Hellenic J Cardiol 2011; 52: 30-40 Review Article The Role of Inflammation in Heart Failure: New Therapeutic Approaches 1 1 1,2 1 EVANGELOS OIKONOMOU , DIMITRIS TOUSOULIS , GERASIMOS SIASOS , MARINA ZAROMITIDOU , 2 1 ATHANASIOS G. PAPAVASSILIOU , CHRISTODOULOS STEFANADIS 1First Department of Cardiology, University of Athens Medical School, ‘Hippokration’ Hospital, 2Department of Biological Chemistry, University of Athens Medical School, Athens, Greece Key words: eart failure (HF) is a syndrome part due to an imbalance between increas- Inflammation, that has shown increasing mor- es in inflammatory and anti-inflammatory heart failure, bidity and mortality during the mediators. Table 1 gives a summary of the proinflammatory H cytokines. last decades. Apart from myocardial hy- many cytokines that are implicated in the pertrophy, the pathogenetic mechanisms pathogenesis of HF. of HF also include deregulation of the neurohormonal system, with disturbance Tumour necrosis factor alpha (TNF-α) of the balance between sympathetic and parasympathetic tone, and disruption of This factor, which is also produced in my- the renin-angiotensin-aldosterone sys- ocardial cells, took its name from the ini- tem.1-5 The important role of inflamma- tial observation that it exerts an inhibi- tion in HF has also been recognised.6 The tory effect on various tumour cells.31,32 It inflammatory process can cause myocar- seems that both TNF-α and other related Manuscript received: dial damage, while inflammatory agents molecules cause apoptosis of myocardial October 21, 2009; Accepted: contribute to the worsening and progres- cells via mechanisms of cell death (Table 6,7 33 February 10, 2010. sion of HF. In this article we will review 2). From an analysis of the VEST trial the latest data concerning the relation be- it was found that levels of this factor were tween HF and inflammation. directly related with the New York Heart Address: Association (NYHA) functional stage of Dimitris Tousoulis patients with HF and that the highest lev- The role of inflammation in heart failure Hippokration Hospital els of TNF-α were associated with a worse 114 Vasilissis Sofias Ave. The first data concerning the relation be- prognosis. According to the investigators, 115 28 Athens, Greece tween HF and inflammation were record- this was due to negative inotropic action e-mail: drtousoulis@ 8 hotmail.com ed in 1955, when a positive correlation and a disturbance of beta-adrenergic re- was found between levels of C-reactive ceptor sensitivity caused by TNF-α via the protein (CRP) and the severity of con- inducible nitric oxide synthase (iNOs) sys- gestive HF. In 1990, Levine et al6 docu- tem.9 Newer data show that in patients mented a positive correlation between tu- with recent onset HF the increased TNF-α mour necrosis factor alpha and chronic levels are associated with a disturbance of HF. Research carried out since then has left atrial function and an advanced de- produced new data concerning the rela- gree of left ventricular diastolic and sys- tion between many cytokines and HF. It tolic dysfunction.38 The effect of TNF-α seems that the HF syndrome is in large appears to be exerted via the TNFR1 and 30 • HJC (Hellenic Journal of Cardiology) Inflammation and Heart Failure Table 1. Proinflammatory and anti-inflammatory agents that are TNFR2 receptors. In a recent study of patients with elevated in patients with heart failure. myocardial infarction, it was shown that TNFR1 was Proinflammatory effects the most powerful independent risk factor for HF and 34 • TNF-α6,9 death. The TNF-α receptors (TNFR1 and TNFR2), • sTNFR19,10 according to experimental data, have opposite effects • sTNFR29,10 as regards the remodelling, hypertrophy, nuclear fac- 11 • sFas tor-kappaB production, inflammation, and apoptosis 12 • CD40L that are observed in HF. TNFR1 appears to promote • TRAIL13 these processes, while TNFR2 seems to inhibit them. • Activin A14,15 • Myeloperoxidase16 Nevertheless, both receptors are necessary in order to 39 • Pentraxin-317 cause these pathophysiological sequelae. • RANTES18 • CRP19-22 Fas protein (apoptosis stimulating fragment) • IL-623 • Cardiotrophin 124 Blood levels of the soluble apoptosis-stimulating pro- 25 • IL-8 tein sFas appear to be positively correlated with the 18 • MCP-1 severity of HF and are an independent prognostic • MIP-1a18 index for outcomes in these patients.11 Indeed, re- Anti-inflammatory effects • IL-1026 cent research has shown that the risk of cardiac death • IL-1327 and hospitalisation for worsening HF increases with • IL-1828 the sFas concentration (p<0.001) and that this risk Proinflammatory and anti-inflammatory effects is two- to threefold greater in patients who are in the • Adiponectin29 highest quartile as regards sFas