Atrial epicardial adipose tissue abundantly secretes myeloperoxidase and activates atrial fibroblasts in patients with atrial fibrillation.

BACKGROUND: Epicardial adipose tissue (EAT) secretome induces fibrosis. Fibrosis, primarily extracellular matrix (ECM) produced by fibroblasts, creates a substrate for atrial fibrillation (AF). Whether the EAT secretome from patients with AF activates human atrial fibroblasts and through which components, remains unexplored. RESEARCH AIMS: (a) To investigate if the EAT secretome from patients with versus without AF increases ECM production in atrial fibroblasts. (b) To identify profibrotic proteins and processes in the EAT secretome and EAT from patients with, who will develop (future onset), and without AF. METHODS: Atrial EAT was obtainded during thoracoscopic ablation (AF, n = 20), or open-heart surgery (future onset and non-AF, n = 35). ECM gene expression of human atrial fibroblasts exposed to the EAT secretome and the proteomes of EAT secretome and EAT were assessed in patients with and without AF. Myeloperoxidase and neutrophil extracellular traps (NETs) were assessed immunohistochemically in patients with paroxysmal, persistent, future onset, and those who remain free of AF (non-AF). RESULTS: The expression of COL1A1 and FN1 in fibroblasts exposed to secretome from patients with AF was 3.7 and 4.7 times higher than in patients without AF (p < 0.05). Myeloperoxidase was the most increased protein in the EAT secretome and EAT from patients with versus without AF (FC 18.07 and 21.57, p < 0.005), as was the gene-set neutrophil degranulation. Immunohistochemically, myeloperoxidase was highest in persistent (FC 13.3, p < 0.0001) and increased in future onset AF (FC 2.4, p = 0.02) versus non-AF. Myeloperoxidase aggregated subepicardially and around fibrofatty infiltrates. NETs were increased in patients with persistent versus non-AF (p = 0.03). CONCLUSION: In AF, the EAT secretome induces ECM gene expression in atrial fibroblasts and contains abundant myeloperoxidase. EAT myeloperoxidase was increased prior to AF onset, and both myeloperoxidase and NETs were highest in persistent AF, highlighting the role of EAT neutrophils in the pathophysiology of AF.

Circulating adipose tissue proteins involved in atrial fibrillation: An explorative scoping review.

Obesity increases the risk of atrial fibrillation (AF), potentially through proteins secreted by adipose tissue (AT) that affect atrial electrical and structural remodeling. We aim to give a comprehensive overview of circulating AT proteins involved in inflammation and fibrosis, that are associated with prevalent AF (paroxysmal or persistent) and the risk on developing new-onset AF. These include adipokines, defined as proteins enriched in AT as adiponectin, but also proteins less specific to AT. We systematically performed an explorative search for studies reporting associations between proteins secreted from cells residing in the AT and AF, and additionally assessed the effect of obesity on these proteins by a secondary search. The AT proteins involved in inflammation were mostly increased in patients with prevalent and new-onset AF, and with obesity, while the AT enriched adipokines were mostly not associated with AF. This review provides insight into circulating adipose tissue proteins involved in AF substrate formation.

Screening for paroxysmal atrial fibrillation in primary care using Holter monitoring and intermittent, ambulatory single-lead electrocardiography.

BACKGROUND: Timely detection of atrial fibrillation (AF) is important because of its increased risk of thrombo-embolic events. Single time point screening interventions fall short in detection of paroxysmal AF, which requires prolonged electrocardiographic monitoring, usually using a Holter. However, traditional 24-48 h Holter monitoring is less appropriate for screening purposes because of its low diagnostic yield. Intermittent, ambulatory screening using a single-lead electrocardiogram (1 L-ECG) device can offer a more efficient alternative. METHODS: Primary care patients of ≥65 years participated in an opportunistic screening study for AF. We invited patients with a negative 12 L-ECG to wear a Holter monitor for two weeks and to use a MyDiagnostick 1 L-ECG device thrice daily. We report the yield of paroxysmal AF found by Holter monitoring and calculate the diagnostic accuracy of the 1 L-ECG device's built-in AF detection algorithm with the Holter monitor as reference standard. RESULTS: We included 270 patients, of whom four had AF in a median of 8.0 days of Holter monitoring, a diagnostic yield of 1.5% (95%-CI: 0.4-3.8%). In 205 patients we performed simultaneous 1 L-ECG screening. For diagnosing AF based on the 1 L-ECG device's AF detection algorithm, sensitivity was 66.7% (95%-CI: 9.4-99.2%), specificity 68.8% (95%-CI: 61.9-75.1%), positive predictive value 3.1% (95%-CI: 1.4-6.8%) and negative predictive value 99.3% (95%-CI: 96.6-99.9%). CONCLUSION: We found a low diagnostic yield of paroxysmal AF using Holter monitoring in elderly primary care patients with a negative 12 L-ECG. The diagnostic accuracy of an intermittently, ambulatory used MyDiagnostick 1 L-ECG device as interpreted by its built-in AF detection algorithm is limited.

Clinical course of sinus node dysfunction after thoracoscopic surgery for atrial fibrillation-analysis of the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery (AFACT) study.

PURPOSE: Sinus node dysfunction (SND) may complicate thoracoscopic surgical atrial fibrillation (AF) ablation. Identifying patients at risk is important, as SND may require temporary or permanent pacing. To determine the incidence of postoperative SND and duration of symptoms in patients who underwent thoracoscopic surgical ablation. METHODS: Patients with paroxysmal or persistent AF included in the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery (AFACT) study underwent pulmonary vein isolation and additional left atrial ablations on indication. Patients were randomized to ganglion plexus ablation or control. SND was defined as symptomatic or asymptomatic junctional rhythm exceeding sinus rate within 30 days postoperatively. The SND risk was assessed by using a univariable logistic regression model. The rate of pacemaker implantation was determined. RESULTS: The AFACT study included 240 patients. SND developed in 17 (7.1%) patients, not affected by randomized treatment, p = 0.18. SND patients more often had persistent AF (88.2%) than patients without SND (57.4%), p = 0.01. After univariable testing, persistent AF (OR 5.57 CI 1.52-35.90, p = 0.02) and additional left atrial ablations (OR 12.10 CI 2.40-220.20, p = 0.02) were associated with postoperative SND. Six (35.3%) patients needed temporary pacing for 1-7 days; permanent pacemakers (PMs) were implanted for SND in five (29.4%) patients. CONCLUSION: Additional left atrial ablations strongly increase the SND risk. The majority of SND was temporary, and sinus rhythm resolved within days, which indicates that a conservative approach with regard to pacemaker implantation should be considered.

Effect of Spironolactone on Atrial Fibrillation in Patients with Heart Failure with Preserved Ejection Fraction: Post-Hoc Analysis of the Randomized, Placebo-Controlled TOPCAT Trial.

BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) reduce the risk of atrial fibrillation (AF) in patients with heart failure (HF) and a reduced ejection fraction. The efficacy of MRAs for AF prevention in patients with HF and a preserved ejection fraction (HFpEF) is unclear. OBJECTIVES: We performed a secondary analysis of a randomized placebo-controlled trial to determine the efficacy of spironolactone in reducing new-onset AF and recurrence of AF in 2733 patients with symptomatic HFpEF. METHODS: Patients with and without prevalent AF at baseline were included, and those with permanent AF were excluded. Patients were randomized 1:1 to spironolactone or placebo. The risk of new-onset AF or the recurrence of AF was quantified using hazard ratios (HRs) with corresponding 95% confidence intervals (CIs). RESULTS: At baseline, 2228 (64.7%) patients had no history of AF (spironolactone, n = 1111; placebo, n = 1117), whereas 505 (18.4%) patients had prevalent AF (spironolactone, n = 260; placebo, n = 245). During a median follow-up of 3.1 years (interquartile range [IQR] 2.0-4.9), the incidence of new-onset AF was similar in both treatment arms: spironolactone 5.2% (n = 58) versus placebo 4.4% (n = 49); p = 0.41. The risk of new-onset AF was similar in both treatment arms: HR 1.19; 95% CI 0.81-1.74; p = 0.38. AF recurrence was also similar in both treatment arms during a median follow-up of 3.3 years (IQR 1.9-4.7): spironolactone 11.5% (n = 30) versus placebo 11.8% (n = 29); p = 1.00. The risk of recurrence of AF did not differ per treatment arm: HR 0.94; 95% CI 0.57-1.58; p = 0.83. CONCLUSION: Spironolactone does not reduce the risk of new-onset AF or AF recurrence in patients with HFpEF. This is in contrast to results in cohorts of patients with HF and a reduced ejection fraction. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier no. NCT00094302 (TOPCAT).

