Distinct contractile and molecular differences between two goat models of atrial dysfunction: AV block-induced atrial dilatation and atrial fibrillation

Atrial dilatation is an independent risk factor for thromboembolism in patients with and without atrial fibrillation (AF). In many patients, atrial dilatation goes along with depressed contractile function of the dilated atria. While some mechanisms causing atrial contractile dysfunction in fibrillating atria have been addressed previously, the cellular and molecular mechanisms of atrial contractile remodeling in dilated atria are unknown. This study characterized in vivo atrial contractile function in a goat model of atrial dilatation and compared it to a goat model of AF. Differences in the underlying mechanisms were elucidated by studying contractile function, electrophysiology and sarcoplasmic reticulum (SR) Ca²⁺ load in atrial muscle bundles and by analyzing expression and phosphorylation levels of key Ca²⁺-handling proteins, myofilaments and the expression and activity of their upstream regulators. In 7 chronically instrumented, awake goats atrial contractile dysfunction was monitored during 3 weeks of progressive atrial dilatation after AV-node ablation (AV block goats (AVB)). In open chest experiments atrial work index (AWI) and refractoriness were measured (10 goats with AVB, 5 goats with ten days of AF induced by repetitive atrial burst pacing (AF), 10 controls). Isometric force of contraction (FC), transmembrane action potentials (APs) and rapid cooling contractures (RCC, a measure of SR Ca²⁺ load) were studied in right atrial muscle bundles. Total and phosphorylated Ca²⁺-handling and myofilament protein levels were quantified by Western blot. In AVB goats, atrial size increased by 18% (from 26.6 ± 4.4 to 31.6 ± 5.5 mm, n = 7 p < 0.01) while atrial fractional shortening (AFS) decreased (from 18.4 ± 1.7 to 12.8 ± 4.0% at 400 ms, n = 7, p < 0.01). In open chest experiments, AWI was reduced in AVB and in AF goats compared to controls (at 400 ms: 8.4 ±0.9, n = 7, and 3.2 ± 1.8, n = 5, vs 18.9 ± 5.3 mm×mmHg, n = 7, respectively, p < 0.05 vs control). FC of isolated right atrial muscle bundles was reduced in AVB (n = 8) and in AF (n = 5) goats compared to controls (n = 9) (at 2 Hz: 2.3 ± 0.5 and 0.7 ± 0.2 vs 5.5 ± 1.0 mN/mm², respectively, p < 0.05). APs were shorter in AF, but unchanged in AVB goats. RCCs were reduced in AVB and AF versus control (AVB, 3.4 ± 0.5 and AF, 4.1 ± 1.4 vs 12.2 ± 3.2 mN/mm², p < 0.05). Protein levels of protein kinase A (PKA) phosphorylated phospholamban (PLB) were reduced in AVB (n = 8) and AF (n = 8) vs control (n = 7) by 37.9 ± 12.4% and 29.7 ± 10.1%, respectively (p < 0.01), whereas calmodulin-dependent protein kinase II (CaMKII) phosphorylated ryanodine channels (RyR2) were increased by 166 ± 55% in AVB (n = 8) and by 146 ± 56% in AF (n = 8) goats (p < 0.01). PKA-phosphorylated myosin-binding protein-C and troponin-I were reduced exclusively in AVB goat atria (by 75 ± 10% and 55 ± 15%, respectively, n = 8, p < 0.05). Atrial dilatation developing during slow ventricular rhythm after complete AV block as well as AF-induced remodeling are associated with atrial contractile dysfunction. Both AVB and AF goat atria show decreased SR Ca²⁺ load, likely caused by PLB dephosphorylation and RYR2 hyperphosphorylation. While shorter APs further compromise contractility in AF goat atria, reduced myofilament phosphorylation may impair contractility in AVB goat atria. Thus, atrial hypocontractility appears to have distinct molecular contributors in different types of atrial remodeling.     

A monounsaturated fatty acid (oleic acid) modulates electrical activity in atrial myocytes with calcium and sodium dysregulation

Background

Obesity and metabolic syndrome are important risk factors for atrial fibrillation. High plasma concentrations of monounsaturated fatty acids, including oleic acid (OLA), are frequently noted in obese individuals and patients with metabolic syndrome. However, it is not clear whether monounsaturated fatty acids (MUFAs) can directly modulate the electrophysiological characteristics of atrial myocytes.

Methods

Whole-cell patch clamp, indo-1 fluorescence, and Western blot analyses were used to record the action potentials (APs), ionic currents, and protein expressions of HL-1 myocytes incubated with and without (control) OLA (0.5 mM) for 24 h.

