing with 600 beats·min(-1) for 1 week), fenofibrate treated (pretreated with fenofibrate before pacing) and fenofibrate alone treated (for 2 weeks) groups. HL-1 cells were subjected to rapid pacing in the presence or absence of fenofibrate, the PPAR-α antagonist GW6471 or sirtuin 1-specific inhibitor EX527. Metabolic factors, circulating biochemical metabolites, atrial electrophysiology, adenine nucleotide levels and accumulation of glycogen and lipid droplets were assessed. KEY RESULTS: The PPAR-α/sirtuin 1/PGC-1α pathway was significantly inhibited in AF patients and in the rabbit/HL-1 cell models, resulting in a reduction of key downstream metabolic factors; this effect was significantly restored by fenofibrate. Fenofibrate prevented the alterations in circulating biochemical metabolites, reduced the level of adenine nucleotides and accumulation of glycogen and lipid droplets, reversed the shortened atrial effective refractory period and increased risk of AF. CONCLUSION AND IMPLICATIONS: Fenofibrate inhibited atrial metabolic remodelling in AF by regulating the PPAR-α/sirtuin 1/PGC-1α pathway. The present study may provide a novel therapeutic strategy for AF.

[Epidemiological study on an outbreak caused by E. coli O157:H7 in Jiangsu province].

OBJECTIVE: To carry out epidemiological study on an outbreak caused by E. coli O157:H7 infection in Jiangsu province in 1999. METHODS: Epidemiological, microbiological and moleculebiological methods were used to find out the source, route of transmission and risk factors. RESULTS: 95 severe O157:H7 infected patients with acute renal failure in 9 counties and districts of 2 municipalities were reported in Jiangsu province, 1999 while 83 of the patients died with a death rate of 87.37%. Most patients were seen in mid or late June. The ratio of male to female was 1 to 1.44 and 88.42% of the patients were over 50 years old. 38 patients occurred in 2000 with 34 deaths. Major factors contributing to the outbreak would include without drinking tap water, eating leftover food, poor sanitary status in kitchen, not washing hands before meal and after bowl movement. 2 strain of O157:H7 was isolated from severe patients and 3 from diarrhea cases. Carrier rate among animals was up to 9.62% and 99.41% of the strains carried toxic gene. Strains isolated from feces of patients and animals belonged to the same colonies. CONCLUSION: This outbreak was severe which caused by O157:H7 and was first seen in China, which was closely related to the high carrier rate of O157:H7 in animals and to the positive rate of high toxic gene of the strains. There were various routes of transmission and the main factors of infection would include poor personal health habits and poor sanitation of the household.

[Surveillance on hemorrhagic fever with renal syndrome in Jiangsu province from 1996 to 2000].

OBJECTIVE: To analyze the incidence rate, animal hosts, and human inapparent infection rate from surveillance data collected in Jiangsu province from 1996 to 2000 and the risk factors of hemorrhagic fever with renal syndrome (HFRS). METHODS: Data on the incidence rate was collected from the whole province to describe the epidemiologic characteristics of HFRS. Data on the density of rats, proportion of rats with virus, index of rats with virus and the human inapparent infection rate were collected in special areas according to the standardised protocol in the project. RESULTS: The incidence rate of HFRS reduced continuously in Jiangsu province, with a 42.17% reduction from 1996 to 2000. The ratio between the incidence rate of autumn-winter peak and spring peak had also reduced. The main host in spring was Rattus norvegicus (with a density of 3.07%), while that in autumn was Apodemus agrarius (with a density of 4.64%). The density of main hosts and mixed species of rats had all reduced during the five years of observation. The proportions of Rattus norvegicus, Apodemus agrarius, Mus musculus with virus were relatively high in spring and autumn. The index of Rattus norvegicus and Mus musculus with virus in spring were 0.025 5 and 0.028 4 respectively, while that of Apodemus agrarius with virus in autumn was 0.030 2. The average human inapparent infection rate was 4.73% in the five years. CONCLUSION: The incidence rate of HFRS in Jiangsu reduced significantly from 1996 to 2000, but the risk factors still widely existed. Suggesting that the surveillance program needs to be carried out steadily in Jiangsu.