Predictors of pacing-induced cardiomyopathy detection and outcomes demonstration after conduction system pacing upgrade on patients with long-term persistent atrial fibrillation.

OBJECTIVE: To identify the predictors of pacing-induced cardiomyopathy (PICM) and illustrate the safety and feasibility of conduction system pacing (CSP) upgrade on patients with long-term persistent atrial fibrillation (AF). METHODS: All patients with long-term persistent AF and normal left ventricular ejection fraction (LVEF) ≥50% were consecutively enrolled from January 2008 to December 2017, and all the patients with atrioventricular block (AVB) and high right ventricular pacing (RVP) percentage of at least 40%. The predictors of PICM were identified, and patients with PICM were followed up for at least 1 year regardless of CSP upgrade. Cardiac performances and lead outcomes were investigated in all patients before and after CSP upgrade. RESULTS: The present study included 139 patients, out of which 37 (26.62%) developed PICM, resulting in a significant decrease in the left ventricular ejection fraction (LVEF) from 56.11 ± 2.56% to 38.10 ± 5.81% (p< .01). The median duration for the development of PICM was 5.43 years. Lower LVEF (≤52.50%), longer paced QRS duration (≥175 ms), and higher RVP percentage (≥96.80%) were identified as independent predictors of PICM. Furthermore, the morbidity of PICM progressively increased with an increased number of predictors. The paced QRS duration (183.90 ± 22.34 ms vs. 136.57 ± 20.71 ms, p < .01), LVEF (39.35 ± 2.71% vs. 47.50 ± 7.43%, p < .01), and left ventricular end-diastolic diameter (LVEDD) (55.53 ± 5.67 mm vs. 53.20 ± 5.78 mm, p = .03) improved significantly on patients accepting CSP upgrade. CSP responses and complete reverse remodeling (LVEF ≥50% and LVEDD < 50 mm) were detected in 80.95% (17/21) and 42.9% (9/21) of patients. The pacing threshold (1.52 ± 0.78 V/0.4 ms vs. 1.27 ± 0.59 V/0.4 ms, p = .16) was stable after follow-up. CONCLUSION: PICM is very common in patients with long-term persistent AF, and CSP upgrade was favorable for better cardiac performance in this patient population.

Brady-arrhythmias in patients with atrial fibrillation and heart failure of reduced ejection fraction: is his-bundle pacing superior to biventricular pacing？.

OBJECTIVE: To investigate the efficacy and safety of His-bundle pacing (HBP) compared with the traditional biventricular pacing (BVP) on patients with brady-arrhythmias, who suffer from permanent atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF). METHODS: All patients with brady-arrhythmias, permanent AF and HFrEF were continuously enrolled from January 2017 to July 2019 and followed up for at least 12 months. The differences in QRS duration (QRSd), New York Heart Association (NYHA) classification, left ventricular ejection fraction (LVEF), tricuspid regurgitation grade, mitral regurgitation grade, left ventricular end-diastolic diameter (LVEDD), and left atrial size were compared. RESULTS: A total of 52 patients were enrolled: 37 patients were with HBP and 15 patients with BVP. There was no electrode dislodged, perforation, infection or thrombosis during the follow-up of 18.12 ± 4.45 months. The success rate for HBP implantation was 88.10%. The capture threshold of his-bundle and the threshold of the left ventricular lead remained stable during follow-up. LVEF increased to higher than 50% in 11 patients with HBP (29.73%). The NYHA classification (both p < .001), LVEF (both p < .001) and LVEDD improved significantly during the follow-up in both groups. NYHA (p = .030), LVEF (p = .013), and LVEDD (p = .003) improved in patients with HBP compared with BVP. CONCLUSION: HBP was safe and more effective in improving the cardiac function and remodeling in patients with brady-arrhythmias, permanent AF and HFrEF compared with BVP.

Serum and salivary ferritin and Hepcidin levels in patients with chronic periodontitis and type 2 diabetes mellitus.

