Abstract 390: End-stage Human Heart Failure is Characterized by a Deficit in Energetic Lipids in Both Diabetic and Non-diabetic Patients

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Kenneth C Bedi ◽  
Nathaniel W Snyder ◽  
Ali Javaheri ◽  
Jeffery Brandimarto ◽  
Clementina Mesaaros ◽  
...  
Keyword(s):  
Heart Failure ◽  
Human Heart ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Orthotopic Heart Transplantation ◽  
P Value ◽  
Diabetic Patients ◽  
Human Heart Failure ◽  
Lipid Species ◽  
End Stage

Introduction: Animal models and human studies have identified increased intramyocardial lipid accumulation and a lipotoxicity hypothesis has been emerging as a mechanism of myocardial dysfunction in diabetes. We have identified a significant decrease in energetic lipids in chronic advanced non-diabetic heart failure. We hypothesized that intramyocardial lipid species would be increased in diabetic as compared to non-diabetic end-stage heart failure patients. Methods: Left ventricular samples procured at the time of orthotopic heart transplantation from non-diabetic (IDCM n=8) and diabetic (DCMDM n=8) patients as well as organ donors with (NFDM) and without a history of diabetes (Donor) were quantitated for lipids with high-resolution mass spectrometry . Stable isotope labeled essential nutrient in cell culture internal standards for acyl-CoAs were generated using [ 13 C 3 15 N 1 ]-pantotheonate in Hepa1c1c7 cells. Results: The lipidomic signature of end-stage failing myocardium marked by a significant decrease in energetic lipids, a decreased myocardial Succinyl CoA (p-value 0.0079 for failing versus non-failing diabetic subjects) and a decreased ratio of [Succinyl CoA]/[Acetyl Coa] consistent with deficient TCA cycling, is indistinguishable in diabetic and non-diabetic patients (Figure 1). Discussion: Despite the known bioenergetic deficits in insulin-resistant diabetes, we have not identified any significant differences between diabetic and non-diabetic subjects in the lipidomic signature of end-stae failing myocardium. Future studies are needed with focused metabolomics to elucidate differences in the diabetic phenotype of human heart failure.

Abstract 20178: Short Chain Acyl-CoA Intermediates in the Failing Heart: Further Evidence of an Energy Starved State

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Nathaniel Snyder ◽  
Kenneth C Bedi ◽  
Ali Javaheri ◽  
Clementina Mesaros ◽  
Ken Margulies ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricular ◽  
Short Chain ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Orthotopic Heart Transplantation ◽  
Potential Marker ◽  
Lipid Species ◽  
Chain Acyl ◽  
End Stage Heart Failure ◽  
End Stage

Introduction: Several studies have implicated energetic deficits in chronic heart failure. Recently, our group has described a state of myocardial substrate deficiency across a broad spectrum of lipid species in non-diabetic end-stage heart failure. We hypothesized that lipid substrate depletion in end-stage heart failure would be associated with dysregulation of short chain acyl-CoA intermediates implicated in important metabolic pathways. Methods: Left ventricular samples were obtained at the time of orthotopic heart transplantation for failing cases with idiopathic dilated cardiomyopathy (DCM) n=16, and brain-dead organ donors without a history of heart failure (NF) n=18. Samples were snap frozen at -80°C for further analysis with liquid chromatography in tandem mass spec LC MS/MS. Stable isotope labeled essential nutrient in cell culture (SILEC) internal standards for acyl-CoAs were generated using 13 C 3 15 N 1 pantotheonate in Hepa1c1c7 cells. Results: In the myocardium of failing as compared to NF, we identified a significant decrease in Succinyl-CoA (Avg 10.5 versus 17.7 pmol/mg, p = 0.004 ), Propionyl-CoA (0.9 versus 1.8 pmol/mg, p=0.004) and a concomitant increase in β-hydroxybutyryl -CoA (BHB-CoA Avg 0.57 versus 0.29 pmol/mg, p =0.008 ). The ratio of myocardial Succinyl-CoA to Acetyl-CoA, a potential marker of tricarboxylic acid cycling, is significantly decreased in end-stage heart failure ( 0.84 versus 1.93, p= 0.005 ). The figure depicts the levels of myocardial acyl-CoA species in the non-diabetic cohort. Conclusion: We have identified important differences in myocardial acyl CoA species—an increase in the ketogenic BHB-CoA and decreased Succinyl-CoA and Propionyl-CoA in end-stage human heart failure. These data, along with the recently identified state of myocardial lipodeficiency, are strongly supporting the concept of a bio-energetic deficit in end-stage heart failure.

