| Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice. It occurs in approximately half of patients with heart valvular diseases, and particularly with mitral stenosis (60%). It can induce and aggravate heart failure (HF) and increase the risk of thromboembolism. In fact, one quarter of stroke patients is caused by AF, and the incidence of thromboembolism in valvular AF patients increases 17-fold compared with age-matched controls. Insight gained through in-depth research on atrial electrical remodeling, concomitant Maze procedure and intraoperative radiofrequency ablation have successfully been used during the past two decades. However, they remain a significant concern for the inevitable risk of perioperative complications and uncertainty regarding their long-term curative effect. Patients may suffer due to open-chest surgery, moreover the persistence of AF makes them be trapped in long-term palpitation, chest distress and dizziness, and contribute to HF, which can significantly reduce the postoperative quality of life and life expectancy. With accumulating studies of AF-related atrial structural remodeling in the recent decade, some novel therapeutic ways targeting atrial structural remodeling ("Upstream treatments") are emerging. They can play an effective role in AF treatment and prevention via inhibiting or reversing the corresponding atrial structural remodeling. However, the precise regulatory mechanisms are unclear. In this thesis, based on our clinical observation, we studied the main structural remodeling and its regulatory mechanisms by molecular biological techniques in the atrial tissue of a relative large population undergoing isolated valvular surgery. The results can advance our understanding of the pathophysiology of AF and provide the theoretical foundation and new therapeutic targets for"Upstream treatments". In addition, screening markers which could reflect the degree of atrial structural remodeling and activity of their regulatory pathways can guide current prophylactic therapies during and after surgery.Part I: Heat Shock Proteins and Atrial Structural RemodelingObjective: A spontaneously restored sinus rhythm in permanent atrial fibrillation patients has been often observed after mitral valve (MV) surgery, but duration of persisting in sinus rhythm varies from patient to patient. Heat shock proteins (Hsps) may be involved in pathogenesis of atrial fibrillation. The aim of this study was to investigate whether stabilization of restored sinus rhythm is associated with atrial structural remodeling and expression of Hsps in atria.Methods: Clinical data, biopsies of right atrial appendage (RAAs) and blood samples were collected from 135 atrial fibrillation patients who spontaneously restored sinus rhythm after conventional isolated MV replacement. Comparison was made between patients who had recurrence of atrial fibrillation within 7 days (AF) vs. patients with persisted sinus rhythm for more than 7 days (SR).Results: SR patients had higher activity of heat shock transcription factor 1 (HSF1) as well as up-regulated expressions of heat shock cognate (Hsc) 70, Hsp70 and Hsp27 in the tissues. The activation of HSF1-Hsps pathway was associated with less aggressive pathogenesis as reflected by lower rates of myolysis, apoptosis, interstitial fibrosis and inflammation in SR patients. However, Hsp60 was lower in both tissue and plasma in SR patients, and was positively correlated with apoptosis, interstitial fibrosis and inflammation.Conclusion: Atrial structural remodeling plays an important role in the recurrence of atrial fibrillation. Hsps may protect stabilization of restored sinus rhythm after MV surgery by inhibiting AF-related atrial structural remodeling in atrial fibrillation patients. Low circulating Hsp60 levels preoperatively, which could reflect less aggressive atrial structural remodeling, might predict a stable spontaneously restored sinus rhythm postoperatively.Part II: Natriuretic Peptides and Atrial Structural RemodelingObjective: Natriuretic peptides (NPs) are excellent diagnostic and prognostic markers of HF, but their roles in AF, particularly of isolated cardiac valvular origin, are unclear. The aim of this study was to gather information about expression of precursor forms of NPs in both atria and plasma, and investigate the relationship between NPs and atrial structural remodeling.Methods: We assessed the mRNA and protein content of pro-atrial natriuretic peptide (pro-ANP) and pro-brain natriuretic peptide (pro-BNP) in right atrial appendages (RAAs) and their N-terminal fragments (nt-proANP and nt-proBNP) in the plasma of 30 patients with paroxysmal AF and 40 patients with persistent AF matched with 34 patients in sinus rhythm (SR) undergoing isolated valvular replacement. To explore the underlying mechanism, fibrosis related examinations were simultaneously carried out in RAAs.Results: Atrial expression of pro-NPs mRNA was notably augmented in the paroxysmal AF subgroup, but not so pronounced in the persistent AF subgroup. Atrial content of pro-NPs proteins and plasma nt-proNPs, between which surprisingly strong positive correlations were found (pro-ANP and nt-proANP: r= 0.918, p <0.001; pro-BNP and nt-proBNP: r= 0.913, p <0.001), were increased analogously in paroxysmal AF and persistent AF subgroups. We identified significantly increasing gradients of atrial collagen volume fraction (CVF), levels of collagen I and collagen III in the SR, paroxysmal AF and persistent AF groups, and convincing negative linear correlations between CVF, levels of collagen I and collagen III, and atrial transcripts of pro-NPs.Conclusion: Atrial fibrosis plays an important role in the pathogenesis and development of AF. The discordance between transcripts and protein contents of pro-NPs was possibly associated with the more outstanding atrial fibrosis in persistent AF. Lower atrial transcripts of pro-NPs could reflect more aggressive atrial fibrosis, and circulating nt-proNPs levels could reflect the corresponding atrial pro-NPs contents in this report.
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