TNFalpha in patients with end-stage heart failure on medical therapy or supported by a left ventricular assist device.
BACKGROUND
In the heart elevated levels of TNFalpha can cause lethal heart failure, like Dilated Cardiomyopathy (DCM). The level of TNFalpha production is in part determined by promoter gene polymorphisms. We investigated whether the TNFalpha promoter gene polymorphism is in this way involved in the outcome of end-stage heart failure and predicts whether patients require left ventricular assist device (LVAD) support or can be kept on medical therapy (MT)while awaiting heart transplantation (HTx). As most patients in this study received a heart transplant, the role of the TNFalpha polymorphisms in transplant rejection was studied as well.


RESULTS
In twenty nine patients with DCM, 35 patients with Ischemic Heart Disease (IHD; both on MT), 26 patients on LVAD support and 61 cardiac transplant donors TNFalpha plasma level was detected by EASIA. In both patients groups high levels of TNFalpha plasma levels was observed however, in patients supported by LVAD this increase was much higher compared to patients on MT. Furthermore, this increase seems to be associated with the TNF 1 allele ('G' at position -308) instead of the TNF2 allele (A at position -308). The promoter polymorphisms at positions -238, -244 and -308 were observed by polymerase chain reaction and sequencing. Polymorphism at positions -238, -244 and -308 did not show any relevant differences between the groups. However, at position -308, a trend of a higher incidence of the TNF2 allele (an "A" at position -308) in DCM patients compared to donors was shown. The distribution of the TNF1 and TNF2 alleles was not different in patients on medical therapy compared to the patients supported by a LVAD. No association was found between patients' TNFalpha promoter gene polymorphism and rejection. However, patients that received a donor heart with the TNF2 allele developed more rejection episodes, compared to patients that received a donor heart with the TNF1 allele.


CONCLUSIONS
TNFalpha levels are high in patients with end-stage heart failure on MT, but even higher in patients on LVAD support. These high TNFalpha plasma levels however, are not correlated with the TNF2 allele but seems to be associated with the TNF1 allele. Furthermore, in HTx the donor TNFalpha gene seem to play a more important role in severity of acute rejection than that of the patient.
Bruggink
A H
AH
Department of Pathology, University Medical Center Utrecht, P.O. Box 85.500, 3508GA Utrecht, The Netherlands. A.H.Bruggink@lab.azu.nl
van Oosterhout
M F M
MF
De Jonge
N
N
Gmelig-Meyling
F H J
FH
De Weger
R A
RA
D000328:Adult; D000483:Alleles; D005838:Genotype; D006084:Graft Rejection / Q000235:genetics*; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000097:blood* / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha