Prediction of ventricular tachyarrhythmia in Brugada syndrome by right ventricular outflow tract conduction delay signs.

BACKGROUND: Brugada syndrome (BrS) is an autosomal dominant disease responsible for sudden cardiac death in young individuals without structural anomalies. The most critical part in the management of this channelopathy is identification of high-risk patients, especially asymptomatic subjects. Prior studies have shown that conduction delay in the right ventricular outflow tract (RVOT) is the main mechanism for developing ventricular tachyarrhythmia (VTA) in BrS patients. The aim of this study was to investigate the significance of electrocardiographic RVOT conduction delay parameters as predictors for development of VTA in patients with BrS. METHODS AND RESULTS: We retrospectively analyzed electrocardiograms obtained from 147 BrS patients (43 ± 15 years, 65% men) and assessed the following electrocardiographic parameters: (1) Tzou criteria (V1R > 0.15 mV, V6S > 0.15 mV, and V6S:R > 0.2), (2) prominent S wave in lead I, lead II, and lead III, (3) SII > SIII, and (4) prominent Q wave in lead III as possible predictors of VTA occurrences during follow-up. Prominent SI, SII, SIII, SII > SIII, QIII, and +ve Tzou criteria occurred more frequently in patients who either presented with VTA or developed VTA during the follow-up of 56 (IQR: 40-76) months. SII > SIII has the highest area under the curve for prediction of VTA (AUC: 0.84, sensitivity: 80%, specificity: 89%). Multivariable regression analysis showed that prominent S waves in lead I, SII > SIII and +ve Tzou criteria are independent predictors for VTA in BrS patients. CONCLUSION: Prominent S in lead I, SII > SIII and +ve Tzou criteria can be used as effective signs for predicting VTA in patients with BrS.

Intraoperative arrhythmias in children with congenital heart disease: transient, innocent events?

Aims: The significance and incidences of intraoperative arrhythmias occurring in the operating room (OR) in children with congenital heart disease (CHD) are unknown. Aims of this study were to determine incidences of intraoperative arrhythmias in children with CHD and to examine whether they are associated with persistent arrhythmias during follow-up. Methods and results: Continuous ECG recordings obtained from 134 consecutive paediatric CHD patients were manually examined from the moment the aortic cross-clamp (ACC) was removed [use of ACC and cardiopulmonary bypass (CPB)], when CPB was stopped (use of only CPB) or when the sternum was closed (no use of ACC and CPB) until departure from the OR. In the OR, 2nd (60%) and 3rd (34%) degree atrioventricular conduction block (AVB), ectopic atrial rhythm (30%), and junctional rhythm (32%) were most often observed in patients who underwent surgery with both ACC and CPB. Incidences of these arrhythmias decreased after cessation of CPB (P < 0.01). (Supra)ventricular premature beats were mostly observed between end of ACC time and sternum closure (64-84%), but decreased before departure from the OR (6-16%, P < 0.01). During a median follow-up of 37 months, 17 patients (13%) had new onset, late post-operative arrhythmias. Of these patients, 88% had intraoperative arrhythmias compared with 85% of patients without late post-operative arrhythmias (P = 1). Conclusion: Intraoperative arrhythmias, mainly 2nd degree AVB and (supra)ventricular premature beats, were frequently observed in children with CHD undergoing cardiac surgery with use of CPB and ACC. Most arrhythmias were short-lasting and transient and appeared not to be related to late post-operative arrhythmias.

Dynamics of Focal Fibrillation Waves during Persistent Atrial Fibrillation.

The incidence and appearance of focal fibrillation waves on the right and left atrial epicardial surface were visualized during 10 seconds of persistent atrial fibrillation in a 71-year-old woman with valvular heart disease. The frequent, nonrepetitive, widespread, and capricious distribution of focal waves suggests that transmural conduction of fibrillation waves is most likely the mechanism underlying focal fibrillation waves.

HALT & REVERSE: Hsf1 activators lower cardiomyocyt damage; towards a novel approach to REVERSE atrial fibrillation.

BACKGROUND: Atrial fibrillation is a progressive arrhythmia, the exact mechanism underlying the progressive nature of recurrent AF episodes is still unknown. Recently, it was found that key players of the protein quality control system of the cardiomyocyte, i.e. Heat Shock Proteins, protect against atrial fibrillation progression by attenuating atrial electrical and structural remodeling (electropathology). HALT & REVERSE aims to investigate the correlation between electropathology, as defined by endo- or epicardial mapping, Heat Shock Protein levels and development or recurrence of atrial fibrillation following pulmonary vein isolation, or electrical cardioversion or cardiothoracic surgery. STUDY DESIGN: This study is a prospective observational study. Three separate study groups are defined: (1) cardiothoracic surgery, (2) pulmonary vein isolation and (3) electrical cardioversion. An intra-operative high-resolution epicardial (group 1) or endocardial (group 2) mapping procedure of the atria is performed to study atrial electropathology. Blood samples for Heat Shock Protein determination are obtained at baseline and during the follow-up period at 3 months (group 2), 6 months (groups 1 and 2) and 1 year (group 1 and 2). Tissue samples of the right and left atrial appendages in patients in group 1 are analysed for Heat Shock Protein levels and for tissue characteristics. Early post procedural atrial fibrillation is detected by continuous rhythm monitoring, whereas late post procedural atrial fibrillation is documented by either electrocardiogram or 24-h Holter registration. CONCLUSION: HALT & REVERSE aims to identify the correlation between Heat Shock Protein levels and degree of electropathology. The study outcome will contribute to novel diagnostic tools for the early recognition of clinical atrial fibrillation. TRIAL REGISTRATIONS: Rotterdam Medical Ethical Committee MEC-2014-393, Dutch Trial Registration NTR4658.

Atrial heat shock protein levels are associated with early postoperative and persistence of atrial fibrillation.

BACKGROUND: Early detection and staging of atrial fibrillation (AF) is of importance for clinical management. Serum (bio)markers, such as heat shock proteins (HSP), may enable AF staging and identify patients at risk for AF recurrence and postoperative AF (PoAF). OBJECTIVE: This study evaluates the relation between serum and atrial tissue HSP levels, stages of AF, AF recurrence after treatment, and PoAF from patients undergoing cardiothoracic surgery. METHODS: Patients without (control) and with paroxysmal, persistent (PerAF), or longstanding persistent (LSPerAF) AF were included. HSPB1, HSPA1, HSPB7, and HSPD1 levels were measured in serum obtained prior to and post intervention. HSPB1, HSPA1, HSPA5, HSPD1, HSPB5, and pHSF1 levels were measured in left and/or right atrial appendages (respectively, LAA and RAA). RESULTS: In RAA, HSPA5 levels were significantly lower in LSPerAF and HSPD1 levels significantly higher in PerAF patients compared to controls. In RAA of controls who developed PoAF, HSPA1 and HSPA5 levels were significantly higher compared to those without PoAF. Also, HSPB1 RAA levels were lower and HSPA5 LAA levels higher in patients undergoing arrhythmia surgery who developed AF recurrence within 1 week after surgery compared to patients who did not. CONCLUSION: HSPA5 RAA and HSPD1 RAA and LAA levels are altered in persistent stages of AF. RAA HSPA1 and HSPA5 levels associate with development of PoAF. Additionally, HSPB1 RAA and HSPA5 LAA levels can predict AF recurrence in patients who underwent arrhythmia surgery. Nevertheless, HSP levels in serum cannot discriminate AF stages from controls, nor predict PoAF or AF recurrence after treatment.

Identification of Low-Voltage Areas: A Unipolar, Bipolar, and Omnipolar Perspective.

[Figure: see text].

Blood-based 8-hydroxy-2'-deoxyguanosine level: A potential diagnostic biomarker for atrial fibrillation.