concentrations, com- • Resistin30 pared with those in the lowest quartile.7 TNF – tumour necrosis factor; sTNFR1/sTNFR2 – soluble TNF receptor 1/2; TRAIL – TNF-α related apoptosis-inducing ligand; RANTES – regulated on activation normally T-cell expressed and secreted; CRP – TRAIL protein (TNF-α related apoptosis-inducing ligand) C-reactive protein; IL – interleukin; MCP – macrophage chemoattractant This apoptosis-inducing protein is a connector mole- protein; MIP – macrophage inflammatory protein. cule that is associated with TNF-α. TRAIL levels are Table 2. Studies of the relation between tumour necrosis factor-alpha (and related molecules) and heart failure. Study Proinflammatory Population Comments molecule Levine et al6 TNF-α 33 HF patients, 33 controls First to document positive correlation between TNF-α and HF Ueland et al12 sCD40L 352 HF patients, 30 controls Positive correlation between sCD40L and acute or chronic HF Niessner et al7 sFas, TRAIL 351 HF patients Endpoints death or rehospitalisation. Positive correlation found for sFas and negative for TRAIL Valmingli M et al (C-Alpha)34 TNFR1 184 patients post AMI Powerful predictive factor for HF or death in these patients Deswal A (VEST)9 TNF 1200 HF patients Positive correlation between TNF-α levels and death Parissis et al35 Fas, Fas-Ligand 137 HF patients Patients with more severe symptoms had higher levels of these molecules Ueland et al36 Osteoprotogerin 230 HF patients post AMI Correlation between high osteoprotogerin levels and adverse outcome Suzuki et al37 IL-1β, IL-6,TNF-α 73 patients with acute Levels elevated in patients up to 4 weeks decompensation of HF, 32 later controls. HF – heart failure; sFas soluble apoptosis-stimulating fragment; AMI – acute myocardial infarction. Other abbreviations as in Table 1. (Hellenic Journal of Cardiology) HJC • 31 E. Oikonomou et al elevated in patients with HF.13 It seems that this pro- Cardiotrophin-1 (CT-1) also belongs to the IL-6 tein plays an important role in the rupture of athero- family, being a cytokine that shares a common recep- matous plaque and in triggering acute myocardial in- tor system with IL-6. This cytokine is associated with a farction, which is one of the main causes of HF.40-42 large range of cardiovascular events and its production However, levels of soluble TRAIL protein have an in- appears to be stimulated by ventricular dilation.46,47 verse relation with the presence of coronary artery dis- It also seems that in patients with congestive HF the ease.43 From a recent study, which examined 351 pa- measurement of CT-1 levels has additional prognos- tients with a severe degree of HF, it was found that el- tic value, either alone or in combination with levels of evated levels of soluble TRAIL were associated with a brain natriuretic peptide.48 better prognosis. Indeed, in patients whose serum lev- els of this protein were in the highest quartile there was Activin A 70% lower mortality compared to patients whose levels of TRAIL were in the lowest quartile (p=0.001).7 Activin A belongs to the family of transforming growth factor-beta. There are ample data to show that this cy- tokine plays some role in the inflammation process, Other molecules that belong to the TNF family as elevated levels have been found in patients with in- Various molecules belonging to the TNF-α family flammatory disorders.14 Elevated levels of serum ac- have been shown to have a receptor-ligand relation. tivin A have also been found in patients with HF, in- Such molecules include CD27/CD27L, CD30/CD30L, creasing with the severity of the disease as determined and CD40/CD40L. These molecules seem to be ex- by clinical, haemodynamic and neurohormonal param- pressed in a higher proportion in the myocardium eters.15 There are data indicating a possible pathoge- of patients with myocarditis and dilated cardiomy- netic role of this cytokine in myocardial remodelling. It opathy.44 Levels of CD40L, in particular, have been appears to cause up-regulation of monocyte chemoat- found to be elevated in patients with acute HF follow- tractant protein-1 by myocardial cells, thus contribut- ing an infarction compared with healthy controls.12 ing to local inflammation.49 It has also been found to Higher levels of CD40L have also been found in pa- increase expression of the genes responsible for atrial tients with chronic HF compared to controls, regard- and brain natriuretic peptides.49 less of whether the HF aetiology was ischaemic or di- lated. An increase in CD40L also appears to be corre- Cytokines originating from adipocytes lated with a worsening of HF.12 Resistin and adiponectin are proteins with proinflam- matory and anti-inflammatory properties whose pro- Interleukin 6 (IL-6) duction by fatty tissue seems to be associated