期刊
JOURNAL OF PHYSIOLOGY-LONDON
卷 600, 期 15, 页码 3497-3516出版社
WILEY
DOI: 10.1113/JP283352
关键词
force-pCa; force-calcium; Hill coefficient; left ventricular myocyte; pCa(50); pCa(50) shift; sarcomere modulators; steady-state force
资金
- Engineering and Physical Sciences Research Council [EP/M012492/1, NS/A000049/1, EP/P01268X/1]
- British Heart Foundation [PG/15/91/31812, PG/13/37/30280, SP/18/6/33805]
- European Research Council [PREDICT-HF 864055]
- Wellcome Trust [WT203148/Z/16/Z]
- King's Health Partners
- Pfizer Inc.
This research reveals the complexity of the impact of sarcomere property changes on whole-heart function using a multiscale mathematical model. Changes in the F-pCa curve are not able to accurately predict changes in cardiac function.
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.
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