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Title: The molecular basis of the Frank-Starling relationship
Author: Zhang, Xuemeng
ISNI:       0000 0004 5921 3561
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2016
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Frank-Starling law of the heart describes a proportional relationship between the end-diastolic ventricular volume and the systolic output in the heart on a beat-to-beat basis. It is largely due to a phenomenon called length dependent activation (LDA) on the level of cardiomyocytes. With the increasing SL, there are two outcomes of LDA: the increasing maximum force production, and the increasing Ca2+ sensitivity. Ca2+ binding to cardiac troponin C (cTnC) triggers a series of changes in thin filament structure that enable heart muscle cells to contract. A polarized fluorescence technique, FISS, was used to investigate the role of cTnC in the LDA. Using a purposely-built experimental set-up, force development and cTnC structural change were measured simultaneously as functions of [Ca2+] at SLs 1.9 and 2.3 μm. With the increasing SL, the Ca2+ sensitivity for force and cTnC structural change increased in a similar fashion, whereas the increase in maximum force production was not accompanied by an increase in the amplitude of cTnC structural change. Although the inhibition of active force by 25 μM blebbistatin reduced the amplitude of cTnC structural change upon Ca2+ activation, the SL-dependent increase in the Ca2+ sensitivity was still presented. These results suggested that the force-generating cross-bridges were not essential for the SL-dependent changes of Ca2+ sensitivity in LDA. Taken together, our results suggested that the LDA was likely controlled via two signalling pathways. The SL-dependent Ca2+ sensitivity was mainly regulated by the thin filament, while the SL-dependent maximum force generation was controlled by the thick filament. In addition, mimicking the SL stretching-induced reduction in interfilament spacing with 1% dextran did not reproduce the SL-dependent increase in the Ca2+ sensitivity, whereas further compression with 4% dextran significantly increased the Ca2+ sensitivity. This suggested that there might be another mechanism in the regulation of Ca2+ sensitivity by osmotic compression, which depends on the degree of the compression rather than the alteration in the interfilament spacing.
Supervisor: Irving, Malcolm ; Sun, Yin-biao Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available