Post-operative atrial fibrillation is associated with a pre-existing structural and electrical substrate in human right atrial myocardium

Abstract

BackgroundPost-operative atrial fibrillation (POAF) is a major health economic burden. However, the precise mechanisms in POAF remain unclear. In other forms of AF, sites of high dominant frequency (DF) in sinus rhythm (SR) may harbour ‘AF nests’. We studied AF inducibility in relation to substrate changes using epicardial electrograms and cardiomyocyte calcium handling in the atria of AF naïve patients.MethodBipolar electrograms were recorded from the lateral right atrial (RA) wall in 34 patients undergoing coronary surgery using a high-density array in sinus rhythm (NSR). RA burst pacing at 200/500/1000 ms cycle lengths (CL) was performed, recording episodes of AF > 30 s. Co-localised RA tissue was snap frozen for RNA and protein extraction.ResultsElectrograms prolonged during AF (76.64 ± 29.35 ms) vs. NSR/pacing (p < 0.001). Compared to NSR, electrogram amplitude was reduced during AF and during pacing at 200 ms CL (p < 0.001). Electrogram DF was significantly lower in AF (75.87 ± 23.63 Hz) vs. NSR (89.33 ± 25.99 Hz) (p < 0.05), and NSR DF higher in AF inducible patients at the site of AF initiation (p < 0.05). Structurally, POAF atrial myocardium demonstrated reduced sarcolipin gene (p = 0.0080) and protein (p = 0.0242) expression vs. NSR. Phospholamban gene and protein expression was unchanged. SERCA2a protein expression remained unchanged, but MYH6 (p = 0.0297) and SERCA2A (p = 0.0343) gene expression was reduced in POAF.ConclusionsHuman atrial electrograms prolong and reduce in amplitude in induced peri-operative AF vs. NSR or pacing. In those sustaining AF, high DF sites in NSR may indicate ‘AF nests’. This electrical remodelling is accompanied by structural remodelling with altered expression of cardiomyocyte calcium handling detectable before POAF. These novel upstream substrate changes offer a novel mechanism and manifestation of human POAF.

Intraoperative Inducibility of Atrial Fibrillation Does Not Predict Early Postoperative Atrial Fibrillation

“…Factors promoting development of EPoAF following cardiothoracic surgery include, for example, inflammatory response, sympathetic activation, and oxidative stress. In addition, EPoAF is not solely initiated by the presence of these triggers, but also depends on the presence and extensiveness of an arrhythmogenic substrate . Atrial alterations on structural, electrical, and contractile levels cause a higher vulnerability for development of AF .…”

“…Table 3 shows additional clinical characteristics of patients with and without LPoAF. Overall time to LPoAF diagnosis was 6 (3-6) months and was similar in patients with (N=40, 6 [3][4][5][6]) and patients without (N=4, 8 [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]) preoperative AF (P=0.708).…”

“…In addition, EPoAF is not solely initiated by the presence of these triggers, but also depends on the presence and extensiveness of an arrhythmogenic substrate. 13,15 Atrial alterations on structural, electrical, and contractile levels cause a higher vulnerability for development of AF. 16 Previous studies showed that, in patients in sinus rhythm, the extent of this arrhythmogenic substrate is highly variable in patients with similar clinical profiles.…”

Editorial commentary: What can lung transplantation teach us about the mechanisms of atrial arrhythmias?

“…This may reflect extra-PV mechanisms for post-operative AF, as supported by a recent randomized trial by Skanes et al, which showed no benefit of intraoperative PVI on development of postoperative AF following coronary artery bypass graft surgery [12]. These findings suggest a role for non-PV triggers or atrial ‘substrate’, i.e., mechanisms that sustain AF after it has been triggered, in post-operative AF, recently shown in the right atrium of patients undergoing elective CABG [13]. …”

Horse gluteus is a null-sarcolipin muscle with enhanced sarcoplasmic reticulum calcium transport

“…Millipore-Sigma reports that ABT13 reacts with rabbit, mouse, and human SLN on immunoblot at 1.5 µg/mL pAb, as corroborated for rabbit SLN using 0.5 µg/mL pAb ABT13 (1:1000 dilution) and fluorescent secondary antibody detection (Figure S8). pAb ABT13 has been validated for SLN immunoblotting using human right atrium homogenate (189) and mouse soleus and diaphragm homogenates (190). Here pAb ABT13 was used for primary labeling at 1:1000 dilution, with positive detection of SLN in rabbit SR (Figure S7), plus synthetic rabbit and human SLN.…”