Abstract 17736: Cardiomyocyte Specific Loss of Diacylglycerol Acyl Transferase 1 (Dgat1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Chad M Trent ◽  
Li Liu ◽  
Xiang Fang ◽  
Ni-Huiping Son ◽  
Hongfeng Jiang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Function ◽  
Severe Heart Failure ◽  
Fatty Acid Uptake ◽  
Metabolic Effects ◽  
Acid Uptake ◽  
Acyl Transferase ◽  
Human Heart Failure ◽  
Protein Kinase Cα ◽  
Ceramide Content

Diacylglycerol acyl transferase 1 (DGAT1) catalyzes the final step in triglyceride (TG) synthesis, the conversion of diacylglycerol (DAG) to TG. Dgat1-/- mice exhibit a number of beneficial metabolic effects including reduced obesity and improved insulin sensitivity and no known cardiac dysfunction. In contrast, failing human hearts have severely reduced DGAT1 expression associated with accumulation of DAGs and ceramides. To test whether DGAT1 loss alone affects heart function we created cardiomyocyte specific DGAT1 knockout (hDgat1-/-) mice. hDgat1-/- mice hearts had 95% increased DAG and 85% increased ceramides compared to floxed controls. 50% of these mice died by 9 months of age. The heart failure marker brain natriuretic peptide (Bnp) increased 5-fold in hDgat1-/- hearts and fractional shortening (FS) was reduced. This was associated with a 30% increase in PPARalpha and a 40% increase in Cd36. We crossed hDgat1-/- mice with previously described enterocyte-specific Dgat1 knockout mice (hiDgat1-/-). This corrected the early mortality, improved FS 40%, and reduced cardiac ceramide and DAG content. Treatment of hDgat1-/- mice with GLP-1 receptor agonist exenatide for 1 week reduced Bnp mRNA by 50%, improved FS, and reduced heart DAG and ceramide content by 30-40%. Increased fatty acid uptake into hDgat1-/- hearts was normalized by exenatide. Reduced activity of protein kinase Cα (PKCα), which is known to be increased by DAG and ceramides, paralleled the reductions in these lipids. Our mouse studies show that loss of DGAT1 reproduces the lipid abnormalities seen in severe human heart failure.

scholarly journals Des-Acyl Ghrelin Has Specific Binding Sites and Different Metabolic Effects from Ghrelin in Cardiomyocytes

Endocrinology ◽  
2010 ◽  
Vol 151 (7) ◽  
pp. 3286-3298 ◽  
Author(s):  
Pamela V. Lear ◽  
María J. Iglesias ◽  
Sandra Feijóo-Bandín ◽  
Diego Rodríguez-Penas ◽  
Ana Mosquera-Leal ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Binding Sites ◽  
Specific Binding ◽  
Fatty Acid Uptake ◽  
Chain Fatty Acid ◽  
Metabolic Effects ◽  
Acid Uptake ◽  
Rat Cardiomyocytes ◽  
Medium Chain ◽  
Specific Binding Sites

The current study aimed to compare the effects of the peptide hormone ghrelin and des-G, its unacylated isoform, on glucose and fatty acid uptake and to identify des-G-specific binding sites in cardiomyocytes. In the murine HL-1 adult cardiomyocyte line, ghrelin and des-G had opposing metabolic effects: des-G increased medium-chain fatty acid uptake (BODIPY fluorescence intensity), whereas neither ghrelin alone nor in combination with des-G did so. Ghrelin inhibited the increase in glucose uptake normally induced by insulin (rate of 2-[3H]deoxy-d-glucose incorporation), but des-G did not; des-G was also able to partially reverse the inhibitory effect of ghrelin. In HL-1 cells and primary cultures of neonatal rat cardiomyocytes, des-G but not ghrelin increased insulin-induced translocation of glucose transporter-4 from nuclear to cytoplasmic compartments (immunohistochemistry and quantitative confocal analysis). AKT was phosphorylated by insulin but not affected by ghrelin or des-G, whereas neither AMP-activated protein kinase nor phosphatase and tensin homolog deleted from chromosome 10 was phosphorylated by any treatments. HL-1 and primary-cultured mouse and rat cardiomyocytes each possessed two independent specific binding sites for des-G not recognized by ghrelin (radioreceptor assays). Neither ghrelin nor des-G affected viability (dimethylthiazol diphenyltetrazolium bromide assays), whereas both isoforms were equally protective against apoptosis. Therefore, in cardiomyocytes, des-G binds to specific receptors and has effects on glucose and medium-chain fatty acid uptake that are distinct from those of ghrelin. Real-time PCR indicated that expression levels of ghrelin O-acyltransferase RNA were comparable between HL-1 cells, human myocardial tissue, and human and murine stomach tissue, indicating the possibility of des-G conversion to ghrelin within our model.