Results

Compared to control myocytes (n = 14), OLA-treated myocytes (n = 16) had shorter APD₉₀ (65 ± 6 vs. 85 ± 6 ms, p < 0.05) and APD₅₀ (24 ± 6 vs. 38 ± 4 ms, p < 0.05) with a higher incidence of delayed afterdepolarizations (35.7% vs. 7%, p < 0.05), which were suppressed by 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS, a blocker of the calcium-activated chloride current). In addition, OLA-treated myocytes (n = 19) exhibited larger calcium transients (0.54 ± 0.06 vs. 0.38 ± 0.05 R410/485, p < 0.05), and sarcoplasmic reticular calcium contents (0.91 ± 0.05 vs. 0.64 ± 0.08 R410/485, p < 0.05) than control myocytes (n = 15). OLA-treated myocytes had larger late sodium currents, smaller sodium–calcium exchanger currents, and smaller sodium–potassium pump currents. Moreover OLA-treated myocytes had higher expressions of sarcoplasmic reticular Ca^2 +-ATPase and calmodulin kinase II, but lower expression of the sodium–potassium ATPase protein than control myocytes.

Conclusions

MUFAs can regulate atrial electrophysiological characteristics with calcium and sodium dysregulation, which may contribute to atrial arrhythmogenesis.     

Distinctive sodium and calcium regulation associated with sex differences in atrial electrophysiology of rabbits

Background

Sex and sodium/calcium regulation play critical roles in cardiac electrophysiology and atrial arrhythmogenesis. We investigated whether sodium and calcium contributed to sex differences in atrial electrophysiology.

Methods

Whole-cell patch clamp techniques and the indo-1 fluorometric ratio technique were used to investigate the ionic current and intracellular calcium in single isolated male and female rabbit myocytes from the left atrium posterior wall (LAPW) and right atrium (RA).

Results

Female LAPW (n = 95) and RA (n = 49) myocytes had larger cell widths (15.1 ± 0.4 vs. 13.8 ± 0.4 μm, p < 0.05; 14.9 ± 0.6 vs. 13.5 ± 0.4 μm, p < 0.05) than male LAPW (n = 142) and RA (n = 57) myocytes. Male LAPW myocytes (n = 26) had a higher incidence (57 vs. 16%, p < 0.05) of delayed afterdepolarizations (DADs) than female LAPW myocytes (n = 24) but there were similar incidences (20 vs. 20%, p > 0.05) of DADs in male and female RA myocytes. The late sodium current, calcium transients, and sarcoplasmic reticulum calcium contents were larger in male than female LAPW myocytes but were similar in male and female RA myocytes. However, the I_Ca-L and nickel-sensitive sodium/calcium exchanger currents were similar between two groups. Different from those in female myocytes, ouabain (10 μM) only induced repeated atrial beats (0 to 45%, p < 0.05) in male myocytes (n = 11). Moreover, ranolazine (3 μM) perfusion (4.5 ± 0.6 vs. 1 min, p < 0.05) was required to decrease the amplitude of DADs in male but not female LAPW myocytes.

Conclusions

Increased late sodium currents and calcium contents may contribute to higher arrhythmogenesis in male LAPW myocytes.     

n-3 polyunsaturated fatty acids prevents atrial fibrillation by inhibiting inflammation in a canine sterile pericarditis model

Objective

It has been recently reported that atrial fibrillation (AF) is associated with inflammation and inflammatory cytokines, and n-3 polyunsaturated fatty acids (PUFAs) might be of anti-inflammatory effects. This study was to evaluate the anti-inflammatory effect of PUFAs on AF in a canine sterile pericarditis model.

Methods

20 dogs were randomly assigned to two groups: control group (10 dogs) and PUFA treatment group (10 dogs), in which sterile pericarditis was created by open-chest operation. PUFAs were administered orally (2 g/day) 4 weeks before the operation till the end of the study. Before and 2 days after the operation, CRP, IL-6, TNF-α levels, the inducibility and maintenance of AF, the atrial effective refractory period (AERPs), and intra-atrial conduction time were determined.

Results

Before the operation, there were no significant differences in any of the parameters between the two groups. On the second postoperative day, the PUFA group had a lower CRP level (7.6 ± 0.5 vs. 11.7 ± 1.3 mg/dl, P < 0.0001), a lower IL-6 level (112.0 ± 37.3 vs. 142.0 ± 19.6 pg/ml, P < 0.01), a lower TNF-α level (83.3 ± 8.5 vs. 112.4 ± 8.2 pg/ml, P < 0.0001), a less AF inducibility (percentage of burst attempts leading to AF episodes: 11 ± 7.4 vs. 28 ± 10.3, P < 0.001) and maintenance [median AF duration: 1105 s (655.8-1406.5) vs. 2516.5 s (1187-3361), P < 0.05], a longer AERP (133.4 ± 4.1 vs. 129.8 ± 4.3 ms, P < 0.05), and a shorter intra-atrial conduction time (46.6 ± 4.4 vs. 51.9 ± 4.8 ms, P < 0.05) than the control group.

Conclusions

Dietary n-3 PUFA supplementation attenuates the inducibility and maintenance of AF in the sterile pericarditis model by reducing the production of proinflammatory cytokines.     

