Search Results (5)

Atrial fibrillation (AF) is the most common arrhythmia worldwide. AF is associated with a deficiency in nitric oxide (NO) production, which contributes to disturbances in the electrical and mechanical function of the atrial myocardium. NO donors are considered promising for the treatment and prevention of AF, but their effects on atrial contractility are unclear. This study examines the direct impact of a low-molecular-weight NO donor, spermine-NONOate (NOC-22), on the contractile function of atrial cardiomyocytes in paroxysmal AF. To study whether an NO donor-induced increase in NO level causes chamber-specific changes in atrial contractility, we measured sarcomere length (SL) dynamics in contracting single cardiomyocytes from the rat left and right atria (LA, RA) using a 7-day acetylcholine-CaCl₂-induced AF model. We showed that in control rats NOC-22 provoked alternans of sarcomere shortening in both LA and RA cardiomyocytes. In AF, NOC-22 decreased the sarcomere-shortening amplitudes and velocities of sarcomere shortening–relengthening and increased the magnitude of sarcomere-shortening alternans only in RA cardiomyocytes. The negative effects of NO donors on RA contractility warrant careful consideration of their use in AF treatment. Full article

Small conductance Ca²⁺-activated K⁺ (SK) channels are expressed in atria and ventricles. However, the data on the contribution of SK channels to atrial action potential (AP) repolarization are inconsistent. We investigated the effect of SK channel modulators on AP morphology in rabbit atrial myocytes and tested the hypothesis that pharmacological activation of SK channels suppresses pacing-induced Ca²⁺ transient (CaT) and AP duration (APD) alternans. At the cellular level, alternans are observed as beat-to-beat alternations in contraction, APD, and CaT amplitude, representing a risk factor for arrhythmias, including atrial fibrillation. Our results show that SK channel inhibition by apamin did not affect atrial APD under basal conditions. However, SK channel activation by NS309 significantly shortened APD, indicating the expression of functional SK channels. Moreover, the activation of SK channels reduced CaT amplitude and sarcoplasmic reticulum Ca²⁺ load. Activation of SK channels also suppressed pacing-induced CaT and APD alternans. K_V7.1 potassium channel inhibition, simulating long QT syndrome type-1 conditions, increased the risk of atrial CaT alternans, which was abolished by the activation of SK channels. In summary, our data suggest that pharmacological modulation of SK channels can potentially reduce atrial arrhythmia risk arising from pathological APD prolongation. Full article

Heart failure (HF) increases the probability of cardiac arrhythmias, including atrial fibrillation (AF), but the mechanisms linking HF to AF are poorly understood. We investigated disturbances in Ca²⁺ signaling and electrophysiology in rabbit atrial myocytes from normal and failing hearts and identified mechanisms that contribute to the higher risk of atrial arrhythmias in HF. Ca²⁺ transient (CaT) alternans—beat-to-beat alternations in CaT amplitude—served as indicator of increased arrhythmogenicity. We demonstrate that HF atrial myocytes were more prone to alternans despite no change in action potentials duration and only moderate decrease of L-type Ca²⁺ current. Ca²⁺/calmodulin-dependent kinase II (CaMKII) inhibition suppressed CaT alternans. Activation of IP₃ signaling by endothelin-1 (ET-1) and angiotensin II (Ang II) resulted in acute, but transient reduction of CaT amplitude and sarcoplasmic reticulum (SR) Ca²⁺ load, and lowered the alternans risk. However, prolonged exposure to ET-1 and Ang II enhanced SR Ca²⁺ release and increased the degree of alternans. Inhibition of IP₃ receptors prevented the transient ET-1 and Ang II effects and by itself increased the degree of CaT alternans. Our data suggest that activation of CaMKII and IP₃ signaling contribute to atrial arrhythmogenesis in HF. Full article

For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an increased amount of fibrous tissue. However, fibrosis is not a singular entity. Various forms can be distinguished, that differ in distribution: replacement fibrosis, endomysial and perimysial fibrosis, and perivascular, endocardial, and epicardial fibrosis. These different forms typically result from diverging pathophysiological mechanisms and can have different consequences for conduction. The impact of fibrosis on propagation depends on exactly how the patterns of electrical connections between myocytes are altered. We will therefore first consider the normal patterns of electrical connections and their regional diversity as determinants of propagation. Subsequently, we will summarize current knowledge on how different forms of fibrosis lead to a loss of electrical connectivity in order to explain their effects on propagation and mechanisms of arrhythmogenesis, including ectopy, reentry, and alternans. Finally, we will discuss a histological quantification of fibrosis. Because of the different forms of fibrosis and their diverging effects on electrical propagation, the total amount of fibrosis is a poor indicator for the effect on conduction. Ideally, an assessment of cardiac fibrosis should exclude fibrous tissue that does not affect conduction and differentiate between the various types that do; in this article, we highlight practical solutions for histological analysis that meet these requirements. Full article

Atrial fibrillation is the most common sustained arrhythmia and its prevalence is rapidly rising with the aging of the population. Cardiac alternans, defined as cyclic beat-to-beat alternations in contraction force, action potential (AP) duration and intracellular Ca²⁺ release at constant stimulation rate, has been associated with the development of ventricular arrhythmias. Recent clinical data also provide strong evidence that alternans plays a central role in arrhythmogenesis in atria. The aim of this article is to review the mechanisms that are responsible for repolarization alternans and contribute to the transition from spatially concordant alternans to the more arrhythmogenic spatially discordant alternans in atria. Full article