BACKGROUND: Iron disorder and abnormal expression of hepcidin play important roles in many diseases, but it is still unclear in chronic periodontitis (CP) and type 2 diabetes mellitus (T2DM). We aimed to assess ferritin and hepcidin levels in serum and saliva of CP patients with or without T2DM. METHODS: Serum and unstimulated whole saliva samples were collected from 88 participants, who were categorized into 4 groups based on the presence or absence of CP or T2DM. Demographics and general health parameters were recorded. Full-mouth clinical periodontal parameters including probing pocket depth, clinical attachment loss, bleeding index, and plaque index were recorded. Chemiluminescence microparticle immunoassay and enzyme-linked immunosorbent assay were used to detect ferritin and hepcidin concentrations, respectively, in serum and saliva. RESULTS: Serum ferritin and hepcidin levels in the CP and CP with T2DM groups were higher than in the control group (P < 0.05). Serum hepcidin and serum ferritin are linear correlated (P < 0.001). Serum hepcidin/ferritin values in the CP with T2DM group were significantly lower than those in the T2DM and control groups. Moreover, salivary ferritin levels in the CP and T2DM groups were higher than those in the control group (P < 0.05). There was positively correlation between salivary ferritin and serum ferritin (P = 0.017). Hepcidin concentrations were relatively low in saliva. CONCLUSIONS: These results suggest that iron overload and hepcidin inadequacy existed in CP with T2DM patients. Salivary ferritin might provide a reference for body iron load. TRIAL REGISTRATION: ChiCTR-ROC-17012780.

Genetic and Pharmacologic Inhibition of the Chemokine Receptor CXCR2 Prevents Experimental Hypertension and Vascular Dysfunction.

BACKGROUND: The recruitment of leukocytes to the vascular wall is a key step in hypertension development. Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases. However, the role of CXCR2 in hypertension development and the underlying mechanisms remain unknown. METHODS: Angiotensin II (490 ng·kg-1·min-1) or deoxycorticosterone acetate (DOCA) salt-induced mouse hypertensive models in genetic ablation, pharmacologic inhibition of CXCR2, and adoptive bone marrow transfer mice were used to determine the role of CXCR2 in hypertension (measured by radiotelemetry and tail-cuff system), inflammation (verified by flow cytometry and quantitative real-time polymerase chain reaction [PCR] analysis), vascular remodeling (studied by haematoxylin and eosin and Masson's trichrome staining), vascular dysfunction (assessed by aortic ring), and oxidative stress (indicated by nicotinamide adenine dinucleotide phosphate [NADPH] oxidase activity, dihydroethidium staining, and quantitative real-time PCR analysis). Moreover, the blood CXCR2+ cells in normotensive controls and hypertension patients were analyzed by flow cytometry. RESULTS: Angiotensin II significantly upregulated the expression of CXCR2 mRNA and protein and increased the number of CD45+ CXCR2+ cells in mouse aorta (n=8 per group). Selective CXCR2 knockout (CXCR2-/-) or pharmacological inhibition of CXCR2 markedly reduced angiotensin II- or DOCA-salt-induced blood pressure elevation, aortic thickness and collagen deposition, accumulation of proinflammatory cells into the vascular wall, and expression of cytokines (n=8 per group). CXCR2 inhibition also ameliorated angiotensin II-induced vascular dysfunction and reduced vascular superoxide formation, NADPH activity, and expression of NADPH oxidase subunits (n=6 per group). Bone marrow reconstitution of wild-type mice with CXCR2-/- bone marrow cells also significantly abolished angiotensin II-induced responses (n=6 per group). It is important to note that CXCR2 blockade reversed established hypertension induced by angiotensin II or DOCA-salt challenge (n=10 per group). Furthermore, we demonstrated that CXCR2+ proinflammatory cells were higher in hypertensive patients (n=30) compared with normotensive individuals (n=20). CONCLUSIONS: Infiltration of CXCR2+ cells plays a pathogenic role in arterial hypertension and vascular dysfunction. Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat hypertension.

Circulating E3 ligases are novel and sensitive biomarkers for diagnosis of acute myocardial infarction.

Ubiquitin ligase (E3) is a decisive element of the ubiquitin-proteasome system (UPS), which is the main pathway for intracellular protein turnover. Recently, circulating E3 ligases have been increasingly considered as cancer biomarkers. In the present study, we aimed to determine if cardiac-specific E3 ligases in circulation can serve as novel predictors for early diagnosis of acute myocardial infarction (AMI). By screening and verifying their tissue expression patterns with microarray and real-time PCR analysis, six of 261 E3 ligases, including cardiac-specific Rnf207 and cardiac- and muscle-enriched Fbxo32/atrogin-1, Trim54/MuRF3, Trim63/MuRF1, Kbtbd10/KLHL41, Asb11 and Asb2 in mouse heart, were selected for the present study. In the AMI rats, the levels of five E3 ligases including Rnf207, Fbxo32, Trim54, Trim63 and Kbtbd10 in the plasma were significantly increased compared with control animals. Especially, the plasma levels of Rnf207 was markedly increased at 1 h, peaked at 3 h and decreased at 6-24 h after ligation. Further evaluation of E3 ligases in AMI patients confirmed that plasma Rnf207 level increased significantly compared with that in healthy people and patients without AMI, and showed a similar time course to that in AMI rats. Simultaneously, plasma level of cardiac troponin I (cTnI) was measured by ELISA assays. Finally, receiver operating characteristic (ROC) curve analysis indicated that Rnf207 showed a similar sensitivity and specificity to the classic biomarker troponin I for diagnosis of AMI. Increased cardiac-specific E3 ligase Rnf207 in plasma may be a novel and sensitive biomarkers for AMI in humans.

[Long term outcome of atrial fibrillation patients with KCNA5 and NPPA mutations post circumferential pulmonary vein ablation].

OBJECTIVE: The outcome of atrial fibrillation patients with genetic mutations post ablation was not well evaluated. METHODS AND RESULTS: Three atrial fibrillation patients with evidence of mutations in KCNA5 and NPPA post successful circumferential pulmonary vein ablation were included. Mutation in KCNA5 was found in one male patient with paroxysmal atrial fibrillation. He was free of atrial fibrillation post ablation after 46 months follow-up. Mutations in NPPA were found in two male patients with persistent atrial fibrillation and they were free from atrial fibrillation after 64 months and 38 months follow-up post circumferential pulmonary vein ablation, roof line and mitral isthmus line ablation. CONCLUSION: Satisfactory long term results are observed in atrial fibrillation patients with KCNA5 and NPPA mutations post circumferential pulmonary vein ablation.

Left ventricular lead position for cardiac resynchronization: a comprehensive cinegraphic, echocardiographic, clinical, and survival analysis.

AIMS: We sought to determine the clinical and survival outcomes of cardiac resynchronization therapy (CRT) associated with left ventricular (LV) lead location. The lateral left ventricle has been considered the optimal LV lead location for CRT. METHODS AND RESULTS: Left ventricular lead cinegrams taken in 30° right and left anterior oblique views were evaluated in 457 recipients of CRT with a pacemaker or a defibrillator from 1 January 2002 to 31 December 2008 in this retrospective study. Left ventricular lead placement was prioritized at implantation into posterolateral (PL), anterolateral (AL), middle cardiac, and anterointerventricular coronary veins. Using echocardiographic LV 16-segment analysis, we grouped the leads as anterior, AL, PL, and posterior locations. New York Heart Association (NYHA) class and echocardiography were assessed before and after CRT. Clinical and survival outcomes after CRT were compared among the four LV lead locations.  Patient baseline demographic characteristics were similar among these four groups. Improvement in NYHA class was significantly greater in the AL (P= 0.04) and PL (P= 0.03) locations than in the anterior location. There was a tendency for greater improvement in LV ejection fraction among the AL (P= 0.11) and PL (P= 0.08) locations than the anterior location. Kaplan-Meier survival estimate at 4 years varied for location: AL, 72%; anterior, 48%; PL, 62%; and posterior, 72% (P= 0.003). CONCLUSION: Cardiac resynchronization therapy recipients are profiting from all lead positions. However, LV lead placed in the AL and PL positions is more preferential for achieving optimal CRT benefit than leads placed in the anterior position.

[Predictive value of HATCH score on atrial fibrillation recurrence post radiofrequency catheter ablation].