Analysis of oxidative stress expressed by urinary level of 8-hydroxy-2′-deoxyguanosine and biopyrrin in atrial fibrillation: Effect of sinus rhythm restoration

Background

Oxidative stress is considered to contribute to the pathological consequences of atrial fibrillation (AF). We examined the level of oxidative stress in AF patients and changes in its level following sinus rhythm restoration.

Methods

Oxidative stress level was evaluated by urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, and urinary biopyrrin, an oxidative metabolite of bilirubin. In Study 1, we compared 8-OHdG/creatinine levels between patients with permanent AF (AF-group, n = 40) and sinus rhythm (SR-group, n = 133). In Study 2, we examined the changes in 8-OHdG and biopyrrin levels in 36 patients with persistent AF following sinus rhythm restoration by electrical or pharmacological cardioversion (n = 15) and radiofrequency catheter ablation (n = 21).

Results

In Study 1, 8-OHdG/creatinine levels were significantly higher in AF-group than in SR-group (19.1 ± 8.6 vs. 12.3 ± 5.5 ng/mg, p < 0.001). Multivariate analysis showed that the presence of AF was an independent factor that significantly correlated with 8-OHdG/creatinine level after adjustment for other covariates to oxidative stress (β = 0.36, p < 0.001). Sinus rhythm was maintained at the chronic phase in patients of all Study 2 (7.2 ± 5.8 months after cardioversion or catheter ablation). 8-OHdG/creatinine and biopyrrin/creatinine levels at the chronic phase were significantly lower than those before cardioversion or catheter ablation (8.7 ± 3.2 vs. 21.7 ± 15.1 ng/mg, p < 0.0001 and 1.7 ± 1.1 vs. 3.0 ± 1.9 mU/mg, p < 0.0001).

Conclusions

Oxidative stress level is significantly increased in AF patients, but can be improved by restoration of sinus rhythm. The results suggest that the pathogenic process of AF is promoted by AF itself through the production of oxidative stress.     

Infiltrated atrial fat characterizes underlying atrial fibrillation substrate in patients at risk as defined by the ARIC atrial fibrillation risk score

Background

It is known that expanded epicardial fat is associated with atrial fibrillation (AF). However, infiltrated intraatrial fat has not been previously quantified in individuals at risk as determined by the ARIC AF risk score.

Methods

Patients in sinus rhythm (N = 90, age 57 ± 10 years; 55 men [63.2%]), in 3 groups at risk of AF as determined by the ARIC AF risk score [low (≤ 11 points; n = 15), moderate (12–18 points; n = 40), high (≥ 19 points; n = 23) risk of AF], and paroxysmal AF (n = 12) underwent cardiac magnetic resonance study. Intraatrial and epicardial fat was analyzed with a Dark-blood DIR-prepared Fat-Water-separated sequence in the horizontal longitudinal axis. OsiriX DICOM viewer (Geneva, Switzerland) was used to quantify the intraatrial fat area. Width of the cephalad portion of the interatrial septum was measured at the level of the fossa ovalis.

Results

Intraatrial fat monotonically increased with growing AF risk in study groups (low AF risk 16 ± 4 vs. moderate AF risk 32 ± 18 vs. high AF risk 81 ± 83 mm²; ANOVA P = 0.012). Log-transformed intraatrial fat predicted ARIC AF risk score in multivariate ordered probit regression after adjustment for sex, race, left and right atrial area indices, and body mass index (β-coefficient 0.50 [95% CI 0.03–0.97]; P = 0.037), whereas epicardial fat did not. Interatrial septum width showed similar association (3.0 ± 1.4 vs. 5.0 ± 1.8 vs. 7.1 ± 2.7 mm; ANOVA P < 0.001; adjusted β-coefficient 2.80 [95% CI 1.19–4.41]; P = 0.001).

Conclusions

Infiltrated intraatrial fat characterizes evolving substrate in individuals at risk of AF.     

Calreticulin overexpression correlates with integrin-α5 and transforming growth factor-β1 expression in the atria of patients with rheumatic valvular disease and atrial fibrillation

Objectives

The aim of this study was to determine whether altered calreticulin expression and distribution contribute to the pathogenesis of atrial fibrillation (AF) associated with valvular heart disease (VHD).

Background

AF affects electrophysiological and structural changes that exacerbate AF. Atrial remodeling reportedly underlies AF generation, but the precise mechanism of atrial remodeling in AF remains unclear.

Methods

Right and left atrial specimens were obtained from 68 patients undergoing valve replacement surgery. The patients were divided into sinus rhythm (SR; n = 25), paroxysmal AF (PaAF; n = 11), and persistent AF (PeAF; AF lasting > 6 months; n = 32) groups. Calreticulin, integrin-α5, and transforming growth factor-β1 (TGF-β1) mRNA and protein expression were measured. We also performed immunoprecipitation for calreticulin with either calcineurin B or integrin-α5.

