scholarly journals CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases

Circulation ◽  
2021 ◽  
Author(s):  
Nikolaus Berndt ◽  
Johannes Eckstein ◽  
Iwona Wallach ◽  
Sarah Nordmeyer ◽  
Marcus Kelm ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Energy Demand ◽  
Heart Diseases ◽  
Cardiac Metabolism ◽  
Production Reserve ◽  
Energy Status ◽  
Tissue Samples ◽  
Atp Production ◽  
Mechanic Energy

Background: Many heart diseases can develop a reduced pumping capacity of the heart muscle. A mismatch between ATP demand and ATP production of cardiomyocytes is one of the possible causes. Assessment of the relation between the myocardial ATP production (MV ATP ) and cardiac workload is important for better understanding disease development and choice of nutritional or pharmacological treatment strategies. As there is currently no method for the measurement of MV ATP in vivo , the use of physiology-based metabolic models in conjunction with protein abundance data is an attractive approach. Methods: We developed a comprehensive kinetic model of the cardiac energy metabolism (CARDIOKIN1), which recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts and in vivo studies with humans. We used the model to assess the energy status of the left ventricle (LV) of healthy subjects and patients with aortic stenosis (AS) and mitral valve insufficiency (MI). Maximal enzyme activities were individually scaled by means of protein abundances in LV tissue samples. The energy status of the LV was quantified by the ATP consumption at rest (MV ATP (rest)), at maximal workload (MV ATP (max)), and by the myocardial ATP production reserve (MAPR) representing the span between MV ATP (rest) and MV ATP (max). Results: Compared with controls, in both groups of patients, MV ATP (rest) was increased and MV ATP (max) was decreased resulting in a decreased MAPR, although all patients had preserved ejection fraction. Notably, the variance of the energetic status was high ranging from decreased to normal values. In both patient groups, the energetic status was tightly associated with mechanic energy demand. Moreover, a decrease of MV ATP (max) was associated with a decrease of the cardiac output indicating that cardiac functionality and energetic performance of the ventricle are closely coupled. Conclusions: Our analysis suggests that the ATP producing capacity of the LV of patients with valvular dysfunction is generally diminished and correlates positively with mechanic energy demand and cardiac output. However, large differences exist in the energetic state of the myocardium even in patients with similar clinical or image-based markers of hypertrophy and pump function.

Abstract MP247: Mitochondrial Complex V Is Regulated By GRK2 In The Heart

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Kimberly Ferrero ◽  
Jessica M Pfleger ◽  
Kurt Chuprun ◽  
Eric Barr ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Atp Synthase ◽  
Cardiac Injury ◽  
Atp Synthesis ◽  
Cardiac Metabolism ◽  
Neonatal Rat ◽  
Interacting Proteins ◽  
Atp Production

The GPCR kinase GRK2 is highly expressed the heart; importantly, during cardiac injury or heart failure (HF) both levels and activity of GRK2 increase. The role of GRK2 during HF is canonically studied upstream of β-adrenergic desensitization. However, GRK2 has a large interactome and noncanonical functions for this kinase are being uncovered. We have discovered that in the heart, GRK2 translocates to mitochondria ( mtGRK2 ) following injury and is associated with negative effects on cardiac metabolism. Thus, we have sought to identify the mechanism(s) by which GRK2 can regulate mitochondrial function. We hypothesize that mtGRK2 interacts with proteins which regulate bioenergetics and substrate utilization, and this never-before-described role may partially explain the altered mitochondrial phenotype seen following cardiac injury or HF. Stress-induced mitochondrial translocation of GRK2 was validated in neonatal rat ventricular myocytes, murine heart tissue and a cardiac-derived cell line. Consequently, the GRK2 interactome was mapped basally and under stress conditions in vitro, in vivo , and with tagged recombinant peptides. GRK2-interacting proteins were isolated via immunoprecipitation and analyzed via liquid chromatography-mass spectroscopy (LCMS). Proteomics analysis (IPA; Qiagen) identified mtGRK2 interacting proteins which were also involved in mitochondrial dysfunction. Excitingly, Complexes I, II, IV and V (ATP synthase) of the electron transport chain (ETC) were identified in the subset of mtGRK2-dysfunction partners. Several mtGRK2-ETC interactions were increased following stress, particularly those in Complex V. We further established that mtGRK2 phosphorylates some of the subunits of Complex V, particularly the ATP synthase barrel which is critical for ATP production in the heart. Specific amino acid residues on these subunits have been identified using PTM-LCMS and are currently being validated in a murine model of myocardial infarction. To support these data, we have also determined that alterations in either the levels or kinase activity of GRK2 appear to alter the enzymatic activity of Complex V in vitro , thus altering ATP production. In summary, the phosphorylation of the ATP synthesis machinery by mtGRK2 may be regulating some of the phenotypic effects of injured or failing hearts such as increased ROS production and reduced fatty acid metabolism. Research is ongoing in our lab to elucidate the novel role of GRK2 in regulating mitochondrial bioenergetics and cell death, thus uncovering an exciting, druggable novel target for rescuing cardiac function in patients with injured and/or failing hearts.

scholarly journals Metabolic Aspects of Anthracycline Cardiotoxicity

2021 ◽  
Vol 22 (2) ◽  
Author(s):  
Michele Russo ◽  
Angela Della Sala ◽  
Carlo Gabriele Tocchetti ◽  
Paolo Ettore Porporato ◽  
Alessandra Ghigo
Keyword(s):  
Heart Failure ◽  
Anticancer Agents ◽  
Energy Demand ◽  
Cardiac Metabolism ◽  
Current Evidence ◽  
Anthracycline Cardiotoxicity ◽  
Cardiac Side Effects ◽  
The Impact

Opinion statementHeart failure (HF) is increasingly recognized as the major complication of chemotherapy regimens. Despite the development of modern targeted therapies such as monoclonal antibodies, doxorubicin (DOXO), one of the most cardiotoxic anticancer agents, still remains the treatment of choice for several solid and hematological tumors. The insurgence of cardiotoxicity represents the major limitation to the clinical use of this potent anticancer drug. At the molecular level, cardiac side effects of DOXO have been associated to mitochondrial dysfunction, DNA damage, impairment of iron metabolism, apoptosis, and autophagy dysregulation. On these bases, the antioxidant and iron chelator molecule, dexrazoxane, currently represents the unique FDA-approved cardioprotectant for patients treated with anthracyclines.A less explored area of research concerns the impact of DOXO on cardiac metabolism. Recent metabolomic studies highlight the possibility that cardiac metabolic alterations may critically contribute to the development of DOXO cardiotoxicity. Among these, the impairment of oxidative phosphorylation and the persistent activation of glycolysis, which are commonly observed in response to DOXO treatment, may undermine the ability of cardiomyocytes to meet the energy demand, eventually leading to energetic failure. Moreover, increasing evidence links DOXO cardiotoxicity to imbalanced insulin signaling and to cardiac insulin resistance. Although anti-diabetic drugs, such as empagliflozin and metformin, have shown interesting cardioprotective effects in vitro and in vivo in different models of heart failure, their mechanism of action is unclear, and their use for the treatment of DOXO cardiotoxicity is still unexplored.This review article aims at summarizing current evidence of the metabolic derangements induced by DOXO and at providing speculations on how key players of cardiac metabolism could be pharmacologically targeted to prevent or cure DOXO cardiomyopathy.

Maximum oxidative phosphorylation capacity of the mammalian heart

1997 ◽  
Vol 272 (2) ◽  
pp. H769-H775 ◽  
Author(s):  
V. K. Mootha ◽  
A. E. Arai ◽  
R. S. Balaban
Keyword(s):  
Oxidative Phosphorylation ◽  
Oxidative Capacity ◽  
In Vivo Studies ◽  
Production Reserve ◽  
Myocardial Performance ◽  
Atp Production ◽  
Mammalian Heart ◽  
Intact Heart ◽  
Mitochondrial Respiratory

It is difficult to estimate the maximum in vivo aerobic ATP production rate of the intact heart independent of limitations imposed by blood flow, oxygen delivery, and maximum mechanical power. This value is critical for establishing the kinetic parameters that control oxidative phosphorylation, as well as for providing insights into the limits of myocardial performance. In this study, the maximum ADP-P(i)-driven heart mitochondrial respiratory rate (MV(O2 mito)) was determined with saturating levels of oxygen, substrates, and cofactors at 37 degrees C. These rates were normalized to cytochrome alpha1 alpha3 (cytochrome oxidase; Cyt a) content. To extrapolate this rate to the intact heart, the Cyt a content of the myocardium (nmol Cyt a/g wet wt myocardium) was determined in the same hearts. The maximum ADP-P(i)-driven mitochondrial respiratory rates were 676 +/- 31 and 665 +/- 65 nmol O2 x min(-1) x nmol Cyt a(-1) in the dog and pig, respectively. The Cyt a content in the two species was 43.6 +/- 2.4 and 36.6 +/- 3.1 nmol Cyt a/g wet wt, respectively. With these values, the MV(O2 mito) was calculated to be 29.5 (dog) and 24.3 (pig) micromol O2 x min(-1) x g wet wt myocardium(-1). Comparison with in vivo studies shows that the exercising heart can utilize 80-90% of its maximum oxidative capacity, implying there is little aerobic ATP production reserve in the mammalian heart.

scholarly journals Muscle energetics changes throughout maturation: a quantitative 31P-MRS analysis

2010 ◽  
Vol 109 (6) ◽  
pp. 1769-1778 ◽  
Author(s):  
Anne Tonson ◽  
Sébastien Ratel ◽  
Yann Le Fur ◽  
Christophe Vilmen ◽  
Patrick J. Cozzone ◽  
...  
Keyword(s):  
Energy Demand ◽  
Recovery Period ◽  
Exercise Bout ◽  
Oxidative Capacity ◽  
Recovery Phase ◽  
Resonance Spectroscopy ◽  
Compensatory Mechanism ◽  
Muscle Energetics ◽  
Atp Production

We quantified energy production in 7 prepubescent boys (11.7 ± 0.6 yr) and 10 men (35.6 ± 7.8 yr) using 31P-magnetic resonance spectroscopy to investigate whether development affects muscle energetics, given that resistance to fatigue has been reported to be larger before puberty. Each subject performed a finger flexions exercise at 0.7 Hz against a weight adjusted to 15% of their maximal voluntary strength for 3 min, followed by a 15-min recovery period. The total energy cost was similar in both groups throughout the exercise bout, whereas the interplay of the different metabolic pathways was different. At the onset of exercise, children exhibited a higher oxidative contribution (50 ± 15% in boys and 25 ± 8% in men, P < 0.05) to ATP production, whereas the phosphocreatine breakdown contribution was reduced (40 ± 10% in boys and 53 ± 12% in men, P < 0.05), likely as a compensatory mechanism. The anaerobic glycolysis activity was unaffected by maturation. The recovery phase also disclosed differences regarding the rates of proton efflux (6.2 ± 2.5 vs. 3.8 ± 1.9 mM·pH unit−1·min−1, in boys and men, respectively, P < 0.05), and phosphocreatine recovery, which was significantly faster in boys than in men (rate constant of phosphocreatine recovery: 1.3 ± 0.5 vs. 0.7 ± 0.4 min−1; Vmax: 37.5 ± 14.5 vs. 21.1 ± 12.2 mM/min, in boys and men, respectively, P < 0.05). Our results obtained in vivo clearly showed that maturation affects muscle energetics. Children relied more on oxidative metabolism and less on creatine kinase reaction to meet energy demand during exercise. This phenomenon can be explained by a greater oxidative capacity, probably linked to a higher relative content in slow-twitch fibers before puberty.

scholarly journals Argininosuccinate synthetase regulates hepatic AMPK linking protein catabolism and ureagenesis to hepatic lipid metabolism

2016 ◽  
Vol 113 (24) ◽  
pp. E3423-E3430 ◽  
Author(s):  
Anila K. Madiraju ◽  
Tiago Alves ◽  
Xiaojian Zhao ◽  
Gary W. Cline ◽  
Dongyan Zhang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Energy Demand ◽  
High Energy ◽  
Argininosuccinate Synthetase ◽  
Protein Catabolism ◽  
Energy Status ◽  
Hepatic Lipid Metabolism ◽  
Metabolic Switch ◽  
Hepatic Lipid

A key sensor of cellular energy status, AMP-activated protein kinase (AMPK), interacts allosterically with AMP to maintain an active state. When active, AMPK triggers a metabolic switch, decreasing the activity of anabolic pathways and enhancing catabolic processes such as lipid oxidation to restore the energy balance. Unlike oxidative tissues, in which AMP is generated from adenylate kinase during states of high energy demand, the ornithine cycle enzyme argininosuccinate synthetase (ASS) is a principle site of AMP generation in the liver. Here we show that ASS regulates hepatic AMPK, revealing a central role for ureagenesis flux in the regulation of metabolism via AMPK. Treatment of primary rat hepatocytes with amino acids increased gluconeogenesis and ureagenesis and, despite nutrient excess, induced both AMPK and acetyl-CoA carboxylase (ACC) phosphorylation. Antisense oligonucleotide knockdown of hepaticASS1expression in vivo decreased liver AMPK activation, phosphorylation of ACC, and plasma β-hydroxybutyrate concentrations. Taken together these studies demonstrate that increased amino acid flux can activate AMPK through increased AMP generated by ASS, thus providing a novel link between protein catabolism, ureagenesis, and hepatic lipid metabolism.

scholarly journals Lactate and Myocadiac Energy Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuohui Dong ◽  
Linhui Qian ◽  
Zhiqiang Cheng ◽  
Chang Chen ◽  
Kexin Wang ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cardiac Disease ◽  
Heart Diseases ◽  
Physiological State ◽  
Cardiac Metabolism ◽  
Metabolic Flexibility ◽  
New Paradigm ◽  
Atp Production ◽  
Pathological Conditions ◽  
The Face

The myocardium is capable of utilizing different energy substrates, which is referred to as “metabolic flexibility.” This process assures ATP production from fatty acids, glucose, lactate, amino acids, and ketones, in the face of varying metabolic contexts. In the normal physiological state, the oxidation of fatty acids contributes to approximately 60% of energy required, and the oxidation of other substrates provides the rest. The accumulation of lactate in ischemic and hypoxic tissues has traditionally be considered as a by-product, and of little utility. However, recent evidence suggests that lactate may represent an important fuel for the myocardium during exercise or myocadiac stress. This new paradigm drives increasing interest in understanding its role in cardiac metabolism under both physiological and pathological conditions. In recent years, blood lactate has been regarded as a signal of stress in cardiac disease, linking to prognosis in patients with myocardial ischemia or heart failure. In this review, we discuss the importance of lactate as an energy source and its relevance to the progression and management of heart diseases.

