Myocardial substrate metabolism in the normal and failing heart

The alterations in myocardial energy substrate metabolism that occur in heart failure, and the causes and consequences of these abnormalities, are poorly understood. There is evidence to suggest that impaired substrate metabolism contributes to contractile dysfunction and to the progressive left ventricular remodeling that are characteristic of the heart failure state. The general concept that has recently emerged is that myocardial substrate selection is relatively normal during the early stages of heart failure; however, in the advanced stages there is a downregulation in fatty acid oxidation, increased glycolysis and glucose oxidation, reduced respiratory chain activity, and an impaired reserve for mitochondrial oxidative flux. This review discusses 1) the metabolic changes that occur in chronic heart failure, with emphasis on the mechanisms that regulate the changes in the expression of metabolic genes and the function of metabolic pathways; 2) the consequences of these metabolic changes on cardiac function; 3) the role of changes in myocardial substrate metabolism on ventricular remodeling and disease progression; and 4) the therapeutic potential of acute and long-term manipulation of cardiac substrate metabolism in heart failure

Dynamic analysis of optimality in myocardial energy metabolism under normal and ischemic conditions

To better understand the dynamic regulation of optimality in metabolic networks under perturbed conditions, we reconstruct the energetic-metabolic network in mammalian myocardia using dynamic flux balance analysis (DFBA). Additionally, we modified the optimal objective from the maximization of ATP production to the minimal fluctuation of the profile of metabolite concentration under ischemic conditions, extending the hypothesis of original minimization of metabolic adjustment to create a composite modeling approach called M-DFBA. The simulation results are more consistent with experimental data than are those of the DFBA model, particularly the retentive predominant contribution of fatty acid to oxidative ATP synthesis, the exact mechanism of which has not been elucidated and seems to be unpredictable by the DFBA model. These results suggest that the systemic states of metabolic networks do not always remain optimal, but may become suboptimal when a transient perturbation occurs. This finding supports the relevance of our hypothesis and could contribute to the further exploration of the underlying mechanism of dynamic regulation in metabolic networks

Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy.

Under resting conditions, the failing heart shifts fuel use toward greater glucose and lower free fatty acid (FFA) oxidation. We hypothesized that chronic metabolic abnormalities in patients with dilated cardiomyopathy (DCM) are associated with the absence of the normal increase in myocardial glucose uptake and maintenance of cardiac mechanical efficiency in response to pacing stress. In 10 DCM patients and 6 control subjects, we measured coronary flow by intravascular ultrasonometry and sampled arterial and coronary sinus blood. Myocardial metabolism was determined at baseline, during atrial pacing at 130 beats/min, and at 15 min of recovery by infusion of [(3)H]oleate and [(13)C]lactate and measurement of transmyocardial arteriovenous differences of oxygen and metabolites. At baseline, DCM patients showed depressed coronary flow, reduced uptake and oxidation of FFA, and preferential utilization of carbohydrates. During pacing, glucose uptake increased by 106% in control subjects but did not change from baseline in DCM patients. Lactate release increased by 122% in DCM patients but not in control subjects. Cardiac mechanical efficiency in DCM patients was not different compared with control subjects at baseline but was 34% lower during stress. Fatty acid uptake and oxidation did not change with pacing in either group. Our results show that in DCM there is preferential utilization of carbohydrates, which is associated with reduced flow and oxygen consumption at rest and an impaired ability to increase glucose uptake during stress. These metabolic abnormalities might contribute to progressive cardiac deterioration and represent a target for therapeutic strategies aimed at modulating cardiac substrate utilization

Metabolic manipulation in chronic heart failure: study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Heart failure is a major cause of morbidity and mortality in society. Current medical therapy centres on neurohormonal modulation with angiotensin converting enzyme inhibitors and β-blockers. There is growing evidence for the use of metabolic manipulating agents as adjunctive therapy in patients with heart failure. We aim to determine the effect of perhexiline on cardiac energetics and alterations in substrate utilisation in patients with non-ischaemic dilated cardiomyopathy.</p> <p>Methods</p> <p>A multi-centre, prospective, randomised double-blind, placebo-controlled trial of 50 subjects with non-ischaemic dilated cardiomyopathy recruited from University Hospital Birmingham NHS Foundation Trust and Cardiff and Vale NHS Trust. Baseline investigations include magnetic resonance spectroscopy to assess cardiac energetic status, echocardiography to assess left ventricular function and assessment of symptomatic status. Subjects are then randomised to receive 200 mg perhexiline maleate or placebo daily for 4 weeks with serum drug level monitoring. All baseline investigations will be repeated at the end of the treatment period. A subgroup of patients will undergo invasive investigations with right and left heart catheterisation to calculate respiratory quotient, and mechanical efficiency. The primary endpoint is an improvement in the phosphocreatine to adenosine triphosphate ratio at 4 weeks. Secondary end points are: i) respiratory quotient; ii) mechanical efficiency; iii) change in left ventricular (LV) function.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00841139">NCT00841139</a></p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN2887836">ISRCTN2887836</a></p

