TNFα in patients with end-stage heart failure on medical therapy or supported by a left ventricular assist device

Abstract

Background: In the heart elevated levels of TNFα can cause lethal heart failure, like Dilated Cardiomyopathy (DCM). The level of TNFα production is in part determined by promoter gene polymorphisms. We investigated whether the TNFα 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 TNFα polymorphisms in transplant rejection was studied as well. Methods and 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 TNFα plasma level was detected by EASIA. In both patients groups high levels of TNFα 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' TNFα 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. Conclusion: TNFα levels are high in patients with end-stage heart failure on MT, but even higher in patients on LVAD support. These high TNFα plasma levels however, are not correlated with the TNF2 allele but seems to be associated with the TNF1 allele. Furthermore, in HTx the donor TNFα gene seem to play a more important role in severity of acute rejection than that of the patient.

Markers of Inflammation in Recipients of Continuous-Flow Left Ventricular Assist Devices

“…42 Similarly, plasma TNF-α levels were higher in heart failure patients treated with medical therapy compared with the healthy control subjects, and even higher in patients supported by PF-LVADs. 43 Unlike our study, the devices used in these previous studies were pulsatile pumps. Nevertheless, the findings of the previous studies which used pulsatile devices may be due to more advanced heart failure symptoms in device recipients, but may also raise the possibility that the device itself contributes to increased inflammation.…”

Tumor Necrosis Factor-α Gene Polymorphism (G-308A) and Dilated Cardiomyopathy

“…Consequently, a total of 1338 DCM cases and 1677 controls were subjected to our metaanalysis. [23][24][25][34][35][36][37][38][39] Of the 9 articles, 5 studied Caucasians, 3 studied Asians, and 1 studied Africans. With regard to the matching situation between case and control groups, 4 studies were at least age-matched healthy controls and 5 were healthy or unrelated individuals.…”

Genetic polymorphisms in dilated cardiomyopathy

“…An increase of TNF-alpha in the heart can cause lethal pump failure (27). An increased expression of TNFalpha has been observed in the failing human heart (24).…”

“…Moreover, it has been shown that patients that received a donor heart with the TNF2 polymorphism had more severe rejection episodes during the first six months after HTx than patients that received a donor heart with TNF1 polymorphism. In HTx the donor TNF-alpha gene seem to play a more important role in severity of acute rejection than that of the patient (27).…”