Calcium sensitivity of force in human ventricular cardiomyocytes from donor and failing hearts.
In failing human myocardium changes occur, in particular, in isoform composition and phosphorylation level of the troponin T (TnT) and troponin I (TnI) subunits of the actin filament and the myosin light chains (MLC-1 and -2), but it is unclear to what extent they influence cardiac performance. This overview concentrates on the relation between contractile function, contractile protein composition and phosphorylation levels in small biopsies from control (donor) hearts, from biopsies obtained during open heart surgery (NYHA Class I-IV) and from end-stage failing (explanted, NYHA class IV) hearts. Furthermore, attention is paid to the effect of the catalytic subunit of protein kinase A on isometric force development in single Triton-skinned human cardiomyocytes isolated from donor and end-stage failing left ventricular myocardium at different resting sarcomere lengths. A reduction in sarcomere length from 2.2 to 1.8 microm caused reductions in maximum isometric force by approximately 35% both in donor and in failing cardiomyocytes. The midpoints of the calcium sensitivity curves (pCa50) of donor and end-stage failing hearts differed markedly at all sarcomere lengths (mean delta pCa50 = 0.22). Our findings indicate that 1) TnI phosphorylation contributes to the differences in calcium sensitivity between donor and end-stage failing hearts, 2) human ventricular myocardium is heterogeneous with respect of the phosphorylation of TnT, MLC-2 and the isoform distribution of MLC-1 and MLC-2, and 3) the Frank-Starling mechanism is preserved in end-stage failing myocardium.
van der Velden
J
J
Laboratory for Physiology, Institute for Cardiovascular Research (ICaR-VU), Vrije Universiteit, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
Boontje
N M
NM
Papp
Z
Z
Klein
L J
LJ
Visser
F C
FC
de Jong
J W
JW
Owen
V J
VJ
Burton
P B J
PB
Stienen
G J M
GJ
D002118:Calcium / Q000378:metabolism*; D002303:Cardiac Output, Low / Q000503:physiopathology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000494:pharmacology; D016027:Heart Transplantation; D006801:Humans; D009124:Muscle Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D012518:Sarcomeres / Q000502:physiology; D014019:Tissue Donors; D016276:Ventricular Function
D009124:Muscle Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium