Atrial remodeling in permanent atrial fibrillation : Mechanisms and pharmacological implications

Atrial fibrillation (AF), the most prevalent rhythm disorder in clinical practice, is currently significantly contributing to morbidity and mortality of the ageing population. In the past decades, a tremendous amount of research resulted in valuable insights into AF pathophysiology, with a primary focus on atrial remodeling. Defined as a persistent change in atrial function and structure, remodeling has the intrinsic properties to enhance the probability of focal (ectopic) and/or re-entrant pursuits, thus supporting AF persistence. The hallmark of structural remodeling is represented by atrial fibrosis, a multifactorial process involving an interaction between neurohormonal and cellular mediators. This paper provides a brief summary of the recent knowledge with respect to electrical and structural remodeling and novel insights into the pathogenesis of atrial fibrosis. Since current drug options for AF treatment are far from being optimal we also discuss the therapeutic principles and current alternatives for counteracting atrial fibrosis, and thus preventing arrhythmia recurrence

The Cardiac Pacemaker Story-Fundamental Role of the Na+/Ca2+ Exchanger in Spontaneous Automaticity

The electrophysiological mechanism of the sinus node automaticity was previously considered exclusively regulated by the so-called “funny current”. However, parallel investigations increasingly emphasized the importance of the Ca$^{2+}$-homeostasis and Na+/ Ca$^{2+}$ exchanger (NCX). Recently, increasing experimental evidence, as well as insight through mechanistic in silico modeling demonstrates the crucial role of the exchanger in sinus node pacemaking. NCX had a key role in the exciting story of discovery of sinus node pacemaking mechanisms, which recently settled with a consensus on the coupled-clock mechanism after decades of debate. This review focuses on the role of the Na$^{+}$/Ca$^{2+}$ exchanger from the early results and concepts to recent advances and attempts to give a balanced summary of the characteristics of the local, spontaneous, and rhythmic Ca$^{2+}$ releases, the molecular control of the NCX and its role in the fight-or-flight response. Transgenic animal models and pharmacological manipulation of intracellular Ca$^{2+}$ concentration and/or NCX demonstrate the pivotal function of the exchanger in sinus node automaticity. We also highlight where specific hypotheses regarding NCX function have been derived from computational modeling and require experimental validation. Nonselectivity of NCX inhibitors and the complex interplay of processes involved in Ca$^{2+}$ handling render the design and interpretation of these experiments challenging

The Inhibition of the Small-Conductance Ca2+-Activated Potassium Channels Decreases the Sinus Node Pacemaking during Beta-Adrenergic Activation

Sinus pacemaking is based on tight cooperation of intracellular Ca2+ handling and surface membrane ion channels. An important player of this synergistic crosstalk could be the small-conductance Ca2+-activated K+-channel (ISK) that could contribute to the sinoatrial node (SAN) pacemaking driven by the intracellular Ca2+ changes under normal conditions and beta-adrenergic activation, however, the exact role is not fully clarified. SK2 channel expression was verified by immunoblot technique in rabbit SAN cells. Ionic currents and action potentials were measured by patch-clamp technique. The ECG R-R intervals were obtained by Langendorff-perfusion method on a rabbit heart. Apamin, a selective inhibitor of SK channels, was used during the experiments. Patch-clamp experiments revealed an apamin-sensitive current. When 100 nM apamin was applied, we found no change in the action potential nor in the ECG R-R interval. In experiments where isoproterenol was employed, apamin increased the cycle length of the SAN action potentials and enhanced the ECG R-R interval. Apamin did not amplify the cycle length variability or ECG R-R interval variability. Our data indicate that ISK has no role under normal condition, however, it moderately contributes to the SAN automaticity under beta-adrenergic activation

The reverse mode of the Na+/Ca2+ exchanger contributes to the pacemaker mechanism in rabbit sinus node cells

Sinus node (SN) pacemaking is based on a coupling between surface membrane ion-channels and intracellular Ca 2+ -handling. The fundamental role of the inward Na + /Ca 2+ exchanger (NCX) is firmly established. However, little is known about the reverse mode exchange. A simulation study attributed important role to reverse NCX activity, however experimental evidence is still missing. Whole-cell and perforated patch-clamp experiments were performed on rabbit SN cells supplemented with fluorescent Ca 2+ -tracking. We established 2 and 8 mM pipette NaCl groups to suppress and enable reverse NCX. NCX was assessed by specific block with 1 μM ORM-10962. Mechanistic simulations were performed by Maltsev–Lakatta minimal computational SN model. Active reverse NCX resulted in larger Ca 2+ -transient amplitude with larger SR Ca 2+ -content. Spontaneous action potential (AP) frequency increased with 8 mM NaCl. When reverse NCX was facilitated by 1 μM strophantin the Ca 2+ i and spontaneous rate increased. ORM-10962 applied prior to strophantin prevented Ca 2+ i and AP cycle change. Computational simulations indicated gradually increasing reverse NCX current, Ca 2+ i and heart rate with increasing Na + i . Our results provide further evidence for the role of reverse NCX in SN pacemaking. The reverse NCX activity may provide additional Ca 2+ -influx that could increase SR Ca 2+ -content, which consequently leads to enhanced pacemaking activity

The reverse mode of the Na+^+/Ca2+^{2+} exchanger contributes to the pacemaker mechanism in rabbit sinus node cells

Sinus node (SN) pacemaking is based on a coupling between surface membrane ion-channels and intracellular Ca$^{2+}$-handling. The fundamental role of the inward Na$^+$/Ca$^{2+}$ exchanger (NCX) is firmly established. However, little is known about the reverse mode exchange. A simulation study attributed important role to reverse NCX activity, however experimental evidence is still missing. Whole-cell and perforated patch-clamp experiments were performed on rabbit SN cells supplemented with fluorescent Ca$^{2+}$-tracking. We established 2 and 8 mM pipette NaCl groups to suppress and enable reverse NCX. NCX was assessed by specific block with 1 μM ORM-10962. Mechanistic simulations were performed by Maltsev–Lakatta minimal computational SN model. Active reverse NCX resulted in larger Ca$^{2+}$-transient amplitude with larger SR Ca$^{2+}$-content. Spontaneous action potential (AP) frequency increased with 8 mM NaCl. When reverse NCX was facilitated by 1 μM strophantin the Ca$^{2+}$$_i$ and spontaneous rate increased. ORM-10962 applied prior to strophantin prevented Ca$^{2+}$$_i$ and AP cycle change. Computational simulations indicated gradually increasing reverse NCX current, Ca$^{2+}$$_i$ and heart rate with increasing Na$^+$$_i$. Our results provide further evidence for the role of reverse NCX in SN pacemaking. The reverse NCX activity may provide additional Ca$^{2+}$-influx that could increase SR Ca$^{2+}$-content, which consequently leads to enhanced pacemaking activity

Novel Na+/Ca2+ Exchanger Inhibitor ORM-10962 Supports Coupled Function of Funny-Current and Na+/Ca2+ Exchanger in Pacemaking of Rabbit Sinus Node Tissue

Background and Purpose: The exact mechanism of spontaneous pacemaking is not fully understood. Recent results suggest tight cooperation between intracellular Ca$^{2+}$ handling and sarcolemmal ion channels. An important player of this crosstalk is the Na$^{+}$/ Ca$^{2+}$ exchanger (NCX), however, direct pharmacological evidence was unavailable so far because of the lack of a selective inhibitor. We investigated the role of the NCX current in pacemaking and analyzed the functional consequences of the I$_{f-}$NCX coupling by applying the novel selective NCX inhibitor ORM-10962 on the sinus node (SAN). Experimental Approach: Currents were measured by patch-clamp, Ca$^{2+}$-transients were monitored by fluorescent optical method in rabbit SAN cells. Action potentials (AP) were recorded from rabbit SAN tissue preparations. Mechanistic computational data were obtained using the Yaniv et al. SAN model. Key Results: ORM-10962 (ORM) marginally reduced the SAN pacemaking cycle length with a marked increase in the diastolic Ca$^{2+}$ level as well as the transient amplitude. The bradycardic effect of NCX inhibition was augmented when the funny-current (I$_{f}$) was previously inhibited and vice versa, the effect of I$_{f}$ was augmented when the Ca$^{2+}$ handling was suppressed. Conclusion and Implications: We confirmed the contribution of the NCX current to cardiac pacemaking using a novel NCX inhibitor. Our experimental and modeling data support a close cooperation between I$_{f}$ and NCX providing an important functional consequence: these currents together establish a strong depolarization capacity providing important safety factor for stable pacemaking. Thus, after individual inhibition of I$_{f}$ or NCX, excessive bradycardia or instability cannot be expected because each of these currents may compensate for the reduction of the other providing safe and rhythmic SAN pacemaking