Abstract
Cardiac dysfunction, in particular of the left ventricle, is a common and early event in sepsis, and is strongly associated with an increase in patients’ mortality. Acid sphingomyelinase (SMPD1)—the principal regulator for rapid and transient generation of the lipid mediator ceramide—is involved in both the regulation of host response in sepsis as well as in the pathogenesis of chronic heart failure. This study determined the degree and the potential role to which SMPD1 and its modulation affect sepsis-induced cardiomyopathy using both genetically deficient and pharmacologically-treated animals in a polymicrobial sepsis model. As surrogate parameters of sepsis-induced cardiomyopathy, cardiac function, markers of oxidative stress as well as troponin I levels were found to be improved in desipramine-treated animals, desipramine being an inhibitor of ceramide formation. Additionally, ceramide formation in cardiac tissue was dysregulated in SMPD1+/+ as well as SMPD1−/− animals, whereas desipramine pretreatment resulted in stable, but increased ceramide content during host response. This was a result of elevated de novo synthesis. Strikingly, desipramine treatment led to significantly improved levels of surrogate markers. Furthermore, similar results in desipramine-pretreated SMPD1−/− littermates suggest an SMPD1-independent pathway. Finally, a pattern of differentially expressed transcripts important for regulation of apoptosis as well as antioxidative and cytokine response supports the concept that desipramine modulates ceramide formation, resulting in beneficial myocardial effects. We describe a novel, protective role of desipramine during sepsis-induced cardiac dysfunction that controls ceramide content. In addition, it may be possible to modulate cardiac function during host response by pre-conditioning with the Food and Drug Administration (FDA)-approved drug desipramine.
Highlights
Sepsis-induced cardiac dysfunction (SCD) is a common phenomenon in sepsis/septic shock, leading to an increase in mortality [1,2]
We conclude that increased ceramide generation plays an essential and decisive role in cardiac integrity and dysfunction during the acute phase of sepsis
Desipramine pretreatment is able to adjust pathophysiological cardiac alterations during sepsis, an effect of treatment following triggering of host response has to be substantiated in further studies
Summary
Sepsis-induced cardiac dysfunction (SCD) is a common phenomenon in sepsis/septic shock, leading to an increase in mortality [1,2]. Observational studies have demonstrated an association between increased troponin I levels, cardiac dysfunction and unfavourable outcome in sepsis [4,5,6]. Sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection [7]. SCD is present in almost 50% of sepsis cases [8] and has been documented as one of the major predictors of morbidity and mortality related to sepsis. SCD can be reversible [9], its occurrence increases the mortality of septic patients to up to 70% [10,11]
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