Myocardial energetics in heart failure

Nickel, Alexander; Löffler, Joachim; Maack, Christoph

doi:10.1007/s00395-013-0358-9

Cited by 122 publications

(98 citation statements)

References 213 publications

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“…S3 L and M), consistent with previous observations in failing human hearts (6). Further studies are needed to investigate in detail other systems, including neurohormonal and (epi)genetic mechanisms, endoplasmic reticulum (ER) stress, necrosis/apoptosis, and autophagy, that might participate in the regulation of bioenergetic homeostasis in HF (5,6,19,25,29).…”

Section: Significancesupporting

confidence: 84%

“…Both increased and reduced mitochondrial Ca 2+ levels have been implicated in mitochondrial dysfunction and increased reactive oxygen species (ROS) production in heart failure (HF) (6,7,(9)(10)(11)(12)(13)(14)(15)(16)(17). Albeit Ca 2+ is required for activation of key enzymes (i.e., pyruvate dehydrogenase phosphatase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase) in the tricarboxylic acid (also known as Krebs) cycle (18, 19), excessive mitochondrial Ca 2+ uptake has been associated with cellular dysfunction (14,20).…”

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confidence: 99%

“…RyR2 is essential for cardiac excitation-contraction (E-C) coupling (2), whereas the role of IP3R2 in cardiomyocytes is less well understood (3). E-C coupling requires energy in the form of ATP produced primarily by oxidative phosphorylation in mitochondria (4)(5)(6)(7)(8).…”

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confidence: 99%

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Mitochondrial calcium overload is a key determinant in heart failure

Santulli

Xie

Reiken

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

454

352

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Calcium (Ca 2+ ) released from the sarcoplasmic reticulum (SR) is crucial for excitation-contraction (E-C) coupling. Mitochondria, the major source of energy, in the form of ATP, required for cardiac contractility, are closely interconnected with the SR, and Ca 2+ is essential for optimal function of these organelles. However, Ca 2+ accumulation can impair mitochondrial function, leading to reduced ATP production and increased release of reactive oxygen species (ROS). Oxidative stress contributes to heart failure (HF), but whether mitochondrial Ca 2+ plays a mechanistic role in HF remains unresolved. Here, we show for the first time, to our knowledge, that diastolic SR Ca 2+ leak causes mitochondrial Ca 2+ overload and dysfunction in a murine model of postmyocardial infarction HF. There are two forms of Ca 2+ release channels on cardiac SR: type 2 ryanodine receptors (RyR2s) and type 2 inositol 1,4,5-trisphosphate receptors (IP3R2s). Using murine models harboring RyR2 mutations that either cause or inhibit SR Ca 2+ leak, we found that leaky RyR2 channels result in mitochondrial Ca 2+ overload, dysmorphology, and malfunction. In contrast, cardiacspecific deletion of IP3R2 had no major effect on mitochondrial fitness in HF. Moreover, genetic enhancement of mitochondrial antioxidant activity improved mitochondrial function and reduced posttranslational modifications of RyR2 macromolecular complex. Our data demonstrate that leaky RyR2, but not IP3R2, channels cause mitochondrial Ca 2+ overload and dysfunction in HF.ryanodine receptor | heart failure | mitochondria | calcium | IP3 receptor T ype 2 ryanodine receptor/Ca 2+ release channel (RyR2) and type 2 inositol 1,4,5-trisphosphate receptor (IP3R2) are the major intracellular Ca 2+ release channels in the heart (1-3). RyR2 is essential for cardiac excitation-contraction (E-C) coupling (2), whereas the role of IP3R2 in cardiomyocytes is less well understood (3). E-C coupling requires energy in the form of ATP produced primarily by oxidative phosphorylation in mitochondria (4-8).Both increased and reduced mitochondrial Ca 2+ levels have been implicated in mitochondrial dysfunction and increased reactive oxygen species (ROS) production in heart failure (HF) (6,7,(9)(10)(11)(12)(13)(14)(15)(16)(17). Albeit Ca 2+ is required for activation of key enzymes (i.e., pyruvate dehydrogenase phosphatase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase) in the tricarboxylic acid (also known as Krebs) cycle (18, 19), excessive mitochondrial Ca 2+ uptake has been associated with cellular dysfunction (14,20). Furthermore, the exact source of mitochondrial Ca 2+ has not been clearly established. Given the intimate anatomical and functional association between the sarcoplasmic reticulum (SR) and mitochondria (6, 21, 22), we hypothesized that SR Ca 2+ release via RyR2 and/or IP3R2 channels in cardiomyocytes could lead to mitochondrial Ca 2+ accumulation and dysfunction contributing to oxidative overload and energy depletion. Results and DiscussionIncreased Mitochondrial Ca...

