Background: Patients with advanced heart failure with reduced ejection fraction (HFrEF) have an increased inflammatory load and impaired cardiac oxidative phosphorylation of lipids. However, mitochondrial dysfunction was not reproduced in all stages of heart failure. Moreover, increased inflammatory load is a hallmark of all cardiovascular diseases. Potentially, early characteristic dysregulations can be overlooked when assessing patients only under resting conditions. We therefore exposed HFrEF patients to a physical exertion challenge by cardiopulmonary exercise testing (CPET) and monitored acute changes in inflammatory and metabolic parameters, as well as their further course during a subsequent 2-hour resting period. 

Methods: Participants with HFrEF (n = 16) and age and sex matched controls (CON, n = 13) were investigated at baseline (T1), immediately after CPET (T2), and after 2 hours of resting (T3). Symptom-limited CPET was performed according to modified Jones protocol. In addition to clinical and physiological parameters, blood counts of leukocyte subtypes, their morphology, aggregation with platelets and microvesicle release, as well as plasma cytokines and metabolites were assessed at all three time points. Inflammatory and metabolic parameters were assessed using the ThermoFischer ProcartaPlex Human Inflammation-Panel and Biocrates MxP® Quant 500 kit, respectively. Non-parametric tests were chosen and all multiple tests were adjusted by the Benjamini-Hochberg method.

Results: CON and HFrEF were similar with regard to their cardiovascular risk profile. However, HFrEF had a lower left ventricular ejection fraction and a greater left ventricular enddiastolic diameter. We found no differences between groups for leukocyte, cytokine or metabolic parameters at T1. Immediately after CPET, 20 parameters were significantly altered in both groups, including an increase of lactate, natural killer (NK) and NK T cell blood counts. In addition to these, 131 inflammatory and metabolic parameters were altered only in HFrEF, as compared to 17 only in CON. HFrEF-increased parameters included platelet aggregates with NK cells, CD8+ cytotoxic T cells and “classical” CD14++CD16-monocytes, 58 different phosphatidylcholines and 21 triglycerides. At T3 almost all altered parameters returned to baseline in CON. In HFrEF, blood counts and morphological markers of inflammatory effector cell types, including NK cells, CD8+ T cells and neutrophils, as well as genomic nuclear DNA, an indicator of cell death, remained elevated. Moreover, several triglycerides did not return to baseline in HFrEF. In these patients, but not in CON, the different lipids (i.e. phosphatidylcholine, triglycerides) strongly correlated with pro-inflammatory cytokines and NK cells.

Conclusion: Our data support the concept of impaired fatty acid utilization and inflammation-mediated metabolic dysregulation in HFrEF. However, the correlations between metabolic and inflammatory parameters were not evident at baseline in comparison to a control group with similar cardiovascular risk profile. Therefore, investigating patients in response to a physical or metabolic challenge might reveal early pathologic changes and might aid the development of metabolically active therapies – such as SGLT2 inhibitors, but also early implementation of prevention measures, to maximize therapy success for the patient.