Abstract P029: Resolving Discordance of Human Cardiomyogenesis Estimates in the Healthy Adult Heart
Rationale: Estimates of the endogenous cell turnover rates in healthy human hearts conflict, varying from 0% to over 30%. Turnover rate age-dependence is also controversial with some studies indicating decreasing turnover with advancing age and other studies suggesting that turnover increases with age.
Methods/Results: We created a hybrid mathematical model encompassing two prominent analyses of human adult cardiomyogenesis that concluded highly disparate turnover rates. The model was programmed to accept input parameters for age-dependent cardiomyogenesis and apoptosis. High-turnover input parameters (10%–30%, increasing with age), extracted from a recent publication by Kajstura, et. al., were used to create 12 model patient hearts with ages and birthdates corresponding to the 12 patients analyzed by a C14 fate-mapping technique in a publication by Bergmann, et. al., which reported low turnover rates of 1%–0.45%, decreasing with age. Modeled hearts parameterized with high, age-increasing input turnovers produced low (5%–0.5%), age-decreasing estimates of turnover when the C14 analysis technique was applied. This systematic underestimation reflects the inability of fate-mapping models to account for turnover events in which myocytes created after patient birth are destroyed prior to patient death. This effect may underestimate true turnover events by over 90% and is more severe for patients with longer lifespans, predisposing such techniques to report decreasing turnover with advancing age. We next evaluated the effect of input parameter uncertainty on the hybrid model. We observed non-linear sensitivity of fate-mapping algorithms to polyploidization correction factors, with 20% variation in correction factor leading to approximately 30% changes in reported turnover. The Kajstura model was acutely sensitive to estimates of myocyte half-life (Δ20% produced a 45% change in average myocyte age) and stem cell expansion coefficient (Δ20% produced a 2-fold change in reported turnover).
Conclusions: Accounting for short-lived myocytes in fate-mapping models reconciles apparent differences between the models. Recognition of realistic input parameter uncertainty improves interpretation of these models.
- © 2011 by American Heart Association, Inc.