Biomedical applications: Pitfalls in the practice

1994 ◽  
Vol 52 ◽  
pp. 378-379
Author(s):  
J. D. Shelburne ◽  
Peter Ingram ◽  
Victor L. Roggli ◽  
Ann LeFurgey
Keyword(s):  
Operating Room ◽  
Liquid Nitrogen ◽  
Lung Tissue ◽  
Biomedical Applications ◽  
Microprobe Analysis ◽  
Tissue Sample ◽  
Cellular Level ◽  
Tissue Samples ◽  
Asbestos Fibers

At present most medical microprobe analysis is conducted on insoluble particulates such as asbestos fibers in lung tissue. Cryotechniques are not necessary for this type of specimen. Insoluble particulates can be processed conventionally. Nevertheless, it is important to emphasize that conventional processing is unacceptable for specimens in which electrolyte distributions in tissues are sought. It is necessary to flash-freeze in order to preserve the integrity of electrolyte distributions at the subcellular and cellular level. Ideally, biopsies should be flash-frozen in the operating room rather than being frozen several minutes later in a histology laboratory. Electrolytes will move during such a long delay. While flammable cryogens such as propane obviously cannot be used in an operating room, liquid nitrogen-cooled slam-freezing devices or guns may be permitted, and are the best way to achieve an artifact-free, accurate tissue sample which truly reflects the in vivo state. Unfortunately, the importance of cryofixation is often not understood. Investigators bring tissue samples fixed in glutaraldehyde to a microprobe laboratory with a request for microprobe analysis for electrolytes.

Potential Uses of Vinegar as a Medicine and Related in vivo Mechanisms

2016 ◽  
Vol 86 (3-4) ◽  
pp. 127-151 ◽  
Author(s):  
Zeshan Ali ◽  
Zhenbin Wang ◽  
Rai Muhammad Amir ◽  
Shoaib Younas ◽  
Asif Wali ◽  
...  
Keyword(s):  
Chemical Structure ◽  
Review Paper ◽  
Heart Diseases ◽  
Folk Medicine ◽  
Active Role ◽  
Current Review ◽  
Different Types ◽  
Positive Effect

While the use of vinegar to fi ght against infections and other crucial conditions dates back to Hippocrates, recent research has found that vinegar consumption has a positive effect on biomarkers for diabetes, cancer, and heart diseases. Different types of vinegar have been used in the world during different time periods. Vinegar is produced by a fermentation process. Foods with a high content of carbohydrates are a good source of vinegar. Review of the results of different studies performed on vinegar components reveals that the daily use of these components has a healthy impact on the physiological and chemical structure of the human body. During the era of Hippocrates, people used vinegar as a medicine to treat wounds, which means that vinegar is one of the ancient foods used as folk medicine. The purpose of the current review paper is to provide a detailed summary of the outcome of previous studies emphasizing the role of vinegar in treatment of different diseases both in acute and chronic conditions, its in vivo mechanism and the active role of different bacteria.

Scintigraphic Detection of Experimental Myocardial Infarction with 99mTc-2,3-Dimercaptosuccinic Acid

1984 ◽  
Vol 23 (06) ◽  
pp. 317-319
Author(s):  
J. Novák ◽  
Y. Mazurová ◽  
J. Kubíček ◽  
J. Yižd’a ◽  
P. Kafka ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Intravenous Administration ◽  
Experimental Myocardial Infarction ◽  
Myocardial Infarctions ◽  
Clinical Use ◽  
Scintigraphic Imaging ◽  
Tissue Samples ◽  
Scintigraphic Finding

SummaryAcute myocardial infarctions were produced by ligature of the left frontal descending coronary artery in 9 dogs. The possibility of scintigraphic imaging with 99mTc-DMSA 4 hrs after intravenous administration was studied. The infarctions were 4, 24 and 48 hrs old. The in vivo scan was positive in only one dog with a 4-hr old infarction. The in vivo scans were confirmed by the analysis of the radioactivity in tissue samples. The accumulation of the radiopharmaceutical increased slightly in 48-hr old lesions; however, this increase was not sufficient for a positive scintigraphic finding. Thus, we do not recommend 99mTc-DMSA for clinical use in acute lesions.

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