title: Correlations between alterations in length-dependent Ca2+ activation of cardiac myofilaments and the end-systolic pressure-volume relation.
abstract: 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 (E(es)) 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 Ca(2+) 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 E(es) relation between NTG and TG-ssTnI groups. However, during ISO stimulation the E(es) 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 E(es). 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.
authors: Department of Medicine, Section of Cardiology, Center for Cardiovascular Research, University of Illinois at Chicago, 840 S. Wood Street (M/C 715), Chicago, IL 60612, USA.
authors: Grzegorz
authors: G
authors: Nowak
authors: James R
authors: JR
authors: Peña
authors: Dalia
authors: D
authors: Urboniene
authors: David L
authors: DL
authors: Geenen
authors: R John
authors: RJ
authors: Solaro
authors: Beata M
authors: BM
authors: Wolska
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006339:Heart Rate / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D009200:Myocardial Contraction / Q000235:genetics; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D019210:Troponin I / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D019210:Troponin I; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium