Myocardial Interstitium: From Histophysiology to Cardiosclerosis and Ectopic Calcification

Introduction. A fundamental paradigm shift has occurred in modern cardiology: the myocardial interstitium (stroma) is no longer considered a passive scaffold, but a highly dynamic, metabolically active neuro-immune-vascular niche that maintains structural homeostasis, regulates electrophysiology and contractility, and determines the trajectory of pathological cardiac remodeling. Aim. To systematize current data on the structural and cellular organization of the myocardial stroma and to characterize the mechanisms of crosstalk between stromal elements and cardiomyocytes underlying fibrosis and ectopic calcification. Materials and Methods. A systematic review of PubMed/MEDLINE, Scopus, and Web of Science was performed; 48 of over 200 identified sources (2005–2026), predominantly from Q1-Q2 journals, were selected for analysis. Results. The myocardial architecture possesses a laminar spatial organization formed by collagen fibers of the endomysium and perimysium. The cellular composition of the interstitium is highly heterogeneous. Telocytes form a three-dimensional scaffold via telopodes, physically integrating tissue structures while stimulating cardiomyocyte maturation and maintaining regenerative potential through microRNA secretion. Pericytes control capillary blood flow — their pathological spasm underlies the “no-reflow” phenomenon during ischemia — and orchestrate regeneration through a secretome that stimulates neoangiogenesis and limits fibrosis. Cardiac fibroblasts govern matrix biosynthesis; their stepwise activation into myofibroblasts and matrifibrocytes drives replacement or reactive fibrosis, and fibroblast-derived TGF-β directly suppresses cardiomyocyte contractility. Beyond fibrosis, disrupted collagen turnover and ectopic stromal calcification (e.g., due to Fetuin-A deficiency) produce myocardial stiffness and diastolic dysfunction (HFpEF) refractory to pharmacological treatment. Conclusions. The physiological and pathological state of the heart depends entirely on bidirectional crosstalk between cardiomyocytes and the stroma; future cardiological and regenerative therapies must target the integrated multi-tissue microenvironment rather than the isolated cardiomyocyte.