Immunological mechanisms of pentoxifylline in chronic heart failure

Abstract

The progressive syndrome of chronic heart failure (CHF) represents a common disease pathway that may be derived from a host of varying insults (including myocardial ischaemia and infarction, hypertension, viral infection, pregnancy, etc). Despite this multifarious aetiology, a common phenomena observed in CHF patients is elevated levels of tumour necrosis factor (TNF)-alpha. This has led to the widespread concept that TNF-alpha is directly involved in the pathophysiology of CHF and as such, attempts have been made to inhibit TNF-alpha production in this cohort. However, to date, there have been no clear beneficial effects from TNF-alpha inhibition and indeed trials of direct anti-TNF therapy have provoked worsening of clinical outcomes. Conversely, a possible exception is pentoxifylline (PTX), a putative TNF-alpha inhibitor with possible (but ill-defined) vasodilatory properties. Several small clinical trials assessing the use of PTX in CHF have suggested beneficial effects on multiple surrogate clinical markers. Interestingly, these trials failed to show a concordant effect on circulating TNF despite the clinical improvement, suggesting other key beneficial properties of this novel agent. This review article provides an insight into the potential beneficial mode of the action of PTX in CHF and calls for more investigation of this interesting agent.

Figure 1

The theoretical effects of tumour necrosis factor-α (TNF-α) on the failing human heart. Damaged myocardium secretes tumour necrosis factor-α, leading to negative inotropy, apoptosis, and endothelial dysfunction. Tumour necrosis factor-α is secreted into the circulation, where a systemic immune response ensues. Leucocyte activation occurs, resulting in more tumour necrosis factor-α secretion. The net effect results in collateral myocardial death, which is presented symptomatically as chronic heart failure. PBMC, peripheral blood mononuclear cell.

Figure 2

Immunomodulatory mechanisms of pentoxifylline. Pentoxifylline has many reported immunomodulatory effects. These include immune cell effects such as the prevention of leucocyte proliferation and the inhibition of direct (perforin/granzyme) and indirect (cytokine production) cytotoxic responses. Pentoxifylline also modulates the endothelium via the down-regulation of cell surface adhesion molecule expression and chemokine production, and also via moderation of apoptotic pathways. PBMC, peripheral blood mononuclear cell.