Inflammation in chronic heart failure: what is familiar, what is unfamiliar?

Introduction

Inflammation is commonly observed in patients with chronic heart failure (CHF), and portends a worsening functional capacity and poorer prognosis. The recognition of inflammation as a common, important, and treatable condition in CHF has contributed to intensified research for an effective anti-inflammatory therapy in CHF. However, when sequential multicentre placebo-controlled studies^1–5 failed to show any clinical benefit, it became uncertain whether anti-inflammatory therapy really does influence CHF outcome. We may, in fact, wonder what is really familiar and what is unfamiliar about inflammation in CHF, despite tremendous efforts in the last two decades.

What is familiar?

Inflammation affects, more or less, almost all CHF patients. Weight of evidence has shown that the presence of inflammation and higher degrees of inflammation are powerful predictors of adverse outcome in CHF. However, cause and effect has so far not been proven, although it is tempting to believe that the inhibition of inflammation in CHF is likely to be beneficial. In simple terms, a biomarker associated with a condition does not necessarily imply causality, in particular, in CHF with its heterogeneous aetiology. There are several pre-clinical studies showing that proinflammatory cytokines such as TNF-α are of pathogenic importance.^6,7 However, these findings are not sufficient to indicate that proinflammatory cytokines are also physiologically important in humans with CHF.

What is unfamiliar?

There is much more we are unfamiliar with. Uncertainty remains regarding the underlying pathophysiology of inflammation in the setting of CHF. In this regard, there are several fundamental issues to be dealt with. Is inflammation in CHF the same as that in conditions such as cancer or rheumatoid arthritis, in terms of cytokine activation, despite differences in the degree of inflammation? Is inflammation the same among different heart failure aetiologies, and between acute heart failure and CHF? If inflammation is redundant in heart failure, theoretically it is not rational to focus intervention on individual cytokines rather than on the cytokine network. This raises a very serious concern as to whether inflammation can be regarded as a therapeutic target in CHF. In many cases, inflammation and autoimmunity are highly interactive entities. Consequently, autoimmunity occurs in a subgroup of heart failure patients. How inflammation and autoimmunity affect each other, however, remains unresolved. Much work is therefore needed to clarify the physiological role of both individual cytokines and cytokine networks, in different stages of heart failure, due to different aetiologies, and compared with other known inflammatory diseases.

Two comprehensive reviews in this issue

In this issue of Eur J Heart Fail, there are two reviews on inflammation in heart failure. One is a consensus summary from an expert group of the Heart Failure Association (HFA) of the European Society of Cardiology⁸ and the other is a review of the potential beneficial mode of action of pentoxifylline (PTX), a putative TNF-α inhibitor, in CHF.⁹

In the consensus paper, Dr Heymans et al.⁸ recommend more careful and precise patient selection for upcoming clinical trials of anti-inflammatory agents in heart failure. Moreover, they propose more fundamental pre-clinical studies including better animal models and improved understanding of the underlying mechanisms. In their opinion, anti-TNF-α therapy cannot yet be discarded. However, this document is based on a standpoint that inflammation is implicated in HF pathophysiology, which is not clear as discussed above.

In the paper by Shaw et al.,⁹ available clinical data using PTX are reviewed. Several trials have reported improved clinical outcome following PTX treatment, but without a concordant effect on TNF-α modulation, suggesting that these beneficial effects may not necessarily occur through TNF-α inhibition, but may be mediated by other subtle effects on arterial vasculature. These data provide further evidence to suggest that TNF-α inhibition does not contribute to clinical improvement.

Why research on inflammation should continue despite failed clinical trials?

In spite of treatment with optimal neurohormonal blockade, both mortality and morbidity in CHF remain high; a better understanding of the underlying pathophysiology may lead to improved therapy. Since the syndrome of heart failure is very heterogeneous, a tailored approach is considered appropriate, with current guideline recommended therapy as basic and aetiology-targeted therapy as complementary. If inflammation turns out to be an important mediator in a subgroup of CHF patients with significant inflammation of pathogenic importance, anti-inflammatory therapy may be indicated.

Summary

The concept of cytokine activation and inflammation in CHF is still alive despite failed clinical trials. Since inflammation is present in CHF, improved understanding of this mechanism is important. In this regard, we are still in the starting block.