Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia seen in clinical settings, which has been associated with substantial rates of mortality and morbidity. However, clinically available drugs have limited efficacy and adverse effects. We aimed to investigate the mechanisms of action of andrographolide (Andr) with respect to AF. We used network pharmacology approaches to investigate the possible therapeutic effect of Andr. To define the role of Andr in AF, HL-1 cells were pro-treated with Andr for 1 h before rapid electronic stimulation (RES) and rabbits were pro-treated for 1 d before rapid atrial pacing (RAP). Apoptosis, myofibril degradation, oxidative stress, and inflammation were determined. RNA sequencing (RNA-seq) was performed to investigate the relevant mechanism. Andr treatment attenuated RAP-induced atrial electrophysiological changes, inflammation, oxidative damage, and apoptosis both in vivo and in vitro. RNA-seq indicated that oxidative phosphorylation played an important role. Transmission electron microscopy and adenosine triphosphate (ATP) content assay respectively validated the morphological and functional changes in mitochondria. The translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the molecular docking suggested that Andr might exert a therapeutic effect by influencing the Keap1-Nrf2 complex. In conclusions, this study revealed that Andr is a potential preventive therapeutic drug toward AF via activating the translocation of Nrf2 to the nucleus and the upregulation of heme oxygenase-1 (HO-1) to promote mitochondrial bioenergetics.
Animals ; Rabbits ; Atrial Fibrillation/metabolism* ; Kelch-Like ECH-Associated Protein 1/metabolism* ; Signal Transduction ; NF-E2-Related Factor 2/pharmacology* ; Molecular Docking Simulation ; Oxidative Stress ; Energy Metabolism ; Mitochondria/metabolism* ; Inflammation/metabolism* ; Heme Oxygenase-1

Atrial Ca²⁺ handling abnormalities, mainly involving the dysfunction of ryanodine receptor (RyR) and sarcoplasmic reticulum Ca²⁺-ATPase (SERCA), play a role in the pathogenesis of atrial fibrillation (AF). Previously, we found that the expression and function of transient receptor potential vanilloid subtype 4 (TRPV4) are upregulated in a sterile pericarditis (SP) rat model of AF, and oral administration of TRPV4 inhibitor GSK2193874 alleviates AF in this animal model. The aim of this study was to investigate whether oral administration of GSK2193874 could alleviate atrial Ca²⁺ handling abnormalities in SP rats. A SP rat model of AF was established by daubing sterile talcum powder on both atria of Sprague-Dawley (SD) rats after a pericardiotomy, to simulate the pathogenesis of postoperative atrial fibrillation (POAF). On the 3rd postoperative day, Ca²⁺ signals of atria were collected in isolated perfused hearts by optical mapping. Ca²⁺ transient duration (CaD), alternan, and the recovery properties of Ca²⁺ transient (CaT) were quantified and analyzed. GSK2193874 treatment reversed the abnormal prolongation of time to peak (determined mainly by RyR activity) and CaD (determined mainly by SERCA activity), as well as the regional heterogeneity of CaD in SP rats. Furthermore, GSK2193874 treatment relieved alternan in SP rats, and reduced its incidence of discordant alternan (DIS-ALT). More importantly, GSK2193874 treatment prevented the reduction of the S2/S1 CaT ratio (determined mainly by RyR refractoriness) in SP rats, and decreased its regional heterogeneity. Taken together, oral administration of TRPV4 inhibitor alleviates Ca²⁺ handling abnormalities in SP rats primarily by blocking the TRPV4-Ca²⁺-RyR pathway, and thus exerts therapeutic effect on POAF.
Administration, Oral ; Animals ; Atrial Fibrillation/etiology* ; Calcium/metabolism* ; Myocytes, Cardiac/metabolism* ; Pericarditis/pathology* ; Rats ; Rats, Sprague-Dawley ; Ryanodine Receptor Calcium Release Channel/pharmacology* ; Sarcoplasmic Reticulum/pathology* ; TRPV Cation Channels

BACKGROUNDShensong Yangxin (SSYX), a traditional Chinese herbal medicine, has long been used clinically to treat arrhythmias in China. However, the mechanism of SSYX on atrial fibrillation (AF) is unknown. In this study, we tested the hypothesis that the effect of SSYX on the progression of paroxysmal AF is correlated with the regulation of autonomic nerve activity.

METHODSEighteen mongrel dogs were randomly divided into control group (n = 6), pacing group (n = 6), and pacing + SSYX group (n = 6). The control group was implanted with pacemakers without pacing; the pacing group was implanted with pacemakers with long-term intermittent atrial pacing; the pacing + SSYX group underwent long-term intermittent atrial pacing and SSYX oral administration.

