Metabolic and Proteomic Defects in Human Hypertrophic Cardiomyopathy

Rationale: Impaired cardiac energetics in hypertrophic cardiomyopathy (HCM) is thought to result from increased ATP utilization at the sarcomere and is believed to be central to pathophysiology. However, the precise defects in cardiac metabolism and substrate availability in human HCM have not been defined. Objective: The purpose of this study is to define major disease pathways and determine the pool sizes of intermediary metabolites in human HCM. Methods and Results: We conducted paired proteomic and metabolomic analyses of septal myectomy samples from patients with HCM and compared results to non-failing control human hearts. Increased abundance of extracellular matrix and intermediate filament / Z-disc proteins, and decreased abundance of proteins involved in fatty acid oxidation and cardiac energetics was evident in HCM compared to controls. Acyl carnitines, byproducts of fatty acid oxidation, were markedly depleted in HCM samples. Conversely, the ketone body 3-hydroxybutyrate, lactate, and the 3 branched chain amino acids, were all significantly increased in HCM hearts, suggesting that they may serve as alternate fuel sources for the production of ATP. ATP, nicotinamide adenine dinucleotide (NADH), NADP and NADPH, and acetyl CoA were also severely depleted in HCM hearts. Based on measurements from human skinned muscle fibers, the magnitude of observed reduction in ATP content in the HCM hearts would be expected to decrease the rate of cross-bridge detachment, implying a direct effect of energy depletion on myofilament function that could contribute to diastolic dysfunction. Conclusions: HCM hearts display profound deficits in cardiac energetics, marked by depletion of fatty acid derivatives and compensatory increases in other metabolites that could serve as alternate fuel sources. These results lend support to the paradigm that energy depletion contributes to the pathophysiology of HCM and also have important therapeutic implications for the future design of metabolic modulators to treat HCM.

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Abstract 328: Med13 regulates cardiac metabolism

Circulation Research ◽

10.1161/res.113.suppl_1.a328 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Kedryn K Baskin ◽

Chad E Grueter ◽

Christine M Kusminski ◽

Philipp E Scherer ◽

Rhonda Bassel-Duby ◽

...

Keyword(s):

Oxygen Consumption ◽

Fatty Acid ◽

Glucose Uptake ◽

Fatty Acid Oxidation ◽

Electron Flow ◽

Krebs Cycle ◽

Cardiac Metabolism ◽

Acid Oxidation ◽

Intermediary Metabolites ◽

Consumption Rates

Background: The heart is a metabolic organ that primarily utilizes fatty acids as energy substrate. While it is well established that the heart is metabolically flexible, the transcriptional network regulating cardiac metabolism is only partially understood. We have previously demonstrated that cardiac overexpression of Med13, a component of the Mediator Complex that regulates transcription, results in a lean phenotype with enhanced basal metabolic rates. We now investigate the mechanisms contributing to metabolic changes in mice with cardiac over-expression of Med13(Med13cTg). Methods and Results: Cardiac fludeoxyglucose (18F-FDG)-PET imaging analysis revealed that Med13cTg hearts take up more glucose than wild type littermates. To determine pathways responsible for enhanced glucose uptake, ventricles from Med13cTg mice were subjected to RNA-seq and metabolomic analysis. The expression of fatty acid oxidation genes was decreased in Med13cTg hearts, accompanied by an increase in acyl CoA and a decrease in acetyl CoA. These data suggest that beta oxidation is decreased in Med13cTg hearts. Mitochondria function was therefore determined in Med13cTg hearts by performing electron-flow analyses and assessing oxygen consumption rates. Indeed, oxygen consumption rates were decreased in mitochondria isolated from Med13cTg hearts. Expression of Krebs Cycle genes and corresponding intermediary metabolites were also decreased in Med13cTg hearts, suggesting decreased flux through this pathway as well. Conclusions: Overexpression of Med13 in the heart increases glucose uptake and decreases fatty acid oxidation in the heart. We speculate that Med13 transcriptionally regulates key mediators of cardiac metabolism. The mechanisms by which this occurs are currently under investigation.