Acetylcholine Delays Atrial Activation to Facilitate Atrial Fibrillation.

BACKGROUND: Acetylcholine (ACh) shortens action potential duration (APD) in human atria. APD shortening facilitates atrial fibrillation (AF) by reducing the wavelength for reentry. However, the influence of ACh on electrical conduction in human atria and its contribution to AF are unclear, particularly when combined with impaired conduction from interstitial fibrosis. OBJECTIVE: To investigate the effect of ACh on human atrial conduction and its role in AF with computational, experimental, and clinical approaches. METHODS: S1S2 pacing (S1 = 600 ms and S2 = variable cycle lengths) was applied to the following human AF computer models: a left atrial appendage (LAA) myocyte to quantify the effects of ACh on APD, maximum upstroke velocity (V max ), and resting membrane potential (RMP); a monolayer of LAA myocytes to quantify the effects of ACh on conduction; and 3) an intact left atrium (LA) to determine the effects of ACh on arrhythmogenicity. Heterogeneous ACh and interstitial fibrosis were applied to the monolayer and LA models. To corroborate the simulations, APD and RMP from isolated human atrial myocytes were recorded before and after 0.1 µM ACh. At the tissue level, LAAs from AF patients were optically mapped ex vivo using Di-4-ANEPPS. The difference in total activation time (AT) was determined between AT initially recorded with S1 pacing, and AT recorded during subsequent S1 pacing without (n = 6) or with (n = 7) 100 µM ACh. RESULTS: In LAA myocyte simulations, S1 pacing with 0.1 µM ACh shortened APD by 41 ms, hyperpolarized RMP by 7 mV, and increased V max by 27 mV/ms. In human atrial myocytes, 0.1 µM ACh shortened APD by 48 ms, hyperpolarized RMP by 3 mV, and increased V max by 6 mV/ms. In LAA monolayer simulations, S1 pacing with ACh hyperpolarized RMP to delay total AT by 32 ms without and 35 ms with fibrosis. This led to unidirectional conduction block and sustained reentry in fibrotic LA with heterogeneous ACh during S2 pacing. In AF patient LAAs, S1 pacing with ACh increased total AT from 39.3 ± 26 ms to 71.4 ± 31.2 ms (p = 0.036) compared to no change without ACh (56.7 ± 29.3 ms to 50.0 ± 21.9 ms, p = 0.140). CONCLUSION: In fibrotic atria with heterogeneous parasympathetic activation, ACh facilitates AF by shortening APD and slowing conduction to promote unidirectional conduction block and reentry.

Should Every Patient With Atrial Fibrillation and a CHA2DS2-VASc Score of 1 Be Anticoagulated? A Systematic Review of 37,030 Patients.

Patients with atrial fibrillation (AF) are at risk of thromboembolic events. The CHA2DS2-VASc (congestive heart failure, hypertension, age 65-74, diabetes, female sex and vascular disease, which all count for 1 point, and previous transient ischemic stroke/stroke or age ≥ 75 years, which count for two points) score stratifies this risk and consequently indicates whether anticoagulation is required but leaves room for debate regarding patients with a CHA2DS2-VASc score of 1, irrespective of sex. A score of 1, irrespective of sex, is derived from varying risk factors and may represent different risks. We systematically searched PubMed from inception to July 31, 2017, for studies describing thromboembolic risk per risk factor of the CHA2DS2-VASc score in patients with AF not treated with an anticoagulant. Two independent reviewers selected, appraised, and extracted the data to determine the thromboembolic risk per risk factor. Per study, risk factors were ranked for highest through lowest risk. Five studies were included, comprising 37,030 subjects with a CHA2DS2-VASc score of 1. Numerically, the highest event rates were seen in patients without comorbidities, but aged 65-74 years, while event rates in patients with vascular disease tended to be the lowest. Age 65-74 years is associated with the highest risk, hazard ratios ranging from 1.9 (95% confidence interval, 1.7-2.1) to 3.9 (95% confidence interval, 2.3-6.6), while comorbid cardiovascular conditions are associated with lower, but still considerably increased, risks. The thromboembolic risk differed between the risk factors of the CHA2DS2-VASc score in patients with AF, with age 65-74 years associated with the highest and most consistent risk. However, all show a significantly and clinically relevant increased thromboembolic risk. Besides the differences between risk factors of the CHA2DS2-VASc score, differences within risk factors may also alter stroke risk.

