Determining exercise training responders through inflammatory status in heart failure

It has been proven that exercise training has numerous beneficial effects on heart failure patients, the most prevalent of which are the improvement of functional capacity and quality of life. There is also evidence of a complementary anti-inflammatory effect through an observed reduction of inflammatory markers such as tumour necrosis factor-alpha (TNFα), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in both circulation1 and skeletal muscles.2 Such intervention is made important in all stages of heart failure due to these effects and can possibly contribute to morbidity and mortality reduction,3 having previously taken into account the patients’ clinical condition and individual preferences for a more personalized approach. On the other hand, several studies report no significant changes in pro-inflammatory cytokines4 while others did not manage to prove any connection between exercise training and patient survival.5 These inconsistencies are difficult to explain, mainly due to the high heterogeneity of the patient populations enrolled and the exercise training programmes used in each study. However, attempts to explain these results often attribute them to low patient adherence to an exercise programme or to different clinical characteristics. The study by Fernandes-Silva et al.6 provides the first evidence of an underlying pathophysiological process. The authors showed that patients with different inflammatory profiles responded differently to exercise training. Specifically, patients were classified according to the levels of the inflammatory biomarkers IL-6, TNFα and galectin-3. Patients with low levels showed significant changes in their functional capacity in contrast to patients with high levels. Inflammation has a well-studied effect on exercise capacity in heart failure patients. A proposed mechanism describes the induction and effects of the inducible nitric oxide synthase (iNOS) on skeletal muscle tissue. Inflammatory cytokines, mainly interleukin-1beta (IL-1β) and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (usually elevated as part of the heart failure syndrome), have been found to promote iNOS expression in skeletal muscles7 which sequentially is associated with reduced expression of the mitochondrial creatine kinase and exercise capacity.8 Furthermore, cytokines, especially TNFα may directly affect skeletal muscle cells through promotion of apoptosis.9 These effects suggest that increased inflammation is associated with reduced exercise capacity, also creating the question of whether a reverse relationship is also present; whether increased exercise capacity, achieved by exercise training, is associated with reduced inflammation. As noted above, despite some promising findings, not all patients respond to the intervention. Some earlier studies aimed at classifying patients into responders and non-responders to exercise training using different methods. A sub-study of the Heart Failure-A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION)10 classified patients into four distinct phenotypes through cluster analysis, each with a different prognosis and response to exercise training. Interestingly, the responders had, among other characteristics, non-ischaemic cardiomyopathy, low rates of comorbidities and higher socioeconomic status and quality of life. Kemps et al.11 approached the problem using oxygen recovery kinetics after exercise as a differentiating criterion, adding another parameter in the predictive model. Schmid et al.12 suggested that impaired chronotropic competence, expressed by heart rate (HR) recovery, HR reserve at 1 min and peak HR, also has the potential to predict exercise training responders. As a result, until now, the available predictive model consisted mainly of demographic characteristics and clinical parameters. The current study of Fernandes-Silva et al. is the first step towards adding biological factors into this model. Despite the above-mentioned significant implications, it is also important to note the limitations of the study. As presented in the article, the randomisation was not stratified by the patients’ inflammatory status. In addition, the low inflammation group consisted mainly of patients in a better clinical condition New York Heart Association class II (NYHA II) compared to the high inflammation group New York Heart Association class III (NYHA III). As a result, doubts still remain whether the observed correlation is accurate or if the inflammatory profile is just a confounding factor with the underline clinical condition being the true independent variable. Other confounding factors that may have affected the observed finding could be the aetiology,13 intensity of exercise14 or severity of heart failure.15 Nevertheless, these findings should prompt further research on the effects of inflammation on exercise training response, especially in regard to heart failure patients. SA and CD contributed to the conception or design of the work, drafted the manuscript, critically revised it, gave final approval and agreed to be accountable for all aspects of work ensuring integrity and accuracy. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.