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Abstract 15649: Pharmacological Inhibition of Aldose Reductase by AT001 Prevents Abnormal Cardiac Energy Metabolism and Improves Heart Function in an Animal Model of Diabetic Cardiomyopathy

Circulation ◽

10.1161/circ.142.suppl_3.15649 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Keshav Gopal ◽

Qutuba Karwi ◽

Seyed Amirhossein Tabatabaei Dakhili ◽

Riccardo Perfetti ◽

Ravichandran Ramasamy ◽

...

Keyword(s):

Fatty Acid ◽

Energy Metabolism ◽

Fatty Acid Oxidation ◽

Diabetic Cardiomyopathy ◽

Acid Oxidation ◽

Cardiac Energetics ◽

Cardiac Efficiency ◽

Oxidation Rates ◽

Cardiac Energy Metabolism ◽

Cardiac Energy

Introduction: Diabetic Cardiomyopathy (DCM) is a major cause of death in people with type 2 diabetes (T2D). Alterations in cardiac energy metabolism including increased fatty acid oxidation rates and reduced glucose oxidation rates are key contributing factors to the development of DCM. Studies have shown that Aldose Reductase (AR), an enzyme activated under hyperglycemic conditions, can modulate myocardial glucose and fatty acid oxidation, and promotes cardiac dysfunction. Hypothesis: Pharmacological inhibition of AR using a next-generation inhibitor AT-001, can mitigate DCM in mice by modulating cardiac energy metabolism and improving cardiac efficiency. Methods: Male human AR overexpressing (hAR-Tg) and C57BL/6J (Control) mice were subjected to experimental T2D (high-fat diet [60% kcal from lard] for 10-wk with a single intraperitoneal streptozotocin injection of 75 mg/kg) and treated for the last 3-wk with AT-001 (40mg/kg/day) or vehicle via oral gavage. Cardiac energy metabolism and in vivo cardiac function were assessed via isolated working heart perfusions and ultrasound echocardiography, respectively. Results: AT-001 treatment significantly improved cardiac energetics in a murine model of DCM (hAR-Tg mice with T2D). Particularly, AT-001-treated mice exhibited decreased cardiac fatty acid oxidation rates compared to the vehicle-treated mice (342 ± 53 vs 964 ± 130 nmol/min/g dry wt.). Concurrently, there was a significant decrease in cardiac oxygen consumption in the AT-001-treated compared to the vehicle-treated mice (41 ± 12 vs 60 ± 11 μmol/min/g dry wt.), suggesting increased cardiac efficiency. Furthermore, treatment with AT-001 prevented cardiac structural and functional abnormalities present in DCM, including diastolic dysfunction as reflected by an increase in the tissue Doppler E’/A’ ratio and decrease in E/E’ ratio. Moreover, AT-001 treatment prevented cardiac hypertrophy as reflected by a decrease in LV mass in AT-001-treated mice. Conclusions: AR inhibition with AT-001 prevents cardiac structural and functional abnormalities in a mouse model of DCM, and normalizes cardiac energetics by shifting cardiac metabolism towards a non-diabetic metabolic state.

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Modulation of Cardiac Metabolism in Heart Failure

International Cardiovascular Forum Journal ◽

10.17987/icfj.v17i0.597 ◽

2019 ◽

Vol 17 ◽

Author(s):

Giuseppe Rosano ◽

Andrew Coats

Keyword(s):

Heart Failure ◽

Fatty Acid ◽

Free Fatty Acid ◽

Fatty Acid Oxidation ◽

Skeletal Muscles ◽

Cardiac Metabolism ◽

Acid Oxidation ◽

Patients With Heart Failure ◽

Free Fatty Acid Oxidation ◽

Capacity Modulation

Heart failure is associated with altered cardiac metabolism, in part, due to maladaptive mechanisms, in part secondary to comorbidities such as diabetes and ischaemic heart disease. The metabolic derangements taking place in heart failure are not limited to the cardiac myocytes, but extend to skeletal muscles and the vasculature causing changes that contribute to the worsening of exercise capacity. Modulation of cardiac metabolism with partial inhibition of free fatty acid oxidation has been shown to be beneficial in patients with heart failure. At the present, the bulk of evidence for this class of drugs comes from Trimetazidine. Newer compounds partially inhibiting free fatty acid oxidation or facilitating the electron transport on the mitochondrial cristae are in early phase of their clinical development.

