Ceramide Is Upregulated and Associated With Mortality in Patients With Chronic Heart Failure

Yu, Jingjia; Pan, Wei; Shi, Ruizheng; Yang, Tianlun; Li, Yuan‐Jian; Yu, Guopan; Bai, Yongping; Schuchman, Edward H.; He, Xingxing; Zhang, Guogang

doi:10.1016/j.cjca.2014.12.007

Cited by 79 publications

(57 citation statements)

References 31 publications

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“…In sepsis, lymphohistiocytosis, systemic inflammatory response syndrome and chronic heart failure, high S-ASM activity is associated with higher mortality (Claus et al, 2005;Doehner et al, 2007;Jenkins et al, 2013;Kott et al, 2014). In accordance with this, the plasma ceramide content is an independent risk factor for mortality in patients with chronic heart failure (Yu et al, 2015). High S-ASM activity has been related to reduced skeletal muscle strength (Doehner et al, 2007).…”

Section: Cross-sectional Clinical Studiessupporting

confidence: 56%

Secretory sphingomyelinase in health and disease

Kornhuber

Rhein

Müller

et al. 2015

Biological Chemistry

120

138

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Acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism, hydrolyzes sphingomyelin to ceramide and phosphorylcholine. In mammals, the expression of a single gene, SMPD1, results in two forms of the enzyme that differ in several characteristics. Lysosomal ASM (L-ASM) is located within the lysosome, requires no additional Zn 2+ ions for activation and is glycosylated mainly with high-mannose oligosaccharides. By contrast, the secretory ASM (S-ASM) is located extracellularly, requires Zn 2+ ions for activation, has a complex glycosylation pattern and has a longer in vivo half-life. In this review, we summarize current knowledge regarding the physiology and pathophysiology of S-ASM, including its sources and distribution, molecular and cellular mechanisms of generation and regulation and relevant in vitro and in vivo studies. Polymorphisms or mutations of SMPD1 lead to decreased S-ASM activity, as detected in patients with Niemann-Pick disease B. Thus, lower serum/ plasma activities of S-ASM are trait markers. No genetic causes of increased S-ASM activity have been identified. Instead, elevated activity is the result of enhanced release (e.g., induced by lipopolysaccharide and cytokine stimulation) or increased enzyme activation (e.g., induced by oxidative stress). Increased S-ASM activity in serum or plasma is a state marker of a wide range of diseases. In particular, high S-ASM activity occurs in inflammation of the endothelium and liver. Several studies have demonstrated a correlation between S-ASM activity and mortality induced by severe inflammatory diseases. Serial measurements of S-ASM reveal prolonged activation and, therefore, the measurement of this enzyme may also provide information on past inflammatory processes. Thus, S-ASM may be both a promising clinical chemistry marker and a therapeutic target.

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Section: Cross-sectional Clinical Studiessupporting

confidence: 56%

Secretory sphingomyelinase in health and disease

Kornhuber

Rhein

Müller

et al. 2015

Biological Chemistry

120

138

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“…Here, we showed that activation of proapoptotic caspases mediates ceramide-associated LCM prior to detectable loss of cardiomyocytes. This suggests that moderate levels of caspase activation may be related to defective cardiac remodeling before cardiomyocyte death, which is generally associated with late-stage cardiac failure (de Jonge et al, 2003; Kostin, 2011; Lu et al, 2013) and mortality in patients with chronic heart failure (Yu et al, 2015). Indeed, rats fed a high-fat diet show a gradual accumulation of ceramide and the LCM pathogenesis follows a progressive course (Harasim et al, 2015).…”

