bims-hafaim 2022-01-23 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2022‒01‒23
eleven papers selected by
Kyle McCommis
Saint Louis University

Nicotinamide riboside kinase-2 inhibits JNK pathway and limits dilated cardiomyopathy in mice with chronic pressure overload.
Dapagliflozin reduces uric acid concentration, an independent predictor of adverse outcomes in DAPA-HF.
Overexpression of NOX2 Exacerbates AngII-Mediated Cardiac Dysfunction and Metabolic Remodelling.
Cardioprotective Effects of n-3 Polyunsaturated Fatty Acids: Orchestration of mRNA Expression, Protein Phosphorylation, and Lipid Metabolism in Pressure Overload Hearts.
Myocardial Rev-erb-Mediated Diurnal Metabolic Rhythm and Obesity Paradox.
Deranged Myocardial Fatty Acid Metabolism in Heart Failure.
Mitophagy-regulated mitochondrial health strongly protects the heart against cardiac dysfunction after acute myocardial infarction.
Prognostic Benefit of New Drugs for HFrEF: A Systematic Review and Network Meta-Analysis.
Intermittent Fasting Improves High-Fat Diet-Induced Obesity Cardiomyopathy via Alleviating Lipid Deposition and Apoptosis and Decreasing m6A Methylation in the Heart.
Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD+ biosynthesis and sustain cardiac function.
Implication of Sphingolipid Metabolism Gene Dysregulation and Cardiac Sphingosine-1-Phosphate Accumulation in Heart Failure.

Clin Sci (Lond). 2022 Jan 20. pii: CS20210964. [Epub ahead of print]

Nicotinamide riboside kinase-2 inhibits JNK pathway and limits dilated cardiomyopathy in mice with chronic pressure overload.

Syeda Kiran Shahzadi, Hezlin Marzook, Rizwan Qaisar, Firdos Ahmad.

  Nicotinamide riboside kinase-2 (NRK-2) has recently emerged as a critical regulator of cardiac remodeling however, underlying molecular mechanisms is largely unknown. To explore the same, NRK2 knockout (KO) and littermate control mice were subjected to trans-aortic constriction (TAC) or sham surgeries and cardiac function was assessed by serial M-mode echocardiography. A mild cardiac contractile dysfunction was observed in the KOs at the early adaptive phase of remodeling followed by a significant deterioration during the maladaptive cardiac remodeling phase. Consistently, NRK2 KO hearts displayed increased cardiac hypertrophy and heart failure reflected by morphometric parameters as well as increased fetal genes ANP and BNP expressions. Histological assessment revealed an extensive left ventricular (LV) chamber dilatation accompanied by elevated cardiomyopathy and fibrosis in the KO hearts post-TAC. In a gain-of-function model, NRK-2 overexpressing in AC16 cardiomyocytes displayed significantly attenuated fetal genes ANP and BNP expression. Consistently, NRK-2 overexpression attenuated angiotensin II- induced cardiomyocyte death. Mechanistically, we identified NRK-2 as a regulator of JNK MAP kinase and mitochondrial function where NRK-2 overexpression in human cardiomyocytes markedly suppressed the angiotensin II- induced JNK activation and mitochondrial depolarization. Thus, our results demonstrate that NRK-2 plays protective roles in pressure overload- induced dilatative cardiac remodeling and, genetic ablation exacerbates dilated cardiomyopathy, interstitial collagen deposition, and cardiac dysfunction post-TAC due, in part, to increased JNK activation and mitochondrial dysfunction.

Keywords:  Dilated cardiomyopathy; JNK MAP Kinases; MIBP; Mitochondrial dysfunction; NMRK-2; Pressure Overload

DOI:  https://doi.org/10.1042/CS20210964
Eur J Heart Fail. 2022 Jan 22.

Dapagliflozin reduces uric acid concentration, an independent predictor of adverse outcomes in DAPA-HF.

Kirsty McDowell, Paul Welsh, Kieran F Docherty, David A Morrow, Pardeep S Jhund, Rudolf A De Boer, Eileen O'Meara, Silvio E Inzucchi, Lars Køber, Mikhail N Kosiborod, Felipe A Martinez, Piotr Ponikowski, Ann Hammarstedt, Anna Maria Langkilde, Mikaela Sjöstrand, Daniel Lindholm, Scott D Solomon, Naveed Sattar, Marc S Sabatine, John J V McMurray.