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Propionate-induced changes in cardiac metabolism, notably CoA trapping, are not altered by l-carnitine

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00081.2018 ◽

2018 ◽

Vol 315 (4) ◽

pp. E622-E633 ◽

Cited By ~ 10

Author(s):

Yingxue Wang ◽

Bridgette A. Christopher ◽

Kirkland A. Wilson ◽

Deborah Muoio ◽

Robert W. McGarrah ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Metabolic Flux ◽

Tricarboxylic Acid Cycle ◽

Propionic Acidemia ◽

Cardiac Metabolism ◽

Acid Oxidation ◽

New Findings ◽

High Concentrations ◽

Induced Changes

High concentrations of propionate and its metabolites are found in several diseases that are often associated with the development of cardiac dysfunction, such as obesity, diabetes, propionic acidemia, and methylmalonic acidemia. In the present work, we employed a stable isotope-based metabolic flux approach to understand propionate-mediated perturbation of cardiac energy metabolism. Propionate led to accumulation of propionyl-CoA (increased by ~101-fold) and methylmalonyl-CoA (increased by 36-fold). This accumulation caused significant mitochondrial CoA trapping and inhibited fatty acid oxidation. The reduced energy contribution from fatty acid oxidation was associated with increased glucose oxidation. The enhanced anaplerosis of propionate and CoA trapping altered the pool sizes of tricarboxylic acid cycle (TCA) metabolites. In addition to being an anaplerotic substrate, the accumulation of proprionate-derived malate increased the recycling of malate to pyruvate and acetyl-CoA, which can enter the TCA for energy production. Supplementation of 3 mM l-carnitine did not relieve CoA trapping and did not reverse the propionate-mediated fuel switch. This is due to new findings that the heart appears to lack the specific enzyme catalyzing the conversion of short-chain (C3 and C4) dicarboxylyl-CoAs to dicarboxylylcarnitines. The discovery of this work warrants further investigation on the relevance of dicarboxylylcarnitines, especially C3 and C4 dicarboxylylcarnitines, in cardiac conditions such as heart failure.

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Hearts lacking plasma membrane KATP channels display changes in basal aerobic metabolic substrate preference and AMPK activity

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00612.2016 ◽

2017 ◽

Vol 313 (3) ◽

pp. H469-H478 ◽

Cited By ~ 2

Author(s):

Nermeen Youssef ◽

Scott Campbell ◽

Amy Barr ◽

Manoj Gandhi ◽

Beth Hunter ◽

...

Keyword(s):

Plasma Membrane ◽

Fatty Acid ◽

Protein Kinase ◽

Fatty Acid Oxidation ◽

Glucose Oxidation ◽

Metabolic Stress ◽

Cardiac Metabolism ◽

Acid Oxidation ◽

Metabolic Substrate ◽

Amp Activated Protein Kinase

Cardiac ATP-sensitive K+ (KATP) channels couple changes in cellular metabolism to membrane excitability and are activated during metabolic stress, although under basal aerobic conditions, KATP channels are thought to be predominately closed. Despite intense research into the roles of KATP channels during metabolic stress, their contribution to aerobic basal cardiac metabolism has not been previously investigated. Hearts from Kir6.2+/+ and Kir6.2−/− mice were perfused in working mode, and rates of glycolysis, fatty acid oxidation, and glucose oxidation were measured. Changes in activation/expression of proteins regulating metabolism were probed by Western blot analysis. Despite cardiac mechanical function and metabolic efficiency being similar in both groups, hearts from Kir6.2−/− mice displayed an approximately twofold increase in fatty acid oxidation and a 0.45-fold reduction in glycolytic rates but similar glucose oxidation rates compared with hearts from Kir6.2+/+ mice. Kir6.2−/− hearts also possessed elevated levels of activated AMP-activated protein kinase (AMPK), higher glycogen content, and reduced mitochondrial density. Moreover, activation of AMPK by isoproterenol or diazoxide was significantly blunted in Kir6.2−/− hearts. These data indicate that KATP channel ablation alters aerobic basal cardiac metabolism. The observed increase in fatty acid oxidation and decreased glycolysis before any metabolic insult may contribute to the poor recovery observed in Kir6.2−/− hearts in response to exercise or ischemia-reperfusion injury. Therefore, KATP channels may play an important role in the regulation of cardiac metabolism through AMPK signaling. NEW & NOTEWORTHY In this study, we show that genetic ablation of plasma membrane ATP-sensitive K+ channels results in pronounced changes in cardiac metabolic substrate preference and AMP-activated protein kinase activity. These results suggest that ATP-sensitive K+ channels may play a novel role in regulating metabolism in addition to their well-documented effects on ionic homeostasis during periods of stress.

