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Barth Syndrome: Connecting Cardiolipin to Cardiomyopathy.
Ikon, N, Ryan, RO
Lipids. 2017;(2):99-108
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Abstract
The Barth syndrome (BTHS) is caused by an inborn error of metabolism that manifests characteristic phenotypic features including altered mitochondrial membrane phospholipids, lactic acidosis, organic acid-uria, skeletal muscle weakness and cardiomyopathy. The underlying cause of BTHS has been definitively traced to mutations in the tafazzin (TAZ) gene locus on chromosome X. TAZ encodes a phospholipid transacylase that promotes cardiolipin acyl chain remodeling. Absence of tafazzin activity results in cardiolipin molecular species heterogeneity, increased levels of monolysocardiolipin and lower cardiolipin abundance. In skeletal muscle and cardiac tissue mitochondria these alterations in cardiolipin perturb the inner membrane, compromising electron transport chain function and aerobic respiration. Decreased electron flow from fuel metabolism via NADH ubiquinone oxidoreductase activity leads to a buildup of NADH in the matrix space and product inhibition of key TCA cycle enzymes. As TCA cycle activity slows pyruvate generated by glycolysis is diverted to lactic acid. In turn, Cori cycle activity increases to supply muscle with glucose for continued ATP production. Acetyl CoA that is unable to enter the TCA cycle is diverted to organic acid waste products that are excreted in urine. Overall, reduced ATP production efficiency in BTHS is exacerbated under conditions of increased energy demand. Prolonged deficiency in ATP production capacity underlies cell and tissue pathology that ultimately is manifest as dilated cardiomyopathy.
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Common variants associated with changes in levels of circulating free fatty acids after administration of glucose-insulin-potassium (GIK) therapy in the IMMEDIATE trial.
Ellis, KL, Zhou, Y, Rodriguez-Murillo, L, Beshansky, JR, Ainehsazan, E, Selker, HP, Huggins, GS, Cupples, LA, Peter, I
The pharmacogenomics journal. 2017;(1):76-83
Abstract
Glucose-insulin-potassium (GIK) therapy may promote a shift from oxygen-wasteful free fatty acid (FFA) metabolism to glycolysis, potentially reducing myocardial damage during ischemia. Genetic variation associated with FFA response to GIK was investigated in an IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) sub-study (n=117). In patients with confirmed acute coronary syndromes, associations between 132 634 variants and 12-h circulating FFA response were assessed. Between initial and 6-h measurements, three LINGO2 variants were associated with increased levels of total FFA (P-value for 2 degree of freedom test, P2df ⩽5.51 × 10-7). Lead LINGO2 single-nucleotide polymorphism, rs12003487, was nominally associated with reduced 30-day ejection fraction (P2df=0.03). Several LINGO2 signals were linked to alterations in epigenetic profile and gene expression levels. Between 6 and 12 h, rs7017336 nearest to IMPA1/FABP12 showed an association with decreased saturated FFAs (P2df=5.47 × 10-7). Nearest to DUSP26, rs7464104 was associated with a decrease in unsaturated FFAs (P2df=5.51 × 10-7). Genetic variation may modify FFA response to GIK, potentially conferring less beneficial outcomes.
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Low myocardial glucose uptake in Turner syndrome is unaffected by growth hormone: a randomized, placebo-controlled FDG-PET study.
Trolle, C, Hjerrild, B, Mortensen, KH, Knorr, S, Søndergaard, HM, Christiansen, JS, Gravholt, CH
Clinical endocrinology. 2015;(1):133-40
Abstract
BACKGROUND An unfavourable cardiovascular and metabolic phenotype causes threefold excess mortality in Turner syndrome (TS), and perturbed cardiac substrate metabolism is increasingly recognized as a common component of cardiovascular and metabolic diseases. We therefore hypothesized that myocardial glucose uptake (MGU) is reduced in TS and that growth hormone (GH) treatment improves MGU. To this end, this controlled trial elucidates MGU in TS and the impact of 6 months of growth hormone treatment on MGU. METHODS AND RESULTS Women with TS (n = 9) were examined at baseline, sequentially treated with either Norditropin(®) SimpleXx or placebo and re-examined after 6 months. MGU and myocardial blood flow (MBF) were measured using 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) during a hyperinsulinaemic euglycaemic clamp (at baseline and 6 months). Blood pressure measurement, blood sampling, echocardiography and dual energy X-ray absorptiometry scan were also performed. Age-matched female controls (n = 9) were examined once. Baseline MGU was reduced in TS (0.24 ± 0.08 vs. 0.36 ± 0.13 μmol/g/min in controls; P = 0.036) despite similar insulin sensitivity (whole body glucose uptake (M-value): 9.69 ± 1.86 vs. 9.86 ± 2.58 mg/(min*kg) in controls; P = 0.9). Six months of GH carried no impact on MGU (0.25 ± 0.08 vs. 0.26 ± 0.12 μmol/g/min in the placebo group; P = 0.8). Plasma glucose, low-density cholesterol and triglycerides increased, while M-value and exercise capacity decreased during 6 months of GH treatment. CONCLUSION MGU is reduced in TS despite normal insulin sensitivity. GH treatment does not alter MGU despite decreased whole body insulin sensitivity. A perturbed cardiac glucose uptake appears to be a feature of TS.