Results

Calreticulin, integrin-α5, and TGF-β1 mRNA and protein expression were increased in the AF groups, especially in the left atrium in patients with mitral valve disease. Calreticulin interacted with both calcineurin B and integrin-α5. Integrin-α5 expression correlated with TGF-β1 expression, while calreticulin expression correlated with integrin-α5 and TGF-β1 expression. Despite similar cardiac function classifications, calreticulin expression was greater in the PeAF group than in the SR group.

Conclusions

Calreticulin, integrin-α5, and TGF-β1 expression was increased in atrial tissue in patients with AF and was related to AF type, suggesting that calreticulin is involved in the pathogenesis of AF in VHD patients.     

Long duration of radiofrequency energy delivery is an independent predictor of clinical recurrence after catheter ablation of atrial fibrillation: Over 500 cases experience

Background

Although radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) is an effective rhythm control strategy, there is a substantial amount of recurrence. We explored the predictors of AF recurrence after RFCA with consistent ablation strategy.

Methods and results

This study included 575 patients (77% male, 56 ± 11 years old) with AF (65.7% paroxysmal AF [PAF], 34.3% persistent AF [PeAF]) who underwent RFCA. We evaluated the clinical, serological, and electrophysiological parameters thereof. Results: 1. During 15 ± 7 months of follow-up, patients who experienced AF recurrence (21.8%) were older (58 ± 10 vs. 55 ± 11 years old, p = 0.019) and more likely to have PeAF (50.4% vs. 29.4%, p < 0.001) and greater LA volume (137.3 ± 49.1 vs. 116.6 ± 37.9 mL, p < 0.001). 2. In patients with clinical recurrence after RFCA, both ablation time (110.1 ± 43.8 vs. 92.3 ± 30.1 min, p < 0.001) and procedure time (222.7 ± 79.6 vs. 205.8 ± 58.8 min, p < 0.001) were prolonged, and the early recurrence rate within 3 months of the procedure was higher (63.0% vs. 26.4%, p < 0.001) than those without clinical recurrence. 3. In logistic regression analysis, LA volume (OR 1.008, CI 1.001–1.014), ablation time (per quartile, OR 1.380, CI 1.031–1.847), and early recurrence (OR 3.858, CI 2.420–6.150) were independent risk factors for recurrence of AF after RFCA.

Conclusion

In this single center consistent study of over 500 cases of AF ablation, patients with AF recurrence had a larger atrium, longer ablation time, and a higher chance of early recurrence than those remained in sinus rhythm. Inadvertent, long duration of ablation was an independent predictor of worse clinical outcomes after catheter ablation of AF.     

Effect of lifetime endurance training on left atrial mechanical function and on the risk of atrial fibrillation

Background

Left atrium (LA) dilation and P-wave duration are linked to the amount of endurance training and are risk factors for atrial fibrillation (AF). The aim of this study was to evaluate the impact of LA anatomical and electrical remodeling on its conduit and pump function measured by two-dimensional speckle tracking echocardiography (STE).

Method

Amateur male runners > 30 years were recruited. Study participants (n = 95) were stratified in 3 groups according to lifetime training hours: low (< 1500 h, n = 33), intermediate (1500 to 4500 h, n = 32) and high training group (> 4500 h, n = 30).

Results

No differences were found, between the groups, in terms of age, blood pressure, and diastolic function. LA maximal volume (30 ± 5, 33 ± 5 vs. 37 ± 6 ml/m², p < 0.001), and conduit volume index (9 ± 3, 11 ± 3 vs. 12 ± 3 ml/m², p < 0.001) increased significantly from the low to the high training group, unlike the STE parameters: pump strain − 15.0 ± 2.8, − 14.7 ± 2.7 vs. − 14.9 ± 2.6%, p = 0.927; conduit strain 23.3 ± 3.9, 22.1 ± 5.3 vs. 23.7 ± 5.7%, p = 0.455. Independent predictors of LA strain conduit function were age, maximal early diastolic velocity of the mitral annulus, heart rate and peak early diastolic filling velocity. The signal-averaged P-wave (135 ± 11, 139 ± 10 vs. 148 ± 14 ms, p < 0.001) increased from the low to the high training group. Four episodes of non-sustained AF were recorded in one runner of the high training group.

Conclusion

The LA anatomical and electrical remodeling does not have a negative impact on atrial mechanical function. Hence, a possible link between these risk factors for AF and its actual, rare occurrence in this athlete population, could not be uncovered in the present study.     

Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts

This study compared the effects of ATP-regulated potassium channel (K_ATP) openers, diazoxide and pinacidil, on diseased and normal human atria and ventricles. We optically mapped the endocardium of coronary-perfused right (n = 11) or left (n = 2) posterior atrial-ventricular free wall preparations from human hearts with congestive heart failure (CHF, n = 8) and non-failing human hearts without (NF, n = 3) or with (INF, n = 2) infarction. We also analyzed the mRNA expression of the K_ATP targets K_ir6.1, K_ir6.2, SUR1, and SUR2 in the left atria and ventricles of NF (n = 8) and CHF (n = 4) hearts. In both CHF and INF hearts, diazoxide significantly decreased action potential durations (APDs) in atria (by − 21 ± 3% and − 27 ± 13%, p < 0.01) and ventricles (by − 28 ± 7% and − 28 ± 4%, p < 0.01). Diazoxide did not change APD (0 ± 5%) in NF atria. Pinacidil significantly decreased APDs in both atria (− 46 to −80%, p < 0.01) and ventricles (− 65 to − 93%, p < 0.01) in all hearts studied. The effect of pinacidil on APD was significantly higher than that of diazoxide in both atria and ventricles of all groups (p < 0.05). During pinacidil perfusion, burst pacing induced flutter/fibrillation in all atrial and ventricular preparations with dominant frequencies of 14.4 ± 6.1 Hz and 17.5 ± 5.1 Hz, respectively. Glibenclamide (10 μM) terminated these arrhythmias and restored APDs to control values. Relative mRNA expression levels of K_ATP targets were correlated to functional observations. Remodeling in response to CHF and/or previous infarct potentiated diazoxide-induced APD shortening. The activation of atrial and ventricular K_ATP channels enhances arrhythmogenicity, suggesting that such activation may contribute to reentrant arrhythmias in ischemic hearts.     

Expression of spliceosome assembly factor SC-35 in TUNEL-positive atrial cardiomyocytes in mitral and tricuspid regurgitation: Viability of atrial cardiomyocytes

Background

Most of the atrial cardiomyocytes with positive terminal deoxynucleotidyl transferase (TdT)-mediated dUTP in situ nick end-labelling (TUNEL) reaction are not apoptotic in patients with mitral and tricuspid valve diseases. The TUNEL-positive myocytes with expression of spliceosome assembly factor SC-35, an indicator of increased RNA synthesis, should be living cardiomyocytes.

Methods

This study analyzed twenty-three patients with significant mitral and tricuspid regurgitation. Fifteen patients had persistent atrial fibrillation, and eight had sinus rhythm. Atrial appendageal tissues were obtained during surgery. Immunohistochemical study was performed.

Results

Immunohistochemical study of fibrillating right atrial myocardium demonstrated that 44.8 ± 24.6% of myocytes had TUNEL-positive nuclei whereas 39.4 ± 21.4% of myocytes had TUNEL-positive nuclei in sinus right atrial myocardium (p = 0.682). However, most (81.6%) nuclei of TUNEL-positive myocytes in the fibrillating right atria also expressed proliferating cell nuclear antigen (PCNA), an indicator of DNA replication and repair, and most nuclei (91.8%) of TUNEL-positive myocytes also expressed SC-35. In fibrillating left atria, most (88.1%) nuclei of TUNEL-positive myocytes also expressed SC-35. Similarly, in sinus right atrial myocardium, most (78.0%) nuclei of TUNEL-positive myocytes expressed PCNA, and most (91.4%) nuclei of TUNEL-positive myocytes also expressed SC-35, but none expressed Ki-67, a replication-associated antigen. Additionally, the percentage of TUNEL-positive myocytes in the right atria significantly and positively correlated with the percentage of PCNA-positive myocytes (r = 0.826, p < 0.001) and SC-35 positive myocytes (r = 0.713, p < 0.001).

Conclusions

Most TUNEL-positive atrial cardiomyocytes in patients with mitral and tricuspid regurgitation are living cardiomyocytes.     

Short-term functional outcome of ischemic stroke in the elderly: A comparative study of atrial fibrillation and non-atrial fibrillation patients

The purpose of this study was to evaluate whether atrial fibrillation affects the short-term functional outcome of elderly patients with ischemic stroke, undergoing post-acute in-hospital rehabilitation. We studied 919 consecutive patients admitted for ischemic stroke rehabilitation, out of whom 19.6% were diagnosed with atrial fibrillation. The Functional outcome of atrial fibrillation (AF) and non-atrial fibrillation (Non-AF) patients were assessed by the Functional Independence Measurement scale (FIM™) at admission and discharge. Data were analyzed by t-test, Chi-square test and by multiple linear regression analysis. Compared with Non-AF, patients with AF were slightly older (p < 0.001), and had lower Mini-Mental State Examination (MMSE) scores (p = 0.001). Discharge total FIM scores were significantly higher in Non-AF compared with AF patients (84.34 ± 29.44 vs. 79.02 ± 30.68, p = 0.031). However, total and motor FIM gains at discharge were similar in the two groups. A multiple linear regression analysis showed that age (p < 0.001), admission total and motor FIM (p < 0.001) and MMSE score (p < 0.001) emerged as the only independent predictors of total, motor and gain FIM scores at discharge. AF was not predictive, whatsoever, of adverse FIM scores (total, motor, gain) at discharge (β = −0.024, p = 0.303; β = −0.019, p = −0.455 and β = −0.04, p = 0.303, respectively). The finding suggests that Non-AF ischemic stroke elderly show higher total discharge FIM scores, compared with AF patients. However, both groups achieve similar FIM gains during rehabilitation period. AF should not be considered as adversely affecting the short-term rehabilitation process of such patients.     