  BACKGROUND: Blood uric acid (UA) levels are frequently elevated in patients with HFrEF, may lead to gout and are associated with worse outcomes. Reduction in UA is desirable in HFrEF and sodium-glucose cotransporter 2 (SGLT2) inhibitors may have this effect.OBJECTIVES: To examine the association between UA and outcomes, the effect of dapagliflozin according to baseline UA level, and the effect of dapagliflozin on UA in patients with HFrEF in the DAPA-HF trial.
METHODS AND RESULTS: The association between UA and the primary composite outcome of cardiovascular death or worsening HF, its components, and all-cause mortality was examined using Cox regression analyses among 3119 patients using tertiles of UA, after adjustment for other prognostic variables. Change in UA from baseline over 12 months was also evaluated. Patients in tertile 3 (UA ≥6.8 mg/dL) versus tertile 1 (<5.4 mg/dL) were younger (66.3 ± 10.8 vs 68 ± 10.2 years), more often male (83.1% vs 71.5%), had lower eGFR (58.2 ± 17.4 vs 70.6 ± 18.7 mL/min/1.73m2 ), and more often treated with diuretics. Higher UA was associated with a greater risk of the primary outcome (adjusted HR tertile 3 vs. tertile 1 = 1.32 [95%CI 1.06, 1.66; P = 0.01). The risk of HF hospitalization and CV death increased by 7% and 6% respectively per 1 mg/dL unit increase of UA. (P = 0.04, 0.07) Spline analysis revealed a linear increase in risk above a cut off UA value of 7.09 mg/dL. Compared with placebo, dapagliflozin reduced UA by 0.84 mg/dL (95% CI -0.93, -0.74) over 12 months (P < 0.001). Dapagliflozin improved outcomes, irrespective of baseline UA concentration.
CONCLUSION: UA remains an independent predictor of worse outcomes in a well-treated contemporary HFrEF population. Compared with placebo, dapagliflozin reduced UA and improved outcomes irrespective of UA concentration.

Keywords:  Heart failure; SGLT2; diabetes; mortality; uric acid

DOI:  https://doi.org/10.1002/ejhf.2433
Antioxidants (Basel). 2022 Jan 10. pii: 143. [Epub ahead of print]11(1):

Overexpression of NOX2 Exacerbates AngII-Mediated Cardiac Dysfunction and Metabolic Remodelling.

Synne S Hansen, Tina M Pedersen, Julie Marin, Neoma T Boardman, Ajay M Shah, Ellen Aasum, Anne D Hafstad.

  The present study aimed to examine the effects of low doses of angiotensin II (AngII) on cardiac function, myocardial substrate utilization, energetics, and mitochondrial function in C57Bl/6J mice and in a transgenic mouse model with cardiomyocyte specific upregulation of NOX2 (csNOX2 TG). Mice were treated with saline (sham), 50 or 400 ng/kg/min of AngII (AngII50 and AngII400) for two weeks. In vivo blood pressure and cardiac function were measured using plethysmography and echocardiography, respectively. Ex vivo cardiac function, mechanical efficiency, and myocardial substrate utilization were assessed in isolated perfused working hearts, and mitochondrial function was measured in left ventricular homogenates. AngII50 caused reduced mechanical efficiency despite having no effect on cardiac hypertrophy, function, or substrate utilization. AngII400 slightly increased systemic blood pressure and induced cardiac hypertrophy with no effect on cardiac function, efficiency, or substrate utilization. In csNOX2 TG mice, AngII400 induced cardiac hypertrophy and in vivo cardiac dysfunction. This was associated with a switch towards increased myocardial glucose oxidation and impaired mitochondrial oxygen consumption rates. Low doses of AngII may transiently impair cardiac efficiency, preceding the development of hypertrophy induced at higher doses. NOX2 overexpression exacerbates the AngII -induced pathology, with cardiac dysfunction and myocardial metabolic remodelling.

Keywords:  NOX2; angiotensin II; cardiac disease; cardiac efficiency; cardiac hypertrophy; hypertension

DOI:  https://doi.org/10.3390/antiox11010143
Front Cardiovasc Med. 2021 ;8 788270

Cardioprotective Effects of n-3 Polyunsaturated Fatty Acids: Orchestration of mRNA Expression, Protein Phosphorylation, and Lipid Metabolism in Pressure Overload Hearts.

