Pathophysiology of sepsis-related cardiac dysfunction: driven by inflammation, energy mismanagement, or both?

Abstract

Sepsis is a systemic inflammatory response that follows bacterial infection. Cardiac dysfunction is an important consequence of sepsis that affects mortality and has been attributed to either elevated inflammation or suppression of both fatty acid and glucose oxidation and eventual ATP depletion. Moreover, cardiac adrenergic signaling is compromised in septic patients and this aggravates further heart function. While anti-inflammatory therapies are important for the treatment of the disease, administration of anti-inflammatory drugs did not improve survival in septic patients. This review article summarizes findings on inflammatory and other mechanisms that are triggered in sepsis and affect cardiac function and mortality. Particularly, it focuses on the effects of the disease in metabolic pathways, as well as in adrenergic signaling and the potential interplay of the latter with inflammation. It is suggested that therapeutic approaches should include combination of anti-inflammatory treatments, stimulation of energy production, and restoration of adrenergic signaling in the heart.

Fig. 1

Schematic illustration of the βAR-elicited signaling pathways modulating apoptosis/inflammation in the heart, discussed in the present article. Potential therapeutic strategies for cardiac sepsis are also depicted. See text for details and for molecular acronym descriptions

Fig. 2

Cardiac fatty acid metabolism in health and in sepsis—a cardiac fatty acid oxidation in normal hearts: fatty acids are taken up by cardiomyocytes via CD36 or with the contribution of lipoprotein remnant receptors, such as VLDLr and LRP. Cardiomyocyte fatty acids can be stored in triglycerides or used for ATP production via β-oxidation in mitochondria. b During sepsis, CD36, lipoprotein lipase, and lipoprotein remnant receptors are downregulated, leading to increased fatty acid and triglyceride-carrying lipoprotein content in the circulation. In addition, cardiac β-oxidation is inhibited and mitochondrial number is reduced via mitophagy, resulting in intracellular accumulation of the unused fatty acids in triglycerides