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.     

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.     

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.     

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.     

Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin

Atrial fibrosis influences the development of atrial fibrillation (AF), particularly in the setting of structural heart disease where angiotensin-inhibition is partially effective for reducing atrial fibrosis and AF. Histone-deacetylase inhibition reduces cardiac hypertrophy and fibrosis, so we sought to determine if the HDAC inhibitor trichostatin A (TSA) could reduce atrial fibrosis and arrhythmias. Mice over-expressing homeodomain-only protein (HopX^Tg), which recruits HDAC activity to induce cardiac hypertrophy were investigated in 4 groups (aged 14-18 weeks): wild-type (WT), HopX^Tg, HopX^Tg mice treated with TSA for 2 weeks (TSA-HopX) and wild-type mice treated with TSA for 2 weeks (TSA-WT). These groups were characterized using invasive electrophysiology, atrial fibrosis measurements, atrial connexin immunocytochemistry and myocardial angiotensin II measurements. Invasive electrophysiologic stimulation, using the same attempts in each group, induced more atrial arrhythmias in HopX^Tg mice (48 episodes in 13 of 15 HopX^Tg mice versus 5 episodes in 2 of 15 TSA-HopX mice, P < 0.001; versus 9 episodes in 2 of 15 WT mice, P < 0.001; versus no episodes in any TSA-WT mice, P < 0.001). TSA reduced atrial arrhythmia duration in HopX^Tg mice (1307 ± 289 ms versus 148 ± 110 ms, P < 0.01) and atrial fibrosis (8.1 ± 1.5% versus 3.9 ± 0.4%, P < 0.001). Atrial connexin40 was lower in HopX^Tg compared to WT mice, and TSA normalized the expression and size distribution of connexin40 gap junctions. Myocardial angiotensin II levels were similar between WT and HopX^Tg mice (76.3 ± 26.0 versus 69.7 ± 16.6 pg/mg protein, P = NS). Therefore, it appears HDAC-inhibition reverses atrial fibrosis, connexin40 remodeling and atrial arrhythmia vulnerability independent of angiotensin II in cardiac hypertrophy.     

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.     

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.     

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.     

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.     

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.     

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.     

Heart rate turbulence for predicting new-onset atrial fibrillation in patients undergoing coronary artery bypass grafting

Background

Cardiac autonomic dysfunction reportedly contributes to the AF triggering and maintenance. Heart rate turbulence (HRT) is a promising noninvasive measure of cardiac autonomic function. We investigated whether ambulatory ECG-based HRT measurement could predict in-hospital new-onset atrial fibrillation (AF) after coronary artery bypass graft (CABG) surgery.

Methods

HRT onset (TO) and slope (TO) were prospectively measured from 24-h Holter recording in 113 consecutive patients prior to CABG. Abnormal HRT was defined as at least one abnormal value in TO (> 0%) and TS (< 2.5 ms/RR).

Results

Patients with abnormal HRT (n = 60) showed a significantly higher AF incidence (47% versus 21%, P = 0.005) and AF burden (29 ± 9 versus 7 ± 5 h, P = 0.043) than those with normal HRT (n = 53). Abnormal HRT were identified as independent predictors for the new-onset postoperative AF. During the follow-up period (12.0 ± 10.5 months), the abnormal HRT group showed a worse prognosis versus the normal HRT group regarding the AF recurrence/postoperative stroke (P = 0.018). Additionally, the postoperative AF incidence, in-hospital AF burden, and the rate of AF recurrence/postoperative stroke gradually elevated as the number of abnormal HRT values increased from 0 to 2.

Conclusions

Preoperative abnormal HRT was significantly associated with worse short-term (in-hospital new-onset AF) and long-term outcomes (post-discharge AF recurrence/postoperative stroke) after CABG surgery. Additional studies incorporating preventive interventions depending on the preoperative HRT results might be worthwhile in this patient group.     

Combined circular multielectrode catheter and point-by-point ablation is superior to point-by-point ablation alone in eliminating atrial fibrillation

Background

Besides conventional point-by-point ablation, novel multielectrode catheters emerge for ablation of atrial fibrillation (AF). We sought to evaluate the clinical utility of a pulmonary vein (PV) isolation approach combining the advantages of both technologies.

Methods

The study included 240 consecutive AF patients (60 ± 11 years, 68% males, 62% paroxysmal). In the combined ablation group (n = 120), PV isolation was performed with a circular multielectrode catheter (PVAC, Medtronic Ablation Frontiers) and completed by conventional point-by-point ablation (NaviStar ThermoCool Catheter, Lasso/CARTO technology, Biosense Webster). In the point-by-point ablation group (n = 120), PV isolation was performed with point-by-point ablation alone.

