Atrial Fibrillation ; metabolism ; Connexin 43 ; metabolism ; Humans ; Oxidative Stress

Atrial fibrillation (AF) is the most common sustained dysrhythmia in clinical practice. The bulk of evidence suggests that inflammatory processes, oxidative stress and matrix metalloproteinase are associated with development of AF. However, these agents may be involved in high mobility group box 1 protein (HMGB1). We hypothesized that HMGB1 may be a possible pathogenic link to AF. A growing body of evidence supports these hypotheses. First, the level of serum HMGB1 is significantly increased in patients with AF including paroxysmal and persistent AF. Second, HMGB1 has been identified as a new pro-inflammatory cytokine in cardiovascular diseases, along with tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C-reactive protein, and there is cross-talk between HMGB1 and inflammatory cytokines. Third, oxidative stress is involved in the release of the pro-inflammatory cytokine, HMGB1, indicating there is cross-talk between oxidative stress and inflammation, and oxidative stress may reinforce the effect of inflammation on the pathogenesis of AF and inflammation may play a more important role in the pathogenesis of AF. Fourth, HMGB1 can promote matrix metalloproteinase-9 upregulation and activation. Fifth, HMGB1 receptors (receptor for advanced glycation end products, Toll-like receptor-2,4) may mediate the atrial structural remodeling or be up-regulated in patients with non-valvular AF. These results suggest that HMGB1 may participate in the pathogenesis of AF and provide a potential target for pharmacological interruption of AF.
Atrial Fibrillation ; metabolism ; HMGB1 Protein ; metabolism ; Humans ; Metalloendopeptidases ; metabolism ; Oxidative Stress ; physiology

OBJECTIVETo investigate the mRNA and protein expression of mineralocorticoid receptor (MR) in patients with atrial fibrillation.

METHODSTwenty-five patients with rheumatic heart valve disease, 12 in sinus rhythm and 13 in chronic atrial fibrillation (>or= 6 months), underwent transthoracic echocardiography and right and left atrial lateral wall tissue samples were obtained from these patients during mitral/aortic valve replacement operation. Realtime quantitative PCR and Western blot were used to determine the mRNA and protein expression of MR in atria specimens. The distribution of MR in human atria was analyzed by specific immunohistochemical staining.

RESULTSThe left atrial diameters increased markedly in atrial fibrillation group compared with that in sinus rhythm group (P<0.01). And the results showed that the level of mRNA and protein of MR were increased significantly in atrial fibrillation group compared with those in sinus rhythm group (P<0.01 or 0.05), whereas the expression of mRNA and protein of MR were found to be no difference between left atria and right atria both in fibrillation and sinus groups (all P>0.05). The special immunohistochemical staining demonstrated that MR was abundant in the human atrial myocardium and MRs were located mainly in the cytoplasm of atrial cells, which were more evident in atrial fibrillation group than those in sinus rhythm group.

CONCLUSIONThese findings suggested that MRs were upregulated in atrial fibrillation and aldosterone antagonists may be effective in treating atrial fibrillation.

Adult ; Atrial Fibrillation ; metabolism ; Humans ; Male ; Middle Aged ; Myocardium ; metabolism ; RNA, Messenger ; genetics ; Receptors, Mineralocorticoid ; metabolism

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

Animals ; Atrial Fibrillation ; physiopathology ; Atrial Remodeling ; physiology ; Calcium ; metabolism ; Humans ; Inflammation ; etiology ; Ion Channels ; physiology ; MicroRNAs ; physiology ; Oxidative Stress

OBJECTIVETo study the relation of the structural remodeling processes and activation of calpain I.

METHODSFifteen dogs were randomly divided into three groups. The dogs in pacing group (n=5) and inhibitor group (n=5) were subjected to 3 weeks of rapid atrial pacing at 600 beats/min, control dogs (n=5) were in sham-operated group. The dogs in inhibitor group were administered intravenous N-Acetyl-Leu-Leu-Met (ALLM), a calpain inhibitor, and in pacing group and sham-operated group were administered intravenous DMSO. The activity of calpain I was measured by hydrolyzing Suc-Leu-Leu-Val-Tyr-7-amino-4-methyl-coumarin. The ultrastructure of atrium was examined by light and electron microscopy. TnT expression was assessed by Western blot. Echocardiography examination was performed in all the three groups.

RESULTSCalpain I activity was significantly increased in pacing group (2.3-fold, P<0.01), and decreased in inhibitor group (1.1-fold, P>0.05), compared to sham-operated group respectively. The percentages of myolysis were (76.7 +/- 5.9)% and (20.8 +/- 8.1)% in pacing group and inhibitor group respectively (P<0.01). TnT expression decreased in the rapid pacing-induced persistent atrial fibrillation, and these effects were inhibited by calpain I inhibitor ALLM. The area and volume of left atrium tended to increase after 3 weeks ALLM treatment in inhibitor group, but the change was not as prominent as in pacing group (P<0.05).