Effects of long-term omega-3 polyunsaturated fatty acid supplementation on paroxysmal atrial tachyarrhythmia burden in patients with implanted pacemakers: Results from a prospective randomised study

Background

Sino-atrial node disease and aging increase AF risk. We investigated if long-term fish oil supplementation reduces paroxysmal atrial tachycardia/fibrillation (AT/AF) burden in patients aged ≥ 60 years with sinoatrial node disease and dual chamber pacemakers.

Methods

Following a run-in period of 6 months (p1) where AT/AF burden was logged,78 patients were randomised to control or fish oil group(total omega-3 6 g/d) and AT/AF burden evaluated after 6 months(p2; 39 controls, 39 fish oil) and 12 months (p3; 39 controls; 18 fish oil). A subset of 21 fish oil patients crossed over to controls in the final 6 months (crossover group).

Results

Median AT/AF burden increased significantly in controls (1.5%, 3.2%, 4.3%, P < .001) but not in fish oil patients at 6 months (1.4% to 2%, P = .46) or those continuing for 12 months (1.5%, 0.98%, 1%, P = .16). Time to first episode of AT/AF > 1 min was not significantly different between the groups (P = .9). There was a rebound increase in AT/AF burden in p3 in cross over patients (2.2% to 5.8%, P = .01) reaching a level similar to controls (crossover vs. controls, 5.8% vs. 4.3%, P = .63) and higher than those who continued fish oil for 12 months (crossover vs. continued intake 5.8% vs. 1.2%, P = .02). Fish oil patients had shorter duration episodes of AT/AF with no difference in frequency compared to controls.

Conclusion

Long-term fish oil supplementation did not suppress AT/AF burden but may have attenuated its temporal progression related to aging and sinus node disease.     

Longitudinal assessment of liver stiffness in patients undergoing antiviral treatment for hepatitis C

Background

Liver stiffness has been suggested as a parameter of fibrosis progression/regression in hepatitis C virus (HCV) patients.

Aim

To evaluate stiffness before and after peginterferon–ribavirin treatment.

Methods

Stiffness was prospectively measured in 74 HCV patients, 32 genotypes 1/4 (43.25%) and 42 genotypes 2/3 (56.75%), before, at end of treatment, and after 3 years of follow-up (49 patients). On the same study day, 21 patients underwent liver biopsy.

Results

In 55 patients with sustained virological response (74.32%), liver stiffness decreased significantly at end of therapy (6.8 ± 4.9 kPa) vs. baseline (9.5 ± 6.9 kPa, p = 0.04). The decrease vs. baseline was maintained in 30 sustained virological response patients after 3 years follow-up (6.8 ± 4.6 kPa vs. 10.8 ± 8.5 kPa, p = 0.0141). No difference was found at end of treatment vs. baseline (10.1 ± 4.7 kPa vs. 9.7 ± 4.2 kPa, p = 0.825) and after 3 years of follow-up vs. baseline (10.2 ± 3.4 kPa vs. 9.7 ± 4.2 kPa, p = 0.765) in null responders. Similar results were found in relapsers at end of treatment vs. baseline (13.7 ± 7.7 kPa vs. 15.2 ± 8.2 kPa, p = 0.74), and after 3 years of follow-up vs. baseline (16.9 ± 10.0 kPa vs. 15.2 ± 8.2 kPa, p = 0.734). Pre-treatment stiffness >12 kPa was significantly associated with no SVR (p < 0.025), RR = 2.44 (95% C.I. 1.17–5.07).

Conclusion

Liver stiffness may be useful to assess long-term antiviral treatment response.     

Increased lysyl oxidase expression and collagen cross-linking during atrial fibrillation

