Correlations between alterations in length-dependent Ca2+ activation of cardiac myofilaments and the end-systolic pressure–volume relation
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We have tested the hypothesis that alterations in length dependent activation (LDA) of cardiac myofilaments represent an important regulatory mechanism affecting the Frank–Starling mechanism as determined by the slope (Ees) of the relation between left ventricular (LV) volume and end-systolic pressure. We employed a transgenic (TG) mouse model in which the cardiac isoform of TnI (cTnI) has been completely replaced with slow skeletal TnI (ssTnI), the embryonic/neonatal isoform in the heart. Compared to non-transgenic (NTG) controls, myofilaments from TG–ssTnI hearts demonstrate an increase in Ca2+ sensitivity and a substantially blunted LDA that is unaffected by PKA-dependent phosphorylation. We measured in situ LV pressure and volume relations during basal conditions and isoproterenol (ISO) stimulation. In the basal state in TG–ssTnI hearts there was significant increase in end-systolic pressure and slight decrease in heart rate. ISO stimulation resulted in a significant increase in heart rate, ejection fraction, maximum dP/dt, preload-recruitable stroke work, maximum dP/dt versus end diastolic volume and cardiac output in both groups. During basal conditions there was no difference in the Ees relation between NTG and TG–ssTnI groups. However, during ISO stimulation the Ees relation was significantly different between NTG and TG–ssTnI groups. Our study provides the first direct evidence that enhancement in differences in LDA between cardiac myofilaments from NTG and TG–ssTnI hearts induced by post-translational modifications of sarcomeric proteins are reflected in the in situ beating heart by a different change in Ees. Thus, changes in LDA should be considered in interpreting results from in situ experiments on inotropic effects associated with physiological and patho-physiological states of the heart.
KeywordsLength-dependent activation Frank–Starling law Pressure–volume relation
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