Abnormal Calcium Leak from Cardiac Sarcoplasmic Reticulum: New Insights Offered by Statistical Physics

Abstract

Heart muscle contraction is activated by a synchronized systolic Ca release from sarcoplasmic reticulum (SR) via Ca sparks. In disease, Ca sparks fail to terminate, causing a diastolic Ca leak that decreases contraction amplitude and increases the risk of arrhythmia. The mechanisms and treatment of the abnormal Ca leak remain unclear. We have recently shown that spark termination emerges as collective behavior (synchronized closings) of Ca release channels (RyRs) that is identical to synchronization of spin orientation in ferromagnets described by a phase transition in Ising model. We employed the Ising approach to investigate and classify mechanisms of spark termination failure and Ca leak. Methods and Results: The key parameters determining whether spark termination succeeds or fails are SR Ca and RyR opening/closing rates. They define analogues of magnetic field h and the inverse temperature (β) in Ising model. Sparks terminate via a phase transition known as “h polarity reversal” and the leak emerges when h fails to change its sign. This happens when the SR depletes insufficiently and RyR openings remained partially synchronized via Ca-induced-Ca-release, generating long-lasting sparks. Leak can also occur via β, known as Onsager's “order-disorder” transition. This happens at low SR Ca, reducing RyR current and RyRs interactions, resulting in independent RyR openings. The disorder leak is distinguished from synchronized leak by larger Peierls contour lengths reflecting degree of disorder. Abnormal leak results from either a probability imbalance during synchronized firing of RyRs or from disordered RyR firing. Each leak type requires different and balanced treatment to shift RyR operation towards normal spark termination.