Molecular Mechanisms of Cardiac Fibrosis: A Pathologist’s Perspective

Figure 1. Perivascular fibrosis in adult human myocardium (47-year-old individual). Representative images of original observations obtained from formalin-fixed, paraffin-embedded left ventricular myocardial tissue collected at autopsy. (A) Hematoxylin-Eosin staining shows concentric accumulation of extracellular matrix around an intramyocardial vessel (black arrow; scale bar: 500 µm; original magnification 20×). (B) Masson’s trichrome staining shows perivascular collagen deposition (black arrow; scale bar: 500 µm; original magnification 20×).

Figure 2. Replacement fibrosis in adult human myocardium (63-year-old individual). Representative images of original observations obtained from formalin-fixed, paraffin-embedded left ventricular myocardial tissue collected at autopsy. (A) Hematoxylin-Eosin staining shows replacement of necrotic myocardial tissue with a dense fibrous scar, characterized by loss of cardiomyocytes and deposition of extracellular matrix (black arrow; scale bar: 250 µm; original magnification 40×). (B) Masson’s trichrome staining shows extensive collagen deposition with replacement of myocardial fibers (black arrow; scale bar: 250 µm; original magnification 40×).

Figure 3. Integrated schematic representation of molecular pathways, histopathological patterns, and clinical consequences of cardiac fibrosis. The diagram illustrates the major profibrotic signaling pathways involved in myocardial fibrogenesis, including TGF-β/SMAD, RAAS (angiotensin II and aldosterone), Wnt/β-catenin, and Hippo-YAP/TAZ signaling, as well as emerging regulators such as SRF and mitochondrial dysfunction/SIRT pathways. These molecular mechanisms converge on cardiac fibroblast activation and transdifferentiation into α-SMA-positive myofibroblasts, leading to excessive extracellular matrix deposition and collagen cross-linking. The resulting structural remodeling generates distinct histopathological patterns (interstitial, perivascular, and replacement fibrosis), which contribute to myocardial stiffening, electrical conduction abnormalities, heart failure, ventricular arrhythmias, and SCD.