A single exercise exertion initiates antioxidant and vascular-protective mechanisms in patients with heart failure
Authors: Swaminathan K , Koc A , Kaczmarek S , Lehnert K , Urbaneck I , Domanska G , Landmesser U , Felix S , Doerr M , Bahls M , Kraenkel N 
Published: May 2023

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DZHK (German Centre for Cardiovascular Research).

Background
Increased systemic inflammation and metabolic dysfunction at rest are observed in heart failure with reduced ejection fraction (HFrEF). Regular (endurance) exercise training can alleviate both. On the other hand, cardiorespiratory exercise testing (CPET) exerts a physical challenge thereby initiating the acute activation of the immune system and several metabolic pathways.

Aim
To characterize the differences and similarities acute inflammatory and metabolic activation in response to an acute exercise challenge, and their resolution after 2 hours of rest in patients with HFrEF as compared to controls.

Methods
Participants with HFrEF (n = 16) as well as age and sex matched controls (CON, n = 13) were investigated at baseline (T1), immediately after CPET (T2), and after 2 hours of resting post-CPET (T3). Clinical and physiological parameters, leukocyte profile, plasma cytokines and metabolites were assessed along with inflammatory and metabolic parameters at all three time points.

Results and Discussion
Cardiovascular risk profile as well as leukocyte, cytokine and metabolic parameters at T1 was similar in CON and HFrEF. Immediately after CPET, lactate, natural killer (NK) and NK-T cell blood counts, among others, were significantly increased in both groups. In HFrEF specifically, platelet aggregates with NK cells, CD8+ cytotoxic T cells and "classical" CD14++CD16-monocytes as well as phosphatidylcholines and triglycerides were increased. After 2h of rest post-CPET, almost all altered parameters returned to baseline in CON. In HFrEF, blood counts and morphological markers of inflammatory effector cell types, including CD8+ T cells and neutrophils remained elevated. Blood levels of inflammatory cytokines were associated to elevated levels of various phosphatidycholines in HFrEF, but not in CON, potentially pointing towards a link to cell death. Blood levels of methionine sulfoxide-to-methionine, declined at T3 versus T1 in both groups, potentially indicating activation of anti-oxidant methionine sulfoxide reductases. In addition, trigonelline, an inhibitor of trimethylamine N-oxide (TMAO) synthesis from choline was elevated by CPET in both groups and this increase correlated inversely with TMAO-to-choline ratio. This might indicate a so far unexplored exercise-induced vascular-protective mechanism by limiting the pro-atherogenic effects of TMAO.

Conclusion
CPET induced a complex acute immuno-metabolic response, whose restitution to baseline levels differed between HFrEF and healthy controls. Despite longer persistence of pro-inflammatory and metabolic mediators present in the circulation after the end of an acute exercise session, novel anti-oxidant and vascular protective mechanisms of exercise have been identified and appear to be still active in patients with HFrEF.