The aim of the study is to characterize the signal transduction leading to interstitial fibrosis in the pathogenesis of atrial fibrillation (AF) and atrial remodeling.Samples of the left atrial appendage (LA) from patients with AF showed higher collagen content (73 ± 5 vs. 38 ± 2 μg/mg protein) and 2.5-fold increased collagen crosslinking compared to patients with sinus rhythm (SR). Affymetrix-assays, RT-PCR and western Blot analysis revealed that LA of AF patients are characterized by increased lysyl oxidase (LOX) mRNA (218 ± 42%) and protein (253 ± 11%) expression. This was associated with increased expression of connective tissue growth factor (CTGF), fibronectin and Rac1 activity compared to SR. In neonatal cardiac fibroblasts, the Rac1 specific small molecule inhibitor NSC23766 prevented angiotensin II (AngII) induced upregulation of LOX (214 ± 16%) expression. Inhibition of CTGF by siRNA transfections completely inhibited AngII induced LOX expression. The LOX specific small molecule inhibitor BAPN prevented AngII and CTGF induced fibronectin expression. Left atria of transgenic mice with cardiac overexpression of Rac1 (RacET) that develop AF at high age exhibited upregulation of CTGF as well as LOX (187 ± 7%) and fibronectin (627 ± 146%) expression. Atria of RacET showed increased collagen content (28 ± 2 μg/mg protein) and crosslinking (10 ± 0.7) compared to wildtypes (20 ± 0.4 μg/mg protein; 5 ± 0.9).Left atrial myocardium of patients with atrial fibrillation is characterized by increased lysyl oxidase and fibronectin expression as well as collagen cross-linking. In cardiac fibroblasts, Rac1 GTPase mediates upregulation of fibronectin via LOX and CTGF. Inhibition of this signaling pathway may therefore represent a target for the prevention of fibrotic atrial remodeling.     

Analysis of atrial fibrillatory rate during spontaneous episodes of atrial fibrillation in humans using implantable loop recorder electrocardiogram

Atrial fibrillatory rate (AFR) can predict outcome of interventions for atrial fibrillation (AF); however, AFR behavior at AF onset in humans is poorly described. We studied AFR during spontaneous AF episodes in patients with lone paroxysmal AF who received implantable loop recorders and had AF episodes of 1 hour or more recorded (n = 4). Mean AFR per minute was assessed from continuous implantable loop recorder electrocardiogram using spatiotemporal QRST cancellation and time-frequency analysis. Atrial fibrillatory rate increased from 290 ± 20 to 326 ± 39 fibrillations per minute during the first 3 hours (P < .05) and reached plateau then. Atrial fibrillatory rate beyond the initial 3 hours can, therefore, be considered stable and may be evaluated for prediction of intervention effect.     

Distinct prognostic impacts of both atrial volumes on outcomes after radiofrequency ablation of nonvalvular atrial fibrillation: Three-dimensional imaging study using multidetector computed tomography

Background

Left atrial (LA) enlargement is associated with atrial fibrillation (AF) recurrence after radiofrequency ablation (RFA). However, impact of right atrial (RA) size on outcomes after RFA is unclear.

Methods

Patients who underwent RFA of AF (n = 242, 197 men, 57 ± 11 years) were enrolled (159 paroxysmal [PaAF] and 83 persistent [PeAF]). Three-dimensional RA and LA volumes were measured before RFA with multidetector computed tomography and indexed to body surface area (RAVI and LAVI).

Results

After a 3-month blanking period, 66 patients (27%) failed to maintain sinus rhythm during follow-up (556 ± 322 days). Despite similar clinical characteristics, LAVI was larger (77 ± 21 vs. 91 ± 27 ml/m², P < 0.001) and RAVI showed a trend to be greater (85 ± 26 vs. 92 ± 25 ml/m², P = 0.06) in patients with future recurrence than without recurrence. Additionally, patients with larger RA or LA experienced recurrences more frequently and earlier during follow-up (log rank, P < 0.05 for all). In Cox regression analysis, LAVI was independently associated with outcomes (10 ml/m² increase; HR: 1.22, 95% CI: 1.09–1.36, P < 0.001), whereas RAVI was not. In subgroup analysis, 25 PaAF patients (16%) experienced recurrence and both atrial volumes failed to predict the outcome independently, despite borderline significance of RAVI (10 ml/m² increase; HR: 1.21, 95% CI: 1.00–1.48, P = 0.05). Meanwhile, 41 patients (49%) in PeAF group experienced AF recurrence and LAVI was an independent prognosticator (10 ml/m² increase; HR: 1.19, 95% CI: 1.03–1.36).

Conclusions

RA size might affect the outcome after RFA in PaAF patients. LA enlargement, rather than RA size, influence outcomes after RFA, especially in PeAF.     

Heart failure epicardial fat increases atrial arrhythmogenesis

Background

Obesity is an important risk factor for atrial fibrillation (AF) and heart failure (HF). The effects of epicardial fat on atrial electrophysiology were not clear. This study was to evaluate whether HF may modulate the effects of epicardial fat on atrial electrophysiology.

Methods

Conventional microelectrodes recording was used to record the action potential in left (LA) and right (RA) atria of healthy (control) rabbits before and after application of epicardial fat from control or HF (ventricular pacing of 360–400 bpm for 4 weeks) rabbits. Adipokine profiles were checked in epicardial fat of control and HF rabbits.