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NRIP1/RIP140 siRNA-mediated attenuation counteracts mitochondrial dysfunction in Down syndrome.
Izzo, A, Manco, R, Bonfiglio, F, Calì, G, De Cristofaro, T, Patergnani, S, Cicatiello, R, Scrima, R, Zannini, M, Pinton, P, et al
Human molecular genetics. 2014;(16):4406-19
Abstract
Mitochondrial dysfunction, which is consistently observed in Down syndrome (DS) cells and tissues, might contribute to the severity of the DS phenotype. Our recent studies on DS fetal hearts and fibroblasts have suggested that one of the possible causes of mitochondrial dysfunction is the downregulation of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α or PPARGC1A)--a key modulator of mitochondrial function--and of several nuclear-encoded mitochondrial genes (NEMGs). Re-analysis of publicly available expression data related to manipulation of chromosome 21 (Hsa21) genes suggested the nuclear receptor interacting protein 1 (NRIP1 or RIP140) as a good candidate Hsa21 gene for NEMG downregulation. Indeed, NRIP1 is known to affect oxidative metabolism and mitochondrial biogenesis by negatively controlling mitochondrial pathways regulated by PGC-1α. To establish whether NRIP1 overexpression in DS downregulates both PGC-1α and NEMGs, thereby causing mitochondrial dysfunction, we used siRNAs to decrease NRIP1 expression in trisomic human fetal fibroblasts. Levels of PGC-1α and NEMGs were increased and mitochondrial function was restored, as shown by reactive oxygen species decrease, adenosine 5'-triphosphate (ATP) production and mitochondrial activity increase. These findings indicate that the Hsa21 gene NRIP1 contributes to the mitochondrial dysfunction observed in DS. Furthermore, they suggest that the NRIP1-PGC-1α axe might represent a potential therapeutic target for restoring altered mitochondrial function in DS.
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Study design for the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care (IMMEDIATE) Trial: A double-blind randomized controlled trial of intravenous glucose, insulin, and potassium for acute coronary syndromes in emergency medical services.
Selker, HP, Beshansky, JR, Griffith, JL, D'Agostino, RB, Massaro, JM, Udelson, JE, Rashba, EJ, Ruthazer, R, Sheehan, PR, Desvigne-Nickens, P, et al
American heart journal. 2012;(3):315-22
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Abstract
BACKGROUND Experimental studies suggest that metabolic myocardial support by intravenous (IV) glucose, insulin, and potassium (GIK) reduces ischemia-induced arrhythmias, cardiac arrest, mortality, progression from unstable angina pectoris to acute myocardial infarction (AMI), and myocardial infarction size. However, trials of hospital administration of IV GIK to patients with ST-elevation myocardial infarction (STEMI) have generally not shown favorable effects possibly because of the GIK intervention taking place many hours after ischemic symptom onset. A trial of GIK used in the very first hours of ischemia has been needed, consistent with the timing of benefit seen in experimental studies. OBJECTIVE The IMMEDIATE Trial tested whether, if given very early, GIK could have the impact seen in experimental studies. Accordingly, distinct from prior trials, IMMEDIATE tested the impact of GIK (1) in patients with acute coronary syndromes (ACS), rather than only AMI or STEMI, and (2) administered in prehospital emergency medical service settings, rather than later, in hospitals, after emergency department evaluation. DESIGN The IMMEDIATE Trial was an emergency medical service-based randomized placebo-controlled clinical effectiveness trial conducted in 13 cities across the United States that enrolled 911 participants. Eligible were patients 30 years or older for whom a paramedic performed a 12-lead electrocardiogram to evaluate chest pain or other symptoms suggestive of ACS for whom electrocardiograph-based acute cardiac ischemia time-insensitive predictive instrument indicated a ≥75% probability of ACS, and/or the thrombolytic predictive instrument indicated the presence of a STEMI, or if local criteria for STEMI notification of receiving hospitals were met. Prehospital IV GIK or placebo was started immediately. Prespecified were the primary end point of progression of ACS to infarction and, as major secondary end points, the composite of cardiac arrest or in-hospital mortality, 30-day mortality, and the composite of cardiac arrest, 30-day mortality, or hospitalization for heart failure. Analyses were planned on an intent-to-treat basis, on a modified intent-to-treat group who were confirmed in emergency departments to have ACS, and for participants presenting with STEMI. CONCLUSION The IMMEDIATE Trial tested whether GIK, when administered as early as possible in the course of ACS by paramedics using acute cardiac ischemia time-insensitive predictive instrument and thrombolytic predictive instrument decision support, would reduce progression to AMI, mortality, cardiac arrest, and heart failure. It also tested whether it would provide clinical and pathophysiologic information on GIK's biological mechanisms.