OBJECTIVE: To determine the predictive value of HATCH score on recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA). METHODS: The data of 123 consecutive AF patients (74 paroxysmal and 49 persistent AF) who underwent RFCA between April 2009 and December 2010 in our department were retrospectively analyzed. Of theses patients, 65 (52.9%) patients had HATCH score = 0, 41 (33.3%) patients had HATCH score = 1, and 17 (13.8%) patients had HATCH score ≥ 2 (HATCH = 2 in 11 patients, HATCH = 3 in 5 patients, HATCH = 4 in 1 patient). The recurrence was defined as atrial tachyarrhythmia lasting more than 30 seconds after 3 months post RFCA. The patients were divided into recurrence group and no recurrence group. Relationship between HATCH score and recurrence was observed. RESULTS: There were 43 cases in recurrence group and 80 cases in no recurrence group. After 12 months follow-up, HATCH score was significant higher in recurrence group than in non-recurrence group [(0.91 ± 0.94) score vs. (0.53 ± 0.80) score, P < 0.05]. The ratio of patients with HATCH ≥ 2 in recurrence group was higher than in non-recurrence group [23.3% (10/43) vs. 8.8% (7/80), P < 0.01]. The sensitivity and specificity of HATCH ≥ 2 to define the risk of recurrence was 25.0%, 92.4% respectively. Cumulative non-recurrence rate of patients with HATCH score ≥ 2 was lower than patients with HATCH score = 0 and 1 (P < 0.05). CONCLUSION: Higher HATCH score is associated with increased risk of AF recurrence post RFCA.

[Effects of ventricular demand and dual-chamber pacing models on the long-term clinical outcome and cardiac remodeling in patients with symptomatic bradycardia].

OBJECTIVE: To assess the effects of VVI (ventricular demand) and DDD (dual-chamber) pacing models on cardiac remodeling and the long-term clinical outcome of patients with symptomatic bradycardia. METHODS: All patients with DDD and VVI pacing models at our hospital from January 1991 to January 2003 were retrospectively analyzed. RESULTS: After a follow-up period of over 8 years in DDD and VVI groups (97 ± 27, 107 ± 44 months), left atrial diameter [(45 ± 12) mm vs (39 ± 12) mm, P < 0.01] and left ventricular end-diastolic diameter [(53 ± 11) mm vs (50 ± 9) mm, P = 0.01] in 57 patients with VVI pacing model were markedly enlarged than those at pre-implantation. And tricuspid regurgitation increased (42.4% vs 16.9%, P < 0.05). But in 59 patients with DDD pacing model, except for increased tricuspid regurgitation (42.1% vs 10.5%, P < 0.01), left atrial diameter [(37 ± 5) mm vs. (35 ± 5) mm, P = 0.07] and left ventricular end-diastolic diameter [(47 ± 7) mm vs (47 ± 5) mm, P = 0.32] were not significantly different. Mitral regurgitation significantly increased only in the VVI group (P < 0.01). The increases of left ventricular end-diastolic diameter (P = 0.04), mitral valve (P = 0.02) and tricuspid regurgitation (P < 0.01) were much more pronounced in the VVI group than those in the DDD group. Left ventricular ejection fraction (LVEF) showed no difference with that at pre-implantation (P = 0.11 in DDD group, P = 0.05 in VVI group). But the LVEF value was lower (P = 0.04) while the incidence of thrombosis was higher (P = 0.03) in the VVI group than those in the DDD group at post-implantation. However, the incidence of atrial fibrillation (P = 0.14), hospitalization (P = 0.08) and survival (P = 0.77) showed no significant difference between two groups. CONCLUSION: DDD pacing offers more benefits over VVI pacing through improving cardiac functions and arresting left ventricular remodeling. However, neither groups showed any difference in decreasing mortality rate and hospitalization. Moreover, both pacing modes fail to reverse cardiac electrical and anatomical remodeling. It is imperative to explore more physiological pacing site and rational atrioventricular (AV) interval to improve the prognosis of patients.

[Efficacy of ibutilide for cardioversion of persistent atrial fibrillation during radiofrequency ablation].

