Exercise training, inflammation and heart failure: working out to cool down

Heart failure (HF) is a common end-stage phenotype of a variety of conditions that impair myocardial performance and/or cause long-term cardiac overload. The HF syndrome involves progressive functional impairment due to ongoing remodelling that may outlast the initiating cause. Awareness of the importance of adverse remodelling has led to extensive investigation of the underlying mechanisms and potential preventive interventions. Sustained adrenergic stimulation plays a key role in the progression of HF. While optimizing short-term cardiac performance by increasing heart rate and contractile force, adrenergic stimulation leads in the long term to apoptotic cell death, maladaptive remodelling, and arrhythmogenic cardiomyocyte Ca2+ mishandling (Triposkiadis et al. 2009), explaining why β-adrenoceptor antagonists are beneficial for long-term treatment of HF patients despite short-term risk of haemodynamic impairment. Renin–angiotensin–aldosterone system (RAS) activation, commonly associated with adrenergic enhancement, also contributes to HF progression by inducing vasoconstriction, antinatriuresis, apoptosis, superoxide production, pathological remodelling and arrhythmogenesis (Paul et al. 2006). Inhibitors of both adrenergic and RAS pathways (β-adrenoceptor antagonists, angiotensin converting-enzyme inhibitors, angiotensin or aldosterone receptor blockers) improve the prognosis in HF patients (Jessup et al. 2009). There has been increasing interest in the role of inflammation in HF progression (Mann & Young, 1994). Pro-inflammatory cytokines are small molecules that mediate the host response to infection and tissue injury. Although reparative in early phases, continuous cytokine production can lead to tissue damage, fibrosis and necrosis (Tracey, 2007). Tumour necrosis factor-α (TNFα), and interleukins (IL)-1 and -6 are principal pro-inflammatory cytokines whereas IL-10 is anti-inflammatory. Pro-inflammatory cytokine production is increased in HF, both systemically and locally, where they are secreted in response to cardiac injury. Recombinant TNFα injection impairs cardiac function (Pagani et al. 1992) and inflammatory cytokine administration causes cardiac hypertrophy, apoptosis, fibrosis and dilated cardiomyopathy (Krown et al. 1996; Sivasubramanian et al. 2001). In addition, inflammatory cytokines promote skeletal-muscle wasting and the ‘cardiac cachexia’ syndrome, which has a particularly negative prognosis (von Haehling et al. 2007). Circulating TNFα and IL-6 concentrations correlate with the functional class of HF patients and independently predict mortality (Deswal et al. 2001). An interesting recent development is insight into the role of impaired intestinal microcirculation and cytokine production by the gut in the inflammatory and metabolic derangements in HF (Sandek et al. 2009). Chronic β-adrenoceptor stimulation induces inflammatory cytokine synthesis in healthy cardiomyocytes (Murray et al. 2000). RAS activation initiates tissue inflammation through paracrine actions, inducing local secretion of TNF-α and IL-6, along with proinflammatory/profibrotic growth factors like TGF-β (Phillips & Kagiyama, 2002). Treatment with β-blockers and RAS inhibitors suppresses production of TNFα and IL-6 in animal CHF models and HF patients (Tatli & Kurum, 2005; Tian et al. 2009). Thus, inflammation induced by adrenergic and RAS activation may constitute a final common pathway for cardiac deterioration.