Hybrid Mathematical Model of Cardiomyocyte Turnover in the Adult Human Heart

Abstract

RationaleThe 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%).ObjectiveCreate a hybrid mathematical model to critically examine rates of cardiomyocyte turnover derived from alternative methodologies.Methods and ResultsExamined 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.ConclusionsAssignment 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.

Cardiomyocyte‐Specific Telomere Shortening is a Distinct Signature of Heart Failure in Humans

“…Telomere shortening occurs when proliferating cells undergo each cell cycle, finally leading to cell senescence and apoptosis . However, the role of telomere attrition in the setting of HF and specifically in human cardiomyocytes, classically known as post‐mitotic cells, is undefined. To investigate TL in HCM cardiomyocytes, human cardiac tissues from patients with HCM and NFDs were subjected to Q‐FISH (Figure A).…”

Cardiac regeneration based on mechanisms of cardiomyocyte proliferation and differentiation

“…AMS provides a tissue-average, which poses a challenge since in cardiomyocytes, S-phase can be connected with cell division and differentiation. Hence, the analysis relied on additional assumptions that had to be made for mathematical modeling of the data (22), including assumptions about potential changes of the number of cardiomyocytes after birth, rates of cardiomyocyte cell death, and the extent of non-proliferative cell cycles (multinucleation and ploidy) with age (23). …”

New Myocyte Formation in the Adult Heart

“…Moreover, these rates of cardiac myocyte formation via 14 C incorporation are highly dependent on assumptions and parameters used in the mathematical models. Independent analysis of these data has suggested that variations in parameters such as atmospheric 14 C levels or myocyte attrition rates can confound the interpretation of human cardiomyogenesis via 14 C incorporation 68 . The modeling approaches using 14 C incorporation also concluded that new myocyte formation ceases in the early postnatal human heart, whereas other studies have documented indices of myocyte proliferation in young human heart tissues 69 , albeit only at the post-mortem histological level.…”