Cardiac Expression of Microsomal Triglyceride Transfer Protein Is Increased in Obesity and Serves to Attenuate Cardiac Triglyceride Accumulation

Obesity causes lipid accumulation in the heart and may lead to lipotoxic heart disease. Traditionally, the size of the cardiac triglyceride pool is thought to reflect the balance between uptake and β-oxidation of fatty acids. However, triglycerides can also be exported from cardiomyocytes via secretion of apolipoproteinB-containing (apoB) lipoproteins. Lipoprotein formation depends on expression of microsomal triglyceride transfer protein (MTP); the mouse expresses two isoforms of MTP, A and B. Since many aspects of the link between obesity-induced cardiac disease and cardiac lipid metabolism remain unknown, we investigated how cardiac lipoprotein synthesis affects cardiac expression of triglyceride metabolism-controlling genes, insulin sensitivity, and function in obese mice. Heart-specific ablation of MTP-A in mice using Cre-loxP technology impaired upregulation of MTP expression in response to increased fatty acid availability during fasting and fat feeding. This resulted in cardiac triglyceride accumulation but unaffected cardiac insulin-stimulated glucose uptake. Long-term fat-feeding of male C57Bl/6 mice increased cardiac triglycerides, induced cardiac expression of triglyceride metabolism-controlling genes and attenuated heart function. Abolishing cardiac triglyceride accumulation in fat-fed mice by overexpression of an apoB transgene in the heart prevented the induction of triglyceride metabolism-controlling genes and improved heart function. The results suggest that in obesity, the physiological increase of cardiac MTP expression serves to attenuate cardiac triglyceride accumulation albeit without major effects on cardiac insulin sensitivity. Nevertheless, the data suggest that genetically increased lipoprotein secretion prevents development of obesity-induced lipotoxic heart disease

Chromosomal-level assembly of the Asian Seabass genome using long sequence reads and multi-layered scaffolding

We report here the ~670 Mb genome assembly of the Asian seabass (Lates calcarifer), a tropical marine teleost. We used long-read sequencing augmented by transcriptomics, optical and genetic mapping along with shared synteny from closely related fish species to derive a chromosome-level assembly with a contig N50 size over 1 Mb and scaffold N50 size over 25 Mb that span ~90% of the genome. The population structure of L. calcarifer species complex was analyzed by re-sequencing 61 individuals representing various regions across the species' native range. SNP analyses identified high levels of genetic diversity and confirmed earlier indications of a population stratification comprising three clades with signs of admixture apparent in the South-East Asian population. The quality of the Asian seabass genome assembly far exceeds that of any other fish species, and will serve as a new standard for fish genomics

Fractal Dimensions and Scaling Laws in the Interstellar Medium and Galaxy Distributions: a new Field Theory Approach

We develop a field theoretical approach to the cold interstellar medium (ISM) and large structure of the universe. We show that a non-relativistic self- gravitating gas in thermal equilibrium with variable number of atoms or fragments is exactly equivalent to a field theory of a scalar field phi(x) with exponential self-interaction. We analyze this field theory perturbatively and non-perturbatively through the renormalization group(RG).We show scaling behaviour (critical) for a continuous range of the physical parameters as the temperature. We derive in this framework the scaling relation M(R) \sim R^{d_H} for the mass on a region of size R, and Delta v \sim R^\frac12(d_H -1) for the velocity dispersion. For the density-density correlations we find a power-law behaviour for large distances \sim |r_1 - r_2|^{2D - 6}.The fractal dimension D turns to be related with the critical exponent \nu by D = 1/ \nu. Mean field theory yields \nu = 1/2, D = 2. Both the Ising and the mean field values are compatible with the present ISM observational data:1.4\leq D \leq 2. We develop a field theoretical approach to the galaxy distribution considering a gas of self-gravitating masses on the FRW background, in quasi-thermal equi- librium. We show that it exhibits scaling behaviour by RG methods. The galaxy correlations are computed without assuming homogeneity. We find \sim r^{D-3} $. The theory allows to compute the three and higher density correlators without any assumption.We find that the connected N-points density scales as r_1^{N(D-3)}, when$ r_1 >> r_i