Results

Complete 1-year ablation success (freedom from any atrial arrhythmia off antiarrhythmic drugs) was more frequently observed in the combined ablation group (58.0% versus 43.3%, hazard ratio 1.72, 95% confidence interval 1.19–2.48, p = 0.004). Also clinical success (≥ 90% reduction of arrhythmia burden on/off antiarrhythmic drugs) was significantly associated with the combined ablation approach (p = 0.001). These associations remained significant after multivariable adjustment (both p ≤ 0.005) and were not dependent on the type of AF. The rate of major adverse events (3.3% versus 2.5%) and the procedure time did not differ between groups. The fluoroscopy time, however, was significantly shorter in the combined ablation group (p < 0.001) reflecting the reduced need for radiation during multielectrode catheter ablation.

Conclusions

A combined PV isolation approach based on multielectrode catheter ablation and complementary point-by-point ablation is superior to point-by-point ablation alone and reveals to be safe. A potential explanation for these findings is the improved durability of ablation lesion after the combined ablation approach.     

Frailty in patients affected by atrial fibrillation

Atrial fibrillation (AF) is the most common arrhythmia among elderly people. However its relationship with the frailty syndrome is not well understood. It has been suggested that AF may be a marker of frailty in elderly, leading to the loss of independence in performing of routine daily activities. The aim of this study is to investigate the association between AF, frailty and cognitive decline in elderly patients. A total of 140 hospitalized patients, mean age 79.2 ± 7.4 years were enrolled in our study. Of these, 70 were affected by parossistic, persistent or permanent AF and 70, matched for age and gender, were concurrently studied as control. Cognitive impairment and frailty state has been evaluated in each patient using the Mini Mental State Examination (MMSE) and a standard score of accumulated deficits for constructing a frailty index. We have observed a higher number of frail patients in the AF group as compared with controls (88.6% vs 67.1%, p = 0.004). The group of patients with frailty syndrome had MMSE score significantly lower than those of the nonfrail group (16.8 ± 9.8 vs 22.2 ± 6.4, p = 0.005). Furthermore, a negative correlation between MMSE score and frailty index (rho = −0.517, p < 0.001) has been shown. Our study points out a statistical association between frailty and AF. Atrial fibrillation could worsen the frailty state, but perspective studies are necessary to confirm an increased mortality in patients affected by AF and frailty.     

Left atrial size and function as predictors of new-onset of atrial fibrillation in patients with asymptomatic aortic stenosis: The simvastatin and ezetimibe in aortic stenosis study

Background

Left atrial (LA) size and function change with chronically increased left ventricular (LV) filling pressures. It remains unclear whether these variations in LA parameters can predict new-onset atrial fibrillation (AF) in asymptomatic patients with aortic stenosis (AS).

Methods

Data were obtained in asymptomatic patients with mild-to-moderate AS (2.5 ≤ transaortic Doppler velocity ≤ 4.0 m/s), preserved LV ejection fraction (EF), no previous AF, and were enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis study. Peak-aortic velocity, LA_max volume & LA_min volume were measured by echocardiography. LA conduit (LA_con) volume was defined as LV stroke volume − LA stroke volume. LA function was expressed as LA-EF (LA_max − LA_min volume/LA_max).

Results

In the 1159 patients included, new-onset AF occurred in 71 patients (6.1%) within a mean follow-up of 4.2 ± 0.9 years. Mean age was 66 ± 9.7 years, aortic valve area index 0.6 ± 0.2 cm²/m², LV mass 99.2 ± 29.7 g/m², LA_max volume 34.6 ± 12.0 mL/m², LA_min volume 17.9 ± 9.3 mL/m², LA-EF 50 ± 15% and LA_con volume 45 ± 21 mL/m². Baseline LA_min volume predicted new-onset AF in Cox multivariable analysis (HR:2.3 [95%CI:1.3–4.4], P < 0.01), and added prognostic information on AF development beyond conventional risk factors (likelihood ratio, P < 0.01). In comparison of c-indexes LA_min volume was superior to all other LA measurements. Net reclassification index improved by 15.9% when adding LA_min volume to a model with classic risk factors for AF (P = 0.01).

Conclusion

LA_min volume independently predicted new-onset AF in patients with asymptomatic AS and was superior to LA-EF, LA_con and LA_max volumes and conventional risk factors.     