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Section: Significancesupporting

confidence: 84%

mentioning

confidence: 99%

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Mitochondrial calcium overload is a key determinant in heart failure

Santulli

Xie

Reiken

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

454

352

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“…PGC-1α is an essential regulator of mitochondrial energy metabolism and biogenesis. 18) CPT-1 is involved in fatty acid oxidation 19) and GLUT4 plays an important role in the oxidation of glucose. 20) To determine the potential mechanisms underlying the protective effects of ALLO, the mRNA expression of molecular markers (XO, PGC-1α, CPT-1, and GLUT4) was subjected to qRT-PCR analysis in the sham, AMI and ALLO groups.…”

Section: He Staining and Transmission Electron Microscopy (Tem)mentioning

confidence: 99%

“…18) CPT-1 is involved in the oxidation of fatty acids. 19) GLUT4 is an important enzyme in the oxidation of glucose. 20) We examined the protein and mRNA expression of crucial signaling molecules (XO, PGC-1α, CPT-1 and GLUT4) to determine the molecular mechanism underlying the activity of ALLO in AMIinduced CHF.…”

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confidence: 99%

Effect of Allopurinol on Myocardial Energy Metabolism in Chronic Heart Failure Rats After Myocardial Infarct

et al. 2016

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SummaryTo determine the effect of the xanthine oxidase (XO) inhibitor allopurinol on myocardial energy metabolism in a chronic heart failure rat model after myocardial infarct.An AMI model was established in 6-week-old rats via the ligation of the anterior descending coronary artery. Thirty-five rats were randomly divided into the following 3 groups: an ALLO group, an AMI group, and a Sham group. Heart failure was successfully diagnosed via echocardiography and blood tests. Xanthine oxidase (XO), malondialdehyde (MDA), PGC-1α, CPT-1, and GLUT4 were monitored in the myocardium.The TEM results demonstrated that myofilament lysis and mitochondrial swelling were alleviated in the ALLO group compared with the AMI group (without ALLO). The results also demonstrated that cardiac function was significantly improved in the ALLO group compared with the AMI group. Compared with the AMI group, the ALLO group exhibited increased respiratory-chain enzyme activity, as well as increased PGC-1α and CPT-1 mRNA and protein expression, decreased MDA content, and decreased XO and GLUT4 mRNA and protein expression.ALLO improves myocardial energy metabolism in rats with chronic heart failure, which may result from the regulation of PGC-1α in the setting of glycolipid metabolism, enhancing the production of ATP. (Int Heart J 2016; 57: 753-759) Key words: Reactive oxygen species (ROS), Mitochondria C hronic heart failure (CHF) is the terminal stage of heart disease and is the leading cause of death in affected patients. 1-4) The incidence of CHF in adults is nearly 1~2% in developed countries and is above 10% among patients older than 70 years of age.5) Synthetic treatments and assist devices have been introduced to improve myocardial remodeling, strengthen myocardial contraction, and alleviate cardiac overload. 6,7)Editorial p.661 Improving cardiomyocyte energy metabolism has attracted attention as a potential therapy for CHF. As early as 1934, Decherd, et al 8) observed that cardiomyocytes exist in a state of "energy starvation" in the setting of CHF. Recent studies have demonstrated that the activity of respiratory-chain enzymes decreases and changes in glycolipid metabolism in the setting of CHF, resulting in decreased myocardial ATP production. Additionally, the levels of reactive oxygen species (ROS) increase rapidly following myocardial infarction. An important source of reactive oxygen species ROS, 9,10) xanthine oxidase (XO), is over-expressed in CHF, 11,12) causes mitochondrial injury, and inhibits the activity of various respiratory-chain enzymes.13) Additionally, increased evidence indicates that cardiomyocyte glycolipid metabolism is disrupted in CHF. 14,15) Opie, et al 16) observed increased concentrations of high-energy phosphate among patients with CHF following the intravenous administration of ALLO, an XO inhibitor. However, the mechanisms underlying the activity of ALLO in the setting of CHF remain poorly understood. In this study, rat models of CHF introduced via the ligation of coronary arteries were constructe...

