Analysis of age-related left ventricular collagen remodeling in living donors: Implications in arrhythmogenesis

Age-related fibrosis in the left ventricle (LV) has been mainly studied in animals by assessing collagen content. Using second-harmonic generation microscopy and image processing, we evaluated amount, aggregation and spatial distribution of LV collagen in young to old pigs, and middle-age and elder living donors. All collagen features increased when comparing adult and old pigs with young ones, but not when comparing adult with old pigs or middle-age with elder individuals. Remarkably, all collagen parameters strongly correlated with lipofuscin, a biological age marker, in humans. By building patient-specific models of human ventricular tissue electrophysiology, we confirmed that amount and organization of fibrosis modulated arrhythmia vulnerability, and that distribution should be accounted for arrhythmia risk assessment. In conclusion, we characterize the age associated changes in LV collagen and its potential implications for ventricular arrhythmia development. Consistency between pig and human results substantiate the pig as a relevant model of age-related LV collagen dynamics. This work was supported by Ministerio de Ciencia e Innovacio´ n (Spain) (PID2019-105674RB-I00), by Gobierno de Arago´ n (LMP94_21) and (LMP128_21), by the European Research Council through grant ERC-StG 638284 and by European Social Fund and by Gobierno de Arago´ n (Reference Group BSICoS T39-20R) cofunded by FEDER 2014–2020 ‘‘Building Europe from Aragon‘‘. L.G-M was supported by a predoctoral fellowship from the Departamento de Ciencia, Universidad y Sociedad del Conocimiento from the Gobierno de Arago´ n 2016–2020 cofounded by Programa Operativo del Fondo Social Europeo Arago´ n (C150/2016), EMBO Short-Term fellowship (7710), and Ibercaja-CAI Estancias de Investigacio´ n IT18/18. Authors would like to acknowledge the Experimental Surgery Service of Aragon Health Sciences Institute (CIBA, Zaragoza, Spain), Mercazaragoza slaughterhouse (Zaragoza, Spain), and The Pink Pig slaughterhouse (Zuera, Spain) for their collaboration in the collection of young, adult, and boar tissue specimens, respectively.