Additional Ganglion Plexus Ablation During Thoracoscopic Surgical Ablation of Advanced Atrial Fibrillation: Intermediate Follow-Up of the AFACT Study.

OBJECTIVES: The authors report the 2-year follow-up results of the AFACT (Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery) study. BACKGROUND: The AFACT study randomized patients with advanced atrial fibrillation (AF) to thoracoscopic AF ablation with or without additional ganglion plexus (GP) ablation. At 1 year, there was no difference in AF freedom between the groups, but autonomic modification may exert beneficial effects during longer follow-up. METHODS: Patients underwent thoracoscopic pulmonary vein isolation, with additional left atrial lines in persistent AF patients, and were randomized 1:1 to ablation of the 4 major GP and Marshall ligament or no GP ablation (control). Patients were followed every 3 months up to 18 months and at 24 months. After an initial 3-month blanking period, all antiarrhythmic drugs were discontinued. RESULTS: The authors randomized 240 patients (age 59 ± 8 years, 73% men, 68% enlarged left atrium, 60% persistent AF), of whom 228 patients (95%) completed follow-up. Freedom of any atrial tachyarrhythmia did not differ significantly between the GP group (55.6%) and control group (56.1%) (p = 0.91), with no difference in paroxysmal (p = 0.60) or persistent AF patients (p = 0.88). Documented AF recurrences were similar between treatment arms: 11.8% (GP) versus 11.0% (control) had >3 recurrences/year (p = 0.82). More persistent AF patients (17.0%) than paroxysmal (3.2%) had >3 recurrences per year (p < 0.01). Despite this, 78% of patients were off antiarrhythmic drugs after 2 years. No procedural-related complications occurred in the second year. CONCLUSIONS: Additional GP ablation during thoracoscopic surgery for advanced AF does not affect freedom of AF recurrence. As GP ablation is associated with more major procedural complications, it should not routinely be performed. (Atrial Fibrillation Ablation and Autonomic Modulation via Thorascopic Surgery [AFACT]; NCT01091389).

Persistent atrial fibrillation: A systematic review and meta-analysis of invasive strategies.

BACKGROUND: Persistent atrial fibrillation (AF) is associated with higher stroke and mortality risk than paroxysmal AF (pAF). Outcomes of catheter or surgical ablation are worse in patients with persistent AF than in pAF, and the optimal invasive rhythm control strategy has not been established. PURPOSE: We provide a contemporary systematic overview on efficacy and safety of catheter and minimally-invasive surgical ablation for persistent AF. METHODS: We systematically searched EMBASE, MEDLINE and CENTRAL from inception to July 2018 for randomized trials on surgical and catheter ablation, and included all study arms on persistent AF. Outcome was AF freedom after ≥12 months follow-up without AAD use. Random effects models were used to calculate proportions with 95%-confidence intervals. Safety consisted of adverse events during treatment and follow-up. RESULTS: We included 6 studies on minimally-invasive surgical ablation and 56 on catheter ablation, involving 7624 patients with persistent AF. AF Freedom at 12 months was 69% (95%CI 64-74%) after surgical and 51% (95%CI 46-56%) after catheter ablation. More severe procedural adverse events occurred with surgery than with catheter ablation. CONCLUSIONS: In persistent AF patients, minimally-invasive surgical ablation is associated with more procedural complications, but higher AF freedom. As adverse events after surgical ablation appear more severe than in catheter ablation, a patient-tailored therapy choice is warranted.

Quality of life improves after thoracoscopic surgical ablation of advanced atrial fibrillation: Results of the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery (AFACT) study.