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Metabolic remodelling of the failing heart: the cardiac burn-out syndrome?
van Bilsen, M, Smeets, PJ, Gilde, AJ, van der Vusse, GJ
Cardiovascular research. 2004;(2):218-26
Abstract
It has been postulated that the failing heart suffers from chronic energy starvation, and that derangements in cardiac energy conversion are accessory to the progressive nature of this disease. The molecular mechanisms driving this 'metabolic remodelling' process and their significance for the development of cardiac failure are still open to discussion. Next to changes in mitochondrial function, the hypertrophied heart is characterized by a marked shift in substrate preference away from fatty acids towards glucose. It has been argued that the decline in fatty acid oxidation is not fully compensated for by a rise in glucose oxidation, thereby imposing an additional burden on overall ATP generating capacity. Several lines of evidence suggest that these metabolic adaptations are brought about, at least in part, by alterations in the rate of transcription of genes encoding for proteins involved in substrate transport and metabolism. Here, the principal metabolic changes are reviewed and the various molecular mechanisms that are likely to play a role are discussed. In addition, the potential significance of these changes for the aetiology of heart failure is evaluated.
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Imaging of cardiac metabolism using radiolabelled glucose, fatty acids and acetate.
Visser, FC
Coronary artery disease. 2001;:S12-8
Abstract
The heart metabolizes a wide variety of substrates such as free fatty acids, glucose, lactate, pyruvate, ketone bodies and amino acids, but under normal conditions, free fatty acids and glucose are the major sources of energy. In contrast, in ischaemia with less than normal delivery of oxygen, oxidative metabolism of free fatty acids is decreased and exogenous glucose becomes the preferred substrate and the production of energy mainly depends on anaerobic glycolysis. These metabolic changes under various pathophysiological conditions of the myocardium stress the importance of metabolism for the function of the heart and allow metabolic imaging of important cardiovascular diseases. For the detection of cardiac energy metabolism, three different tracers have been developed and validated; namely radiolabelled glucose, fatty acids and acetate. [18F]-fluorodeoxyglucose (FDG) is a glucose analogue and the initial uptake of [18F]-fluorodeoxyglucose is almost identical to that of glucose. After uptake, [18F]-fluorodeoxyglucose undergoes phosphorylation but, unlike glucose-6-phosphate, FDG-6-PO4 does not undergo further metabolism and remains trapped in the myocardium. This trapping of FDG allows imaging of FDG by positron-emission-tomography and single photon emission computed tomography (SPECT) cameras. Use of FDG for assessing acute and chronic ischaemic syndromes has been studied, but it is mainly used in clinical practice to assess dysfunction of viable myocardium, which has the ability to improve in function. FDG data have been shown to adequately predict regional and global function improvement after revascularization of patients with chronic left ventricular dysfunction and coronary artery disease (CAD). They can also be a powerful predictor of prognosis in these patients. Fatty-acid metabolism can be studied after labelling with 1-123. Beta-methyl iodine phenylpentadecanoic acid is a structurally modified fatty acid, which is used to trace uptake of fatty acids in the myocardium. Similarly to the case with FDG distinct uptake patterns have been observed in patients with CAD, and preliminary data concerning detection of myocardial viability assessment of prognosis are available. Interesting data suggest that fatty-acid imaging is the most sensitive technique for assessing metabolic changes in patients with hypertrophic cardiomyopathy. [11C]-Acetate immediately enters the tricarboxylic-acid (TCA) cycle and metabolism of [11C]-acetate is dependent solely on the TCA-cycle activity. Because the TCA-cycle activity is directly coupled to myocardial oxygen consumption, clearance rates of [11C]-acetate are used to assess regional myocardial consumption of oxygen. [11C]-acetate imaging has been validated for normal subjects and patients with CAD and appears to be as effective as use of FDG for assessing viability. The unique feature of this technique is to measure the regional consumption of oxygen non-invasively. Thus myocardial metabolic imaging is a promising approach for achieving direct insight into the processes underlying functional abnormalities of the myocardium.
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Metabolic effects of glucose-insulin infusions: myocardium and whole body.
Quiñones-Galvan, A, Ferrannini, E
Current opinion in clinical nutrition and metabolic care. 2001;(2):157-63
Abstract
In target organs, insulin switches substrate utilization from free fatty acids to glucose, a change that: (i) is oxygen-efficient; (ii) repletes glycogen stores; (iii) removes potentially toxic fatty acids; and (iv) restores intracellular potassium. During or after an ischaemic challenge, the insulin metabolic mode should protect cellular functions provided that insulin can reach the ischaemic tissue. Insulin, however, also exerts non-metabolic effects, such as membrane hyperpolarization, the stimulation of adrenergic activity, and inhibition of parasympathetic tone, which may counter its beneficial metabolic actions. The net balance between the favourable and unfavourable effects of insulin on ischaemic tissues depends on: (i) the dose-response of the various effects; (ii) the presence of insulin resistance; (iii) the coexistence of hyperglycaemia; and (iv) the stage of ischaemic tissue damage. At present, a role for glucose-insulin-potassium infusions in clinical practice seems to be clearly established in the case of diabetic patients with acute coronary syndromes, and in patients undergoing urgent or elective cardiac surgery. Its role as an adjunctive therapy in the management of myocardial infarction in non-diabetic individuals has been tested in several clinical trials; however, the evidence emerging from them is inconclusive.