Number 33, 2006
Arrhythmia and metabolism

Cellular changes in atrial fibrillation

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Jolanda van der Velden, Nadiya A. Narolska, Ger J.M. Stienen
Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands
Correspondence: J. van der Velden, Laboratory for Physiology, Institute for Cardiovascular Research, VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Tel: +31 20 4448113; fax: +31 20 4448255; e-mail: J.vandervelden@vumc.nl

Introduction
Atrial fibrillation, the most common sustained cardiac arrhythmia in humans, is characterized by severe electrophysiological and structural changes. A profound cellular remodeling process takes place during persistent atrial fibrillation, which is reversible after cardioversion [1,2]. However, upon cardioversion, reversal of the atrial contractile dysfunction that is induced by atrial fibrillation varies with the duration of the atrial fibrillation before cardioversion, and may take weeks to months [3].
Reduced atrial contractility may be caused by ultrastructural and functional changes (Figure 1). The structural alterations involved in cellular remodeling in response to chronic atrial fibrillation include loss of myofibrils (myolysis) [1,4], accumulation of glycogen, changes in mitochondrial shape and size, and fragmentation of the sarcoplasmic reticulum [1]. These ultrastructural changes are representative for dedifferentiated cardiac tissue as observed during cardiac development. Apart from ultrastructural changes, impaired cardiomyocyte function may also contribute to reduced atrial contraction induced by chronic atrial fibrillation. This may also be detrimental after cardioversion, when the normal electric rhythm is restored.

Factors involved in cardiomyocyte function
Cardiomyocyte contractility is determined by the amount of calcium released into the cytosol and the responsiveness of the contractile apparatus to calcium. During an action potential, voltage-dependent L-type calcium channels are opened and calcium enters the cell (Figure 2). This calcium influx induces the release of calcium stored inside the sarcoplasmic reticulum via the ryanodine receptor into the cytosol: the calcium-induced calcium release mechanism [5]. The cardiomyocyte contracts when a molecular interaction takes place between the contractile proteins, actin and myosin, which is triggered by the increase in cytosolic calcium and is driven by the energy from ATP hydrolysis. Calcium binds to the troponin complex, inducing cardiomyocyte contraction by the formation of crossbridges between the thin (actin) and thick (myosin) myofilaments. Relaxation results from detachment of calcium from the troponin complex and removal of calcium from the cell via the sarcolemmal Na⁺–Ca²⁺ exchanger and back into the sarcoplasmic reticulum via the sarcoplasmic reticulum Ca²⁺-ATPase, the activity of which is regulated by an associated protein, phospholamban. Depressed cardiomyocyte contractility may originate from impaired calcium handling, myofilament contraction, or both, as a result of alterations in the regulatory proteins involved.

Reduced cardiomyocyte contractility in chronic atrial fibrillation
The contractile force measured in atrial muscle strips from patients with persistent atrial fibrillation (that is, of at least 3 months’ duration) was reduced by 75% in comparison with that in patients in sinus rhythm [6]. The reduction in force development could be partly explained by myolysis (reduction in contractile proteins). Although contractile remodeling of the atria has been recognized for several decades [7], the intrinsic cellular mechanisms responsible for contractile dysfunction induced by atrial fibrillation remain poorly understood.
Altered calcium handling contributes significantly to this contractile dysfunction, and mainly involves alterations in transmembrane calcium transport, rather than changes in calcium handling by the sarcoplasmic reticulum. A decreased function of the L-type calcium channels most probably explains reduced availability of cytosolic calcium during activation [6,8]. Impairment of the L-type calcium current is probably caused by altered phosphorylation of the channels involved, as a result of increased phosphatase activity [9]. In addition, upregulation of the Na⁺–Ca²⁺ exchanger might increase removal of calcium from the cell, further diminishing the amount of calcium available for contraction [8]. Calcium storage in the sarcoplasmic reticulum seems to be preserved, as no changes have been found in the expression of sarcoplasmic reticulum calcium ATPase, phospholamban, and the ryanodine receptor [8].
In addition to impaired calcium handling, a reduction in the force-generating capacity of the contractile apparatus may contribute to reduced cellular contractility. Recent studies on the composition of contractile proteins, comparing patients with chronic atrial fibrillation and those in sinus rhythm, revealed several changes, in the status of both the expression and the phosphorylation of contractile proteins.
Each myosin molecule is composed of two heavy chains (MHC), each with two light chains (LC-1 and LC-2). Human atrial tissue predominantly expresses the faster (higher ATPase activity) α-MHC, but also contains the slower β-MHC [10]. The relative expression of β-MHC is increased in patients with chronic atrial fibrillation [11,12]. Despite a reduction in speed of contraction, the shift from α- to β-MHC may be beneficial because less energy is required to maintain pump function at rest. However, as the contribution of atrial contraction to cardiac output becomes more important in patients with ventricular dysfunction [13], reduced velocity of atrial contraction may impair ventricular filling and reduce cardiac output in patients with heart failure.
The essential light chain (LC-1) and regulatory light chain (LC-2) tune the function of the myosin head [14] and influence the maximum force-generating capacity and its sensitivity to calcium. In patients with atrial fibrillation, a decrease was observed in the expression of both atrial light chains normalized to actin, suggesting a loss (∼25%) of atrial light chains in patients with atrial fibrillation [15]. Increased proteolysis of light chains may be the result of increased calpain activity, as observed in human atrial fibrillation [4]. In contrast, desmin content in the patients with atrial fibrillation was markedly increased, as was evident from a large increase (70%) in the desmin : actin ratio [15]. In addition, the phosphorylation status of troponin T was increased in human atrial fibrillation. Studies in rodent myocardium indicated a central role for protein kinase C-mediated phosphorylation of the troponin T in decreasing maximal force. Force measurements in permeabilized atrial cardiomyocytes (Figure 3) showed a reduction of 33% in the maximum force-generating capacity in human atrial fibrillation and a decrease in contraction. Thus, apart from myolysis and impaired calcium handling, a reduction in velocity of contraction and in the maximal force-generating capacity of the contractile apparatus may contribute to the contractile dysfunction induced by atrial fibrillation.

Future research
Recent evidence suggests an important role for oxidative stress in reducing myocardial function during atrial fibrillation [11,16–18]. Mihm et al. [11] showed an increased prevalence of protein oxidation, protein nitration, and protein carbonyl formation in patients with atrial fibrillation. Kim et al. [18] showed that myocardial activation of NAD(P)H oxidase and uncoupling of nitric oxide synthase have important roles in patients with paroxysmal and permanent atrial fibrillation. The major reactive oxygen species and their derivatives, reactive nitrogen species, are superoxide radicals (O₂⁻), hydroperoxyl radicals (HO₂), nitric oxide, and peroxynitrite (ONOO⁻). Collectively, these radicals cause a loss of biological function through oxidation of the protein backbone or amino acid side chains, or both, which may lead to protein fragmentation and the formation of protein–protein crosslinkages, respectively. However, little is known about the target proteins and the functional implications of oxidative modifications in atrial fibrillation. Hence the prevention of protein oxidation provides new therapeutic strategies directed towards the prevention of structural remodeling and reduced contractility.

Summary
Upon cardioversion of chronic atrial fibrillation, both structural and functional cellular alterations contribute to a reduction in atrial contractile function. Atrial dysfunction induced by atrial fibrillation increases the risk of development of thromboembolisms and impairs ventricular filling and cardiac output in patients with ventricular heart disease. Insight to the mechanisms underlying the atrial remodeling that is induced by atrial fibrillation will provide a basis for new therapeutic strategies.

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