Thin-filament-based modulation of contractile performance in human heart failure.
BACKGROUND
The contribution of the sarcomere's thin filament to the contractile dysfunction of human cardiomyopathy is not well understood.


RESULTS
We have developed techniques to isolate and functionally characterize intact (native) thin filaments obtained from failing and nonfailing human ventricular tissue. By use of in vitro motility and force assays, native thin filaments from failing ventricular tissue exhibited a 19% increase in maximal velocity but a 27% decrease in maximal contractile force compared with nonfailing myocardium. Native thin filaments isolated from human myocardium after left ventricular assist device support demonstrated a 37% increase in contractile force. Dephosphorylation of failing native thin filaments resulted in a near-normalization of thin-filament function, implying a phosphorylation-mediated mechanism. Tissue expression of the protein kinase C isoforms alpha, beta1, and beta2 was increased in failing human myocardium and reduced after left ventricular assist device support.


CONCLUSIONS
These novel findings demonstrate that (1) the thin filament is a key modulator of contractile performance in the failing human heart, (2) thin-filament function is restored to near normal levels after LVAD support, and (3) the alteration of thin-filament function in failing human myocardium is mediated through phosphorylation, most likely through activation of protein kinase C.
Cardiovascular Research Center, University of Vermont, College of Medicine, Burlington, VT 05405, USA.
Teruo
T
Noguchi
Mark
M
Hünlich
Phillip C
PC
Camp
Kelly J
KJ
Begin
Mohamed
M
El-Zaru
Richard
R
Patten
Bruce J
BJ
Leavitt
Frank P
FP
Ittleman
Norman R
NR
Alpert
Martin M
MM
LeWinter
Peter
P
VanBuren
D008841:Actin Cytoskeleton / Q000737:chemistry / Q000502:physiology*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000150:complications; D002645:Chickens; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000648:ultrastructure; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000502:physiology* / Q000648:ultrastructure; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
C496628:PRKCA protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D013755:Tetradecanoylphorbol Acetate