BACKGROUND: Recent research findings have revealed a key role of oxidative DNA damage in the pathogenesis of atrial fibrillation (AF). Therefore, the circulating oxidative DNA damage marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) may represent a biomarker for staging AF and identifying patients at risk for AF recurrence and postoperative atrial fibrillation (POAF) after treatment. OBJECTIVE: The purpose of this study was to investigate whether serum levels of 8-OHdG correlate with the stage of AF, recurrence after AF treatment, and onset of POAF after cardiac surgery. METHODS: In this prospective observational study, 8-OHdG levels were detected by enzyme-linked immunosorbent assay in human serum samples. Blood samples were collected from control patients without AF history; patients with paroxysmal AF and persistent AF undergoing electrical cardioversion or pulmonary vein isolation (PVI); and patients with sinus rhythm (SR) undergoing cardiac surgery. AF recurrence was determined during 12-month follow-up. Univariate and multivariate analyses were used to identify changes in 8-OHdG levels between the groups. RESULTS: Compared to the control group, 8-OHdG levels in the patient groups gradually and significantly increased during arrhythmia progression. 8-OHdG levels in AF patients showing AF recurrence after PVI treatment were significantly increased compared to patients without AF recurrence. Moreover, in SR patients undergoing cardiac surgery, 8-OHdG levels were significantly elevated in those showing POAF compared to patients without POAF. CONCLUSION: 8-OHdG level may represent a potential diagnostic biomarker for AF staging as well as for predicting AF recurrence and POAF after treatment.

Cell-Free Circulating Mitochondrial DNA: A Potential Blood-Based Marker for Atrial Fibrillation.

Atrial fibrillation (AF), the most common, progressive tachyarrhythmia is associated with serious complications, such as stroke and heart failure. Early recognition of AF, essential to prevent disease progression and therapy failure, is hampered by the lack of accurate diagnostic serum biomarkers to identify the AF stage. As we previously showed mitochondrial dysfunction to drive experimental and human AF, we evaluated whether cell-free circulating mitochondrial DNA (cfc-mtDNA) represents a potential serum marker. Therefore, the levels of two mtDNA genes, COX3 and ND1, were measured in 84 control patients (C), 59 patients undergoing cardiac surgery without a history of AF (SR), 100 paroxysmal (PAF), 116 persistent (PeAF), and 20 longstanding-persistent (LS-PeAF) AF patients undergoing either cardiac surgery or AF treatment (electrical cardioversion or pulmonary vein isolation). Cfc-mtDNA levels were significantly increased in PAF patients undergoing AF treatment, especially in males and patients with AF recurrence after AF treatment. In PeAF and LS-PeAF, cfc-mtDNA levels gradually decreased. Importantly, cfc-mtDNA in serum may originate from cardiomyocytes, as in vitro tachypaced cardiomyocytes release mtDNA in the medium. The findings suggest that cfc-mtDNA is associated with AF stage, especially in males, and with patients at risk for AF recurrence after treatment.

Early markers of atrial fibrillation recurrence after pulmonary vein isolation.

BACKGROUND: Postprocedural atrial extrasystole (AES) frequency predicts atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) in patients with paroxysmal AF. However, the predictive value of preprocedural AES frequency is unknown. We investigate whether preprocedural AES frequency is a feasible marker to predict (timing of) AF recurrence after PVI. METHODS: Patients (N = 684) with paroxysmal or persistent AF undergoing first-time PVI were evaluated for (a) the frequency of AES/day on Holter recordings without AF prior to PVI, (b) AF episodes during the 90 days blanking period, and (c) AF recurrences afterward. The correlation between AES/day and both development and timing of AF recurrences was tested. RESULTS: Preprocedural AES/day was similar in patients with paroxysmal (66 [20-295] AES/day) and persistent AF (115 [12-248] AES/day, P = .915). During the blanking period, 302 (44.2%) patients showed AF episodes. AF recurred in 379 (55.4%) patients at 203 (105-400) days after PVI. AF recurred more frequently in patients with persistent (N = 104 [69.3%]) than in patients with paroxysmal AF (N = 275 [51.5%], P < .001). Frequency of AES prior to PVI was not correlated with development (P = .203) or timing (P = .478) of AF recurrences. AF recurrences occurred both more frequently (P < .001) and earlier (P < .000) in patients with AF during the blanking period. CONCLUSION: AES/day prior to PVI is not correlated with (timing of) AF during the blanking period or AF recurrences, and is therefore not a feasible marker for AF recurrences in patients with PAF. AF during the blanking period is correlated with AF recurrence.

The impact of obesity on early postoperative atrial fibrillation burden.