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Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma

et al. 2019

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Aims Our aim was to investigate the glucose uptake in cancer patients suffering from different entities, using 18F‐FDG positron emission tomography–computed tomography scans. We further aimed at identifying potential variables altering cardiac and skeletal muscle glucose metabolism. Methods and results In a retrospective cohort study, we analysed cardiac and skeletal muscle 18F‐FDG uptake in onco‐positron emission tomography–computed tomography scans in adult patients suffering from Hodgkin's lymphoma, non‐Hodgkin's lymphoma, and non‐lymphatic cancer including patients suffering from thyroid cancer, bronchial carcinoma, and malignant melanoma. Univariate logistic regression models were created for increased cardiac and skeletal muscle 18F‐FDG uptake using cancer entity, sex, age, previous radiation, previous chemotherapy, diabetes, obesity, serum glucose levels, renal function, and thyroid function as parameters. Multivariate models were created by selecting variables according to Akaike's information criterion in a step‐down approach. Between 2014 and 2018, a total of 337 consecutive patients suffering from Hodgkin's lymphoma (n = 52), non‐Hodgkin's lymphoma (n = 57), and non‐lymphatic cancer (n = 228) were included in the analysis. Univariate logistic regression models showed high serum glucose levels to be associated with lower absorption rates in both cardiac and skeletal muscle (odds ratio [OR] 0.38 [0.23, 0.60, 95% confidence interval—CI], P < 0.0001, and 0.52 [0.33, 0.82, 95% CI], P < 0.005, respectively). Hodgkin's lymphoma was associated with an increase in cardiac uptake (OR 2.4 [1.3, 4.5, 95% CI], P < 0.005). Decreased skeletal muscle 18F‐FDG uptake was noted in elderly and obese patients. In our multivariate analysis, Hodgkin's lymphoma patients showed higher cardiac 18F‐FDG uptake, while non‐Hodgkin's lymphoma patients did not differ significantly from non‐lymphatic cancer patients (OR 1.6 [0.7, 3.3, 95% CI], P = 0.24). High serum glucose levels and prior chemotherapy were both associated with a significantly decreased cardiac 18F‐FDG uptake (OR 0.40 [0.24, 0.65, 95% CI], P < 0.0005, and 0.50 [0.27, 0.90, 95% CI], P < 0.05, respectively). Notably, prior chemotherapy did not influence FDG uptake in skeletal muscle to the same extent. Obesity and older age were both significantly associated with decreased gluteal 18F‐FDG uptake (OR 0.49 [0.27, 0.89, 95% CI], P < 0.05, and 0.47 [0.25, 0.87, 95% CI], P < 0.05). Conclusions Our data provide evidence for metabolic alterations in patients with Hodgkin's lymphoma related to cardiac glucose uptake in humans. This effect was independent from skeletal muscle metabolism.

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Myocardial energetics in heart failure

Cited by 122 publications

References 213 publications

Mitochondrial calcium overload is a key determinant in heart failure

Mitochondrial calcium overload is a key determinant in heart failure

Effect of Allopurinol on Myocardial Energy Metabolism in Chronic Heart Failure Rats After Myocardial Infarct

Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma

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