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A Comparison between Ranolazine and CVT-4325, a Novel Inhibitor of Fatty Acid Oxidation, on Cardiac Metabolism and Left Ventricular Function in Rat Isolated Perfused Heart during Ischemia and Reperfusion

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.106.115519 ◽

2007 ◽

Vol 321 (1) ◽

pp. 213-220 ◽

Cited By ~ 49

Author(s):

Peipei Wang ◽

Heather Fraser ◽

Steven G. Lloyd ◽

Jeffrey J. McVeigh ◽

Luiz Belardinelli ◽

...

Keyword(s):

Fatty Acid ◽

Left Ventricular Function ◽

Ventricular Function ◽

Fatty Acid Oxidation ◽

Cardiac Metabolism ◽

Left Ventricular ◽

Acid Oxidation ◽

Ischemia And Reperfusion ◽

Isolated Perfused Heart ◽

Perfused Heart

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Impaired Mitochondrial Oxidative Phosphorylation and Fatty Acid Oxidation with Enhanced Mitochondrial Oxidative Stress in Spontaneously-occurring Feline Hypertrophic Cardiomyopathy

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2014.07.098 ◽

2014 ◽

Vol 20 (10) ◽

pp. S147

Author(s):

Takashi Yokota ◽

Liselotte B. Christiansen ◽

Flemming Dela

Keyword(s):

Oxidative Stress ◽

Fatty Acid ◽

Hypertrophic Cardiomyopathy ◽

Oxidative Phosphorylation ◽

Fatty Acid Oxidation ◽

Acid Oxidation ◽

Mitochondrial Oxidative Phosphorylation ◽

Mitochondrial Oxidative Stress

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Prevention by L-Carnitine of Interleukin-2-Related Cardiac Toxicity during Cancer Immunotherapy

Tumori Journal ◽

10.1177/030089169307900309 ◽

1993 ◽

Vol 79 (3) ◽

pp. 202-204 ◽

Cited By ~ 5

Author(s):

Paolo Lissoni ◽

Maria Albina Galli ◽

Gabriele Tancini ◽

Sandro Barni

Keyword(s):

Fatty Acid ◽

Cancer Immunotherapy ◽

Cancer Patients ◽

Fatty Acid Oxidation ◽

Cardiac Toxicity ◽

Interleukin 2 ◽

Cardiac Metabolism ◽

Cardiac Complications ◽

Acid Oxidation ◽

Advanced Cancer Patients

Aims and Background Cardiac toxicity has been observed during IL-2 cancer immunotherapy. Because of its trophic action on the myocardial tissue, the use of L-carnitine has been evaluated during IL-2 therapy in advanced cancer patients with clinically important cardiac diseases. Methods The study included 30 cancer patients, who were randomized to treatment with IL-2 alone or IL-2 plus L-carnitine (1000 mg/day orally). IL-2 was injected subcutaneously at a daily dose of 6 million IU for 5 days/week for 4-6 weeks. Results The percentage of cardiac complications was significantly lower in patients concomitantly treated with L-carnitine than those receiving IL-2 alone (0/15 vs 4/15; P < 0.05), whereas no difference was seen in mean creatine phosphokinase levels on study. Conclusions The results would suggest that L-carnitine may be used successfully to prevent cardiac complications during IL-2 immunotherapy in cancer patients with clinically relevant cardiac disorders. Since cardiac metabolism depends mainly on fatty acid oxidation, the stimulatory role of L-carnitine on fatty acid oxidation could explain at least in part its ability to prevent heart disturbances in response to IL-2 administration.

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