Myocardial expression of the arginine:glycine amidinotransferase gene is elevated in heart failure and normalized after recovery: potential implications for local creatine synthesis.
BACKGROUND
Combination therapy consisting of mechanical unloading using a left ventricular assist device (LVAD) and pharmacological intervention can promote recovery from end-stage heart failure, but the mechanism is unknown. Preliminary microarray analysis revealed a significant and unexpected decrease in myocardial arginine:glycine amidinotransferase (AGAT) gene expression during recovery in these patients. The aim of this study was to evaluate the expression and role of AGAT expression in heart failure and recovery.


RESULTS
We used quantitative real time (TaqMan) polymerase chain reaction to examine myocardial AGAT mRNA expression in implant and explant samples from recovering patients after combination therapy (n=12), end-stage heart failure (ESHF) samples from stable patients undergoing transplantation without LVAD support (n=10), and donor hearts with normal hemodynamic function (n=8). AGAT mRNA expression was significantly elevated in all heart failure patients relative to donors (4.3-fold [P<0.001] and 2.7-fold [P<0.005] in LVAD and ESHF relative to donors, respectively) and returned to normal levels after recovery. AGAT enzyme activity was detectable in both human and rat myocardia and was elevated in heart failure.


CONCLUSIONS
Our data highlight local and potentially regulated expression of AGAT activity in the myocardium and suggest a specific response to heart failure involving elevated local creatine synthesis. These findings have implications both for the management of recovery patients undergoing combination therapy and for heart failure in general.
Cullen
Martin E
ME
National Heart and Lung Institute, Imperial College London, Heart Science Centre, Harefield, Middlesex, UB9 6JH, UK.
Yuen
Ada H Y
AH
Felkin
Leanne E
LE
Smolenski
Ryszard T
RT
Hall
Jennifer L
JL
Grindle
Suzanne
S
Miller
Leslie W
LW
Birks
Emma J
EJ
Yacoub
Magdi H
MH
Barton
Paul J R
PJ
D000293:Adolescent; D000328:Adult; D000579:Amidinotransferases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002648:Child; D003199:Computer Systems; D003289:Convalescence; D003401:Creatine / Q000378:metabolism; D004734:Energy Metabolism; D004790:Enzyme Induction; D005260:Female; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000601:surgery; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006801:Humans; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats
D012333:RNA, Messenger; D000579:Amidinotransferases; C020681:glycine amidinotransferase; D003401:Creatine