Regional epinephrine kinetics in human heart failure: evidence for extra-adrenal, nonneural release

1995 ◽  
Vol 269 (1) ◽  
pp. H182-H188 ◽  
Author(s):  
D. M. Kaye ◽  
J. Lefkovits ◽  
H. Cox ◽  
G. Lambert ◽  
G. Jennings ◽  
...  
Keyword(s):  
Heart Failure ◽  
Release Rate ◽  
Mental Arithmetic ◽  
Sympathetic Neurons ◽  
Severe Heart Failure ◽  
Sympathetic Nerves ◽  
Whole Body ◽  
Plasma Epinephrine ◽  
Human Heart Failure ◽  
Arterial Plasma

A number of neurohumoral processes are activated in heart failure, including an increase in the plasma concentration of epinephrine. Radiotracer methods were applied in 42 patients with severe heart failure and 31 healthy volunteers to ascertain the rate at which epinephrine is released to plasma and to evaluate the contribution of extra-adrenal sources. The increase in arterial plasma epinephrine observed in the heart failure patients was explained principally by a 34% (P < 0.001) reduction in the whole body clearance rate of epinephrine from plasma. Regional venous sampling from the heart, lungs, and hepatomesenteric beds was performed in a subgroup of the study population, revealing a significant increase in the release rate of epinephrine to plasma from these organs in heart failure which accounted for 26% of the whole body plasma epinephrine appearance rate. To establish whether the cardiac epinephrine release was of neuronal origin, a physical (cycling) or mental (difficult mental arithmetic) stressor was applied as a sympathoexcitatory stimulus, given that a proportional release of norepinephrine and epinephrine could be expected if sympathetic nerves were the source. These interventions caused significant increases in the regional spillover of norepinephrine to plasma but not that of epinephrine. These findings suggest that nonadrenal tissues contribute significantly to the whole body epinephrine release rate in heart failure and that this may arise from a site other than sympathetic neurons.

scholarly journals Hemodialysis vascular access affects heart function and outcomes: Tips for choosing the right access for the individual patient

2020 ◽  
pp. 112972982096931
Author(s):  
Jan Malik ◽  
Carlo Lomonte ◽  
Joris Rotmans ◽  
Eva Chytilova ◽  
Ramon Roca-Tey ◽  
...  
Keyword(s):  
Heart Failure ◽  
Vascular Access ◽  
Heart Function ◽  
Clinical Status ◽  
Severe Heart Failure ◽  
Dialysis Patients ◽  
Av Fistula ◽  
Hemodialysis Vascular Access ◽  
Cardiovascular Morbidity And Mortality ◽  
The Individual

Chronic kidney disease is associated with increased cardiovascular morbidity and mortality. A well-functioning vascular access is associated with improved survival and among the available types of vascular access the arterio-venous (AV) fistula is the one associated with the best outcomes. However, AV access may affect heart function and, in some patients, could worsen the clinical status. This review article focuses on the specific cardiovascular hemodynamics of dialysis patients and how it is affected by the AV access; the effects of an excessive increase in AV access flow, leading to high-output heart failure; congestive heart failure in CKD patients and the contraindications to AV access; pulmonary hypertension. In severe heart failure, peritoneal dialysis (PD) might be the better choice for cardiac health, but if contraindicated suggestions for vascular access selection are provided based on the individual clinical presentation. Management of the AV access after kidney transplantation is also addressed, considering the cardiovascular benefit of AV access ligation compared to the advantage of having a functioning AVF as backup in case of allograft failure. In PD patients, who need to switch to hemodialysis, vascular access should be created timely. The influence of AV access in patients undergoing cardiac surgery for valvular or ischemic heart disease is also addressed. Cardiovascular implantable electronic devices are increasingly implanted in dialysis patients, but when doing so, the type and location of vascular access should be considered.

scholarly journals Myocardial fatty acid uptake during dobutamine stress is increased in dogs with chronic heart failure but not in normal dogs

2002 ◽  
Vol 39 ◽  
pp. 187
Author(s):  
Margaret P. Chandler ◽  
William C. Stanley ◽  
Bridgette A. Roth ◽  
Hideaki Morita ◽  
George Suzuki ◽  
...  
Keyword(s):  
Heart Failure ◽  
Fatty Acid ◽  
Chronic Heart Failure ◽  
Fatty Acid Uptake ◽  
Dobutamine Stress ◽  
Acid Uptake ◽  
Myocardial Fatty Acid

