Cardiac excitation‐contraction (E‐C) coupling is influenced by (at least) three dynamic systems that couple and feedback to one another (see Abstract Figure). Here we review the mechanical effects on cardiomyocytes that include mechano‐electro‐transduction (commonly referred to as mechano‐electric coupling, MEC) and mechano‐chemo‐transduction (MCT) mechanisms at cell and molecular levels which couple to Ca²⁺‐electro and E‐C coupling reviewed elsewhere. These feedback loops from muscle contraction and mechano‐transduction to the Ca²⁺ homeodynamics and to the electrical excitation are essential for understanding the E‐C coupling dynamic system and arrhythmogenesis in mechanically loaded hearts. This white paper comprises two parts, each reflecting key aspects from the 2018 UC Davis symposium: MEC (how mechanical load influences electrical dynamics) and MCT (how mechanical load alters cell signalling and Ca²⁺ dynamics). Of course, such separation is artificial since Ca²⁺ dynamics profoundly affect ion channels and electrogenic transporters and vice versa. In time, these dynamic systems and their interactions must become fully integrated, and that should be a goal for a comprehensive understanding of how mechanical load influences cell signalling, Ca²⁺ homeodynamics and electrical dynamics. In this white paper we emphasize current understanding, consensus, controversies and the pressing issues for future investigations. Space constraints make it impossible to cover all relevant articles in the field, so we will focus on the topics discussed at the symposium. image

The Frank-Starling law and Anrep effect describe two intrinsic mechanisms that regulate contraction force in the heart. Based on recent advancements and the historical literature, we propose new perspectives and address several critical issues in this review. ( a ) The Frank-Starling mechanism and Anrep effect are dynamically linked and act synergistically. ( b ) An open question is how cardiomyocytes sense mechanical load and transduce to biochemical signals (called mechano-chemo-transduction or MCT) to regulate contraction in response to load changes. ( c ) One research focus is to identify various mechanosensors and decipher their downstream MCT pathways. ( d ) Innovative experimental techniques engage different mechanosensors that detect different local strain and stress in the cell architecture. ( e ) Closed-loop MCT feedback in the dynamic excitation-Ca ²⁺ signaling-contraction system enables autoregulation of contraction in response to physiological load changes. ( f ) However, pathological overload such as volume and pressure overload lead to excessive MCT-Ca ²⁺ gain, cardiac remodeling, and heart diseases.