OBJECTIVE: The aim of this study was to investigate the efficiency and safety of ibutilide for cardioversion of persistent atrial fibrillation (AF) during radiofrequency ablation. METHODS: Eighteen patients (16 males) with persistent atrial fibrillation were enrolled in this study. All patients underwent circumferential pulmonary vein ablation guided by a Carto three-dimensional mapping system. In addition, linear ablation at the top of the left atrium and the isthmus of mitral valves and complex fractionated atrial electrogram (CAFE) ablation were performed. All patients were still in either atrial fibrillation or atrial flutter after ablation, the patients were treated with 1 mg intravenous ibutilide injection within 10 minutes after unsuccessful ablation. Intravenous injection was stopped in case of sinus rhythm (SR) restoration or occurrence of severe adverse reactions such as ventricular tachycardia. Cardioversion rate within 30 min and adverse reactions within 4 h were observed. Patients were divided into either conversion group or non-conversion group according to whether AF was converted to sinus rhythm within 30 minutes after injection. RESULTS: Eleven patients (61.11%) converted to SR after ibutilide injection. There were no significant differences in gender, age, body mass index, left atrium and left ventricular function between conversion group and non-conversion groups. The average conversion time was (13.80 ± 7.64) min, left atrium scar area ratio was significantly larger in non-conversion group (12.40 ± 11.03)% than in conversion group (5.12 ± 3.83)%, P < 0.05. Ibutilide significantly prolonged the average wavelength of the AF wave (171.8 ± 29.5) ms vs. (242.0 ± 40.0) ms at baseline, P < 0.01. The QT interval at 30 min after ibutilide injection (0.39 ± 0.21) s was significantly longer than before injection (0.51 ± 0.08) s, P < 0.05. There was no serious arrhythmias or other adverse reactions post ibutilide injection. CONCLUSIONS: Ibutilide is highly effective and safe agent for cardioversion in patients underwent unsuccessful ablation. Left atrium scar area ratio is an important determinant for the conversion rate in this cohort.

[Restitution of atrial repolarization and atrial fibrillation in canine atrium].

OBJECTIVE: Electrical restitution was believed to be a determinant responsible for the stability of heart rhythm. Although numerous studies focused on the role of action potential duration restitution (APDR) in the initiation and maintenance of ventricular fibrillation (VF), the relationship between atrial APDR and atrial fibrillation (AF) has not been fully understood. This study aims to investigate the characteristics of APDR of left atrium (LA) and right atrium (Rs) in canines and the relevance to induction of AF. METHODS: Monophasic action potential (MAP) was recorded from LA and RA in 14 canines using the MAP recording-pacing combination catheter. APDR, plotted as action potential duration (APD) on the preceding diastolic interval (DI), was assessed by use of programmed stimulation with a single extrastimulus (S1S2) at LA and RA. Episodes of AF were recorded and analyzed. RESULTS: APD90 was significantly shorter in the LA than that in the RA [(157.4 +/- 43.5) ms vs. (170.9 +/- 37.9) ms, P < 0.05]. The mean slope of the APDR curve by S1S2 in the LA was significantly greater than that in the RA (1.3 +/- 0.4 vs. 0.9 +/- 0.3, P < 0.05). The incidence of induced AF was significantly higher in the LA than in the RA (11/18 vs. 7/18, P < 0.05). CONCLUSIONS: The APDR and MAP characteristics are not uniform between atrium, which may be one of the important mechanisms responsible for the initiation of AF. Heterogeneity of APDR between LA and RA might create critical gradients or a dispersion of repolarization and substrate for re-entrant arrhythmias and vulnerability to AF.

[Chronic outcome of patients with paroxysmal atrial fibrillation post catheter ablation].

OBJECTIVE: High short-term successful rate was reported for catheter ablation in patients with paroxysmal atrial fibrillation (AF), we analyzed the long-term outcome (success rate, anticoagulation therapy and embolism event, anti-arrhythmic therapy and death post procedure) of catheter ablation for paroxysmal AF in this study. METHODS: From January 2000 to December 2004, 106 consecutive patients with drug-refractory paroxysmal AF underwent catheter ablation and were followed-up for (60.7 + or - 11.8) months. Segmental pulmonary vein isolation (SPVI) was routinely performed by radiofrequency energy under the guidance of circular mapping catheter. The patients were followed up with 24 h-holter, ECG, telephone or letter. Data on recurrence of AF, the anticoagulation medication and the incidence of embolism, anti-arrhythmic therapy were obtained. RESULTS: There were 9 patients lost to follow up. In the remaining 97 patients [65 males, (54.8 + or - 11.2) years old], 3 cases died from cancer, sinus rhythm was maintained in 68 patients (Group S, 72.3%) and AF recurrence evidenced in 26 patients (Group R, 27.7%). In Group S, 56 patients (82.4%) discontinued anticoagulation medication, and 12 patients continued to take aspirin. There was no embolism event in Group S during follow-up. In Group R, 1 patient continued to take warfarin; 11 patients continued to take aspirin and 2 patients suffered from cerebral embolism. Anticoagulation medication was discontinued in 14 patients (53.8%) and 1 patient suffered form cerebral embolism. The incidence of embolism event in Group R is significantly higher than in Group S (P < 0.01). More patients discontinued anti-arrhythmic medication in Group S than in Group R (80.9% vs. 56.0%, P < 0.05). CONCLUSION: Catheter ablation is associated with satisfactory long-term success rate, reduced anti-arrhythmia medication, improved quality of life in patients with paroxysmal AF.