Abstract 10: Antifibrotic Effect of CCN5 in a Murine Model of Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Dongtak Jeong ◽  
Changwon Kho ◽  
Ahyoung Lee ◽  
Woo Jin Park ◽  
Roger Hajjar
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Western Blot ◽  
Cardiac Fibrosis ◽  
Cell Function ◽  
Heart Function ◽  
Pcr Analysis ◽  
Tgf Beta ◽  
Human Heart Failure ◽  
Ccn Family

CCN family members are matricellular proteins with diverse roles in cell function. Recently, we showed that the differential expression of CCN2 and CCN5 during cardiac remodeling suggests that these two members of the CCN family play opposing roles during the development of cardiac hypertrophy and fibrosis. Since it is reported that an underlying morphological correlate of diastolic dysfunction is cardiac fibrosis, which leads to increased stiffness of the heart, we aimed to evaluate the role of CCN5 on cardiac fibrosis and function by the gene delivery using the cardiotropic AAV9 vector. We generated pressure-overload heart failure models in mouse by TAC operation. After 8-10 weeks of TAC on mice, HF was confirmed by Echocardiography. In those HF mice, AAV9-GFP (control) and AAV9-CCN5 were addressed by IV. Two more months later, cardiac function was evaluated by echocardiography and invasive hemodynamics. Protein and RNA expression levels of CCN5, several types of collagen and conventional TGF-beta signaling related genes were evaluated by western blot and quantitative real time PCR analysis. First, we were able to achieve about 4-5 fold increase of CCN5 expression by AAV9-CCN5 injection without any change in heart function. Second, CCN5 expression level in blood was not significantly altered after AAV9-CCN5 gene transfer because it may be the result of the cardiac tropism of the vector used. The HF model by TAC surgery was confirmed with echocardiography (FS (%)). Overall average FS (%) in HF was 41.87+/− 5.27 (n=16) and in non-surgery control mice was 58.39 +/− 2.06(n=4). After AAV9 injection, cardiac function of CCN5 injected mice was sustained but AAV9-GFP injected mice showed severe cardiac dysfunction and dilation (AAV-GFP (24.29+/− 9.11) vs AAV-CCN5 (42.66 +/− 4.73)). Third, western blot analysis showed that the downstream effectors, namely TGF-beta signaling pathways were significantly down-regulated in CCN5 injected mice. In addition, fibrotic area of the heart was tremendously reduced. Finally, CCN5 expression is significantly decreased in human heart failure patients compared to those in nonfailing donors. Taken together our data would indicate that CCN5 may be a promising therapeutic target to reduce cardiac fibrosis.

Recovery of Heart Function in Children With Acute Severe Heart Failure

2008 ◽  
Vol 85 (7) ◽  
pp. 975-979 ◽  
Author(s):  
John J. OʼSullivan ◽  
Susan L. Roche ◽  
David S. Crossland ◽  
Milind P. Chaudhari ◽  
Richard C. Kirk ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Function ◽  
Severe Heart Failure

Acute haemodynamic and myocardial metabolic effects of intravenous urapidil in severe heart failure

1984 ◽  
Vol 5 (9) ◽  
pp. 745-751 ◽  
Author(s):  
R. Y. C. WANG ◽  
J. S. F. CHOW ◽  
K. H. CHAN ◽  
H. Y. M. PAN ◽  
R. P. Y. WONG
Keyword(s):  
Heart Failure ◽  
Severe Heart Failure ◽  
Metabolic Effects

Lipid inclusions in cardiac myocytes – a rare case of cardiolipotoxicity

2020 ◽  
Author(s):  
Rahul Gupta ◽  
Purva Ranchal ◽  
Sugandhi Mahajan ◽  
Rugved Pattarkine ◽  
Saikrishna Patibandla ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Myocytes ◽  
Amorphous Material ◽  
Restrictive Cardiomyopathy ◽  
Fatty Acid Uptake ◽  
Heart Tissue ◽  
Acid Uptake ◽  
Lipid Inclusions ◽  
History Of ◽  
Accumulation Of Lipids

The heart oxidizes fatty acids for its energy production. The physiological balance between fatty acid uptake and its oxidation prevents lipid accumulation in cardiac myocytes. However, accumulation of lipids due to various processes such as obesity, diabetes, heart failure, myocardial ischemia or infarction can result in damage to the heart tissue, also known as cardiolipotoxicity. We present a unique case of a 69-year-old gentleman with a history of heart failure and ventricular tachycardia. Endomyocardial biopsy to assess for restrictive cardiomyopathy/amyloid showed no evidence of amyloid, significant inflammation or fibrosis, but did show intracellular accumulation of significant amorphous material in most cardiac myocytes. We review the literature regarding the pathogenesis of cardiolipotoxicity, which has no definite cause or treatment yet identified.

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