BACKGROUND: Obesity has been linked to the development of postoperative atrial fibrillation. This study is aimed at investigating the role of body mass index in the evolution of de novo, early postoperative atrial fibrillation by assessing differences between obese and nonobese patients undergoing cardiac surgery. METHODS: Patients with early de novo postoperative atrial fibrillation were included. Continuous cardiac rhythms were recorded during the first 5 postoperative days in obese (N = 67, 66 ± 9 years; 51 [76%] male) and nonobese (N = 89, 69 ± 9; 75 [84%] male) patients without a history of atrial fibrillation undergoing cardiac surgery. Postoperative atrial fibrillation burden was defined as the ratio between total duration of all atrial fibrillation episodes and total recording time (atrial fibrillation burden, %). RESULTS: A total of 1191 (median: 5/patient) postoperative atrial fibrillation episodes were identified in the obese group compared with 1218 (median: 4/patient) in the nonobese group. The median duration and number of prolonged (>60 minutes) postoperative atrial fibrillation episodes were higher in obese patients (250 vs 145 minutes, P = .003, and median of 2 vs 1 episode, P = .031). Obesity was associated with a larger early postoperative atrial fibrillation burden (obese patients: median, 7%; interquartile range, 2.5-19.7 vs nonobese patients: median, 3.2%; interquartile range, 0.5-8.8, P = .001) mainly on the third postoperative day (P = .021). CONCLUSIONS: Obesity predisposes to a larger number of prolonged atrial fibrillation episodes in the early postoperative period after cardiac surgery for coronary artery disease or valvular heart disease. The higher atrial fibrillation burden in the early postoperative period occurred particularly on the third day. Future studies will determine whether obesity prevention may play a key role in reducing the incidence of postoperative atrial fibrillation in patients undergoing cardiac surgery.

Evaluating Serum Heat Shock Protein Levels as Novel Biomarkers for Atrial Fibrillation.

Background: Staging of atrial fibrillation (AF) is essential to understanding disease progression and the accompanied increase in therapy failure. Blood-based heat shock protein (HSP) levels may enable staging of AF and the identification of patients with higher risk for AF recurrence after treatment. Objective: This study evaluates the relationship between serum HSP levels, presence of AF, AF stage and AF recurrence following electrocardioversion (ECV) or pulmonary vein isolation (PVI). Methods: To determine HSP27, HSP70, cardiovascular (cv)HSP and HSP60 levels, serum samples were collected from control patients without AF and patients with paroxysmal atrial fibrillation (PAF), persistent (PeAF) and longstanding persistent (LSPeAF) AF, presenting for ECV or PVI, prior to intervention and at 3-, 6- and 12-months post-PVI. Results: The study population (n = 297) consisted of 98 control and 199 AF patients admitted for ECV (n = 98) or PVI (n = 101). HSP27, HSP70, cvHSP and HSP60 serum levels did not differ between patients without or with PAF, PeAF or LSPeAF. Additionally, baseline HSP levels did not correlate with AF recurrence after ECV or PVI. However, in AF patients with AF recurrence, HSP27 levels were significantly elevated post-PVI relative to baseline, compared to patients without recurrence. Conclusions: No association was observed between baseline HSP levels and the presence of AF, AF stage or AF recurrence. However, HSP27 levels were increased in serum samples of patients with AF recurrence within one year after PVI, suggesting that HSP27 levels may predict recurrence of AF after ablative therapy.

Sinus Rhythm Conduction Properties across Bachmann's Bundle: Impact of Underlying Heart Disease and Atrial Fibrillation.

Valvular heart disease (VHD) is a common risk factor for atrial fibrillation (AF). Conduction abnormalities (CA) during sinus rhythm (SR) across Bachmann's bundle (BB) are associated with AF development. The study goal is to compare electrophysiological characteristics across BB during SR between patients with ischemic (IHD) and/or VHD either with or without ischemic heart disease ((I)VHD), with/without AF history using high-resolution intraoperative epicardial mapping. In total, 304 patients (IHD: n = 193, (I)VHD: n = 111) were mapped; 40 patients (13%) had a history of AF. In 116 patients (38%) there was a mid-entry site with a trend towards more mid-entry sites in patients with (I)VHD vs. IHD (p = 0.061), whereas patients with AF had significant more mid-entry sites than without AF (p = 0.007). CA were present in 251 (95%) patients without AF compared to 39 (98%) with AF. The amount of CA was comparable in patients with IHD and (I)VHD (p > 0.05); AF history was positively associated with the amount of CA (p < 0.05). Receiver operating characteristic (ROC) curve showed 85.0% sensitivity and 86.4% specificity for cut-off values of CA lines of respectively ≤ 6 mm and ≥ 26 mm. Patients without a mid-entry site or long CA lines (≥ 12 mm) were unlikely to have AF (sensitivity 90%, p = 0.002). There are no significant differences in entry-sites of wavefronts and long lines of CA between patients with IHD compared to (I)VHD. However, patients with AF have more wavefronts entering in the middle of BB and a higher incidence of long CA lines compared to patients without a history of AF. Moreover, in case of absence of a mid-entry site or long line of CA, patients most likely have no history of AF.