RESULTSCompared to the pacing group, the parameters of heart rate variability were lower after 8 weeks in the pacing + SSYX group (low-frequency [LF] component: 20.85 ± 3.14 vs. 15.3 ± 1.89 ms 2 , P = 0.004; LF component/high-frequency component: 1.34 ± 0.33 vs. 0.77 ± 0.15, P < 0.001). The atrial effective refractory period (AERP) was shorter and the dispersion of the AERP was higher after 8 weeks in the pacing group, while the changes were suppressed by SSYX intake. The dogs in the pacing group had more episodes and longer durations of AF than that in the pacing + SSYX group. SSYX markedly inhibited the increase in sympathetic nerves and upregulation of tumor necrosis factor-alpha and interleukin-6 expression in the pacing + SSYX group. Furthermore, SSYX suppressed the decrease of acetylcholine and α7 nicotinic acetylcholine receptor protein induced by long-term intermittent atrial pacing.

CONCLUSIONSSSYX substantially prevents atrial electrical remodeling and the progression of AF. These effects of SSYX may have association with regulating the imbalance of autonomic nerve activity and the cholinergic anti-inflammatory pathway.

Acetylcholine ; blood ; Animals ; Atrial Fibrillation ; drug therapy ; metabolism ; Autonomic Pathways ; drug effects ; Blotting, Western ; Dogs ; Drugs, Chinese Herbal ; therapeutic use ; Electrophysiology ; Enzyme-Linked Immunosorbent Assay ; Heart Rate ; drug effects ; Immunohistochemistry ; Interleukin-6 ; blood ; Models, Animal ; Tumor Necrosis Factor-alpha ; blood ; alpha7 Nicotinic Acetylcholine Receptor ; blood

BACKGROUND/AIMS: It is well known that the menopause is related to interference in lipid metabolism, obesity, and a hypercoagulable state. The aim of the present study was to examine the impact of the menopause in middle-aged Korean females with acute myocardial infarction (AMI). METHODS: A total of 1,781 middle-aged females (aged < 65 years) in the Korean Acute Myocardial Infarction registry were enrolled into this study between November 2005 and December 2013. The patients were divided into two groups; the pre-menopause group (≤ 55 years old) and the menopause group (56-64 years old). Major adverse cardiac events (MACE) were analyzed over a one-year follow-up period. RESULTS: The pre-menopause and menopause groups comprised 669 patients (mean age, 49.1 ± 5.6 years) and 1,112 patients (mean age, 60.6 ± 2.6 years), respectively. The incidence of hypertension (42.2% vs. 59.4%, p < 0.001), diabetes mellitus (DM) (27.4% vs. 35.7%, p < 0.001), and dyslipidemia (12.9% vs. 17.7%, p = 0.008) were more frequent in menopausal patients. Additionally, the rates of smoking (20% vs. 12.7%, p < 0.001) and familial history (12% vs. 6.8%, p < 0.001) were higher in the pre-menopause group. The cumulative rates of MACE did not show any differences between the two groups. A history of atrial fibrillation, previous AMI and DM, higher Killip class, and multi-vessel disease were independent risk factors for predicting one-year MACE. CONCLUSIONS: The survival analysis demonstrated that there was no significant difference in MACE rates between the pre-menopause and menopause groups during the one-year follow-up. Therefore, middle-aged pre-menopausal women should be treated more intensively, regardless of whether they are menopausal.
Atrial Fibrillation ; Diabetes Mellitus ; Dyslipidemias ; Female* ; Follow-Up Studies ; Humans ; Hypertension ; Incidence ; Lipid Metabolism ; Menopause ; Myocardial Infarction* ; Obesity ; Premenopause ; Prognosis ; Risk Factors ; Smoke ; Smoking

Vitamin D is a molecule that is actively involved in multiple metabolic pathways. It is mostly known for its implications related to calcium metabolism. It has also been determined that it actively participates in the cardiovascular system, influencing blood pressure, coronary artery disease and other vascular diseases, such as heart failure and atrial fibrillation. Furthermore, it has been established that this vitamin is extensively involved in the regulation of both the renin angiotensin aldosterone system and the immune system. In this review, we present the different vitamin D metabolic pathways associated with the cardiovascular pathophysiology, and we include studies in animal and human models, as well as some of the controversies found in the literature. This review also incorporates an overview of the implications in the molecular biology and public health fields.
Animals ; Atrial Fibrillation ; Blood Pressure ; Calcium ; Cardiovascular Diseases* ; Cardiovascular System ; Coronary Artery Disease ; Heart Failure ; Humans ; Immune System ; Metabolic Networks and Pathways ; Metabolism ; Molecular Biology ; Public Health ; Renin-Angiotensin System ; Vascular Diseases ; Vitamin D* ; Vitamins*

BACKGROUNDCurrent evidence links atrial fibrillation (AF) to the inflammation. Inflammatory indexes such as high-sensitive C-reactive protein (hs-CRP) have been related to the development and persistence of AF. However, the role of inflammation in the atrial electrophysiological remodeling indexed by P-wave dispersion (P d ) remains unclear.

METHODSThe study consisted of 71 patients with lone paroxysmal AF (AF group) and 71 age- and gender-matched controls of paroxysmal supraventricular tachycardia without history of AF (control group). Electrocardiography, P d , hs-CRP, and other clinical characteristics were compared between the two groups.

RESULTSThere was no significant difference between the two groups regarding age, gender, hyperlipidemia, etc. Compared to controls, left atrial diameter (44 ± 7 vs 39 ± 7 mm), P d (49 ± 13 vs 26 ± 8 ms), and hs-CRP (2.17 [1.46-2.89] vs 1.12 [0.74-1.41] mg/L) were increased (P < 0.05), respectively. Linear regression identified hs-CRP as an independent correlation of P d level both in the total population and the AF group (r = 0.464 and 0.313; P < 0.001, respectively). Multiple logistic regression revealed hs-CRP as an independent determinant of AF (odds ratio [OR] =15.430, 95% confidence interval: 6.031-39.476: P <0.001). Further adjusted for P d , both P d and hs-CRP were independent predictors for AF, but the OR for hs-CRP in predicting AF has been attenuated from 15.430 to 6.246.

CONCLUSIONSIn lone AF, P d and plasma hs-CRP concentration are inter-associated and related to AF. The interaction between hs-CRP and AF may be mediated by P d , suggesting an important role of inflammation in the atrial electrophysiological remodeling predisposing to AF.

Aged ; Atrial Fibrillation ; metabolism ; physiopathology ; C-Reactive Protein ; metabolism ; Female ; Humans ; Male ; Middle Aged

PURPOSE: The expression of nerve growth factor-beta (NGF-beta) is related to cardiac nerve sprouting and sympathetic hyper innervation. We investigated the changes of plasma levels of NGF-beta and the relationship to follow-up heart rate variability (HRV) after radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). MATERIALS AND METHODS: This study included 147 patients with AF (117 men, 55.8+/-11.5 years, 106 paroxysmal AF) who underwent RFCA. The plasma levels of NGF-beta were quantified using double sandwich enzyme linked immunosorbent assay method before (NGF-beta(pre)) and 1 hour after RFCA (NGF-beta(post-1hr)). HRV at pre-procedure (HRV(pre)), 3 months (HRV(post-3mo)), and 1 year post-procedure (HRV(post-1yr)) were analyzed and compared with plasma levels of NGF-beta. RESULTS: 1) The plasma levels of NGF-beta significantly increased after RFCA (20.05+/-11.09 pg/mL vs. 29.60+/-19.43 pg/mL, p<0.001). The patients who did not show increased NGF-beta(post-1hr) were older (p=0.023) and had greater left atrial volume index (p=0.028) than those with increased NGF-beta(post-1hr). 2) In patients with NGF-beta(pre) >18 pg/mL, low frequency components (LF)/high-frequency components (HF) (p=0.003) and the number of atrial premature contractions (APCs, p=0.045) in HRV(post-3mo) were significantly higher than those with < or =18 pg/mL. 3) The LF/HF at HRV(post-3mo) was linearly associated with the NGF-beta(pre) (B=4.240, 95% CI 1.114-7.336, p=0.008) and the NGF-beta(post-1hr) (B=7.617, 95% CI 2.106-13.127, p=0.007). 4) Both NGF-beta(pre) (OR=1.159, 95% CI 1.045-1.286, p=0.005) and NGF-beta(post-1hr) (OR=1.098, 95% CI 1.030-1.170, p=0.004) were independent predictors for the increase of LF/HF at HRV(post-3mo). CONCLUSION: AF catheter ablation increases plasma level of NGF-beta, and high plasma levels of NGF-beta(pre) was associated with higher sympathetic nerve activity and higher frequency of APCs in HRV(post-3mo).
Aged ; Atrial Fibrillation/physiopathology/*surgery ; Catheter Ablation/*methods ; Female ; *Heart Rate ; Humans ; Male ; Middle Aged ; Nerve Growth Factor ; Nerve Growth Factors ; Transforming Growth Factor beta/*metabolism ; Treatment Outcome