CONCLUSIONSALLM can decrease calpain I activity, and prevent canine atrial cardiomyocyte structural remodeling during atrial fibrillation. This study provided a capacity of atrial cardiomyocyte protection.

Animals ; Atrial Fibrillation ; metabolism ; physiopathology ; Atrial Function, Left ; Calpain ; antagonists & inhibitors ; metabolism ; Cardiac Pacing, Artificial ; Disease Models, Animal ; Dogs ; Heart Atria ; ultrastructure ; Myocardium ; metabolism ; Troponin T ; metabolism

OBJECTIVEElectrical and structural remodeling are of importance for the occurrence and maintenance of atrial fibrillation. We observed association between atrial connexin protein expression and fibrosis in a canine model of prolonged rapid atrial pacing.

METHODS"J"-type electrodes were placed in the right atrial appendage under the guidance of X-ray in 16 dogs, Animals in model group (n = 8) received fast pacing (400 beats/min) for 10 weeks while animals in control group (n = 8) maintained at sinus rhythm. Limb-lead ECGs were recorded at 2, 4, 6, 8 weeks respectively. Burst stimulation was applied to induce atrial fibrillation in all animals after 10 weeks, animals were sacrificed thereafter and the left atrial tissues were taken for myocardial collagen measurement (Masson staining) and myocardial ultrastructure examination and detection of protein expression of connexin (Cx) 40 and 45 (immune staining). Procollagen type III N-terminal peptide and type IV collagen in serum were also detected by radioimmunoassay.

RESULTSTwo dogs died in model group due to atrial rupture induced cardiac tamponade or lung emboli. Spontaneously atrial fibrillation was not observed in all animals, but two dogs developed atrial flutter and atrial premature beats. Atrial fibrillation was induced by burst stimulation in 4 out of 6 dogs in model group and in none of the dogs in control group. Atrial myocardial collagen volume fraction was significantly increased in model group compared with the control group (P < 0.05). Ultrastructure examination in atrial tissue evidenced disorder, fracture, collagen fiber proliferation, mitochondrial swelling, blurred cristae, and intercalated disc distortion, expansion, part of gap junction disappears in model group. The serum levels of procollagen type III N-terminal peptide and type IV collagen in model group were significantly higher than in the control group (P < 0.05). The protein expression of Cx 40 in atrial myocardium in model group was significantly higher than in control group (P < 0.05), while Cx 45 protein expression was similar between two groups (P > 0.05). The left atrial CVF was positively correlated with Cx 40 (r = 0.671, P < 0.01).

CONCLUSIONIncreased myocardial fibrosis is positively correlated with upregulation of myocardial Cx 40 protein expression in left atrium in rapid atrial paced canine.

Animals ; Atrial Fibrillation ; metabolism ; pathology ; Cardiac Pacing, Artificial ; Connexins ; metabolism ; Disease Models, Animal ; Dogs ; Fibrosis ; Heart Atria ; Myocardium ; metabolism ; pathology

OBJECTIVETo investigate the effects of perindopril and spirolactone on plasma aldosterone (Ald) and left atrial remodeling and function in a canine model of atrial fibrillation (AF).

METHODSAdult dogs were randomly assigned to receive normal diet (group A), perindopril (group B, 1 mgxkg(-1)xd(-1)) and spironolactone (group C, 10 mgxkg(-1)xd(-1), n = 6 each) and rapid paced (500 beats/min) for 8 weeks. Plasma Ald levels as well as atrial dimension and function at baseline and at 4 and 8 weeks after pacing were measured by RIA and echocardiography, respectively. Incidence of maintained AF and AF duration were recorded when pacing was stopped after 8 weeks of pacing. Left and right atrial tissues were collected for measurements of tissue Ald levels and fibrosis.

RESULTSPlasma Ald was similar among groups at baseline (P > 0.05) and significantly increased post 4 and 8 weeks pacing in group A (P < 0.05) while remained unchanged post pacing in group B and C (P > 0.05) compared to respective baseline level. Atrial Ald was significantly lower in group B and C compared that in group A post 8 weeks pacing (P < 0.05). Left atrial dimension, end-systolic and end-diastolic volume were significantly increased while left atrial ejection fraction (LAEF) was significantly reduced post pacing in group A (all P < 0.05 vs. baseline) and thses changes were significantly attenuated in group B and C (P < 0.05 vs. group A). Incidence of maintained AF and AF duration post pacing as well as interstitial collagen volume fraction were significantly lower in group B and C compared those in group A (P < 0.05).