Xiang Li, Weijiang Tan, Shuang Zheng, Junjie Zhang, Caiyi Zhu, Chun Cai, Honghua Chen, Chenqi Yang, Le Kang, Zhanhong Pan, W Glen Pyle, Peter H Backx, Yunzeng Zou, Feng Hua Yang.

  Background: Pressure overload can result in dilated cardiomyopathy. The beneficial effects of n-3 polyunsaturated fatty acids (n-3 PUFAs) on heart disorders have been widely recognized. However, the molecular mechanisms underlying their protective effects against cardiomyopathy remain unclear. Methods: Pressure overload in mice induced by 8 weeks of transverse aortic constriction was used to induce dilated cardiomyopathy. A transgenic fat-1 mouse model carrying the n-3 fatty acid desaturase gene fat-1 gene from Caenorhabditis elegans was used to evaluate the mechanism of n-3 PUFAs in this disease. Echocardiography, transmission electron microscopy, and histopathological analyses were used to evaluate the structural integrity and function in pressure overloaded fat-1 hearts. mRNA sequencing, label-free phosphoprotein quantification, lipidomics, Western blotting, RT-qPCR, and ATP detection were performed to examine the effects of n-3 PUFAs in the heart. Results: Compared with wild-type hearts, left ventricular ejection fraction was significantly improved (C57BL/6J [32%] vs. fat-1 [53%]), while the internal diameters of the left ventricle at systole and diastole were reduced in the fat-1 pressure overload hearts. mRNA expression, protein phosphorylation and lipid metabolism were remodeled by pressure overload in wild-type and fat-1 hearts. Specifically, elevation of endogenous n-3 PUFAs maintained the phosphorylation states of proteins in the subcellular compartments of sarcomeres, cytoplasm, membranes, sarcoplasmic reticulum, and mitochondria. Moreover, transcriptomic analysis predicted that endogenous n-3 PUFAs restored mitochondrial respiratory chain function that was lost in the dilated hearts, and this was supported by reductions in detrimental oxylipins and protection of mitochondrial structure, oxidative phosphorylation, and ATP production. Conclusions: Endogenous n-3 PUFAs prevents dilated cardiomyopathy via orchestrating gene expression, protein phosphorylation, and lipid metabolism. This is the first study provides mechanistic insights into the cardioprotective effects of n-3 PUFAs in dilated cardiomyopathy through integrated multi-omics data analysis.

Keywords:  dilated cardiomyopathy cardioprotection; mitochondrial function; multi-omics analysis; n-3 PUFA; pressure overload

DOI:  https://doi.org/10.3389/fcvm.2021.788270
Circulation. 2022 Jan 17.

Myocardial Rev-erb-Mediated Diurnal Metabolic Rhythm and Obesity Paradox.

Shiyang Song, Chih-Liang Tien, Hao Cui, Paul Basil, Ningxia Zhu, Yingyun Gong, Wenbo Li, Hui Li, Qiying Fan, Jong Min Choi, Weijia Luo, Yanfeng Xue, Rui Cao, Wenjun Zhou, Andrea R Ortiz, Brittany Stork, Vatsala Mundra, Nagireddy Putluri, Brian York, Maoping Chu, Jiang Chang, Sung Yun Jung, Liang Xie, Jiangping Song, Lilei Zhang, Zheng Sun.

