Atrial remodeling during persistent atrial fibrillation: focus on nitric oxide and calcium homeostasis

Abstract

AF is the most common arrhythmia with a life time risk of developing AF of 1 out of 4 in people over 40. Only a minority of patients has AF without underlying heart disease, including arterial hypertension, valvular heart disease, congestive heart failure or coronary artery disease. AF is associated with a significant morbidity and mortality. Stroke resulting from embolization of atrial thrombi is the major determinant of this morbidity. Recent studies have suggested an important role for oxidative stress, induced by production of free radicals, in the development of AF. The production of free radicals is physiologically balanced by its degradation by anti-oxidants. Different pathologies can disrupt the equilibrium, leading to induction of oxidative stress. Increased production of free oxygen radicals can influence bioavailability of NO, which plays an important role in controlling vascular tone and thrombogenesis, and modulates myocardial contraction. The general aim of this thesis was to further investigate the underlying atrial remodeling induced by AF. More specifically, we focused on changes in the NO and oxidative stress pathways, as well as on alterations in Ca2+ handling properties. We used a sheep model, in which AF is induced by continuous rapid atrial pacing.In a first part, we showed that persistent AF was accompanied by increased superoxide production, indicating the presence of oxidative stress. This overproduction was associated with marked accumulation of peroxynitrite, which is produced by the reaction of superoxide with NO. In addition, we have demonstrated decreased expression of NOS3, and significantly lower levels of circulating NO metabolites in AF than in control. These data indicate that persistent AF is associated with oxidativestress and a decreased availability of NO. Second, we hypothesized that increasing the availability of NO may reduce electrical remodeling induced by atrial tachycardia. Short-term electrical remodeling was induced by 4 hours of rapid atrial pacing. Treatment with an NO-donor delayed electrical remodeling. This was accompanied by a significant decrease in systolic blood pressure. To exclude that the effect on electrical remodeling could be explained by this difference in blood pressure, additional experimentswere performed with urapidil, a vasodilator. Despite a similar decrease in blood pressure, treatment with urapidil was unable to prevent or delay the induced electrical remodeling. We could furthermore demonstrate that this delay was based on increased Ca2+ influx induced by NO-donors. On the long term this could therefore be detrimental due to cytotoxic Ca2+ overload of atrial myocytes. In a last part of the study we studied the changes in Ca2+ homeostasis and the link to atrial contractiledysfunction during AF. Reduced fractional Ca2+ release from the SR was observed, but was accompanied by preserved SR Ca2+ content. When Ca2+ release was maximal, however, cell contraction normalized to control levels. These data indicate that alterations in Ca2+ homeostasis, and not deficits in myofilament properties, were responsible for the decreased atrial contraction during AF. The decreased Ca2+ release from the SR was related to a loss in T-tubule density, which results ina decreased number of functional links between L-type Ca2+ channels and RyRs. Finally, we demonstrated that if functional links were present, their efficiency was affected in AF. In summary, persistent AF is associated with increased oxidative stress and attenuated NO availability. Pharmacologically increased NO levels in vivo transiently delayed short-term electrical remodeling induced by atrial tachypacing. The underlying mechanism, however, increases Ca2+ influx in atrial myocytes and therefore might be detrimental on the long term. In persistent AF, reduced fractional Ca2+ release is a major factor in the decreased atrial cell contraction. This is due to a combinationof reduced numbers of Ca2+channel-RyR couplings, due to loss of T-tubules, and decreased efficiency of these subsarcolemmal couplings. Importantly, it may further reduce the actual availability of Ca2+to the myofilaments, which further depresses atrial contraction during AF. These insights may help to optimize the treatment options for patients suffering from AF.nrpages: 126status: publishe