BACKGROUND. While mitochondria play an important role in innate immunity, the relationship between mitochondrial dysfunction and inflammation in heart failure (HF) is poorly understood. In this study we aimed to investigate the mechanistic link between mitochondrial dysfunction and inflammatory activation in peripheral blood mononuclear cells (PBMCs), and the potential antiinflammatory effect of boosting the NAD level. METHODS. We compared the PBMC mitochondrial respiration of 19 hospitalized patients with stage D HF with that of 19 healthy participants. We then created an in vitro model of sterile inflammation by treating healthy PBMCs with mitochondrial damage-associated molecular patterns (MitoDAMPs) isolated from human heart tissue. Last, we enrolled patients with stage D HF and sampled their blood before and after taking 5 to 9 days of oral nicotinamide riboside (NR), a NAD precursor. RESULTS. We demonstrated that HF is associated with both reduced respiratory capacity and elevated proinflammatory cytokine gene expressions. In our in vitro model, MitoDAMP-treated PBMCs secreted IL-6 that impaired mitochondrial respiration by reducing complex I activity. Last, oral NR administration enhanced PBMC respiration and reduced proinflammatory cytokine gene expression in 4 subjects with HF. CONCLUSION. These findings suggest that systemic inflammation in patients with HF is causally linked to mitochondrial function of the PBMCs. Increasing NAD levels may have the potential to improve mitochondrial respiration and attenuate proinflammatory activation of PBMCs in HF. TRIAL REGISTRATION. ClinicalTrials.gov NCT03727646.

Macrophages are key components of innate immunity, and they play critical roles in heart health and diseases. Following acute myocardial infarction (MI), infiltrating macrophages undergo drastic phenotypic transition from pro-inflammatory in the early stage to pro-healing in the late stage. Transcriptome analyses of macrophage in the infarct zone show a time-dependent reprogramming of mitochondrial and metabolic functions, which parallels the changes of macrophage function. These observations suggest that mitochondrial and metabolic targets could be exploited for therapeutic opportunities. In this article, we reviewed the recent work on immunometabolic features of macrophage over the MI time continuum. In addition, we summarized currently proposed mitochondrial pathways involved in the functional polarization of macrophage and discussed their potential relevance to the outcome of MI. We expect that these findings will stimulate further investigations in metabolic modulation of innate immunity in the post-MI setting, which could ultimately lead to new strategies for therapy.

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