Preprodynorphin gene mutation causes progressive cardiac conduction disease: A whole-exome analysis of a pedigree.

AIMS: Progressive cardiac conduction disease (PCCD) is a rare heart disease that usually shows familial inheritance. Potential genetic risk factors for PCCD have been mostly limited to genes that encode ion channels, cardiac transcription factors, T-box transcription factors, gap junction proteins, energy metabolism regulators and structural proteins. MAIN METHODS: Subjects in the present study came from a family who exhibited the autosomal dominant inheritance of PCCD. The primary proband had syncope and an electrocardiogram typical for PCCD, which started in the left bundle branch block, and passed to the atrioventricular block. The patient received a permanent pacemaker in 2013. Pathogenic mutations in the proband's family were identified using whole-exome sequencing and Sanger sequencing. KEY FINDINGS: The results for the family members were verified using Sanger sequencing, while the results for healthy unrelated individuals were verified using SNaPShot. All patients in the family shared two adjacent missense mutations in the preprodynorphin (PDYN) gene (c.581A > T, c.580G > C; p.D194L). SIGNIFICANCE: The PDYN double mutation c.581A > T and c.580G > C (p.D194L) may be linked to the onset of familial PCCD. The effects of these mutations on electrophysiology require further investigation.

Comparison of cryoballoon ablation for atrial fibrillation guided by real-time three-dimensional transesophageal echocardiography vs. contrast agent injection.

BACKGROUND: Pulmonary vein (PV) occlusion generally depends on repetitive contrast agent injection when cryoballoon ablation for atrial fibrillation (AF). The present study was to compare the effect of cryoballoon ablation for AF guided by transesophageal echocardiography (TEE) vs. contrast agent injection. METHODS: Eighty patients with paroxysmal AF (PAF) were enrolled in the study. About 40 patients underwent cryoballoon ablation without TEE (non-TEE group) and the other 40 underwent cryoballoon ablation with TEE for PV occlusion (TEE group). In the TEE group during the procedure, PVs were displayed in 3-dimensional images to guide the balloon to achieve PV occlusion. The patients were followed up at regularly scheduled visits every 2 months. RESULTS: No differences were identified between the groups in regard to the procedure time and cryoablation time for each PV. The fluoroscopy time (6.7 ±â€Š4.2 min vs. 17.9 ±â€Š5.9 min, P < 0.05) and the amount of contrast agent (3.0 ±â€Š5.1 mL vs.18.1 ±â€Š3.4 mL, P < 0.05) in the TEE group were both less than the non-TEE group. At a mean of 13.0 ±â€Š3.3 mon follow-up, success rates were similar between the TEE group and non-TEE group (77.5% vs. 80.0%, P = 0.88). CONCLUSIONS: Cryoballoon ablation with TEE for occlusion of the PV is both safe and effective. Less fluoroscopy time and a lower contrast agent load can be achieved with the help of TEE for PV occlusion during procedure.

Novel Role for the Immunoproteasome Subunit PSMB10 in Angiotensin II-Induced Atrial Fibrillation in Mice.

Angiotensin II (Ang II) and inflammation are associated with pathogenesis of atrial fibrillation (AF), but the underlying molecular mechanisms of these events remain unknown. The immunoproteasome has emerged as a critical regulator of inflammatory responses. Here, we investigated its role in Ang II-induced AF in immunosubunit PSMB10 (also known as ß2i or LMP10) knockout (KO) mice. AF was induced by Ang II infusion (2000 ng/min per kg). PSMB10 expression and trypsin-like activity were increased in atrial tissues and serum from Ang II-treated mice or serum from patients with AF. Moreover, Ang II-infused wild-type (WT) mice had a higher AF and increased atrial fibrosis, reactive oxygen species production, and inflammation compared with saline-treated WT animals. These effects were attenuated in PSMB10 KO mice but were aggravated in recombinant adeno-associated virus serotype 9-PSMB10-treated mice. Administration of IKKß-specific inhibitor IMD 0354 reduced Ang II-induced AF, reactive oxygen species production, inflammation, and NF-kB (nuclear factor-kB) activation. Mechanistically, Ang II infusion upregulated PSMB10 expression to promote PTEN (phosphatase and tensin homolog deleted on chromosome ten) degradation and AKT1 activation, which not only activated TGF-ß-Smad2/3 signaling leading to cardiac fibrosis but also induced IKKß activation and ubiquitin-mediated degradation of IkBα ultimately resulting in activation of NF-kB target genes (IL [interleukin]-1ß, IL-6, NOX [NADPH oxidase] 2, NOX4, and CX43 [connexin 43]). Overall, our study identifies immunosubunit PSMB10 as a novel regulator that contributes to Ang II-induced AF and suggests that inhibition of PSMB10 may represent a potential therapeutic target for treating hypertensive AF.