scholarly journals ISCHEMIC VERSUS NON-ISCHEMIC RIGHT VENTRICULAR TRANSCRIPTOME IN END-STAGE HUMAN HEART FAILURE

2014 ◽  
Vol 63 (12) ◽  
pp. A921
Author(s):  
Thomas Gerard Di Salvo ◽  
Cristi Galindo ◽  
Yan Guo ◽  
Yan Ru Su ◽  
Tarek bsi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Right Ventricular ◽  
Human Heart ◽  
Human Heart Failure ◽  
End Stage

Abstract 100: Integrated Cardiac Metabolism In End-Stage Human Heart Failure

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Emily Flam ◽  
Cholsoon Jang ◽  
Ken Bedi ◽  
Danielle Murashige ◽  
Yifan Yang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Human Heart ◽  
Glycogen Synthesis ◽  
Cardiac Metabolism ◽  
Pentose Phosphate ◽  
Metabolic Changes ◽  
Phospholipid Content ◽  
Human Heart Failure ◽  
Nucleotide Synthesis ◽  
End Stage

Heart failure affects millions of people worldwide with mortality near 50% within five years. This disease is characterized by widespread cardiac and systemic metabolic changes, but a comprehensive evaluation of metabolism in failing human hearts is lacking. Here, we provide a comprehensive depiction of cardiac and systemic metabolic changes in 89 explanted failing and non-failing human hearts through integration of plasma and cardiac tissue metabolomics, genome-wide RNAseq, and proteomic data. The data confirm a profound bioenergetic defect in end-stage human heart failure and demonstrate extensive changes in metabolic homeostasis. The data indicate a substantial defect in fatty acid (FA) use in failing hearts, in particular unsaturated FAs. Reduction of FAs and acyl-carnitines in failing tissue in contrast to concomitant elevations in plasma suggest a defect in import of FAs into the cell, rather than a defect in FA oxidation. Intermediates of glycolysis, the pentose phosphate pathway, and glycogen synthesis are all similarly reduced, as is expression of GLUT1, indicating diminished glucose uptake. However, there was no significant change in tissue pyruvate content, suggesting an increase in lactate utilization. The data suggest increased flux of pyruvate into mitochondria, likely promoting pyruvate oxidation but not pyruvate carboxylation. Blunted anabolic pyruvate flux, in turn, likely leads to insufficient TCA cycle intermediates. Ketone levels were increased in both failing tissue and plasma, as previously reported. The phospholipid content of failing human hearts is greatly increased in both failing tissue and plasma. Nucleotide synthesis pathways also appear to be reprogrammed, with a notable decrease in adenosine metabolism, specifically. Together, these data indicate widespread change in the local cardiac and greater systemic metabolic landscape in severe human heart failure.

scholarly journals Intracellular Dyssynchrony of Diastolic Cytosolic [Ca 2+ ] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure

2013 ◽  
Vol 113 (5) ◽  
pp. 527-538 ◽  
Author(s):  
Felix Hohendanner ◽  
Senka Ljubojević ◽  
Niall MacQuaide ◽  
Michael Sacherer ◽  
Simon Sedej ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Human Heart ◽  
Cyclopiazonic Acid ◽  
Cardiomyocyte Hypertrophy ◽  
Human Heart Failure ◽  
Mitochondrial Density ◽  
Human Cardiomyocytes ◽  
End Stage ◽  
The Impact

