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An integrative and translational assessment of altered atrial electrophysiology, calcium handling and contractility in patients with atrial fibrillation

dc.contributor.advisorVoigt, Niels Prof. Dr.
dc.contributor.authorFakuade, Funsho Emmanuel
dc.titleAn integrative and translational assessment of altered atrial electrophysiology, calcium handling and contractility in patients with atrial fibrillationde
dc.contributor.refereeVoigt, Niels Prof. Dr.
dc.description.abstractengAtrial fibrillation (AF) is the most prevalent sustained arrhythmia reported in clinical practice, and it is associated with deleterious outcomes such as stroke, that increase patient morbidity and mortality. Previous studies have reported atrial remodelling, including structural and electrophysiological remodelling as well as alterations in Ca2+ handling, as contributors to the initiation and perpetuation of AF. However, the contributory role of these remodelling to the pathophysiology of different forms of AF and their corresponding complications is incompletely understood. Hence, the aims of this study are to (i) assess the role of altered intracellular Ca2+ handling in the atrial contractile dysfunction seen in patients with long-term persistent (‘chronic’) AF (cAF); (ii) investigate the role of abnormal intracellular Ca2+ handling in the arrhythmogenesis of postoperative AF (poAF) and its associated contractile dysfunction; (III) study the alteration in extracellular matrix (ECM) protein secretion and their possible role in poAF and cAF associated contractile dysfunction. In pursuance of these aims, right atrial appendages excised from cardiac surgery patients were obtained. In the first part of this thesis, the role of abnormal Ca2+ handling in the atrial contractile dysfunction associated with cAF was studied. Right atrial myocytes of cAF patients examined by simultaneous measurement of their membrane currents (voltage-clamp), intracellular Ca2+ ([Ca2+]i) and cell fractional shortening, exhibited an impaired contractile response to Ca2+. Expression of cTnC was reduced in cAF patients, which could account for the abnormal contractile response of atrial myocytes from cAF patients. Also, Ca2+ buffering was impaired in cAF myocytes as a consequence of lower Ca2+ buffers which is supported by the reduced cTnC expression observed in cAF patients. Conclusively, the findings in this part of this study suggest that reduced cTnC not only contributes to the atrial contractile dysfunction, but also the impaired buffering seen in cAF patients. In the next chapter, we evaluated the participation of altered intracellular handling of Ca2+ in the development of poAF and its related contractile dysfunction. Analysis of preoperative echocardiography recordings by speckle-tracking revealed diminished left atrial contraction in poAF patients. [Ca2+]i measurements indicated reduced systolic Ca2+ transient (CaT) amplitude and sarcoplasmic reticulum (SR) Ca2+ load in myocytes from poAF patients, with a delay in the sequestration the SR due to reduced SERCA2a activity identified as the underlying cause. In consonance, protein expression of SERCA2a was reduced in poAF patients, but the phosphorylation and expression of its regulatory protein phospholamban were unchanged. Atrial myocytes from poAF patients exhibited increased vulnerability to CaT and AP alternans, which is attributed to the reduced SERCA activity, based on computational modelling. In summary, our findings suggest that SERCA mediated impairment in SR Ca2+ uptake contributes majorly to the proarrhythmic mechanisms responsible for the development of poAF as well as the associated impaired preoperative atrial contractile function. Finally, we assessed the alterations in the secretions of ECM proteins in poAF and cAF patients using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Proteomic analysis of the secretome of atrial appendages from poAF and cAF patients showed minimal changes in ECM protein secretion in the poAF group, with approximately 6% of identified ECM proteins differentially regulated. In comparison, 40% of ECM proteins were differentially regulated in cAF, demonstrating marked alteration in ECM protein secretion. ECM proteins such as collagen I, microfibrillar associated protein, connective tissue growth factor and several other members of the different ECM were identified to contribute to remodelling in atrial ECM protein secretion, with the pro-fibrotic transforming growth factor β1 (TGFβ1), identified by further analysis as a contributor to the modification in ECM protein secretion seen in both poAF and cAF. Altogether this thesis provides novel mechanistic insight on the role of altered Ca2+ handling in the development of cAF and poAF and their associated contractile dysfunction as well as the characteristic remodelling of ECM protein secretion in both forms of
dc.contributor.coRefereeMeyer, Thomas Prof. Dr.
dc.contributor.thirdRefereeMayr, Manuel Prof. Dr.
dc.contributor.thirdRefereeSchwappach, Blanche Prof. Dr.
dc.contributor.thirdRefereeThoms, Sven PD Dr.
dc.contributor.thirdRefereeDressel, Ralf Prof. Dr.
dc.contributor.thirdRefereeKirchhof, Paulus Prof. Dr.
dc.subject.engAtrial fibrillationde
dc.subject.engPostoperative atrial fibrillationde
dc.subject.engAction potentialde
dc.subject.engExtracellular matrixde
dc.affiliation.instituteMedizinische Fakultät
dc.subject.gokfullMedizin (PPN619874732)de

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