Arrhythmogenic cardiac alternans in heart failure is suppressed by late sodium current blockade by ranolazine.

Cardiac alternans is promoted by heart failure (HF)-induced calcium (Ca2+) cycling abnormalities. Late sodium current (INa,L) is enhanced in HF and promotes Ca2+ overload; however, mechanisms underlying an antiarrhythmic effect of INa,L blockade in HF remain unclear. The purpose of this study was to determine whether ranolazine suppresses cardiac alternans in HF by normalizing Ca2+ cycling. Transmural dual optical mapping of Ca2+ transients and action potentials was performed in wedge preparations from 8 HF and 8 control (normal) dogs. Susceptibility to action potential duration alternans (APD-ALT) and Ca2+ transient alternans (Ca-ALT) was compared at baseline and with ranolazine (5-10 μM). HF increased APD- and Ca-ALT compared to normal (both P <.05), and ranolazine suppressed APD- and Ca-ALT in both groups (P <.05). The incidence of spatially discordant alternans (DIS-ALT) was increased by HF (8/8) compared to normal (4/8; P <.05), and ranolazine decreased DIS-ALT in HF (4/8; P <.05).Not only did ranolazine mitigate HF-induced Ca2+ overload, it also attenuated APD-ALT to Ca-ALT gain (amount of APD-ALT produced by Ca-ALT). In HF, APD-ALT to Ca-ALT gain was significantly increased (0.55 ± 0.02) compared to normal (0.44 ± 0.02; P <.05) and was normalized by ranolazine (0.36 ± 0.05; P <.05), representing a complementary mechanism by which INa,L blockade suppressed cardiac alternans. Ranolazine attenuated arrhythmogenic cardiac alternans in HF, both by suppressing Ca-ALT and decreasing the coupling gain of APD-ALT to Ca-ALT. Blockade of INa,L may reverse impaired Ca2+ cycling to mitigate cardiac alternans, representing a mechanism underlying the antiarrhythmic benefit of INa,L blockade in HF.

Fukaya H ，Plummer BN ，Piktel JS ，Wan X ，Rosenbaum DS ，Laurita KR ，Wilson LD ... -  《-》

Heart failure enhances susceptibility to arrhythmogenic cardiac alternans.

Wilson LD ，Jeyaraj D ，Wan X ，Hoeker GS ，Said TH ，Gittinger M ，Laurita KR ，Rosenbaum DS ... -  《-》

Molecular correlates of repolarization alternans in cardiac myocytes.

Wan X ，Laurita KR ，Pruvot EJ ，Rosenbaum DS ... -  《JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY》

Renal Denervation Decreases Susceptibility to Arrhythmogenic Cardiac Alternans and Ventricular Arrhythmia in a Rat Model of Post-Myocardial Infarction Heart Failure.

Chang SN ，Chang SH ，Yu CC ，Wu CK ，Lai LP ，Chiang FT ，Hwang JJ ，Lin JL ，Tsai CT ... -  《JACC-Basic to Translational Science》

Inhibition of Ca(2+)-dependent protein kinase C rescues high calcium-induced pro-arrhythmogenic cardiac alternans in rabbit hearts.

Cardiac alternans closely linked to calcium dysregulation is a crucial risk factor for fatal arrhythmia causing especially sudden death. Calcium overload is well-known to activate Ca2+-dependent protein kinase C (PKC); however, the effects of PKC on arrhythmogenic cardiac alternans have not yet been investigated. This study aimed to determine the contributions of PKC activities in cardiac alternans associated with calcium cycling disturbances. In the present study, action potential duration alternans (APD-ALT) induced by high free intracellular calcium ([Ca2+]i) exerted not only in a calcium concentration-dependent manner but also in a frequency-dependent manner. High [Ca2+]i-induced APD-ALT was suppressed by not only BAPTA-AM but also nifedipine. On the other hand, PKC inhibitors BIM and Gö 6976 eliminated high [Ca2+]i-induced APD-ALT, and PKC activator PMA was found to induce APD-ALT at normal [Ca2+]i condition. Furthermore, BIM effectively prevented calcium transient alternans (CaT-ALT) and even CaT disorders caused by calcium overload. Moreover, BIM not only eliminated electrocardiographic T-wave alternans (TWA) caused by calcium dysregulation, but also lowered the incidence of ventricular arrhythmias in isolated hearts. What's more, BIM prevented the expression of PKC α upregulated by calcium overload in high calcium-perfused hearts. We firstly found that pharmacologically inhibiting Ca2+-dependent PKC over-activation suppressed high [Ca2+]i-induced cardiac alternans. This recognition indicates that inhibition of PKC activities may become a therapeutic target for the prevention of pro-arrhythmogenic cardiac alternans associated with calcium dysregulation.

Zhang PP ，Hu L ，Tian YJ ，Zhang Z ，Zhang PH ，Yang YY ，Li SH ，Ma J ... -  《-》