Action potential shortening rescues atrial calcium alternans

Abstract

Key points Cardiac alternans refers to a beat‐to‐beat alternation in contraction, action potential (AP) morphology and Ca2+ transient (CaT) amplitude, and represents a risk factor for cardiac arrhythmia, including atrial fibrillation. We developed strategies to pharmacologically manipulate the AP waveform with the goal to reduce or eliminate the occurrence of CaT and contraction alternans in atrial tissue. With combined patch‐clamp and intracellular Ca2+ measurements we investigated the effect of specific ion channel inhibitors and activators on alternans. In single rabbit atrial myocytes, suppression of Ca2+‐activated Cl− channels eliminated AP duration alternans, but prolonged the AP and failed to eliminate CaT alternans. In contrast, activation of K+ currents (IKs and IKr) shortened the AP and eliminated both AP duration and CaT alternans. As demonstrated also at the whole heart level, activation of K+ conductances represents a promising strategy to suppress alternans, and thus reducing a risk factor for atrial fibrillation. Abstract At the cellular level alternans is observed as beat‐to‐beat alternations in contraction, action potential (AP) morphology and magnitude of the Ca2+ transient (CaT). Alternans is a well‐established risk factor for cardiac arrhythmia, including atrial fibrillation. This study investigates whether pharmacological manipulation of AP morphology is a viable strategy to reduce the risk of arrhythmogenic CaT alternans. Pacing‐induced AP and CaT alternans were studied in rabbit atrial myocytes using combined Ca2+ imaging and electrophysiological measurements. Increased AP duration (APD) and beat‐to‐beat alternations in AP morphology lowered the pacing frequency threshold and increased the degree of CaT alternans. Inhibition of Ca2+‐activated Cl− channels reduced beat‐to‐beat AP alternations, but prolonged APD and failed to suppress CaT alternans. In contrast, AP shortening induced by activators of two K+ channels (ML277 for Kv7.1 and NS1643 for Kv11.1) abolished both APD and CaT alternans in field‐stimulated and current‐clamped myocytes. K+ channel activators had no effect on the degree of Ca2+ alternans in AP voltage‐clamped cells, confirming that suppression of Ca2+ alternans was caused by the changes in AP morphology. Finally, activation of Kv11.1 channel significantly attenuated or even abolished atrial T‐wave alternans in isolated Langendorff perfused hearts. In summary, AP shortening suppressed or completely eliminated both CaT and APD alternans in single atrial myocytes and atrial T‐wave alternans at the whole heart level. Therefore, we suggest that AP shortening is a potential intervention to avert development of alternans with important ramifications for arrhythmia prevention and therapy.

Interleukin-6-Mediated-Ca2+ Handling Abnormalities Contributes to Atrial Fibrillation in Sterile Pericarditis Rats

“…According to a previous study, AP shortening suppresses or completely eliminates alternans in single atrial cardiomyocytes isolated from rabbits ( 36 ). In the current study, the prolongation and dispersion of APD in the SP atria, consistent with our previous finding ( 2 ), were inhibited by IL-6 neutralization.…”

Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling

“…Electrical remodeling in our models included up-regulation in I NaL , I Ks , and I Kr . Although upregulated I NaL led to APD prolongation (Sossalla et al, 2010), the increase in I Ks and I Kr was found to play an important role in APD shortening (Kanaporis et al, 2019), resulting in an abbreviated WL of excitation waves that facilitated the initiation and maintenance of re-entry. Structural remodeling was modeled by decreasing the diffusion coefficient to simulate the reduced Cx43/(Cx43+Cx40) ratio.…”

ML277 regulates KCNQ1 single-channel amplitudes and kinetics, modified by voltage sensor state

“…Much like several other KCNQ1 activators, the action of ML277 is dependent on the stoichiometry of the KCNQ1/KCNE1 complex, with some finding little ( Xu et al, 2015 ) or no effect ( Yu et al, 2013 , Hou et al, 2019 ) of the drug when KCNQ1 is complexed with a saturating level of KCNE1. However, ML277 enhances I Ks in isolated guinea pig and canine ventricular myocytes ( Xu et al, 2015 ) and rabbit atrial myocytes ( Kanaporis et al, 2019 ) in addition to shortening the action potential in these cells, and in human induced pluripotent stem cell (iPSC)–derived cardiomyocytes from healthy controls and LQT1 patients ( Ma et al, 2015 , Wuriyanghai et al, 2018 , Yu et al, 2013 ). This, as stated earlier and by others ( Yu et al, 2013 ; Xu et al, 2015 ), suggests that I Ks in myocytes may not be fully saturated with KCNE1, and if this is also true of I Ks in the intact human heart, ML277, or a derivative, could potentially be used as a therapeutic to treat patients with LQT1.…”