Targeting Mitochondrial-Endoplasmic Reticulum Contact Sites (MAMs) Bioenergetics to Prevent Myocardial No-Reflow: A Non-Equilibrium Thermodynamic Framework

Abstract

Despite high procedural success rates in primary percutaneous coronary intervention (PCI), acute myocardial infarction remains heavily burdened by the « no-reflow » phenomenon and progressive microvascular obstruction [1, 2]. Current pharmacological strategies fail to address the underlying biophysical failure occurring at the microvascular-cardiomyocyte interface. In this paper, we formulate a non-equilibrium thermodynamic and information-theoretic framework centered on the bioenergetic integrity of Mitochondrial-Endoplasmic Reticulum Contact Sites (MAMs) [1, 7]. Under acute ischemia-reperfusion stress, the uncoupling of the IP3R-GRP75-VDAC1 macromolecular complex triggers runaway cytosolic and mitochondrial calcium overload (J_Ca²⁺), driving massive local entropy production (σ_ent) and mitochondrial permeability transition pore (mPTP) opening [1, 3]. By modeling intracellular signaling fidelity through Shannon channel capacity and cellular Signal-to-Noise Ratio (SNR_bio) [4, 5], we quantify the critical thermodynamic threshold (SNR_crit) below which endothelial and myocardial restorative signaling collapses into stochastic oxidative noise [5, 8]. We demonstrate that pre-reperfusion metabolic stabilization via nano-vectorized lipid carriers quenches oxidative entropy, maintains MAM architecture, and preserves channel capacity (C > 10 bits · s⁻¹), thereby preventing microvascular spasm, capillary plugging, and infarct expansion [8, 9, 10]. This Science 4.0 framework bridges cellular non-equilibrium thermodynamics with bedside interventional cardiology [5, 10].