Rationale : Synchronized release of Ca 2+ into the cytosol during each cardiac cycle determines cardiomyocyte contraction. Objective: We investigated synchrony of cytosolic [Ca 2+ ] decay during diastole and the impact of cardiac remodeling. Methods and Results: Local cytosolic [Ca 2+ ] transients (1-µm intervals) were recorded in murine, porcine, and human ventricular single cardiomyocytes. We identified intracellular regions of slow (slowCaR) and fast (fastCaR) [Ca 2+ ] decay based on the local time constants of decay (TAU local ). The SD of TAU local as a measure of dyssynchrony was not related to the amplitude or the timing of local Ca 2+ release. Stimulation of sarcoplasmic reticulum Ca 2+ ATPase with forskolin or istaroxime accelerated and its inhibition with cyclopiazonic acid slowed TAU local significantly more in slowCaR, thus altering the relationship between SD of TAU local and global [Ca 2+ ] decay (TAU global ). Na + /Ca 2+ exchanger inhibitor SEA0400 prolonged TAU local similarly in slowCaR and fastCaR. FastCaR were associated with increased mitochondrial density and were more sensitive to the mitochondrial Ca 2+ uniporter blocker Ru360. Variation in TAU local was higher in pig and human cardiomyocytes and higher with increased stimulation frequency (2 Hz). TAU local correlated with local sarcomere relengthening. In mice with myocardial hypertrophy after transverse aortic constriction, in pigs with chronic myocardial ischemia, and in end-stage human heart failure, variation in TAU local was increased and related to cardiomyocyte hypertrophy and increased mitochondrial density. Conclusions: In cardiomyocytes, cytosolic [Ca 2+ ] decay is regulated locally and related to local sarcomere relengthening. Dyssynchronous intracellular [Ca 2+ ] decay in cardiac remodeling and end-stage heart failure suggests a novel mechanism of cellular contractile dysfunction.

scholarly journals Dynamic Regulation of Phosphoinositide 3-Kinase-γ Activity and β-Adrenergic Receptor Trafficking in End-Stage Human Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (22) ◽  
pp. 2571-2579 ◽  
Author(s):  
Cinzia Perrino ◽  
Jacob N. Schroder ◽  
Brian Lima ◽  
Nestor Villamizar ◽  
Jeffrey J. Nienaber ◽  
...  
Keyword(s):  
Heart Failure ◽  
Adrenergic Receptor ◽  
Human Heart ◽  
Receptor Trafficking ◽  
Human Heart Failure ◽  
Dynamic Regulation ◽  
Phosphoinositide 3 Kinase ◽  
End Stage

scholarly journals TRP Channels Expression Profile in Human End-Stage Heart Failure

Medicina ◽  
2019 ◽  
Vol 55 (7) ◽  
pp. 380 ◽  
Author(s):  
Martin Dragún ◽  
Andrea Gažová ◽  
Ján Kyselovič ◽  
Michal Hulman ◽  
Marek Máťuš
Keyword(s):  
Heart Failure ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Left Ventricular ◽  
Mrna Levels ◽  
Human Heart Failure ◽  
Systematic Analysis ◽  
Tissue Samples ◽  
End Stage Heart Failure ◽  
End Stage

Objectives: Many studies indicate the involvement of transient receptor potential (TRP) channels in the development of heart hypertrophy. However, the data is often conflicted and has originated in animal models. Here, we provide systematic analysis of TRP channels expression in human failing myocardium. Methods and results: Left-ventricular tissue samples were isolated from explanted hearts of NYHA III-IV patients undergoing heart transplants (n = 43). Quantitative real-time PCR was performed to assess the mRNA levels of TRPC, TRPM and TRPV channels. Analysis of functional, clinical and biochemical data was used to confirm an end-stage heart failure diagnosis. Compared to myocardium samples from healthy donor hearts (n = 5), we detected a distinct increase in the expression of TRPC1, TRPC5, TRPM4 and TRPM7, and decreased expression of TRPC4 and TRPV2. These changes were not dependent on gender, clinical or biochemical parameters, nor functional parameters of the heart. We detected, however, a significant correlation of TRPC1 and MEF2c expression. Conclusions: The end-stage heart failure displays distinct expressional changes of TRP channels. Our findings provide a systematic description of TRP channel expression in human heart failure. The results highlight the complex interplay between TRP channels and the need for deeper analysis of early stages of hypertrophy and heart failure development.

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