The future of atrial fibrillation therapy: Intervention on heat shock proteins influencing electropathology is the next in line

Atrial fibrillation (AF) is the most common agerelated cardiac arrhythmia accounting for one-third of hospitalisations. Treatment of AF is difficult, which is rooted in the progressive nature of electrical and structural remodelling, called electropathology, which makes the atria more vulnerable for AF. Importantly, structural damage of the myocardium is already present when AF is diagnosed for the first time. Currently, no effective therapy is known that can resolve this damage. Previously, we observed that exhaustion of cardioprotective heat shock proteins (HSPs) contributes to structural damage in AF patients. Also, boosting of HSPs, by the heat shock factor-1 activator geranylgeranylacetone, halted AF initiation and progression in experimental cardiomyocyte and dog models for AF. However, it is still unclear whether induction of HSPs also prolongs the arrhythmia-free interval after, for example, cardioversion of AF. In this review, we discuss the role of HSPs in the pathophysiology of AF and give an outline of the HALT&REVERSE project, initiated by the HALT&REVERSE Consortium and the AF Innovation Platform. This project will elucidate whether HSPs (1) reverse cardiomyocyte electropathology and thereby halt AF initiation and progression and (2) represent novel biomarkers that predict the outcome of AF conversion and/or occurrence of post-surgery AF

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

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

Impact of ischemic and valvular heart disease on atrial excitation

Background--The influence of underlying heart disease or presence of atrial fibrillation (AF) on atrial excitation during sinus rhythm (SR) is unknown. We investigated atrial activation patterns and total activation times of the entire atrial epicardial surface during SR in patients with ischemic and/or valvular heart disease with or without AF. Methods and Results--Intraoperative epicardial mapping (N=128/192 electrodes, interelectrode distances: 2 mm) of the right atrium, Bachmann's bundle (BB), left atrioventricular groove, and pulmonary vein area was performed during SR in 253 patients (186 male [74%], age 66±11 years) with ischemic heart disease (N=132, 52%) or ischemic valvular heart disease (N=121, 48%). As expected, SR origin was located at the superior intercaval region of the right atrium in 232 patients (92%). BB activation occurred via 1 wavefront from right-to-left (N=163, 64%), from the central part (N=18, 7%), or via multiple wavefronts (N=72, 28%). Left atrioventricular groove activation occurred via (1) BB: N=108, 43%; (2) pulmonary vein area: N=9, 3%; or (3) BB and pulmonary vein area: N=136, 54%; depending on which route had the shortest interatrial conduction time (P < 0.001). Ischemic valvular heart disease patients more often had central BB activation and left atrioventricular groove activation via pulmonary vein area compared with ischemic heart disease patients (N=16 [13%] versus N=2 [2%]; P=0.009 and N=86 [71%] versus N=59 [45%]; P < 0.001, respectively). Total activation times were longer in patients with AF (AF: 136±20 [92-186] ms; no AF: 114±17 [74-156] ms; P < 0.001), because of prolongation of right atrium (P=0.018) and BB conduction times (P < 0.001). Conclusions--Atrial excitation during SR is affected by underlying heart disease and AF, resulting in alternative routes for BB and left atrioventricular groove activation and prolongation of total activation times. Knowledge of atrial excitation patterns during SR and its electropathological variations, as demonstrated in this study, is essential to further unravel the pathogenesis of AF

Intraoperative inducibility of atrial fibrillation does not predict early postoperative atrial fibrillation

Background--Early postoperative atrial fibrillation (EPoAF) is associated with thromboembolic events, prolonged hospitalization, and development of late PoAF (LPoAF). It is, however, unknown if EPoAF can be predicted by intraoperative AF inducibility. The aims of this study are therefore to explore (1) the value of intraoperative inducibility of AF for development of both EPoAF and LPoAF and (2) the predictive value of de novo EPoAF for recurrence of LPoAF. Methods and Results--Patients (N=496, 75% male) undergoing cardiothoracic surgery for coronary and/or valvular heart disease were included. AF induction was attempted by atrial pacing, before extracorporeal circulation. All patients were on continuous rhythm monitoring until discharge to detect EPoAF. During a follow-up period of 2 years, LPoAF was detected by ECGs and Holter recordings. Sustained AF was inducible in 56% of patients. There was no difference in patients with or without AF before surgery (P=0.159), or between different types of surgery (P=0.687). In patients without a history of AF, incidence of EPoAF and LPoAF was 37% and 2%, respectively. EPoAF recurred in 58% patients with preoperative AF, 53% developed LPoAF. There were no correlations between intraoperative inducibility and EPoAF or LPoAF (P > 0.05). EPoAF was not correlated with LPoAF in patients without a history of AF (P=0.116), in contrast to patients with AF before surgery (P < 0.001). Conclusions--Intraoperative AF inducibility does not predict development of either EPoAF or LPoAF. In patients with AF before surgery, EPoAF is correlated with LPoAF recurrences. This correlation is absent in patients without AF before surgery

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

QUest for the Arrhythmogenic Substrate of Atrial fibRillation in Patients Undergoing Cardiac Surgery (QUASAR Study): Rationale and Design

The heterogeneous presentation and progression of atrial fibrillation (AF) implicate the existence of different pathophysiological processes. Individualized diagnosis and therapy of the arrhythmogenic substrate underlying AF may be required to improve treatment outcomes. Therefore, this single-center study aims to identify t

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

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 therap

Atrial Fibrillation from a Sinus Rhythm Point of View

In this thesis we evaluate whether electrophysiological parameters, as obtained by epicardial mapping during sinus rhythm and atrial fibrillation, several clinical parameters and the biomarker named Heat Shock Proteins can identify the presence of AF and it's stage in the individual patient