Dynamical effects of mechano-chemo-transduction on cardiac alternans

In every heartbeat, cardiac muscle cells perform excitation-Ca²⁺ signaling-contraction (EC) coupling to pump blood against the vascular resistance. Cardiomyocytes can sense the mechanical load and activate mechano-chemo-transduction (MCT) mechanism, which provides feedback regulation of EC coupling. MCT feedback is important for the heart to upregulate contraction in response to increased load to maintain cardiac output. MCT feedback enhances the L-type Ca²⁺ current, sensitizes ryanodine receptors (RyRs), and augments SERCA pump activity, thereby maintaining contraction amplitude despite increased load. However, under certain conditions, MCT feedback can also promote cardiac alternans, seen as beat-to-beat variations in action potential duration, Ca²⁺ transients, and contraction strength, which is a precursor to arrhythmias. While alternans can arise from instabilities in either membrane voltage or intracellular Ca²⁺ cycling, underlying mechanisms of MCT-induced alternans, particularly electromechanically discordant alternans where stronger beats are paradoxically associated with shorter action potentials, remain unclear. In this study, we used a mathematical model of the ventricular myocyte to investigate the effects of MCT feedback on the dynamical system that generates alternans. We systematically analyzed how MCT feedback, acting through L-type Ca²⁺ channels (LTCCs), RyRs, or SERCA, affects the stability of membrane voltage and Ca²⁺ cycling, as well as the coupling between them. Our results show that MCT feedback can generally promote both concordant and discordant alternans in action potential and Ca²⁺ transients, depending on the underlying instability mechanism. We found that MCT feedback through RyRs predominantly increases Ca²⁺ instability, while LTCC and SERCA feedback have complex effects due to the interplay between stability and coupling alterations. We also showed how to determine underlying mechanisms from experimental and clinical observations. Our modeling studies provide new insights into the complex dynamics underlying cardiac alternans and highlight the importance of MCT feedback in the development of life-threatening arrhythmias in the heart under mechanical load.