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.

Altogether, these data suggest that increased levels of miR-195 in failing myocardium regulate a novel pathway that involves direct SIRT3 suppression and enzymatic inhibition via increased acetylation of PDH and ATP synthase that are essential for cardiac energy metabolism.

Background Hypertrophic cardiomyopathy (HCM) is caused by mutations in different structural genes and induces pathological hypertrophy with sudden cardiac death as a possible consequence. HCM can be separated into hypertrophic non-obstructive and obstructive cardiomyopathy (HNCM/HOCM) with different clinical treatment approaches. We here distinguished between HNCM, HOCM, cardiac amyloidosis and aortic stenosis by using microRNA profiling and investigated potential interactions between circulating miRNA levels and the most common mutations in MYH7and MYBPC3 genes. Methods Our study included 4 different groups: 23 patients with HNCM, 28 patients with HOCM, 47 patients with aortic stenosis and 22 healthy controls. Based on previous findings, 8 different cardiovascular known microRNAs (miR-1, miR-21, miR-29a, miR-29b, miR-29c, miR-133a, miR-155 and miR-499) were studied in serum of all patients and compared with clinically available patient data. Results We found miR-29a levels to be increased in patients with HOCM and correlating markers of cardiac hypertrophy. This was not the case in HNCM patients. In contrast, we identified miR-29c to be upregulated in aortic stenosis but not the other patient groups. ROC curve analysis of miR-29a/c distinguished between HOCM patients and aortic stenosis patients. MiR-29a and miR-155 levels discriminated HNCM patients from patients with senile cardiac amyloidosis. MiR-29a increased mainly in HOCM patients with a mutation in MYH7, whereas miR-155 was decreased in hypertrophic cardiomyopathy patients with a mutation in MYBPC3. Conclusion We demonstrated that miR-29a and miR-29c show a specific signature to distinguish between aortic stenosis, hypertrophic non-obstructive and obstructive cardiomyopathies and thus could be developed into clinically useful biomarkers.

Following the publication of our article, we became aware of a related publication by Reforgiato and coauthors that described increased de novo ceramide synthesis and inflammation adjacent to the necrotic core area in a mouse model of 30 minutes of ischemia and reperfusion injury (1). Similar to the findings of our study in a chronic model of ischemic cardiomyopathy 3 months following myocardial infarction and in a large cohort of patients with advanced heart failure, Reforgiato et al. found that ceramide accumulation was accompanied by increased levels of serine palmitoyltransferase (SPT), which could be inhibited by administration of myriocin, an inhibitor of SPT. Their study, which was performed in an animal model of acute ischemic injury, independently supports the findings of our systematic lipidomic study in patients with advanced heart failure before and after mechanical unloading and cardiomyopathy as well as Sptlc2-deletion mice. We believe the detailed lipidomic analysis in our study provides an important advance to the field. This analysis allowed the differentiation of various ceramide species, and we related specific ceramide chain lengths to the biologic phenotypes described. Further, we linked ceramide metabolism and de novo ceramide synthesis using various expression plasmids (sptlc1, -2 and -3) in cell culture experiments to changes in ceramide species accumulation and dysregulation of oxidative and glycolytic metabolism as typical for the failing myocardium. Thus, we linked the lipids to changes in their metabolic pathways. Together, these studies highlight a key role of de novo ceramide synthesis of distinct ceramide species and their accumulation following acute ischemic injury and in chronically failing myocardium.

Abnormal lipid metabolism may contribute to myocardial injury and remodeling. To determine whether accumulation of very long-chain ceramides occurs in human failing myocardium, we analyzed myocardial tissue and serum from patients with severe heart failure (HF) undergoing placement of left ventricular assist devices and controls. Lipidomic analysis revealed increased total and very long-chain ceramides in myocardium and serum of patients with advanced HF. After unloading, these changes showed partial reversibility. Following myocardial infarction (MI), serine palmitoyl transferase (SPT), the rate-limiting enzyme of the de novo pathway of ceramide synthesis, and ceramides were found increased. Blockade of SPT by the specific inhibitor myriocin reduced ceramide accumulation in ischemic cardiomyopathy and decreased C16, C24:1, and C24 ceramides. SPT inhibition also reduced ventricular remodeling, fibrosis, and macrophage content following MI. Further, genetic deletion of the SPTLC2 gene preserved cardiac function following MI. Finally, in vitro studies revealed that changes in ceramide synthesis are linked to hypoxia and inflammation. In conclusion, cardiac ceramides accumulate in the failing myocardium, and increased levels are detectable in circulation. Inhibition of de novo ceramide synthesis reduces cardiac remodeling. Thus, increased de novo ceramide synthesis contributes to progressive pathologic cardiac remodeling and dysfunction.