Correction: Role of Caveolin-1 in Atrial Fibrillation as an Anti-Fibrotic Signaling Molecule in Human Atrial Fibroblasts.

[This corrects the article DOI: 10.1371/journal.pone.0085144.].

Serum macrophage migration inhibitory factor levels are associated with angiographically complex coronary lesions in patients with coronary artery disease.

BACKGROUND: Rupture of vulnerable plaque with subsequent thrombus formation has been implicated as the most common pathogenic mechanism responsible for acute coronary syndrome (ACS). Angiographic coronary lesion complexity has been reported to reflect plaque vulnerability. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine and might be involved in the pathophysiology of atherosclerotic plaque destabilization. OBJECTIVE: This study was designed to investigate if serum MIF levels are associated with angiographic coronary lesion complexity in patients with coronary artery disease (CAD). MATERIALS AND METHODS: A total of 232 consecutive CAD patients and 76 controls were recruited. CAD patients were subdivided according to the presence of ACS (n=138) or stable angina pectoris (SAP) (n=98). Coronary lesion morphology was assessed by coronary angiography. Serum MIF levels were measured by an enzyme-linked immunosorbent assay. RESULTS: SAP patients had significantly higher serum MIF levels compared with healthy controls, and ACS patients had significantly higher serum MIF levels compared with SAP patients. In SAP patients, serum MIF levels were independently associated with the presence of complex coronary lesion. In ACS patients, serum MIF levels increased in conjunction with the extent of complex lesions. CONCLUSIONS: Serum MIF levels are a potential biomarker for reflecting the presence and severity of angiographically complex coronary lesion in CAD patients.

Role of group I metabotropic glutamate receptors, mGluR1/mGluR5, in connexin43 phosphorylation and inhibition of gap junctional intercellular communication in H9c2 cardiomyoblast cells.

Group I metabotropic glutamate receptors, mGluR1 and mGluR5, are associated with sympathetic nerve activity. Sympathetic nerve stimulation exerts a crucial effect on modulating phosphorylation status and distribution of connexin43 (Cx43) in rat heart. Hence, mGluR1 and mGluR5 have an indirect effect on regulating the function of gap junction channels, which is affected by the availability of Cx43 protein. Additionally, it has been demonstrated that mGluR1/5 are present in ventricular myocardium in particular intercalated disks where Cx43 is the principal component of ventricular gap junction channels. We, therefore, hypothesized that mGluR1/5 might regulate Cx43 phosphorylation and gap junctional intercellular communication (GJIC) directly, independent of sympathetic nerve stimulation. After documenting the presence of mGluR1 and mGluR5 in H9c2 cardiomyoblast cells, addition of the selective mGluR1/5 agonist (S)-3,5-dihydroxyphenylglycine hydrate (DHPG) induced Cx43 phosphorylation and GJIC inhibition in both concentration- and time-dependent manner. The effects of DHPG were abolished by the mGluR1 antagonist LY367385 and the specific inhibitor of MEK1, PD98059 which also reduced phosphorylation of extracellular-signal-regulated protein kinase 1/2 (ERK1/2); but not by the mGluR5 antagonist 6-methyl-2-(phenylethynyl) pyridine hydrochloride or the selective inhibitor of protein kinase C (PKC). In conclusion, in H9c2 cardiomyoblast cells mGluR1 increases Cx43 phosphorylation level and suppresses GJIC involving ERK1/2 but not PKC.

Effect of pulmonary vein isolation on atrial fibrillation recurrence after ablation of paroxysmal supraventricular tachycardia in patients with high dispersion of atrial refractoriness.

PURPOSE: This study aimed to assess pulmonary vein isolation (PVI) efficacy on atrial fibrillation (AF) recurrence and to determine a predictive dispersion of atrial refractoriness (dERP) value for performing PVI in paroxysmal supraventricular tachycardia (PSVT) patients. METHODS: Of 67 PSVT patients with past AF episodes who underwent accessory pathway (AP) or slow pathway of atrioventricular node ablation, 63 (4 lost to follow-up or death) were assigned into two groups (A and B; 29 and 34 patients, respectively) based on whether they underwent or not subsequent PVI, and all were followed-up up to 3 years. Atrial effective refractory period (AERP) and dERP were measured during the ablation procedure. RESULTS: In receiver operating characteristic (ROC) curve analysis, dERP = 74.5 ms effectively predicted AF recurrence in PSVT patients (p = 0.003). Difference in AF recurrence rate between groups did not reach statistical significance (17.2%, 5/29 vs. 29.4%, 10/34, p = 0.203). AF recurrence rate was lower in patients with dERP >74.5 ms who underwent AP or slow-pathway ablation with vs. without PVI (18.2%, 2/11 vs. 77.8%, 7/9, p = 0.012). CONCLUSIONS: PVI addition after successful AP or slow pathway of atrioventricular node ablation significantly reduced AF recurrence in PSVT patients with high atrial vulnerability (dERP >74.5 ms).

