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.

Exercise and HF

In recent years, exercise training has emerged as a promising therapeutic approach for patients with HF. Regular exercise performance improves functional capacity and symptoms, with more limited benefits for cardiac function and long-term survival (O’Connor et al. 2009). Numerous experimental studies have addressed the potential underlying mechanisms. Direct reversion of pathological cascades like calcineurin activation and myocardial fetal gene expression may be important (Oliveira et al. 2009). Additionally, by reducing sympathetic outflow, chronic exercise training suppresses one of the primary HF associated mediators of adverse cardiac remodelling (Benito & Nattel, 2009).

In a recent issue of The Journal of Physiology, Serra et al. (2010) present evidence suggesting that chronic exercise training may improve cardiac function in adrenergically induced HF via anti-inflammatory effects. In their study, rats that had undergone a previous 12 week treadmill training programme were allocated to either isoproterenol or vehicle injection for 8 days. Sustained adrenergic stimulation caused left ventricular hypertrophy, decreased contractility and increased cardiomyocyte stiffness, as well as a proinflamatory environment involving increased TNF-α and IL-6 expression. Regular exercise training prevented cardiac remodelling and suppressed myocardial inflammatory cytokine synthesis, suggesting a local anti-inflammatory mechanism.

Clinical relevance

The paper by Serra et al. (2010) adds to accumulating evidence that exercise has anti-inflammatory therapeutic value. Previous reports have consistently shown beneficial decreases in systemic (Starkie et al. 2003) and local (Gielen et al. 2003) inflammatory markers with exercise. Consequently, exercise training has been recommended for inflammatory muscle diseases (Nader & Lundberg, 2009), systemic inflammatory processes (Gualano et al. 2010) and low-grade inflammatory settings (Nicklas et al. 2005).

In HF patients, training programmes suppress inflammatory biomarkers (Adamopoulos et al. 2002). The results of Serra et al. are consistent with those findings and support the present recommendation of exercise as an adjunctive approach in HF patients (Jessup et al. 2009). The mechanisms participating in the anti-inflammatory effect of exercise are largely unknown. Reduction of sympathetic outflow could play an important role. Recent findings also point to anti-inflammatory properties of cholinergic activation (Borovikova et al. 2000), a known consequence of exercise training. Vagus nerve stimulation prevents damaging effects of cytokine release in experimental sepsis, ischaemia–reperfusion injury, and arthritis, among others (Borovikova et al. 2000), and promising results have been reported in experimental models and preliminary studies in human HF (De Ferrari et al. 2009; Zhang et al. 2009).

Current therapy for HF patients includes dual neurohumoral blockade with β-adrenoceptor blockers and RAS inhibitors, drugs that share indirect anti-inflammatory effects (Tatli & Kurum, 2005). Whether exercise training has additional benefits for HF patients mediated by cooling down cardiac inflammatory processes remains to be shown. An important aspect of the study of Serra et al. is that exercise practice was initiated prior to HF development. Additional information is needed to determine the optimal timing for exercise training programmes and exercise type/intensity that confer the greatest benefits.