OBJECTIVE: We evaluated health-related quality of life at 12 months after thoracoscopic surgical ablation in patients enrolled in the Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery study. The Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery study assessed the efficacy and safety of ganglion plexus ablation in patients with symptomatic advanced atrial fibrillation undergoing thoracoscopic surgical ablation. METHODS: Patients (n = 240) underwent thoracoscopic pulmonary vein isolation with additional ablation lines in patients with persistent atrial fibrillation. Subjects were randomized to additional ganglion plexus ablation or control. Short Form 36 quality of life questionnaires were collected at baseline and at 6 and 12 months of follow-up. RESULTS: A total of 201 patients were eligible for quality of life analysis (age 59 ± 8 years, 72% were men, 68% had an enlarged left atrium, 57% had persistent atrial fibrillation). Patients improved in physical and mental health at 6 months (both P < .01) and 12 months (both P < .01) relative to baseline, with no difference between the ganglion plexus (n = 101) and control (n = 100) groups. Short Form 36 subscores in patients with 1 or no atrial fibrillation recurrences were similar to those in the general Dutch population after 12 months. Patients with multiple atrial fibrillation recurrences (30%) improved in mental (P < .01), but not physical health, and 6 of 8 Short Form 36 subscales remained below those of the general Dutch population. Patients with irreversible, but not with reversible procedural complications had persistently diminished quality of life scores at 12 months. CONCLUSIONS: Thoracoscopic surgery for advanced atrial fibrillation results in improvement in quality of life, regardless of additional ganglion plexus ablation. Quality of life in patients with no or 1 atrial fibrillation recurrence increased to the level of the general Dutch population, whereas in patients with multiple atrial fibrillation recurrences quality of life remained lower. Irreversible but not reversible procedural complications were associated with persistently lower quality of life.

The change in circulating galectin-3 predicts absence of atrial fibrillation after thoracoscopic surgical ablation.

Aims: Galectin-3 (Gal-3) is an important mediator of cardiac fibrosis, particularly in heart failure. Increased Gal-3 concentration (Gal-3), associated with increased risk of developing atrial fibrillation (AF), may reflect atrial fibrotic remodelling underlying AF progression. We aimed to investigate whether the change in serum Gal-3 reflects alterations of the arrhythmogenic atrial substrate following thoracoscopic AF surgery, and predicts absence of AF. Methods and results: Consecutive patients undergoing thoracoscopic AF surgery were included. Left atrial appendages (LAAs) and serum were collected during surgery and serum again 6 months thereafter. Gal-3 was determined in tissue and serum. Interstitial collagen in the LAA was quantified using Picrosirius red staining. Ninety-eight patients (76% male, mean age 60 ± 9 years) underwent thoracoscopic surgery for advanced AF. Patients with increased Gal-3 after ablation compared to baseline had a higher recurrence rate compared to patients with decreased or unchanged Gal-3 (HR 2.91, P = 0.014). These patients more frequently had persistent AF, longer AF duration and thick atrial collagen strands (P = 0.049). At baseline, Gal-3 was similar between patients with and without AF recurrence: 14.8 ± 3.9 µg/L vs. 13.7 ± 3.7 µg/L, respectively in serum (P = 0.16); 94.5 ± 19.4 µg/L vs. 93.3 ± 30.8µg/L, respectively in atrial myocardium (P = 0.83). There was no correlation between serum Gal-3 and left atrial Gal-3 (P = 0.20), nor between serum Gal-3 and the percentage of fibrosis in LAA (P = 0.18). Conclusion: The change of circulating Gal-3, rather than its baseline value, predicts AF recurrence after thoracoscopic ablation. Patients in whom Gal-3 increases after ablation have a high recurrence rate reflecting ongoing profibrotic signalling, irrespective of arrhythmia continuation.

Ganglion Plexus Ablation in Advanced Atrial Fibrillation: The AFACT Study.