CONCLUSIONIncreased Ald might be an important pathogenesis for AF formation and progression, spironolactone and perindopril could attenuate atrial remodeling and improve atrial function by reducing plasma and tissue Ald levels in this model.

Aldosterone ; metabolism ; Animals ; Atrial Fibrillation ; metabolism ; pathology ; physiopathology ; Atrial Function ; Disease Models, Animal ; Dogs ; Male ; Mineralocorticoid Receptor Antagonists ; pharmacology ; Perindopril ; pharmacology ; Spironolactone ; pharmacology

OBJECTIVETo observe the collagen spatial distribution, collagen volume fraction (CVF) and Cx40, Cx43mRNA expressions in rapid atrial pacing dogs post vagal denervation by removing fat pad located between the medial superior vena cava and aortic root (SVC-Ao fat pad).

METHODSTwenty-four dogs were randomly divided into unpaced sham operation group (S group, n = 8), Keeping SVC-Ao fat pad group (K group, n = 8) and Removing SVC-Ao fat pad group (R group, SVC-Ao fat pad was removed by surgical excision before pacing, n = 8). K and R groups were paced for six weeks. Six weeks later, all dogs were sacrificed, left atrium (LA), right atrium (RA), left atrial appendage (LAA), right atrial appendage (RAA) and atrial septum (AS) were collected and stained with HE or Masson Trichrome or frozen in liquid nitrogen for quantifying the expression of Cx40, Cx43 mRNA by Real-time quantitative Reverse Transcription Polymerase Chain Reaction (RT-PCR).

RESULTSSpatial distribution of collagen fibers as well as CVF between S and R group were similar (all P > 0.05). CVF was significantly higher in K group compared to R group, especially at LAA and AS locations (all P < 0.05). Cx40mRNA expression in K group was significantly decreased in LA, RA, and significantly increased in LAA, RAA and AS compared those in S group (all P < 0.05), significantly lower in LA and RA while significantly higher in LAA and RAA compared to R group (all P < 0.05). Cx43mRNA expression in K group was significantly reduced in LA, RA, LAA and RAA while significantly increased in AS compared to S group (all P < 0.05), significantly higher in LA, RA, RAA and AS while significantly lower in LAA compared to R group.

CONCLUSIONPacing induced collagen remodeling and modulation on Cx40mRNA and Cx43 mRNA expressions could be partially attenuated by removing SVC-Ao fat pad suggesting vagal denervation plays a key role in the initiation and preservation of atrial fibrillation.

Animals ; Atrial Fibrillation ; metabolism ; pathology ; Cardiac Pacing, Artificial ; Collagen ; metabolism ; Connexin 43 ; metabolism ; Connexins ; metabolism ; Dogs ; Heart Atria ; metabolism ; pathology ; RNA, Messenger ; genetics

OBJECTIVETo study the expressions of L-type calcium channel alpha1c and potassium channel Kv4.3 at early stages of atrial fibrillation in a rapid paced primary cultured atrial myocyte model.

METHODSPrimary rat atrial myocytes were cultured and a rapid paced cell model was established. The atrial cells were divided into five groups with pacing durations within 0 and 24 h. Reverse transcription-polymerase chain reaction and Western blot were applied to detect the messenger ribonucleic acid (mRNA) and proteins of L-type calcium channel alpha1c and potassium channel Kv4.3, respectively.

RESULTSmRNA expression of L-type calcium channel alpha1c reduced after 6 h of rapid pacing and continued to decline as the pacing process. The decrease of L-type calcium channel alpha1c protein was paralleled with mRNA expression and reached the lowest levels at 24 h. Similarly, changes of potassium channel Kv4.3 protein and mRNA were paralleled. Kv4.3 mRNA was not altered within the first 6 h. It was reduced after 12 h. However, longer pacing periods did not further decrease mRNA and protein expression levels of potassium channel Kv4.3.

CONCLUSIONSExpressions of L-type calcium channel alpha1c and potassium channel Kv4.3 were both reduced at different levels in early phase of rapid pacing atrial myocytes. It implicates the occurrence of ion channel remodeling of atrial myocytes, which may serve as molecular mechanism of electrical remodeling in the development of atrial fibrillation.

Animals ; Atrial Fibrillation ; metabolism ; physiopathology ; Calcium Channels, L-Type ; metabolism ; Cardiac Pacing, Artificial ; Cells, Cultured ; Myocytes, Cardiac ; metabolism ; RNA, Messenger ; metabolism ; Rats ; Rats, Wistar ; Shal Potassium Channels ; metabolism