Distribution of Conduction Disorders in Patients With Congenital Heart Disease and Right Atrial Volume Overload.

OBJECTIVES: This study sought to quantify characteristics of atrial conduction disorders in patients with right atrial (RA) volume overload. BACKGROUND: Patients with an interatrial shunt are prone to developing atrial fibrillation (AF), which may be related to conduction disorders occurring due to atrial stretch. METHODS: Thirty-one patients undergoing surgery for an interatrial shunt (49 ± 14 years of age) underwent epicardial sinus rhythm mapping of the RA, Bachmann's bundle (BB), and left atrium (LA). Conduction delay (CD) was defined as interelectrode conduction time (CT) of 7 to 11 ms and conduction block (CB) as CT ≥12 ms. Prevalence of CD or CB (percentage of mapped region), length of lines, and severity of CB (75th percentile of CTs ≥12 ms) were analyzed. RESULTS: All patients had some degree of CD and CB. Prevalence of CD and CB was higher in the RA and BB than in the LA (p < 0.0083 after Bonferroni correction). The longest CB line within each patient was found in the RA in most patients (52%). Interindividual variation in prevalence and lengths of lines was considerable. CB was more severe in the RA than in the LA (p < 0.0083). Within the RA, conduction disorders were more prevalent and more severe in the intercaval region than in the RA free wall (p < 0.05). CONCLUSIONS: In patients with an interatrial shunt, conduction disorders during sinus rhythm are most pronounced in the RA-particularly the intercaval region-and BB. Knowledge of the conduction during sinus rhythm is essential to determine the relevance of conduction disorders for initiation and perpetuation of AF.

The Effects of Valvular Heart Disease on Atrial Conduction During Sinus Rhythm.

Different arrhythmogenic substrates for atrial fibrillation (AF) may underlie aortic valve (AV) and mitral valve (MV) disease. We located conduction disorders during sinus rhythm by high-resolution epicardial mapping in patients undergoing AV (n = 85) or MV (n = 54) surgery. Extent and distribution of conduction delay (CD) and block (CD) across the entire right and left atrial surface was determined from circa 1880 unipolar electrogram recordings per patient. CD and CB were most pronounced at the superior intercaval area (2.5% of surface, maximal degree 6.6%/cm2). MV patients had a higher maximal degree of CD at the lateral left atrium than AV patients (4.2 vs 2.3%/cm2, p = 0.001). A history of AF was most strongly correlated to CD/CB at Bachmann's bundle and age. Although MV patients have more conduction disorders at the lateral left atrium, disturbed conduction at Bachmann's bundle during sinus rhythm indicates the presence of atrial remodeling which is related to AF episodes.

Atrial fibrillation: A never ending story?

Atrial fibrillation (AF) often recurs after ablative therapy. In our patient, intraoperative epicardial mapping during therapy- resistant AF revealed highly dissociated atrial conduction patterns and that long lines of conduction block throughout the entire atria. Given the extensiveness of the substrate, it is not surprising that ablations were not successful. Conduction patterns during therapy-resistant atrial fibrillation (AF) are highly dissociated and show long lines of conduction block. As long as the presence and extensiveness of the arrhythmogenic substrate underlying AF remains poorly understood and cannot be evaluated in the individual patient, none of the present available antiarrhythmic treatment modalities will be effective.

Ventricular Dysrhythmias During Long-Term Follow-Up in Patients With Inherited Cardiac Arrhythmia.