Background: The nuclear receptor Rev-erbα/β, a key component of the circadian clock, emerges as a drug target for heart diseases, but the function of cardiac Rev-erb has not been studied in vivo. Circadian disruption is implicated in heart diseases, but it is unknown whether cardiac molecular clock dysfunction is associated with the progression of any naturally occurring human heart diseases. Obesity paradox refers to the seemingly protective role of obesity for heart failure, but the mechanism is unclear. Methods: We generated mouse lines with cardiac-specific Rev-erbα/β knockout (KO), characterized cardiac phenotype, conducted multi-omics (RNA-seq, ChIP-seq, proteomics, and metabolomics) analyses, and performed dietary and pharmacologic rescue experiments to assess the time-of-the-day effects. We compared the temporal pattern of cardiac clock gene expression with the cardiac dilation severity in failing human hearts. Results: KO mice display progressive dilated cardiomyopathy (DCM) and lethal heart failure. Inducible ablation of Rev-erbα/β in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, particularly in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, particularly in the dark cycle. Increasing dietary lipids or sugars supply in the dark cycle does not affect cardiac dysfunctions in KO mice. However, obesity coupled with systemic insulin resistance paradoxically ameliorates cardiac dysfunctions in KO mice, associated with rescued expression of lipid oxidation genes only in the light cycle in phase with increased fatty acids availability from adipose lipolysis. Inhibition of glycolysis in the light cycle and lipid oxidation in the dark cycle, but not vice versa, ameliorates cardiac dysfunctions in KO mice. Altered temporal patterns of cardiac Rev-erb gene expression correlate with the cardiac dilation severity in human hearts with DCM. Conclusions: The study delineates temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism at multi-omics levels. The obesity paradox is attributable to increased cardiac lipids supply from adipose lipolysis in the fasting cycle due to systemic insulin resistance and adiposity. Cardiac molecular chronotypes may be involved in human DCM. Myocardial bioenergetics downstream of Rev-erb may be a chronotherapy target in treating heart failure and DCM.

DOI: https://doi.org/10.1161/CIRCULATIONAHA.121.056076
Int J Mol Sci. 2022 Jan 17. pii: 996. [Epub ahead of print]23(2):

Deranged Myocardial Fatty Acid Metabolism in Heart Failure.

Tsunehisa Yamamoto, Motoaki Sano.

  The heart requires fatty acids to maintain its activity. Various mechanisms regulate myocardial fatty acid metabolism, such as energy production using fatty acids as fuel, for which it is known that coordinated control of fatty acid uptake, β-oxidation, and mitochondrial oxidative phosphorylation steps are important for efficient adenosine triphosphate (ATP) production without unwanted side effects. The fatty acids taken up by cardiomyocytes are not only used as substrates for energy production but also for the synthesis of triglycerides and the replacement reaction of fatty acid chains in cell membrane phospholipids. Alterations in fatty acid metabolism affect the structure and function of the heart. Recently, breakthrough studies have focused on the key transcription factors that regulate fatty acid metabolism in cardiomyocytes and the signaling systems that modify their functions. In this article, we reviewed the latest research on the role of fatty acid metabolism in the pathogenesis of heart failure and provide an outlook on future challenges.

Keywords:  ER stress; ERR; MUFA; PPAR; SCD1; SFA; SIRT1; membrane fatty acid composition; triacylglyceride; β-oxidation

DOI:  https://doi.org/10.3390/ijms23020996
J Cell Mol Med. 2022 Jan 18.

Mitophagy-regulated mitochondrial health strongly protects the heart against cardiac dysfunction after acute myocardial infarction.

Chunling Xu, Yangpo Cao, Ruxia Liu, Lei Liu, Weilin Zhang, Xuan Fang, Shi Jia, Jingjing Ye, Yingying Liu, Lin Weng, Xue Qiao, Bo Li, Ming Zheng.

  Autophagy including mitophagy serves as an important regulatory mechanism in the heart to maintain the cellular homeostasis and to protect against heart damages caused by myocardial infarction (MI). The current study aims to dissect roles of general autophagy and specific mitophagy in regulating cardiac function after MI. By using Beclin1+/- , Fundc1 knockout (KO) and Fundc1 transgenic (TG) mouse models, combined with starvation and MI models, we found that Fundc1 KO caused more severe mitochondrial and cardiac dysfunction damages than Beclin1+/- after MI. Interestingly, Beclin1+/- caused notable decrease of total autophagy without detectable change to mitophagy, and Fundc1 KO markedly suppressed mitophagy but did not change the total autophagy activity. In contrast, starvation increased total autophagy without changing mitophagy while Fundc1 TG elevated total autophagy and mitophagy in mouse hearts. As a result, Fundc1 TG provided much stronger protective effects than starvation after MI. Moreover, Beclin1+/- /Fundc1 TG showed increased total autophagy and mitophagy to a level comparable to Fundc1 TG per se, and completely reversed Beclin1+/- -caused aggravation of mitochondrial and cardiac injury after MI. Our results reveal that mitophagy but not general autophagy contributes predominantly to the cardiac protective effect through regulating mitochondrial function.

Keywords:  Beclin1; Fundc1; acute myocardial infarction; autophagy; mitophagy

DOI:  https://doi.org/10.1111/jcmm.17190
J Clin Med. 2022 Jan 11. pii: 348. [Epub ahead of print]11(2):

Prognostic Benefit of New Drugs for HFrEF: A Systematic Review and Network Meta-Analysis.

Matteo Pagnesi, Luca Baldetti, Alberto Aimo, Riccardo Maria Inciardi, Daniela Tomasoni, Enrico Vizzardi, Giuseppe Vergaro, Michele Emdin, Carlo Mario Lombardi.

  BACKGROUND: The new heart failure (HF) therapies of sodium-glucose cotransporter 2 inhibitors (SGLT2i), vericiguat, and omecamtiv mecarbil do not act primarily through the neuro-hormonal blockade, but have shown clinical benefits in patients with HF with reduced ejection fraction (HFrEF). However, their respective efficacies remain unclear. Our aim was to evaluate the relative efficacy of new drugs for HFrEF.METHODS: We performed a network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing SGLT2i, vericiguat, omecamtiv mecarbil, and placebo in HFrEF patients. The primary endpoint was the composite of cardiovascular death (CVD) or HF hospitalization (CVD-HF); secondary endpoints were CVD, all-cause death, and HF hospitalization (HFH).
RESULTS: Twelve RCTs (n = 23,861 patients) were included. A significant reduction in CVD-HF was observed with SGLT2i compared with placebo (risk ratio (RR) 0.77, 95% confidence interval (CI) 0.71-0.83), vericiguat (RR 0.84, 95% CI 0.75-0.93), and omecamtiv mecarbil (RR 0.80, 95% CI 0.72-0.88). No significant difference was observed between vericiguat and omecamtiv mecarbil (RR 0.95, 95% CI 0.87-1.04). SGLT2i were superior to placebo and omecamtiv mecarbil for all individual secondary endpoints (CVD, all-cause death, and HFH), and also to vericiguat for HFH. SGLT2i ranked as the most effective therapy for all endpoints, and vericiguat, omecamtiv mecarbil, and placebo ranked as the second, third, and last options, respectively, for the primary endpoint.
CONCLUSIONS: In patients with HFrEF on standard-of-care therapy, SGLT2i therapy was associated with a reduced risk of CVD-HF compared to placebo, vericiguat, and omecamtiv mecarbil. Furthermore, SGLT2i were superior to placebo and omecamtiv mecarbil for CVD, all-cause death, and HFH, and also to vericiguat for HFH.

Keywords:  SGLT2-inhibitors; ejection fraction; heart failure; network meta-analysis; omecamtiv mecarbil; vericiguat

DOI:  https://doi.org/10.3390/jcm11020348
Nutrients. 2022 Jan 07. pii: 251. [Epub ahead of print]14(2):

Intermittent Fasting Improves High-Fat Diet-Induced Obesity Cardiomyopathy via Alleviating Lipid Deposition and Apoptosis and Decreasing m6A Methylation in the Heart.

Zujie Xu, Ying Qin, Binbin Lv, Zhenjun Tian, Bing Zhang.

  Intermittent fasting (IF) plays an essential role in improving lipid metabolism disorders caused by metabolic cardiomyopathy. Growing evidence revealed that N6-methyladenosine (m6A) RNA methylation is related to obesity and lipid metabolic. Our study aimed to assess the beneficial effects of IF on lipid deposition, apoptosis, and m6A methylation in high-fat diet (HFD)-induced obesity cardiomyopathy. Male C57BL/6J mice were fed a normal diet (ND) or HFD ad libitum for 13 weeks, after which time a subgroup of HFD mice were subjected to IF for 24 h and fed HFD in the other day for 8 weeks. We found that IF intervention significantly improved cardiac functional and structural impairment and serum lipid metabolic disorder induced by HFD. Furthermore, IF intervention decreased the mRNA levels of the fatty acid uptake genes of FABP1, FATP1, and CD36 and the fatty acid synthesis genes of SREBF1, FAS, and ACCα and increased the mRNA levels of the fatty acid catabolism genes of ATGL, HSL, LAL, and LPL in cardiac tissueof HFD-induced obese mice. TUNEL-positive cells, Bax/Bcl-2 ratio, and Cleaved Caspase-3 protein expression in HFD-induced obese mice hearts was down-regulated by IF intervention. In addition, IF intervention decreased the m6A methylation levels and METTL3 expression and increased FTO expression in HFD-induced obesity cardiomyopathy. In conclusion, our findings demonstrate that IF attenuated cardiac lipid deposition and apoptosis, as well as improved cardiac functional and structural impairment in HFD-induced obesity cardiomyopathy, by a mechanism associated with decreased m6A RNA methylation levels.