Elevated Circulating Fibrocytes Is a Marker of Left Atrial Fibrosis and Recurrence of Persistent Atrial Fibrillation.

BACKGROUND: In atrial fibrillation (AF), a more extensively fibrotic left atrium (LA) provides a substrate for arrhythmias and increases risk of relapse following ablation. Fibrocytes are bone marrow-derived circulating mesenchymal progenitors that have been identified in the atrium of patients with AF who have valvular diseases. The present study investigates the associations between circulating fibrocytes and LA fibrosis or the prevalence of recurrence after ablation in patients with persistent AF. METHODS AND RESULTS: We measured the proportion, differentiation, and migration of circulating fibrocytes from patients with persistent AF (n=40), those with paroxysmal AF (n=30), and sinus rhythm controls (n=30). LA low-voltage (fibrosis) area was identified by an electroanatomic mapping system, and patients were followed up for 1 year after ablation. The relationship between circulating fibrocyte percentage and LA low-voltage area or recurrence was assessed by multivariate regression analysis. Circulating fibrocyte percentage positively associated with LA low-voltage area in the persistent AF group, and circulating fibrocyte (≥4.05%) was a significant predictor of 1-year recurrence after ablation. Cultured fibrocytes exhibited enhanced potential of differentiation in the persistent AF group (67.58±1.54%) versus the paroxysmal AF group (56.67±1.52%) and sinus rhythm controls (48.43±1.79%). Furthermore, expression of fibroblast activation markers and cell migratory ability were also elevated in differentiated fibrocytes from patients with persistent AF. Transforming growth factor ß1 and stromal cell-derived factor 1 were elevated in the plasma of patients with persistent AF and were shown to promote fibrocyte differentiation and migration, respectively. CONCLUSIONS: In patients with persistent AF, increased circulating fibrocytes served as a marker of LA fibrosis and recurrence.

Impact of right upper pulmonary vein isolation on atrial vagal innervation and vulnerability to atrial fibrillation.

BACKGROUND: Based on the hypothesis that pulmonary vein isolation could result in the damage of the epicardial fat pads, this study aimed to investigated the impact of right upper pulmonary vein (RUPV) isolation on vagal innervation to atria. METHODS: Bilateral cervical sympathovagal trunks were decentralized in 6 dogs. Metoprolol was given to block sympathetic effects. Multipolar catheters were placed into the right atrium (RA) and coronary sinus (CS). RUPV isolation was performed via transseptal procedure. Atrial effective refractory period (ERP), vulnerability window (VW) of atrial fibrillation (AF), and sinus rhythm cycle length (SCL) were measured at RA and distal coronary sinus (CSd) at baseline and vagal stimulation before and after RUPV isolation. Serial sections of underlying tissues before and after ablation were stained with haematoxylin and eosin. RESULTS: SCL decreased significantly during vagal stimulation before RUPV isolation (197 +/- 21 vs 13 +/- 32 beats per minute, P < 0.001), but remained unchanged after RUPV isolation (162 +/- 29 vs 140 +/- 39 beats per minute, P > 0.05). ERP increased significantly before RUPV isolation compared with that during vagal stimulation [(85.00 +/- 24.29) ms vs (21.67 +/- 9.83) ms at RA, P < 0.001; (90.00 +/- 15.49) ms vs (33.33 +/- 25.03) ms at CSd P < 0.005], but ERP at baseline hardly changed after RUPV isolation compared with that during vagal stimulation [(103.33 +/- 22.50) vs (95.00 +/- 16.43) ms at RA, P = 0.09; (98.33 +/- 24.83) vs (75.00 +/- 29.50) ms at CSd, P = 0.009]. The ERP shortening during vagal stimulation after RUPV isolation decreased significantly [(63.33 +/- 22.51) ms vs (8.33 +/- 9.83) ms at RA, P < 0.005; (56.67 +/- 20.66) ms vs (23.33 +/- 13.66) ms at CSd, P < 0.05]. AF was rarely induced at baseline before and after RUPV isolation (VW close to 0), while VW of AF to vagal stimulation significantly decreased after RUPV isolation [(40.00 +/- 10.95) vs 0 ms at RA, P < 0.001; (45.00 +/- 32.09) vs (15.00 +/- 23.45) ms at CS, P < 0.05]. The architecture of individual ganglia was significantly altered after ablation. CONCLUSIONS: The less ERP shortening to vagal stimulation and altered architecture of individual ganglia after right upper pulmonary vein isolation indicate that isolation may result in damage of the epicardial fat pads, thereby attenuating the vagal innervation to atria. The decreased vulnerability window of atrial fibrillation indicates that vagal denervation may contribute to its suppression.

