Deloading of the left ventricle by ventricular assist device normalizes increased expression of endothelin ET(A) receptors but not endothelin-converting enzyme-1 in patients with end-stage heart failure.
BACKGROUND
Ventricular assist devices (VAD) are implanted in patients with end-stage heart failure for bridging the time until heart transplantation, resulting in hemodynamic unloading of the failing heart, improved cardiac contractile and mitochondrial function, and reversal of cardiac hypertrophy. It is unknown whether VAD unloading may affect the cardiac endothelin (ET) system, which has been proposed as one of the putative pathomechanisms of heart failure.


RESULTS
With the use of standard-calibrated, competitive reverse-transcription-polymerase chain reaction mRNA expression of components of the ET system was analyzed in left ventricular myocardium from nonfailing donor hearts, from failing hearts without and with ACE inhibitor therapy, and from patients with end-stage heart failure at the time of VAD implantation and 103+/-15 days after VAD implantation during removal with subsequent heart transplantation. ET receptor A (ET(A)) was markedly upregulated in failing human myocardium. This increased ET(A) expression was not affected by ACE inhibitor treatment but was normalized by VAD unloading. ET(A) expression before or after VAD implantation did not correlate with duration of VAD implantation or suppression of Pro-ANP mRNA. ET(B) mRNA expression was unaffected by heart failure or VAD. In contrast, increased ET-converting enzyme-1 mRNA and ET-1 peptide levels in failing myocardium were partially normalized by ACE inhibition but not by VAD unloading.


CONCLUSIONS
We conclude that VAD implantation normalizes ET(A) expression in failing human left ventricular myocardium, probably as the result of the beneficial effects of VAD unloading.
Morawietz
H
H
Institute of Pathophysiology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany. henning.morawietz@medizin.uni-halle.de
Szibor
M
M
Goettsch
W
W
Bartling
B
B
Barton
M
M
Shaw
S
S
Koerfer
R
R
Zerkowski
H R
HR
Holtz
J
J
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics; D019332:Endothelin-1 / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016277:Ventricular Function, Left
D000806:Angiotensin-Converting Enzyme Inhibitors; D019332:Endothelin-1; D011498:Protein Precursors; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D009320:Atrial Natriuretic Factor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes