4.5 Article

Blockade of sodium-calcium exchanger via ORM-10962 attenuates cardiac alternans

Journal

JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 153, Issue -, Pages 111-122

Publisher

ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2020.12.015

Keywords

Alternans; Sodium-calcium exchanger; Sodium-calcium exchanger inhibition; Canine myocytes; Cardiac simulation

Funding

  1. National Research Development and Innovation Office [NKFIH PD-125402, FK129117, GINOP-2.3.2-15-2016-00006, GINOP-2.3.2-152016-00012]
  2. LIVE LONGER [EFOP-3.6.2-16-2017-00006]
  3. Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences
  4. EFOP [3.6.3 VEKOP-16-2017-00009]
  5. Hungarian Academy of Sciences
  6. British Heart Foundation [FS/15/8/3115, CH/2000004/12801]
  7. Wellcome Trust [100246/Z/12/Z, 214290/Z/18/Z]
  8. Orion Pharma [ORM-10962]

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The study found that the NCX blocker ORM-10962 can effectively reduce cardiac alternans in both action potential duration and calcium transients, with differential effects on different types of alternans, and indirectly increasing post-repolarization refractoriness by reducing L-type calcium current. Computer simulations confirmed that ORM-10962 acts by reducing sarcoplasmic reticulum release refractoriness through NCX block and indirect reduction in L-type calcium current, suggesting it may be a useful anti-arrhythmic strategy.
Repolarization alternans, a periodic oscillation of long-short action potential duration, is an important source of arrhythmogenic substrate, although the mechanisms driving it are insufficiently understood. Despite its relevance as an arrhythmia precursor, there are no successful therapies able to target it specifically. We hypothesized that blockade of the sodium-calcium exchanger (NCX) could inhibit alternans. The effects of the selective NCX blocker ORM-10962 were evaluated on action potentials measured with microelectrodes from canine papillary muscle preparations, and calcium transients measured using Fluo4-AM from isolated ventricular myocytes paced to evoke alternans. Computer simulations were used to obtain insight into the drug?s mechanisms of action. ORM-10962 attenuated cardiac alternans, both in action potential duration and calcium transient amplitude. Three morphological types of alternans were observed, with differential response to ORM-10962 with regards to APD alternans attenuation. Analysis of APD restitution indicates that calcium oscillations underlie alternans formation. Furthermore, ORM-10962 did not markedly alter APD restitution, but increased post-repolarization refractoriness, which may be mediated by indirectly reduced L-type calcium current. Computer simulations reproduced alternans attenuation via ORM-10962, suggesting that it is acts by reducing sarcoplasmic reticulum release refractoriness. This results from the ORM-10962-induced sodium-calcium exchanger block accompanied by an indirect reduction in L-type calcium current. Using a computer model of a heart failure cell, we furthermore demonstrate that the anti-alternans effect holds also for this disease, in which the risk of alternans is elevated. Targeting NCX may therefore be a useful anti-arrhythmic strategy to specifically prevent calcium driven alternans.

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