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- Title
Quantitative mapping of force–pCa curves to whole-heart contraction and relaxation.
- Authors
Longobardi, Stefano; Sher, Anna; Niederer, Steven A.
- Abstract
The force–pCa (F–pCa) curve is used to characterize steady-state contractile properties of cardiac muscle cells in different physiological, pathological and pharmacological conditions. This provides a reduced preparation in which to isolate sarcomere mechanisms. However, it is unclear how changes in the F–pCa curve impact emergent whole-heart mechanics quantitatively. We study the link between sarcomere and whole-heart function using a multiscale mathematical model of rat biventricular mechanics that describes sarcomere, tissue, anatomy, preload and afterload properties quantitatively. We first map individual cell-level changes in sarcomere-regulating parameters to organ-level changes in the left ventricular function described by pressure–volume loop characteristics (e.g. end-diastolic and end-systolic volumes, ejection fraction and isovolumetric relaxation time). We next map changes in the sarcomere-regulating parameters to changes in the F–pCa curve. We demonstrate that a change in the F–pCa curve can be caused by multiple different changes in sarcomere properties. We demonstrate that changes in sarcomere properties cause non-linear and, importantly, non-monotonic changes in left ventricular function. As a result, a change in sarcomere properties yielding changes in the F–pCa curve that improve contractility does not guarantee an improvement in whole-heart function. Likewise, a desired change in whole-heart function (i.e. ejection fraction or relaxation time) is not caused by a unique shift in the F–pCa curve. Changes in the F–pCa curve alone cannot be used to predict the impact of a compound on whole-heart function.
- Subjects
MULTISCALE modeling; MYOCARDIUM; VENTRICULAR ejection fraction; HEART cells; MATHEMATICAL models; CONTRACTILE proteins; ALDOSTERONE antagonists
- Publication
Journal of Physiology, 2022, Vol 600, Issue 15, p3497
- ISSN
0022-3751
- Publication type
Article
- DOI
10.1113/JP283352