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Hybrid Mathematical Model of Cardiomyocyte Turnover in the Adult Human Heart

RATIONALE: The capacity for cardiomyocyte regeneration in the healthy adult human heart is fundamentally relevant for both myocardial homeostasis and cardiomyopathy therapeutics. However, estimates of cardiomyocyte turnover rates conflict greatly, with a study employing C14 pulse-chase methodology c...

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Autores principales: Elser, Jeremy A., Margulies, Kenneth B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526650/
https://www.ncbi.nlm.nih.gov/pubmed/23284740
http://dx.doi.org/10.1371/journal.pone.0051683
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author Elser, Jeremy A.
Margulies, Kenneth B.
author_facet Elser, Jeremy A.
Margulies, Kenneth B.
author_sort Elser, Jeremy A.
collection PubMed
description RATIONALE: The capacity for cardiomyocyte regeneration in the healthy adult human heart is fundamentally relevant for both myocardial homeostasis and cardiomyopathy therapeutics. However, estimates of cardiomyocyte turnover rates conflict greatly, with a study employing C14 pulse-chase methodology concluding 1% annual turnover in youth declining to 0.5% with aging and another using cell population dynamics indicating substantial, age-increasing turnover (4% increasing to 20%). OBJECTIVE: Create a hybrid mathematical model to critically examine rates of cardiomyocyte turnover derived from alternative methodologies. METHODS AND RESULTS: Examined in isolation, the cell population analysis exhibited severe sensitivity to a stem cell expansion exponent (20% variation causing 2-fold turnover change) and apoptosis rate. Similarly, the pulse-chase model was acutely sensitive to assumptions of instantaneous incorporation of atmospheric C14 into the body (4-fold impact on turnover in young subjects) while numerical restrictions precluded otherwise viable solutions. Incorporating considerations of primary variable sensitivity and controversial model assumptions, an unbiased numerical solver identified a scenario of significant, age-increasing turnover (4–6% increasing to 15–22% with age) that was compatible with data from both studies, provided that successive generations of cardiomyocytes experienced higher attrition rates than predecessors. CONCLUSIONS: Assignment of histologically-observed stem/progenitor cells into discrete regenerative phenotypes in the cell population model strongly influenced turnover dynamics without being directly testable. Alternatively, C14 trafficking assumptions and restrictive models in the pulse-chase model artificially eliminated high-turnover solutions. Nevertheless, discrepancies among recent cell turnover estimates can be explained and reconciled. The hybrid mathematical model provided herein permits further examination of these and forthcoming datasets.
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spelling pubmed-35266502013-01-02 Hybrid Mathematical Model of Cardiomyocyte Turnover in the Adult Human Heart Elser, Jeremy A. Margulies, Kenneth B. PLoS One Research Article RATIONALE: The capacity for cardiomyocyte regeneration in the healthy adult human heart is fundamentally relevant for both myocardial homeostasis and cardiomyopathy therapeutics. However, estimates of cardiomyocyte turnover rates conflict greatly, with a study employing C14 pulse-chase methodology concluding 1% annual turnover in youth declining to 0.5% with aging and another using cell population dynamics indicating substantial, age-increasing turnover (4% increasing to 20%). OBJECTIVE: Create a hybrid mathematical model to critically examine rates of cardiomyocyte turnover derived from alternative methodologies. METHODS AND RESULTS: Examined in isolation, the cell population analysis exhibited severe sensitivity to a stem cell expansion exponent (20% variation causing 2-fold turnover change) and apoptosis rate. Similarly, the pulse-chase model was acutely sensitive to assumptions of instantaneous incorporation of atmospheric C14 into the body (4-fold impact on turnover in young subjects) while numerical restrictions precluded otherwise viable solutions. Incorporating considerations of primary variable sensitivity and controversial model assumptions, an unbiased numerical solver identified a scenario of significant, age-increasing turnover (4–6% increasing to 15–22% with age) that was compatible with data from both studies, provided that successive generations of cardiomyocytes experienced higher attrition rates than predecessors. CONCLUSIONS: Assignment of histologically-observed stem/progenitor cells into discrete regenerative phenotypes in the cell population model strongly influenced turnover dynamics without being directly testable. Alternatively, C14 trafficking assumptions and restrictive models in the pulse-chase model artificially eliminated high-turnover solutions. Nevertheless, discrepancies among recent cell turnover estimates can be explained and reconciled. The hybrid mathematical model provided herein permits further examination of these and forthcoming datasets. Public Library of Science 2012-12-19 /pmc/articles/PMC3526650/ /pubmed/23284740 http://dx.doi.org/10.1371/journal.pone.0051683 Text en © 2012 Elser, Margulies http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Elser, Jeremy A.
Margulies, Kenneth B.
Hybrid Mathematical Model of Cardiomyocyte Turnover in the Adult Human Heart
title Hybrid Mathematical Model of Cardiomyocyte Turnover in the Adult Human Heart
title_full Hybrid Mathematical Model of Cardiomyocyte Turnover in the Adult Human Heart
title_fullStr Hybrid Mathematical Model of Cardiomyocyte Turnover in the Adult Human Heart
title_full_unstemmed Hybrid Mathematical Model of Cardiomyocyte Turnover in the Adult Human Heart
title_short Hybrid Mathematical Model of Cardiomyocyte Turnover in the Adult Human Heart
title_sort hybrid mathematical model of cardiomyocyte turnover in the adult human heart
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526650/
https://www.ncbi.nlm.nih.gov/pubmed/23284740
http://dx.doi.org/10.1371/journal.pone.0051683
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