Reports on development of frequent ventricular premature complexes (fVPC), (non)sustained ventricular tachycardias ([n]sVT), or ventricular fibrillation (VF) and their interrelationship in patients with different inherited cardiac arrhythmia (ICA) have sofar not been reported. The aim of this study is therefore to examine incidences and recurrences rates of sVT and VF ("malignant ventricular tachyarrhythmias, VTA") in addition to the incidence of fVPC and nsVT ("ventricular dysrhythmias, VDR") in patients with various ICA during long-term follow up. Patients (N = 167, 88 male, age 45 ± 15 years) with ICA including definite/borderline arrhythmogenic right ventricular cardiomyopathy (ARVC, N = 47), Brugada syndrome (BrS, N = 71), catecholaminergic polymorphic ventricular tachycardia (CPVT, N = 7), long QT syndrome (LQTS, N = 41) or short QT syndrome (SQTS, N = 1) who had frequent 24-hour Holter monitoring during a follow-up period of 4.6 ± 4.4 years. During the initial screening visit, 15 patients had a history of malignant VTA. fVPC and nsVT was observed in respectively 19% (OHCA/VF/sVT: N = 9) and 13% (OHCA/VF/sVT: N = 4) of all patients. Compared with the ARVC group, patients with BrS and LQTS had less frequent fVPC and nsVT (fVPC: odds ratio [OR] 0.20, 95% confidence interval [CI] 0.08 to 0.49, p <0.000 and OR 0.09, 95% CI 0.02 to 0.33, p <0.000; nsVT:OR 0.17, 95% CI 0.06 to 0.50, p = 0.001 and OR 0.09, 95% CI 0.02 to 0.46, p = 0.003). The recurrence rate of malignant VTA was 33%. In conclusion, variety of VDR and malignant VTA were found during long-term follow-up in patients with ICA. During nearly a 5 years follow-up period, the recurrence rate of malignant VTA was considerable. fVPC, nsVT, and malignant VTA were most often found in patients with an ARVC.

QRS Vector Magnitude as Predictor of Ventricular Arrhythmia in Patients With Brugada Syndrome.

Risk stratification is the most challenging part in management of patients with Brugada syndrome (BrS). Conduction delay in the right ventricular outflow tract (RVOT) is the major mechanism underlying ventricular tachyarrhythmia (VTA) in BrS. However, QRS duration was not useful in stratifying high-risk patients in large registries. Reconstructing the traditional 12-lead electrocardiogram into QRS vector magnitude can be used to quantify depolarization dispersion and identify high-risk BrS patients. The aim of the study is to test the significance of the QRSvm as a predictor for VTA in patients with BrS. In this retrospective cohort, we included 136 patients (47 ± 15 years, 66% male) who visited outpatient clinic for cardiogenetic screening. All medical records were examined, all 12- lead electrocardiograms were reconstructed into QRSvm using Kors' quasiorthogonal method and were assessed for the presence of electrocardiographic signs indicative of RVOT conduction delay including R wave sign, deep SI, SII >SIII pattern, and Tzou criteria. QRSvm was significantly lower in patients who either presented with VTA or developed VTA during follow-up (1.24 ± 0.35 vs 1.78 ± 0.42 mV, p < 0.001). Positive RVOT conduction delay signs occurred more frequently in symptomatic patients (20% vs 7%, p < 0.001).The area under receiver operator characteristic curve for QRSvm was 0.85 (95% confidence interval [CI] 0.77 to 0.92). Using QRSvm cutoff of 1.55 mV, sensitivity and specificity were 89% and 71%, respectively. Multivariate regression analysis showed that QRSvm and RVOT signs are independent predictors for VTA in BrS patients (QRS vector magnitude: odds ratio 3.68, 95% CI 2.4 to 6.2, p = 0.001; RVOT: odds ratio 2.6, 95% CI 1.4 to 4.9, p = 0.001). In conclusion, not only electrocardiographic signs indicative of RVOT conduction delay but also QRSvm can be used as a predictor for VTA events in BrS patients.

Impact of the arrhythmogenic potential of long lines of conduction slowing at the pulmonary vein area.