Differential KATP channel pharmacology in intact mouse heart

Classically, cardiac sarcolemmal K_ATP channels have been thought to be composed of Kir6.2 (KCNJ11) and SUR2A (ABCC9) subunits. However, the evidence is strong that SUR1 (sulfonylurea receptor type 1, ABCC8) subunits are also expressed in the heart and that they play a significant functional role in the atria. To examine this further, we have assessed the effects of isotype-specific potassium channel-opening drugs, diazoxide (specific to SUR1 > SUR2A) and pinacidil (SUR2A > SUR1), in intact hearts from wild-type mice (WT, n =   6), SUR1^−/− (n = 6), and Kir6.2^−/− mice (n = 5). Action potential durations (APDs) in both atria and ventricles were estimated by optical mapping of the posterior surface of Langendorff-perfused hearts. To confirm the atrial effect of both openers, isolated atrial preparations were mapped in both WT (n = 4) and SUR1^−/− (n =   3) mice. The glass microelectrode technique was also used to validate optical action potentials. In WT hearts, diazoxide (300 μM) decreased APD in atria (from 33.8 ± 1.9 ms to 24.2 ± 1.1 ms, p < 0.001) but was without effect in ventricles (APD 60.0 ± 7.6 ms vs. 60.8 ± 7.5 ms, respectively, NS), consistent with an atrial-specific role for SUR1. The absence of SUR1 resulted in loss of efficacy of diazoxide in SUR1^−/− atria (APD 36.8 ± 1.9 ms vs. 36.8 ± 2.8 ms, respectively, NS). In contrast, pinacidil (300 μM) significantly decreased ventricular APD in both WT and SUR1^−/− hearts (from 60.0 ± 7.6 ms to 29.8 ± 3.5 ms in WT, p < 0.001, and from 63.5 ± 2.1 ms to 24.8 ± 3.8 ms in SUR1^−/−, p < 0.001), but did not decrease atrial APD in either WT or SUR1^−/− hearts. Glibenclamide (10 μM) reversed the effect of pinacidil in ventricles and restored APD to control values. The absence of Kir6.2 subunits in Kir6.2^−/− hearts resulted in loss of efficacy of both openers (APD 47.2 ± 2.2 ms vs. 47.6 ± 2.1 ms and 50.8 ± 2.4 ms, and 90.6 ± 5.7 ms vs. 93.2 ± 6.5 ms and 117.3 ± 6.4 ms, for atria and ventricle in control versus diazoxide and pinacidil, respectively). Collectively, these results indicate that in the same mouse heart, significant differential K_ATP pharmacology in atria and ventricles, resulting from SUR1 predominance in forming the atrial channel, leads to differential effects of potassium channel openers on APD in the two chambers.     

Risk factors and incidence of stroke and MACE in Chinese atrial fibrillation patients presenting to emergency departments: A national wide database analysis

Background

Contemporary clinical risk stratification schemata for predicting stroke and thromboembolism in patients with atrial fibrillation (AF) are largely derived from western cohorts. The purpose of the present study is to assess the potential risk factors for stroke and major adverse cardiac events (MACE) in a large population of Chinese AF patients presenting to emergency department.

Methods

The Chinese AF registry is a multicenter, prospective, observational study with 1 year follow up. Patients who presented to an emergency department with atrial fibrillation or atrial flutter were recruited from November 2008 to October 2011. The MACE included all cause mortality, stroke, non-central nervous system systemic embolism and major bleed.

Results

A total of 2016 AF patients (1104 women) were included in the final analysis. Multivariate Cox regression analysis showed that the risk factors for stroke were female gender (1.419 (1.003–2.008), p = 0.048), age ≥ 75 (2.576 (1.111–4.268), p < 0.001), previous stroke/TIA (2.039 (1.415–2.939), p < 0.001), LVSD (1.700 (1.015–2.848), p = 0.044) and previous major bleeding (2.481 (1.141–5.397), p = 0.022). For MACE, age ≥ 75 (3.042 (2.274–4.071), p < 0.001), heart failure (1.371 (1.088–1.728), p = 0.008), previous stroke/TIA (1.560 (1.244–1.957), p < 0.001), LVSD (1.424 (1.089–1.862), p = 0.010) and COPD (1.393 (1.080–1.798), p = 0.011) were independent risk factors. History of hypertension and diabetes was not associated with the events, neither stroke nor MACE. For non-anticoagulation patients, the c-statistic for predicting stroke was 0.685 (0.637–0.732) and for MACE was 0.717 (0.687–0.746), respectively.