PURPOSE: Hyperhomocysteinemia has been identified as an independent risk factor in arterial and venous thrombosis. Mutations in genes encoding methylenetetrahydrofolate reductase (MTHFR), involved in the metabolism of homocysteine, may account for reduced enzyme activity and elevated plasma homocysteine levels. In this study, we investigated the interrelation of MTHFR C677T genotype and level of homocysteine in patients with arterial and venous thrombosis. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 146 patients who were diagnosed as having arterial and venous thrombosis. We excluded patients diagnosed with atrial fibrillation. We examined routinely the plasma concentration of total homocysteine level and MTHFR C677T polymorphism for evaluation of thrombotic tendency in all patients. Screening processes of MTHFR C677T polymorphism were performed by real-time polymerase chain reaction. RESULTS: Investigated groups consisted of thrombotic arterial occlusion in 48 patients and venous occlusion in 63 patients. The distribution of the three genotypes was as follows: homozygous normal (CC) genotype in 29 (26.1%), heterozygous (CT) genotype in 57 (51.4%), and homozygous mutant (TT) genotype in 25 (22.5%) patients. There were no significant differences among individuals between each genotype group for baseline characteristics. Plasma concentration of homocysteine in patients with the TT genotype was significantly increased compared to the CC genotype (P<0.05). CONCLUSION: We observed a significant interaction between TT genotypes and homocysteine levels in our results. The results might reflect the complex interaction between candidate genes and external factors responsible for thrombosis.
Atrial Fibrillation ; Genotype ; Homocysteine* ; Humans ; Hyperhomocysteinemia ; Mass Screening ; Medical Records ; Metabolism ; Methylenetetrahydrofolate Reductase (NADPH2)* ; Plasma* ; Real-Time Polymerase Chain Reaction ; Retrospective Studies ; Risk Factors ; Thrombosis ; Venous Thrombosis

A 73-yr-old Korean man with permanent atrial fibrillation visited outpatient clinic with severely increased International Normalized Ratio (INR) values after taking a usual starting dosage of warfarin to prevent thromboembolism. We found out later from his blood tests that he had hyperthyroidism at the time of treatment initiation. His genetic analysis showed CYP2C9*1/*3 and VKORC1+1173TT genotypes. We suspect that both hyperthyroidism and genetic variant would have contributed to his extremely increased INR at the beginning of warfarin therapy. From this case, we learned that pharmacogenetic and thyroid function test might be useful when deciding the starting dosage of warfarin in patients with atrial fibrillation.
Aged ; Anticoagulants/blood/metabolism/therapeutic use ; Aspirin/therapeutic use ; Atrial Fibrillation/*diagnosis ; Chromatography, High Pressure Liquid ; Cytochrome P-450 CYP2C9/*genetics ; Genotype ; Humans ; Male ; Polymorphism, Single Nucleotide ; Tandem Mass Spectrometry ; Thromboembolism/prevention & control ; Thyrotoxicosis/*diagnosis ; Vitamin K Epoxide Reductases/genetics ; Warfarin/*blood/metabolism/therapeutic use

OBJECTIVESK channels are existed in hearts of mouse, rat, and human. Biochemical evidence indicates that SK2 channels are expressed more in atrial than in ventricular tissue. SK channels are highly sensitive to the calcium concentration of the pipette solution. In the present study, performed whole-cell patch clamp was used to detect the calcium sensitivity of small conductance Ca(2+)-activated K+ channels (SK) currents between sinus ryhthm (SR) and auricular fibrillation (AF).

METHODSThe patients who accepted cardiopulmonary bypass were divided into two groups: 21 patients with SR and 8 patients with AF. The enzymatic dissociation method was improved according to the previous research by our lab. The performed whole cell patch-clamp technique was used to record SK2 currents in both SR and AF groups at room temperature.

RESULTSThe SK2 current density was (-2.92 +/- 0.35) pA/pF in SR group (n = 6) vs (-6.83 +/- 0.19) pA/pF in AF group at -130 mV (n = 3, P < 0.05). In SR group, the SK2 current densities in calcium concentration of the pipette solution are (-1.43 +/- 0.33) pA/pF (n = 7), (-2.92 +/- 0.35) pA/pF (n = 6), (-10.11 +/- 2.15) pA/pF (n = 8, P < 0.05); In AF group, the SK2 current densities are (-2.17 +/- 0.40) pA/pF (n = 4), (-6.83 +/- 0.19) pA/pF (n = 3), (-14.47 +/- 2.89 pA/pF) (n = 4, P < 0.05).

CONCLUSIONThe SK2 currents recorded in this experiment are voltage-independent, inwardly rectifying and apamin-sensitive. When the calcium concentration of the pipette solution is 5 x 10(-7) mol/L, SK2 current density in AF group are significantly larger than those in SR group. It suggests that SK currents involve the cardiomyocytes electric remodeling in AF. In AF group, the SK2 currents are more sensitive to free calcium ion. It shows that the increased sensitivity of SK2 currents to the calcium contribute to the occurrence and maintenance of AF.

Atrial Fibrillation ; metabolism ; physiopathology ; Calcium ; metabolism ; Cells, Cultured ; Heart Atria ; metabolism ; Humans ; Membrane Potentials ; physiology ; Myocytes, Cardiac ; metabolism ; Patch-Clamp Techniques ; Potassium Channels, Calcium-Activated ; physiology