Section: Model For Ceramide Modulation Of Lcm Pathogenesismentioning

confidence: 99%

Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy

et al. 2018

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SUMMARY Lipotoxic cardiomyopathy (LCM) is characterized by abnormal myocardial accumulation of lipids, including ceramide; however, the contribution of ceramide to the etiology of LCM is unclear. Here, we investigated the association of ceramide metabolism and ceramide-interacting proteins (CIPs) in LCM in the Drosophila heart model. We find that ceramide feeding or ceramide-elevating genetic manipulations are strongly associated with cardiac dilation and defects in contractility. High ceramide-associated LCM is prevented by inhibiting ceramide synthesis, establishing a robust model of direct ceramide-associated LCM, corroborating previous indirect evidence in mammals. We identified several CIPs from mouse heart and Drosophila extracts, including caspase activator Annexin-X, myosin chaperone Unc-45, and lipogenic enzyme FASN1, and remarkably, their cardiac-specific manipulation can prevent LCM. Collectively, these data suggest that high ceramide-associated lipotoxicity is mediated, in part, through altering caspase activation, sarcomeric maintenance, and lipogenesis, thus providing evidence for conserved mechanisms in LCM pathogenesis in mammals.

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“…33 In another study, the plasma level of ceramide showed a positive correlation with the severity of HF and with HF death. 34 A diet rich in saturated fatty acids increases cardiomyocyte apoptosis, possibly caused by accumulation of ceramide in cardiac tissue. 35 It was reported that reduction of the cardiac tissue level of ceramide had a cardioprotective effect in a mouse model of cardiomyocyte death.…”

Section: Cardiac Metabolismmentioning

confidence: 99%

Metabolomic Analysis in Heart Failure

Ikegami

Shimizu

Yoshida

et al. 2018

Circ J

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10 s, resulting in the cycling of approximately 6 kg of ATP daily, and the heart displays metabolic flexibility to meet this extremely high demand for energy. 8 Under normal conditions, more than 95% of the ATP consumed in the heart is generated by oxidative phosphorylation, while glycolysis is responsible for approximately 5% and the tricarboxylic acid (TCA) cycle for the remainder. Metabolism of fatty acids generates 70-90% of the ATP required by the heart, with the rest being produced by oxidation of glucose, lactate, ketone bodies, and amino acids. 9 It is well known that utilization of fatty acids is reduced in the failing heart and there is a metabolic shift to generation of ATP from glucose. Such metabolic remodeling is considered to be reasonable because HF is associated with hypoxia and ATP generation per oxygen atom is more efficient when glucose is consumed, compared with fatty acids. 9 In patients with advanced HF, the heart is unable to utilize either metabolite and thus "runs out of fuel". 10 It is reported that the ATP level is approximately 30% lower in failing human hearts compared with non-failing hearts. 11 In addition to this classical premise about the metabolic profile of the failing heart, recent advances in the field of metabolomics have indicated that several metabolites and/or metabolic pathways have a role in HF, as described next. LipidsUnder physiological conditions, the heart mainly generates ATP from fatty acids, but this process declines with progression of HF. Under left ventricular (LV) pressure overload, excessive lipolysis occurs in visceral fat because of increased adrenergic signaling, and this leads to high circulating levels of free fatty acids (FFAs). 12 The serum I t is thought that at least 6,500 low-molecular-weight metabolites exist in humans, and these metabolites have various important roles in biological systems in addition to proteins and genes. 1 Comprehensive assessment of endogenous metabolites is called metabolomics, and recent advances in this field have enabled us to understand the critical role of previously unknown metabolites or metabolic pathways in the maintenance of homeostasis under both physiological and stress conditions. Techniques of metabolomic analysis have been elegantly reported and reviewed elsewhere, 2-4 so the details will not be repeated here. Instead, we will describe the metabolites/metabolic pathways that have been characterized using these techniques and analyzed to improve understanding of various physiological and pathological processes in the field of cardiology. In particular, we will focus on heart failure (HF) and how metabolomic analysis has contributed for improving our understanding of the pathogenesis of this critical condition. Cardiac MetabolismThe number of patients with HF continues to increase and this condition has become a major healthcare issue in many countries. Because the prognosis of severe HF is poor, there are many unmet medical needs for these patients, 5, 6 The pathogenesis of HF is complex and a simple approa...

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Ceramide Is Upregulated and Associated With Mortality in Patients With Chronic Heart Failure

Cited by 79 publications

References 31 publications

Secretory sphingomyelinase in health and disease

Secretory sphingomyelinase in health and disease

Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy

Metabolomic Analysis in Heart Failure

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