BACKGROUND: Patients with long duration of atrial fibrillation (AF), enlarged atria, or failed catheter ablation have advanced AF and may require more extensive treatment than pulmonary vein isolation. OBJECTIVES: The aim of this study was to investigate the efficacy and safety of additional ganglion plexus (GP) ablation in patients undergoing thoracoscopic AF surgery. METHODS: Patients with paroxysmal AF underwent pulmonary vein isolation. Patients with persistent AF also received additional lines (Dallas lesion set). Patients were randomized 1:1 to additional epicardial ablation of the 4 major GPs and Marshall's ligament (GP group) or no extra ablation (control) and followed every 3 months for 1 year. After a 3-month blanking period, all antiarrhythmic drugs were discontinued. RESULTS: Two hundred forty patients with a mean AF duration of 5.7 ± 5.1 years (59% persistent) were included. Mean procedure times were 185 ± 54 min and 168 ± 54 min (p = 0.015) in the GP (n = 117) and control groups (n = 123), respectively. GP ablation abated 100% of evoked vagal responses; these responses remained in 87% of control subjects. Major bleeding occurred in 9 patients (all in the GP group; p < 0.001); 8 patients were managed thoracoscopically, and 1 underwent sternotomy. Sinus node dysfunction occurred in 12 patients in the GP group and 4 control subjects (p = 0.038), and 6 pacemakers were implanted (all in the GP group; p = 0.013). After 1 year, 4 patients had died (all in the GP group, not procedure related; p = 0.055), and 9 were lost to follow-up. Freedom from AF recurrence in the GP and control groups was not statistically different whether patients had paroxysmal or persistent AF. At 1 year, 82% of patients were not taking antiarrhythmic drugs. CONCLUSIONS: GP ablation during thoracoscopic surgery for advanced AF has no detectable effect on AF recurrence but causes more major adverse events, major bleeding, sinus node dysfunction, and pacemaker implantation. (Atrial Fibrillation Ablation and Autonomic Modulation via Thoracoscopic Surgery [AFACT]; NCT01091389).

Documented atrial fibrillation recurrences after pulmonary vein isolation are associated with diminished quality of life.

AIMS: Pulmonary vein isolation (PVI) aims at eliminating symptomatic atrial fibrillation. In this regard, the most relevant indication for this procedure is the reduction of symptoms and improvement of quality of life (QoL) in patients who remain symptomatic despite antiarrhythmic drug treatment. We investigated the relation between documented atrial fibrillation recurrences and QoL in patients after PVI. METHODS: One hundred and six PVIs were performed in 99 patients. Follow-up was mainly performed at referring hospitals. Short Form 36 (SF-36) QoL questionnaires were completed before and 1 year after PVI. Electrocardiographic recordings from the first postprocedural year were retrospectively collected, 3 months blanking excluded. Atrial fibrillation recurrence was defined as any recurrence of atrial arrhythmia documented on ECG or 24-h-Holter. RESULTS: Before PVI, patients had lower QoL than the general Dutch population in 7/8 SF-36 questionnaire subscales (sumQoL 419.4 ±â€Š161 vs. 617.9, P < 0.001). Atrial fibrillation recurred in 52 (49%) patients. In these patients, four subscales increased following PVI (physical functioning P < 0.001, role physical P = 0.006, bodily pain P = 0.011 and social functioning P = 0.047). SumQoL remained lower than the general Dutch population (546.7 ±â€Š157, P = 0.003). In patients without documented recurrences, QoL improved to a level similar to that of the general Dutch population (602.9 ±â€Š148; P = 0.46). The number of electrocardiographic recordings was lower in the group without documented recurrences (2.5 ±â€Š1.8 vs. 3.8 ±â€Š1.7, P = 0.002). CONCLUSION: In patients without documentation of atrial fibrillation, QoL increased up to the level of the general population after PVI, but it remained lower in patients with recurrences. In the latter group more ECGs were done, suggesting that QoL relates particularly to symptomatic episodes. Improvement of QoL is therefore an important attribute of PVI.

Atrial fibrosis and conduction slowing in the left atrial appendage of patients undergoing thoracoscopic surgical pulmonary vein isolation for atrial fibrillation.