BACKGROUND: Areas of conduction delay (CD) or conduction block (CB) are associated with higher recurrence rates after ablation therapy for atrial fibrillation (AF). OBJECTIVE: Thus far, there are no reports on the quantification of the extensiveness of CD and CB at the pulmonary vein area (PVA) and their clinical relevance. METHODS: Intraoperative high-density epicardial mapping of the PVA (interelectrode distance 2 mm) was performed during sinus rhythm in 268 patients (mean ± SD [minimum-maximum] 67 ± 11 [21-84] years) with and without preoperative AF. For each patient, extensiveness of CD (conduction velocity 17-29 cm/s) and CB (conduction velocity <17 cm/s) was assessed and related to the presence and type of AF. RESULTS: CD and CB occurred in, respectively, 242 (90%) and 183 (68%) patients. Patients with AF showed a higher incidence of continuous conduction delay and block (CDCB) lines (AF: n = 37 [76%]; no AF: n = 132 [60%]; P = .046), a 2-fold number of lines per patient (CD: 7 [0-30] vs 4 [0-22], P < .001; CB: 3 [0-11] vs 1 [0-12], P = .003; CDCB: 2 [0-6] vs 1 [0-8], P = .004), and a higher incidence of CD or CB lines ≥6 mm and CDCB lines ≥16 mm (P = .011, P = .025, and P = .027). The extensiveness of CD, CB, and CDCB could not distinguish between the different AF types. CONCLUSION: Patients with AF more often present with continuous lines of adjacent areas of CD and CB, whereas in patients without AF, lines of CD and CB are shorter and more often separated by areas with normal intra-atrial conduction. However, a considerable overlap in the amount of conduction abnormalities at the PVA was observed between patients with a history of paroxysmal and persistent AF.

DNA damage-induced PARP1 activation confers cardiomyocyte dysfunction through NAD+ depletion in experimental atrial fibrillation.

Atrial fibrillation (AF) is the most common clinical tachyarrhythmia with a strong tendency to progress in time. AF progression is driven by derailment of protein homeostasis, which ultimately causes contractile dysfunction of the atria. Here we report that tachypacing-induced functional loss of atrial cardiomyocytes is precipitated by excessive poly(ADP)-ribose polymerase 1 (PARP1) activation in response to oxidative DNA damage. PARP1-mediated synthesis of ADP-ribose chains in turn depletes nicotinamide adenine dinucleotide (NAD+), induces further DNA damage and contractile dysfunction. Accordingly, NAD+ replenishment or PARP1 depletion precludes functional loss. Moreover, inhibition of PARP1 protects against tachypacing-induced NAD+ depletion, oxidative stress, DNA damage and contractile dysfunction in atrial cardiomyocytes and Drosophila. Consistently, cardiomyocytes of persistent AF patients show significant DNA damage, which correlates with PARP1 activity. The findings uncover a mechanism by which tachypacing impairs cardiomyocyte function and implicates PARP1 as a possible therapeutic target that may preserve cardiomyocyte function in clinical AF.

Novel Insights in the Activation Patterns at the Pulmonary Vein Area.

BACKGROUND: Extensiveness of conduction delay and block at the pulmonary vein area (PVA) was quantified in a previous study. We hypothesized that the combination of lines of conduction block with multiple concomitantly entering sinus rhythm wavefronts at the PVA may result in increased arrhythmogenicity and susceptibility to atrial fibrillation (AF). METHODS: Intraoperative high-density epicardial mapping of PVA (N≈450 sites, interelectrode distances: 2 mm) was performed during sinus rhythm in 327 patients (241 male [74%], 67±10 [21-84] years) with and without preoperative AF. For each patient, activation patterns at the PVA were quantified, including the location of entry sites of wavefronts, direction of propagation, and their relative activation times. The association between activation patterns and the presence of AF was examined. RESULTS: Excitation of the PVA occurred via multiple consecutive wavefronts in the vast majority of patient (N=216, 81%). In total, 561 wavefronts were observed, which mostly propagated through the septal or paraseptal regions towards the PVA (N=461, 82%). A substantial dissociation of consecutive wavefronts was observed with Δactivation times of 10.6±8.8 (0-46) ms. No difference was observed in Δactivation times of consecutive wavefronts during sinus rhythm between patients without and with AF. An excitation-based risk factor model, including conduction delay ≥6 mm, conduction block ≥6 mm, and conduction delay and block ≥16 mm, wavefronts via the posteroinferior to posterosuperior regions and multiple opposing wavefronts, demonstrated a 5-fold risk of AF when multiple risk factors were present. CONCLUSIONS: In contrast to previous findings, quantification of activation patterns at the PVA on high-resolution scale demonstrated complex patterns with often multiple entry sites and high interindividual variability. Altered patterns of activation, consisting of multiple opposing wavefronts combined with long lines of conduction slowing, were associated with the presence of AF.