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 Induction of Ankrd1 in Dilated Cardiomyopathy Correlates with the Heart Failure Progression

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Julius Bogomolovas ◽  
Kathrin Brohm ◽  
Jelena Čelutkienė ◽  
Giedrė Balčiūnaitė ◽  
Daiva Bironaitė ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Cardiac Remodeling ◽  
Expression Patterns ◽  
Clinical Manifestations ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Expression Levels ◽  
Potential Marker ◽  
End Stage

Progression of idiopathic dilated cardiomyopathy (IDCM) is marked with extensive left ventricular remodeling whose clinical manifestations and molecular basis are poorly understood. We aimed to evaluate the clinical potential of titin ligands in monitoring progression of cardiac remodeling associated with end-stage IDCM. Expression patterns of 8 mechanoptotic machinery-associated titin ligands (ANKRD1,ANKRD2,TRIM63,TRIM55,NBR1,MLP,FHL2, andTCAP) were quantitated in endomyocardial biopsies from 25 patients with advanced IDCM. When comparing NYHA disease stages, elevatedANKRD1expression levels marked transition from NYHA < IV to NYHA IV.ANKRD1expression levels closely correlated with systolic strain depression and short E wave deceleration time, as determined by echocardiography. On molecular level, myocardialANKRD1and serum adiponectin correlated with lowBAX/BCL-2ratios, indicative of antiapoptotic tissue propensity observed during the worsening of heart failure. ANKRD1 is a potential marker for cardiac remodeling and disease progression in IDCM.ANKRD1expression correlated with reduced cardiac contractility and compliance. The association ofANKRD1with antiapoptotic response suggests its role as myocyte survival factor during late stage heart disease, warranting further studies on ANKRD1 during end-stage heart failure.

Abstract 206: Intramyocardial Lipid Dysregulation in End Stage Heart Failure

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Kenneth C Bedi ◽  
Charles Lim ◽  
Clementina Mesaros ◽  
Moez K Aziz ◽  
Ian A Blair ◽  
...  
Keyword(s):  
Heart Failure ◽  
High Resolution Mass Spectrometry ◽  
Left Ventricular ◽  
Advanced Heart Failure ◽  
Ventricular Assist ◽  
Protein Assay ◽  
Lipid Species ◽  
Before And After ◽  
End Stage Heart Failure ◽  
End Stage

Background: Advanced heart failure (HF) is characterized by metabolic abnormalities but studies conflict about the nature of these defects. Methods: We investigated the presence or absence of toxic intramyocardial lipid species using carefully procured human myocardium from lean, non-diabetic end-stage heart failure patients. Left ventricular myocardial samples were obtained at the time of heart transplant. Cases included idiopathic dilated (n=5) and ischemic (n=2) cardiomyopathy (n=7), and brain-dead organ donors without any history of heart failure (n=12). The failing hearts were examined before and after support with a left ventricular assist device (LVAD, n=7). Frozen samples were evaluated by liquid chromatography and high-resolution mass spectrometry (LC-HRMS) to identify lipid species and further quantitate their abundance. Samples for LC-HRMS were prepared using the Folch extraction method, and the samples were normalized to protein concentration via BCA protein assay. We selected for masses with p-values less than or equal to (p= .005) and a fold change greater than or equal to 2.5 Results: Diacylglycerols (DAGs), ceramides, sphingosines, and cardiolipins (CLs) were lower in failing samples than in non failing. The figure below for L-Palmitoylcarnitine is representative of the quantitative changes in lipids observed between failing and non-failing groups. Conclusion: Excess intramycellular lipid accumulation is not present in advanced heart failure. A significant deficiency in cardiac lipid species has been identified in end stage non-diabetic heart failure. Future studies in diabetic and obese patients with advanced heart failure are warranted.

Abstract 202: Dysregulation of the Small Organic Carnitine Transporter and Carnitine in Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Kenneth C Bedi ◽  
Nathaniel W Snyder ◽  
Jeff Brandimarto ◽  
Clementina Mesaros ◽  
Ian A Blair ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mrna Expression ◽  
Target Genes ◽  
High Resolution Mass Spectrometry ◽  
Left Ventricular ◽  
Carnitine Deficiency ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Orthotopic Heart Transplantation ◽  
Carnitine Transporter ◽  
Lipid Species

Introduction: Advanced heart failure (HF) is characterized by metabolic abnormalities. We have recently shown myocardial lipid species to be significantly decreased in non-diabetic HF. The finding of deficient carnitine species has directed us to examine a key gene SLC22A5 the high-affinity carnitine transporter. Known mutations of this gene lead to primary carnitine deficiency and cardiomyopathy. Methods: Left ventricular samples procured at the time of orthotopic heart transplantation (OHT) from non-diabetic idiopathic dilated cardiomyopathy (DCM) n=16, and brain-dead organ donors without a history of diabetes or HF (NF) n=18 formed the study sample. All hearts received in situ cold cardioplegia. Lipids including carnitines were quantitated with liquid chromatography and high-resolution mass spectrometry (LC-HRMS) following the Folch extraction method. mRNA expression data of target genes including SLC22A5 from a separate study of n=117 DCM patients and n=67 NF patients p≤0.05 were analyzed. Results: Representative trends for all carnitine species assayed were shown to be significantly reduced in DCM. The figure below represents the mRNA expression between DCM and NF patients. There was a statistically significant reduction of SLC22A5 expression in the DCM population (Figure: ***p≤ 0.0001, dots 95 th percentiles). Conclusions: A statistically significant deficiency of carnitine species and a reduction in the expression of the carnitine transporter SLC22A5 was demonstrated in non-diabetic HF. Future studies will attempt to resolve the mechanisms behind these observations.

scholarly journals Orthotopic Heart Transplantation and Mechanical Circulatory Support in Cancer Survivors: Challenges and Outcomes

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Nina Ghosh ◽  
John Hilton
Keyword(s):  
Heart Failure ◽  
Heart Transplantation ◽  
Mechanical Circulatory Support ◽  
Significant Proportion ◽  
Left Ventricular ◽  
Circulatory Support ◽  
Orthotopic Heart Transplantation ◽  
Advanced Therapies ◽  
End Stage Heart Failure ◽  
End Stage

Chemotherapy-induced cardiomyopathy (CCMP) is a significant cause of morbidity and mortality. Compared to cardiomyopathy due to other causes, anthracycline-induced cardiomyopathy is associated with a worse survival. As cancer survival improves, patients with CCMP can be expected to comprise a significant proportion of patients who may require advanced therapies such as inotropic support, cardiac transplantation, or left ventricular assist device (LVAD). Distinct outcomes related to advanced therapies for end-stage heart failure in this patient population may arise due to unique demographic characteristics and comorbidities. We review recent literature regarding the characteristics of patients who have survived cancer undergoing orthotopic heart transplantation and mechanical circulatory support for end-stage heart failure. The challenges and outcomes of advanced therapies for heart failure related specifically to anthracycline-induced cardiomyopathy are emphasized.

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