Keywords:  N6-methyladenosine methylation; apoptosis; high-fat diet; intermittent fasting; lipid deposition; obesity cardiomyopathy

DOI:  https://doi.org/10.3390/nu14020251
Nat Cardiovasc Res. 2022 Jan;1(1): 45-58

Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD+ biosynthesis and sustain cardiac function.

Pieterjan Dierickx, Kun Zhu, Bryce J Carpenter, Chunjie Jiang, Marit W Vermunt, Yang Xiao, Timothy S Luongo, Tsunehisa Yamamoto, Íngrid Martí-Pàmies, Sobuj Mia, Mary Latimer, Abhinav Diwan, Juanjuan Zhao, Amy K Hauck, Brianna Krusen, Hoang C B Nguyen, Gerd A Blobel, Daniel P Kelly, Liming Pei, Joseph A Baur, Martin E Young, Mitchell A Lazar.

The heart is a highly metabolic organ that uses multiple energy sources to meet its demand for ATP production. Diurnal feeding-fasting cycles result in substrate availability fluctuations which, together with increased energetic demand during the active period, impose a need for rhythmic cardiac metabolism. The nuclear receptors REV-ERBα and β are essential repressive components of the molecular circadian clock and major regulators of metabolism. To investigate their role in the heart, here we generated mice with cardiomyocyte (CM)-specific deletion of both Rev-erbs, which died prematurely due to dilated cardiomyopathy. Loss of Rev-erbs markedly downregulated fatty acid oxidation genes prior to overt pathology, which was mediated by induction of the transcriptional repressor E4BP4, a direct target of cardiac REV-ERBs. E4BP4 directly controls circadian expression of Nampt and its biosynthetic product NAD+ via distal cis-regulatory elements. Thus, REV-ERB-mediated E4BP4 repression is required for Nampt expression and NAD+ production by the salvage pathway. Together, these results highlight the indispensable role of circadian REV-ERBs in cardiac gene expression, metabolic homeostasis and function.

DOI: https://doi.org/10.1038/s44161-021-00001-9
Biomedicines. 2022 Jan 08. pii: 135. [Epub ahead of print]10(1):

Implication of Sphingolipid Metabolism Gene Dysregulation and Cardiac Sphingosine-1-Phosphate Accumulation in Heart Failure.

Lorena Pérez-Carrillo, Isaac Giménez-Escamilla, Luis Martínez-Dolz, Ignacio José Sánchez-Lázaro, Manuel Portolés, Esther Roselló-Lletí, Estefanía Tarazón.

  Disturbances in sphingolipid metabolism lead to biological function dysregulation in many diseases, but it has not been described in heart failure (HF). Sphingosine-1-phosphate (S1P) levels have not ever been measured in the myocardium. Therefore, we analyze the gene dysregulation of human cardiac tissue by mRNA-seq (n = 36) and ncRNA-seq (n = 50). We observed most major changes in the expression of genes belonging to de novo and salvage pathways, and the tight gene regulation by their miRNAs is largely dysregulated in HF. We verified using ELISA (n = 41) that ceramide and S1P accumulate in HF cardiac tissue, with an increase in the ceramide/S1P ratio of 57% in HF. Additionally, changes in left ventricular mass and diameters are directly related to CERS1 expression and inversely related to S1P levels. Altogether, we define changes in the main components of the sphingolipid metabolism pathways in HF, mainly de novo and salvage, which lead to an increase in ceramide and S1P in cardiac tissue, as well as an increase in the ceramide/S1P ratio in HF patients. Therapeutic gene modulation focused on restoring ceramide levels or reversing the ceramide/S1P ratio could be a potential therapy to be explored for HF patients.

Keywords:  ceramide synthase 1 (CERS1); ceramide/S1P rheostat; heart failure; sphingolipid metabolism; sphingosine-1-phosphate (S1P)

DOI:  https://doi.org/10.3390/biomedicines10010135