BACKGROUND: Atrial fibrosis is an important component of the arrhythmogenic substrate in patients with atrial fibrillation (AF). We studied the effect of interstitial fibrosis on conduction velocity (CV) in the left atrial appendage of patients with AF. METHODS AND RESULTS: Thirty-five left atrial appendages were obtained during AF surgery. Preparations were superfused and stimulated at 100 beats per minute. Activation was recorded with optical mapping. Longitudinal CV (CVL), transverse CV (CVT), and activation times (> 2 mm distance) were measured. Interstitial collagen was quantified and graded qualitatively. The presence of fibroblasts and myofibroblasts was assessed immunohistochemically. Mean CVL was 0.55 ± 0.22 m/s, mean CVT was 0.25 ± 0.15 m/s, and the mean activation time was 9.31 ± 5.45 ms. The amount of fibrosis was unrelated to CV or patient characteristics. CVL was higher in left atrial appendages with thick compared with thin interstitial collagen strands (0.77 ± 0.22 versus 0.48 ± 0.19 m/s; P = 0.012), which were more frequently present in persistent patients with AF. CVT was not significantly different (P = 0.47), but activation time was 14.93 ± 4.12 versus 7.95 ± 4.12 ms in patients with thick versus thin interstitial collagen strands, respectively (P = 0.004). Fibroblasts were abundantly present and were associated with the presence of thick interstitial collagen strands (P = 0.008). Myofibroblasts were not detected in the left atrial appendage. CONCLUSIONS: In patients with AF, thick interstitial collagen strands are associated with higher CVL and increased activation time. Our observations demonstrate that the severity and structure of local interstitial fibrosis is associated with atrial conduction abnormalities, presenting an arrhythmogenic substrate for atrial re-entry.

Treatment of Atrial and Ventricular Arrhythmias Through Autonomic Modulation.

This paper reviews the contribution of autonomic nervous system (ANS) modulation in the treatment of arrhythmias. Both the atria and ventricles are innervated by an extensive network of nerve fibers of parasympathetic and sympathetic origin. Both the parasympathetic and sympathetic nervous system exert arrhythmogenic electrophysiological effects on atrial and pulmonary vein myocardium, while in the ventricle the sympathetic nervous system plays a more dominant role in arrhythmogenesis. Identification of ANS activity is possible with nuclear imaging. This technique may provide further insight in mechanisms and treatment targets. Additionally, the myocardial effects of the intrinsic ANS can be identified through stimulation of the ganglionic plexuses. These can be ablated for the treatment of atrial fibrillation. New (non-) invasive treatment options targeting the extrinsic cardiac ANS, such as low-level tragus stimulation and renal denervation, provide interesting future treatment possibilities both for atrial fibrillation and ventricular arrhythmias. However, the first randomized trials have yet to be performed. Future clinical studies on modifying the ANS may not only improve the outcome of ablation therapy but may also advance our understanding of the manner in which the ANS interacts with the myocardium to modify arrhythmogenic triggers and substrate.

Disparate response of high-frequency ganglionic plexus stimulation on sinus node function and atrial propagation in patients with atrial fibrillation.

BACKGROUND: In patients with atrial fibrillation (AF), the autonomic nervous system is supposed to play an role in triggering AF; however, little is known of the effect on atrial conduction characteristics. OBJECTIVE: The purpose of this study was to study the effect of ganglionic plexus (GP) stimulation during sinus rhythm on atrial and pulmonary vein conduction in patients during thoracoscopic surgery for AF METHODS: In 25 patients, the anterior right ganglionic plexus (ARGP) was stimulated (16 Hz, at 1, 2, and 5 mA). Epicardial electrograms were recorded using a 48-electrode map from the right pulmonary vein (RPV) or right atrial (RA). Intra-atrial activation time (IAT), local activation time (LAT), and inhomogeneity of conduction (IIC) were determined. ECG parameters (P-P, P-R interval) were measured. RESULTS: P-P interval was 956 ± 157 ms (range 768-1368 ms), and P-R interval was 203 ± 37 ms (range 136-280 ms). After ARGP stimulation, a short-lasting increase of P-P interval was observed, more prominent at higher output (1 mA = 82 ms, 2 mA = 180 ms, 5 mA = 268 ms, all P <.01 vs baseline). P-R interval remained unchanged. IAT was 34.4 ms (range 5.6-50.3 ms) at the RA and 105.8 ms (range 79.7-163.3 ms) at the RPV. After 1-mA stimulation IAT increased, in patients taking beta-blockers (P = .001), or it decreased, and this change persisted after subsequent stimulation at higher current (1 mA, P = .001; 2 mA, P = .401; 5 mA, P = .593). Similar changes were observed for LAT and IIC. CONCLUSION: ARGP stimulation results in a short-lasting, output-dependent decrease in sinus node frequency due to a parasympathetic response. Stimulation of the ARGP induced a prolonged increase or decrease in conduction characteristics in patients with AF, consistent with a persistent differential parasympathetic and/or sympathetic response.