[Transmural optical mapping of pause dependent torsade de pointes in canine long QT models].

OBJECTIVE: To investigate the mechanism of pause dependent torsade de pointes (TdP) in long QT (LQT) conditions. METHODS: Optical mapping was used to measure transmural action potentials from the arterially perfused left ventricular canine wedge preparation. D-sotalol and ATX-II were administered to mimic LQT 2 and LQT 3, respectively. RESULTS: In LQT models, the pause significantly enhanced M cell action potential (control group Steady state stimulation S1S1: (291 +/- 27) ms, after pause: (307 +/- 28) ms, P > 0.05; LQT 2 S1S1: (356 +/- 20) ms, after pause: (381 +/- 25) ms, P < 0.05; LQT 3 S1S1: (609 +/- 92) ms, after pause: (675 +/- 98) ms P < 0.05), dispersion of transmural repolarization (control group S1S1: (24 +/- 6) ms, after pause: (27 +/- 6) ms, P > 0.05; LQT 2 S1S1: (35 +/- 9) ms, after pause: (46 +/- 11) ms, P < 0.05; LQT 3 S1S1: (121 +/- 85) ms, after pause: (171 +/- 98) ms, P < 0.05) and the M cell island-like distribution more clearly compared to baseline pacing. Pause dependent early afterdepolarizations (EADs), EAD-induced triggered activity and TdP more likely occurred under LQT 3 condition (82%, P < 0.05). The triggered beat after pause often broke through at the margin of M cells island where the repolarization gradients was maximal. The unidirectional conduction block and slow conduction were observed vividly at this region. CONCLUSION: These data suggest that M cells island plays an important role in origination and maintenance of pause dependent TdP.

The impact of hypertension on the electromechanical properties and outcome of catheter ablation in atrial fibrillation patients.

BACKGROUND: Although hypertension is associated with atrial fibrillation (AF), the impact of hypertension on the electromechanical properties and outcome of catheter ablation in AF patients is unclear. METHODS: AF patients [n=213, 136 paroxysmal AF (PAF) patients and 77 persistent AF patients] undergoing circumferential pulmonary vein (PV) isolation guided by CARTO mapping were enrolled, and then were divided into normotension group and hypertension group. Several left atrial (LA) electroanatomical parameters determined by the CARTO system were compared between groups. RESULTS: The LA bipolar voltage was lower in PAF patients with than without hypertension (1.44±1.09 vs. 1.92±0.76 mV, P=0.048); a significant difference was also observed in persistent AF patients. Hypertension significantly increased the size of the LA scar and low-voltage zones (LVZs) in both PAF and persistent AF patients. However, hypertension did not significantly affect recurrence in either PAF or persistent AF patients. The LA bipolar voltage was higher in PAF patients without recurrence than in those with recurrence (1.77±1.01 vs. 1.29±0.93 mV, P=0.048); a significant difference was also observed in persistent AF patients. PAF and persistent AF patients with AF recurrence had significantly larger LA scar and LVZs than patients without recurrence. CONCLUSIONS: Hypertension has a significant impact on the LA electromechanical properties in AF patients, and the LA substrate has an important influence on the outcome of catheter ablation.