Conclusions

We demonstrated that, except for the traditional risk factors, clinicians should pay more attention to patients with prior major bleeding or COPD in Chinese AF patients presenting to emergency department.     

Time course of markers of tissue repair after ablation of atrial fibrillation and their relation to left atrial structural changes and clinical ablation outcome

Background

Radiofrequency ablation of atrial fibrillation (AF) creates left atrial (LA) tissue damage with a subsequent healing process. We sought to prospectively assess the time course of biomarkers of tissue repair after ablation and to evaluate their association with clinical variables.

Methods

30 consecutive patients (57.9 ± 1.7 yrs, 63% males) with paroxysmal AF underwent a CARTO-guided LA circumferential ablation, Lasso-guided segmental pulmonary vein isolation and ablation of complex fractionated atrial electrograms. Matrix metalloproteinase-9 (MMP-9) and transforming growth factor-β1 (TGF-β1), both key regulators of tissue repair, and the aminoterminal propeptide of type III procollagen (PIIINP), reflecting collagen synthesis, were determined in blood samples before and 6 h, 1, 2, 7, 30, 90 and 180 days post-ablation.

Results

All markers showed a significant ablation-induced up-regulation (MMP-9: 1.8 ± 0.1-fold, TGF-β1: 2.4 ± 0.4-fold, PIIINP: 1.3 ± 0.1-fold). MMP-9 was significantly up-regulated until day 90, TGF-β1 only on day 2. PIIINP increased from day 2 to 7. The area under the curve (AUC) of MMP-9 and TGF-β1 correlated with the ablation-induced reduction of LA volume (both p < 0.05). The AUC of MMP-9 was additionally associated with the amount of radiofrequency energy delivered during ablation (p < 0.05). At 12 months of follow-up 57% of patients were free of AF off antiarrhythmic drugs. The AUC of PIIINP independently predicted recurrent AF (p < 0.05).

Conclusions

Markers of healing showed a significant up-regulation after AF ablation detectable for up to 90 days. A more pronounced up-regulation of MMP-9 or TGF-β1 is associated with a greater reduction of LA size. High PIIINP levels after ablation predict a poor ablation outcome.     

Electrical stimulation of sympathetic neurons induces autocrine/paracrine effects of NGF mediated by TrkA

Neuronal remodeling with increased sympathetic innervation density has been implicated in the pathogenesis of atrial fibrillation (AF). Recently, increased transcardiac nerve growth factor (NGF) levels were observed in a canine model of AF. Whether atrial myocytes or cardiac sympathetic neurons are the source of neurotrophins, and whether NGF is the main neurotrophic factor contributing to sympathetic nerve sprouting (SNS) in AF still remains unclear. Therefore, neonatal rat atrial myocytes were cultured under conditions of high frequency electrical field stimulation (HFES) to mimic rapid atrial depolarization. Likewise, sympathetic neurons from the superior cervical ganglia of neonatal rats were exposed to HFES to simulate the physiological effect of sympathetic stimulation. Real-time PCR, ELISA and Western blots were performed to analyze the expression pattern of NGF and neurotrophin-3 (NT-3). Baseline NGF and NT-3 content was 3-fold higher in sympathetic neurons than in atrial myocytes (relative NGF protein expression: 1 ± 0.0 vs. 0.37 ± 0.11, all n = 5, p < 0.05). HFES of sympathetic neurons induced a frequency dependent NGF and NT-3 gene and protein up-regulation (relative NGF protein expression: 0 Hz = 1 ± 0.0 vs. 5 Hz = 1.13 ± 0.19 vs. 50 Hz = 1.77 ± 0.08, all n = 5, 0 Hz/5 Hz vs. 50 Hz p < 0.05), with a subsequent increase of growth associated protein 43 (GAP-43) expression and morphological SNS. Moreover, HFES of sympathetic neurons increased the tyrosine kinase A (TrkA) receptor expression. HFES induced neurotrophic effects could be abolished by lidocaine, TrkA blockade or NGF neutralizing antibodies, while NT-3 neutralizing antibodies had no significant effect on SNS. In neonatal rat atrial myocytes, HFES resulted in myocyte hypertrophy accompanied by an increase in NT-3 and a decrease in NGF expression. In summary, this study provides evidence that high-rate electrical stimulation of sympathetic neurons mediates nerve sprouting by an increase in NGF expression that targets the TrkA receptor in an autocrine/paracrine manner.     

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.