Epicardial and endocardial electrophysiological guided thoracoscopic surgery for atrial fibrillation: a multidisciplinary approach of atrial fibrillation ablation in challenging patients.

INTRODUCTION: Patients with atrial fibrillation (AF) with enlarged atria or previous pulmonary vein isolation (PVI) are challenging patients for catheter ablation. Thoracoscopic surgery is an effective treatment for these patients but comes at the cost of an increase in adverse events. Recently, electrophysiological (EP) guided approaches to thoracoscopic surgery have been described which consist of EP guidance by measurement of conduction block across ablation lines. In this study we describe the efficacy and safety of EP-guided thoracoscopic surgery for AF in patients with enlarged atria and/or prior failed catheter ablation. METHODS & RESULTS: A total of 72 patients were included. Two different approaches to EP-guided thoracoscopic surgery were implemented: epicardial or endocardial EP-guidance at the time of surgery. Residual intraoperative conduction requiring additional ablation was detected with epicardial or endocardial mapping techniques in 50% and 11%, respectively. Additional epicardial or endocardial ablation was performed until bidirectional block was confirmed. Follow-up consisted of an ECG and a 24h Holter at 3, 6 and 12 months after the procedure. A total of 57 patients (79%) had freedom of AF and were off anti-arrhythmic drugs at one year follow-up (30 paroxysmal (83%), 27 persistent AF (75%)). Adverse events occurred in 13 patients (6 major). None of our patients died and all events were reversible. CONCLUSION: EP-guidance of thoracoscopic surgery can be safely performed both epicardially and endocardially and is associated with a high rate of long-term maintenance of sinus rhythm in patients with enlarged atria and/or a previously failed ablation.

Electrocardiographic P wave changes after thoracoscopic pulmonary vein isolation for atrial fibrillation.

BACKGROUND: Changes in P wave duration (PWD) and P wave area (PWA) have been described following catheter ablation for atrial fibrillation (AF). We hypothesize that video-assisted thoracoscopic pulmonary vein isolation (VATS-PVI) for AF results in decrease of PWD, PWA and P wave dispersion, which may resemble reverse electrical remodeling of the atrium after restoration of sinus rhythm. METHODS: VATS-PVI consisted of PVI and ganglionic plexus ablation in 29 patients (mean age, 59 ± 7 years; 23 males; 17 paroxysmal AF) and additional left atrial lesions in patients with persistent AF. PWD and PWA were measured in ECG lead II, aVF and V2 of ECGs during sinus rhythm before, directly after, and 6 months postprocedure. P wave dispersion was derived from the 12 lead ECG. RESULTS: Prior to VATS-PVI, PWD did not correlate with left atrial size and no difference in left atrial size was found between patients with paroxysmal or persistent AF (p = 0.27). Following VATS-PVI, PWD initially prolonged in all patients from 115 ± 4.6 ms to 131 ± 3.6 ms (p < 0.01) but shortened to 99 ± 3.2 ms after 6 months (p < 0.01). PWA was 5.60 ± 0.32 mV*ms at baseline, 6.44 ± 0.32 mV*ms post-VATS-PVI (P = NS), and 5.40 ± 0.28 mV*ms after 6 months (p = NS vs. baseline, p < 0.05 vs. post-VATS-PVI). P wave dispersion decreased in the persistent AF group from baseline 67 ± 3.3 to 64 ± 2.5 ms post-VATS-PVI (p = 0.30) and to 61 ± 3.4 ms after 6 months (p < 0.05). CONCLUSIONS: PWD increases significantly directly after successful VATS-PVI in both groups. There was significant decrease in PWD after 6 months. Similarly, P wave dispersion decreased in the persistent group. These changes suggest an immediate procedure related effect, but the later changes may represent reverse electrical atrial remodeling following cessation of AF.