Dynamic alterations of connexin43, matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 during ventricular fibrillation in canine.

The aim of this study is to investigate the dynamic alterations of cardiac connexin 43 (Cx43), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) in the setting of different ventricular fibrillation (VF) duration. In this study, thirty-two dogs were randomly divided into sham control group, 8-min VF group, 12-min VF group, and 30-min VF group. Cx43 and phosphorylated Cx43 (p-Cx43) in tissues were detected by western blot and immunofluorescence analysis. MMP-2 and TIMP-2 were detected by western blot and immunohistochemistry analysis. The results showed that Cx43 levels in three VF groups were significantly decreased compared with sham control group. p-Cx43 levels in 12-min and 30-min VF groups were significantly reduced compared with sham control group. The ratio of p-Cx43/Cx43 was also decreased in VF groups. Compared with sham controls, no significant difference was observed between the sham control group and 8-min VF group in MMP-2 level, but MMP-2 level increased in 12-min and 30-min VF groups. The ratios of MMP-2/TIMP-2 were higher in VF groups, and were correlated with the duration of VF. A remarkable correlation was observed between the ratio of p-Cx43/Cx43 and MMP-2/TIMP-2 (r = -0.93, P < 0.01). In conclusion, the alteration of Cx43 and/or p-Cx43 levels and the imbalance of MMP-2 and TIMP-2 may contribute to the initiation and/or persistence of VF. Maneuvers managed to modulate Cx43 level or normalize the balance of MMP-2/TIMP-2 are promising to ameliorate prognosis of VF.

Role of caveolin-1 in atrial fibrillation as an anti-fibrotic signaling molecule in human atrial fibroblasts.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the general population; yet, the precise mechanisms resulting in AF are not fully understood. Caveolin-1 (Cav-1), the principal structural component of caveolae organelles in cardiac fibroblasts, is involved in several cardiovascular conditions; however, the study on its function in atrium, in particular, in AF, is still lacking. This report examines the hypothesis that Cav-1 confers an anti-AF effect by mediating atrial structural remodeling through its anti-fibrotic action. We evaluated the expression of Cav-1, transforming growth factor-ß1 (TGF-ß1), and fibrosis in atrial specimens of 13 patients with AF and 10 subjects with sinus rhythm, and found that the expression of Cav-1 was significantly downregulated, whereas TGF-ß1 level, collagens I/III contents and atrial fibrosis were markedly increased, in AF. Western blot analysis demonstrated that treatment of human atrial fibroblasts (HAFs) with TGF-ß1 resulted in a concentration- and time-dependent repression of Cav-1. Downregulation of Cav-1 with siRNA increased the TGF-ß1-induced activation of Smad signal pathway and collagens production in HAFs. Furthermore, incubation of HAFs with the peptides derived from Cav-1 to achieve Cav-1 gain-of-function abolished the TGF-ß1-induced production of collagens I/III and decreases of MMP-2/-9 expression. Therefore it was concluded that Cav-1 is an important anti-AF signaling mediator by conferring its anti-fibrotic effects in atrium.

ZP123 reduces energy required for defibrillation by preventing connexin43 remodeling during prolonged ventricular fibrillation in swine.

In ventricular fibrillation, the uncoupling of gap junctions slows conduction velocity and increases action-potential dispersion, which slows and diminishes defibrillation. We studied how the peptide ZP123, a gap-junction enhancer, might lower defibrillation-energy requirements during ventricular fibrillation in live pigs. We randomly assigned 33 pigs into 3 groups: ZP123 (receiving a 1-µg/kg bolus and 10 µg/kg/hr of ZP123), control (receiving saline solution), and sham (undergoing a sham operation). After a 30-min administration of agents, ventricular fibrillation was induced and left untreated for 8 min. Biphasic defibrillation of 50 J was increased by 50-J increments as necessary. Defibrillation-energy requirements were defined as the lowest energy required to achieve defibrillation. Electrocardiographic values were obtained before and after the administration of agents. Western blot and immunofluorescence analyses were performed on ventricular myocardial samples. All but one pig survived. The ZP123 treatment did not alter electrocardiographic variables. In the ZP123 group, the average required defibrillation energy was lower than that in the control group (327.28±269.6 vs 610±192.64 J; P=0.015), and the cumulative percentage of successful defibrillation at upper energy levels was higher (P<0.05). Supraventricular rhythm occurred more often in the ZP123 group than in the control group (72.7% vs 50%, P=0.042). Western-blot and immunofluorescence results showed that ZP123 did not alter the total amount of connexin43 but did prevent its dephosphorylation. We conclude that ZP123 can reduce defibrillation-energy requirements by preventing connexin43 remodeling during prolonged ventricular fibrillation.