Results

The LA 90% of AP duration was prolonged by control epicardial fat (from 77 ± 6 to 87 ± 7 ms, p < 0.05, n = 7), and by HF epicardial fat (from 78 ± 3 to 98 ± 4 ms, p < 0.001, n = 9). However, control or HF epicardial fat did not change the AP morphology in RA. HF epicardial fat increased the contractility in LA (61 ± 11 vs. 35 ± 6 mg, p = 0.001), but not in RA. Control fat did not change the LA or RA contractility. Moreover, control and HF epicardial fat induced early and delayed afterdepolarizations in LA and RA, but only HF epicardial fat provoked spontaneous activity and burst firing in LA (n = 3/9, 33.3% vs. n = 0/7, 0%, n = 0/9, 0%, p < 0.05). Compared to control fat, HF epicardial fat, had lower resistin, C-reactive protein and serum amyloid A, but similar interluekin-6, leptin, monocyte chemotactic protein-1, adiponectin and adipsin.

Conclusions

HF epicardial fat increases atrial arrhythmogenesis, which may contribute to the higher atrial arrhythmia in obesity.     

Benefits and risks of additional ablation of complex fractionated atrial electrograms for patients with atrial fibrillation: A systematic review and meta-analysis

Background

The benefits and risks of additional complex fractionated atrial electrograms (CFAE) ablation in patients with atrial fibrillation (AF) remain unclear.

Methods

Trials were identified in PubMed, Embase, Web of Science, and Cochrane Database, reviews, and reference lists of relevant papers. The primary end point was the recurrence of atrial arrhythmias after a single ablation.

Results

We meta-analyzed 11 studies (total, n = 983) using random-effects model to compare PVI (n = 478) with PVI plus CFAE ablation (PVI + CFAE) (n = 505). Additional CFAE ablation reduced recurrence of atrial tachyarrhythmia after a single procedure (pooled RR 0.73; 95% CI 0.61, 0.88; P = 0.0007) at ≥ 3-month follow-up. There was no evidence of heterogeneity among studies (I² = 33%). Subgroup analysis demonstrated that additional CFAE ablation reduced rates of recurrence in nonparoxysmal AF (RR 0.68; 95% CI 0.47, 0.99; P = 0.05), whereas had no effect on patients with paroxysmal AF (RR 0.79; 95% CI 0.59, 1.06; P = 0.12). Eight studies reported results of post-procedure ATs. The addition of CFAE ablation increased the rate of post-procedure ATs (RR 1.77; 95% CI 1.02, 3.07; P = 0.04). Additional CFAE ablation significantly increased mean procedural times (245.4 + 75.7 vs. 189.5 + 62.3 min, P < 0.001), mean fluoroscopy (72.1 + 25.6 vs. 59.5 + 19.3 min, P < 0.001), and mean RF energy application times (75.3 + 38.6 vs. 53.2 + 27.5 min, P < 0.001).

Conclusions

The adjunctive CFAE ablation could provide additional benefit in terms of reducing recurrence of atrial tachyarrhythmia for patients with nonparoxysmal AF but not for patients with paroxysmal AF after a single procedure with or without antiarrhythmic drugs (AADs). The main risk of adjunctive CFAE ablation is the increasing rate of untraceable postablation ATs.     

Maintenance of sinus rhythm after electrical cardioversion for recurrent atrial fibrillation following mitral valve surgery with or without associated radiofrequency ablation

Background

This study reports the outcomes of patients who underwent electrical cardioversion for atrial fibrillation recurrence following mitral valve surgery and associated radiofrequency ablation compared to those who did not undergo concomitant atrial fibrillation ablation.

Methods

The population consisted of 116 patients with persistent/long-standing persistent AF who underwent mitral valve surgery with (Group A, n = 54) or without (Group B, n = 62) associated radiofrequency ablation between January 2007 and January 2011 at three institutions and who subsequently underwent cardioversion for persistent atrial fibrillation within 12 months of their initial procedure.

Results

The mean follow-up duration was 30.7 ± 9.4 months. Of the 104 patients with acute restoration of SR 42 (40.3%) had AF recurrence. The average time to recurrence after cardioversion was 7.3 ± 4.2 days. Recurrence was significantly lower in patients undergoing ablation surgery (21.4%) than in those undergoing no ablation surgery (78.6%, p < 0.001). Non-performed ablation procedure (p < 0.001), time from surgery ≥ 88 days and left atrial dimensions ≥ 45.5 mm before cardioversion (both, p = 0.005) were multivariable predictors of atrial fibrillation recurrence. In Group B the use of amiodarone was inversely correlated with recurrence of AF (p < 0.001). This correlation was not significant (r = − 0.02, p = 0.85) in Group A.

Conclusions

Electrical cardioversion for recurrent AF showed better results and stable recovery of sinus rhythm in patients undergoing concomitant surgical ablation during mitral valve surgery. This might be attributable to substrate modification caused by surgical lesions. Amiodarone improved the ECV-success rate only in patients with no associate ablation. Further larger randomized studies are necessary to confirm our findings.